19 pages, 3178 KiB  
Article
Dual Effects of Metformin on Adipogenic Differentiation of 3T3-L1 Preadipocyte in AMPK-Dependent and Independent Manners
by Dian Chen, Ying Wang, Kaikai Wu and Xingya Wang
Int. J. Mol. Sci. 2018, 19(6), 1547; https://doi.org/10.3390/ijms19061547 - 23 May 2018
Cited by 53 | Viewed by 6960
Abstract
Metformin has been reported to have body weight lowering effects while treating type 2 diabetes. However, limited studies examined the effects of metformin on adipogenesis in vitro, and available data are inconclusive and contradictory. In this study, we examined the effects of a [...] Read more.
Metformin has been reported to have body weight lowering effects while treating type 2 diabetes. However, limited studies examined the effects of metformin on adipogenesis in vitro, and available data are inconclusive and contradictory. In this study, we examined the effects of a variety of concentrations of metformin on adipocyte differentiation of 3T3-L1 preadipocytes and found metformin exhibits a dual effect on adipogenesis. Metformin at lower concentrations (1.25–2.5 mM) significantly induced adipogenesis while at higher concentrations (5–10 mM) metformin significantly inhibited adipogenesis in 3T3-L1 cells. The biphasic effect of different doses of metformin on adipogenesis was accompanied by increasing or decreasing the expression of adipogenic and lipogenic genes including peroxisome proliferator-activated receptor (PPARγ), CCAAT/enhancer binding protein α (C/EBPα), and fatty acid synthase (FASN) at both messenger RNA (mRNA) and protein levels. Furthermore, only the higher concentrations of metformin induced the phosphorylation of adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), p38, and c-Jun N-terminal kinase (JNK) and reduced the phosphorylation of extracellular regulated protein kinases (ERK) and Akt. Pretreatment with compound C, a specific AMPK inhibitor, significantly countered high concentration of metformin-induced inhibition of adipogenesis. Taken together, these findings demonstrate that the effect of metformin on adipocyte differentiation is biphasic and dose-dependent. Lower concentrations of metformin induce adipogenesis, which could be mediated in an AMPK-independent manner, while higher concentrations of metformin inhibit adipogenesis via AMPK activation. Full article
(This article belongs to the Section Biochemistry)
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19 pages, 2271 KiB  
Review
Fluorescent Proteins for Investigating Biological Events in Acidic Environments
by Hajime Shinoda, Michael Shannon and Takeharu Nagai
Int. J. Mol. Sci. 2018, 19(6), 1548; https://doi.org/10.3390/ijms19061548 - 23 May 2018
Cited by 78 | Viewed by 10690
Abstract
The interior lumen of acidic organelles (e.g., endosomes, secretory granules, lysosomes and plant vacuoles) is an important platform for modification, transport and degradation of biomolecules as well as signal transduction, which remains challenging to investigate using conventional fluorescent proteins (FPs). Due to the [...] Read more.
The interior lumen of acidic organelles (e.g., endosomes, secretory granules, lysosomes and plant vacuoles) is an important platform for modification, transport and degradation of biomolecules as well as signal transduction, which remains challenging to investigate using conventional fluorescent proteins (FPs). Due to the highly acidic luminal environment (pH ~ 4.5–6.0), most FPs and related sensors are apt to lose their fluorescence. To address the need to image in acidic environments, several research groups have developed acid-tolerant FPs in a wide color range. Furthermore, the engineering of pH insensitive sensors, and their concomitant use with pH sensitive sensors for the purpose of pH-calibration has enabled characterization of the role of luminal ions. In this short review, we summarize the recent development of acid-tolerant FPs and related functional sensors and discuss the future prospects for this field. Full article
(This article belongs to the Special Issue Fluorescent Proteins)
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19 pages, 1056 KiB  
Review
Approaches in Polymeric Nanoparticles for Vaginal Drug Delivery: A Review of the State of the Art
by Gerardo Leyva-Gómez, Elizabeth Piñón-Segundo, Néstor Mendoza-Muñoz, María L. Zambrano-Zaragoza, Susana Mendoza-Elvira and David Quintanar-Guerrero
Int. J. Mol. Sci. 2018, 19(6), 1549; https://doi.org/10.3390/ijms19061549 - 23 May 2018
Cited by 93 | Viewed by 11728
Abstract
The vagina is a region of administration with a high contact surface to obtain local or systemic effects. This anatomical area represents special interest for government health systems for different sexually transmitted infections. However, the chemical changes of the vagina, as well as [...] Read more.
The vagina is a region of administration with a high contact surface to obtain local or systemic effects. This anatomical area represents special interest for government health systems for different sexually transmitted infections. However, the chemical changes of the vagina, as well as its abundant mucus in continuous exchange, act as a barrier and a challenge for the development of new drugs. For these purposes, the development of new pharmaceutical forms based on nanoparticles has been shown to offer various advantages, such as bioadhesion, easy penetration of the mucosa, and controlled release, in addition to decreasing the adverse effects of conventional pharmaceutical forms. In order to obtain nanoparticles for vaginal administration, the use of polymers of natural and synthetic origin including biodegradable and non-biodegradable systems have gained great interest both in nanospheres and in nanocapsules. The main aim of this review is to provide an overview of the development of nanotechnology for vaginal drug release, analyzing the different compositions of polymeric nanoparticles, and emphasizing new trends in each of the sections presented. At the end of this review, a section analyzes the properties of the vehicles employed for the administration of nanoparticles and discusses how to take advantage of the properties that they offer. This review aims to be a reference guide for new formulators interested in the vaginal route. Full article
(This article belongs to the Special Issue Nanotechnology in Drug Delivery)
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14 pages, 2045 KiB  
Article
Polymeric Micelles Based on Modified Glycol Chitosan for Paclitaxel Delivery: Preparation, Characterization and Evaluation
by Na Liang, Shaoping Sun, Xianfeng Gong, Qiang Li, Pengfei Yan and Fude Cui
Int. J. Mol. Sci. 2018, 19(6), 1550; https://doi.org/10.3390/ijms19061550 - 23 May 2018
Cited by 31 | Viewed by 4926
Abstract
Amphiphilic polymer of α-tocopherol succinate modified glycol chitosan (TS-GC) was successfully constructed by conjugating α-tocopherol succinate to the skeleton of glycol chitosan and characterized by Fourier-transform infrared (FT-IR) and proton nuclear magnetic resonance (1H-NMR). In aqueous milieu, the conjugates self-assembled to [...] Read more.
Amphiphilic polymer of α-tocopherol succinate modified glycol chitosan (TS-GC) was successfully constructed by conjugating α-tocopherol succinate to the skeleton of glycol chitosan and characterized by Fourier-transform infrared (FT-IR) and proton nuclear magnetic resonance (1H-NMR). In aqueous milieu, the conjugates self-assembled to micelles with the critical aggregation concentration of 7.2 × 10−3 mg/mL. Transmission electron microscope (TEM) observation and dynamic light scattering (DLS) measurements were carried out to determine the physicochemical properties of the micelles. The results revealed that paclitaxel (PTX)-loaded TS-GC micelles were spherical in shape. Moreover, the PTX-loaded micelles showed increased particle sizes (35 nm vs. 142 nm) and a little reduced zeta potential (+19 mV vs. +16 mV) compared with blank micelles. The X-ray diffraction (XRD) spectra demonstrated that PTX existed inside the micelles in amorphous or molecular state. In vitro and in vivo tests showed that the PTX-loaded TS-GC micelles had advantages over the Cremophor EL-based formulation in terms of low toxicity level and increased dose, which suggested the potential of the polymer as carriers for PTX to improve their delivery properties. Full article
(This article belongs to the Special Issue Synthesis and Applications of Biopolymer Composites)
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18 pages, 1935 KiB  
Article
Inhibition of HIF1α-Dependent Upregulation of Phospho-l-Plastin Resensitizes Multiple Myeloma Cells to Frontline Therapy
by Manon Bosseler, Vanessa Marani, Angelina Broukou, Amandine Lequeux, Tony Kaoma, Vincent Schlesser, Jean-Hugues François, Valérie Palissot, Guy J. Berchem, Nasséra Aouali and Bassam Janji
Int. J. Mol. Sci. 2018, 19(6), 1551; https://doi.org/10.3390/ijms19061551 - 23 May 2018
Cited by 9 | Viewed by 5405
Abstract
The introduction of novel frontline agents in multiple myeloma (MM), like immunomodulatory drugs and proteasome inhibitors, has improved the overall survival of patients. Yet, MM is still not curable, and drug resistance (DR) remains the main challenge. To improve the understanding of DR [...] Read more.
The introduction of novel frontline agents in multiple myeloma (MM), like immunomodulatory drugs and proteasome inhibitors, has improved the overall survival of patients. Yet, MM is still not curable, and drug resistance (DR) remains the main challenge. To improve the understanding of DR in MM, we established a resistant cell line (MOLP8/R). The exploration of DR mechanisms yielded an overexpression of HIF1α, due to impaired proteasome activity of MOLP8/R. We show that MOLP8/R, like other tumor cells, overexpressing HIF1α, have an increased resistance to the immune system. By exploring the main target genes regulated by HIF1α, we could not show an overexpression of these targets in MOLP8/R. We, however, show that MOLP8/R cells display a very high overexpression of LCP1 gene (l-Plastin) controlled by HIF1α, and that this overexpression also exists in MM patient samples. The l-Plastin activity is controlled by its phosphorylation in Ser5. We further show that the inhibition of l-Plastin phosphorylation restores the sensitivity of MOLP8/R to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Our results reveal a new target gene of DR, controlled by HIF1α. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies in Multiple Myeloma)
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20 pages, 4024 KiB  
Article
Importance of Hydrophilic Groups on Modulating the Structural, Mechanical, and Interfacial Properties of Bilayers: A Comparative Molecular Dynamics Study of Phosphatidylcholine and Ion Pair Amphiphile Membranes
by Ching-an Tian and Chi-cheng Chiu
Int. J. Mol. Sci. 2018, 19(6), 1552; https://doi.org/10.3390/ijms19061552 - 23 May 2018
Cited by 10 | Viewed by 3604
Abstract
An ion pair amphiphile (IPA), a molecular complex composed of two oppositely charged amphiphiles, is a phospholipid mimic which differs from a phospholipid only in the hydrophilic compositions. Here, we utilized molecular dynamics (MD) simulations to compare the bilayer systems composed of phosphatidylcholines [...] Read more.
An ion pair amphiphile (IPA), a molecular complex composed of two oppositely charged amphiphiles, is a phospholipid mimic which differs from a phospholipid only in the hydrophilic compositions. Here, we utilized molecular dynamics (MD) simulations to compare the bilayer systems composed of phosphatidylcholines (PC) and alkyltrimethylammonium-alkylsulfate IPAs with various alkyl chain lengths. The membrane properties for both liquid-disordered (Ld) and gel (S) phase bilayers were examined via running simulations above and below the main transition temperatures. The electrostatic attraction between the IPA hydrophilic groups leads to a more ordered molecular packing within both S and Ld phase IPA membranes, as revealed by the molecular area, deuterium order parameter, and gauche conformation analyses. Furthermore, IPA bilayers possess a higher area compressibility modulus, molecular tilt modulus, and effective bending rigidity than PC systems. The variation of hydrophilic groups of IPA also leads to fewer hydrogen bonds on the membrane surface and smaller electrostatic potentials for the biomimetic bilayer. The non-covalently linked head groups of IPA further decouple alkyl tilting and surface water retention. The combined results reveal the importance of hydrophilic groups of amphiphiles on modulating the membrane properties, which also provides insights for designs of biomimetic membranes. Full article
(This article belongs to the Section Molecular Biophysics)
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14 pages, 2175 KiB  
Article
The Cold-Regulated Genes of Blueberry and Their Response to Overexpression of VcDDF1 in Several Tissues
by Aaron Walworth and Guo-qing Song
Int. J. Mol. Sci. 2018, 19(6), 1553; https://doi.org/10.3390/ijms19061553 - 23 May 2018
Cited by 14 | Viewed by 3488
Abstract
Expression of blueberry cold-regulated genes (VcCORs) could play a role in the variable cold hardiness of blueberry tissues. In this study, transcriptome comparisons were conducted to reveal expression of VcCORs in non-acclimated leaves, flower buds, and flowers of both non-transgenic and transgenic blueberries [...] Read more.
Expression of blueberry cold-regulated genes (VcCORs) could play a role in the variable cold hardiness of blueberry tissues. In this study, transcriptome comparisons were conducted to reveal expression of VcCORs in non-acclimated leaves, flower buds, and flowers of both non-transgenic and transgenic blueberries containing an overexpressed blueberry DWARF AND DELAYED FLOWERING gene (VcDDF1) as well as in fully chilled flower buds of non-transgenic blueberry. In non-transgenic blueberries, 57.5% of VcCOR genes showed differential expression in at least one of the three pairwise comparisons between non-acclimated leaves, flower buds, and flowers, and six out of nine dehydration-responsive element-binding factors showed differential expression. In addition, expression of VcDDF1 was not cold-inducible in non-transgenic blueberries and had higher expression in flowers than in leaves or non-acclimated flower buds. In transgenic blueberries, overexpression of VcDDF1 resulted in higher VcDDF1 expression in leaves than in flower buds and flowers. VcDDF1 overexpression enhanced expression of blueberry CBF1 and CBF3 in leaves and repressed expression of CBF3 in both flower buds and flowers. Overall, the results revealed tissue-specific expression patterns of VcCORs. The responses of VcCORs to overexpression of VcDDF1 suggest that it is possible to increase plant cold hardiness through overexpression of a non-cold-inducible gene. Full article
(This article belongs to the Section Molecular Plant Sciences)
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21 pages, 1703 KiB  
Review
Immunological Processes Driving IgE Sensitisation and Disease Development in Males and Females
by Jonatan Leffler, Philip A. Stumbles and Deborah H. Strickland
Int. J. Mol. Sci. 2018, 19(6), 1554; https://doi.org/10.3390/ijms19061554 - 23 May 2018
Cited by 42 | Viewed by 10152
Abstract
IgE sensitisation has increased significantly over the last decades and is a crucial factor in the development of allergic diseases. IgE antibodies are produced by B cells through the process of antigen presentation by dendritic cells, subsequent differentiation of CD4+ Th2 cells, [...] Read more.
IgE sensitisation has increased significantly over the last decades and is a crucial factor in the development of allergic diseases. IgE antibodies are produced by B cells through the process of antigen presentation by dendritic cells, subsequent differentiation of CD4+ Th2 cells, and class switching in B cells. However, many of the factors regulating these processes remain unclear. These processes affect males and females differently, resulting in a significantly higher prevalence of IgE sensitisation in males compared to females from an early age. Before the onset of puberty, this increased prevalence of IgE sensitisation is also associated with a higher prevalence of clinical symptoms in males; however, after puberty, females experience a surge in the incidence of allergic symptoms. This is particularly apparent in allergic asthma, but also in other allergic diseases such as food and contact allergies. This has been partly attributed to the pro- versus anti-allergic effects of female versus male sex hormones; however, it remains unclear how the expression of sex hormones translates IgE sensitisation into clinical symptoms. In this review, we describe the recent epidemiological findings on IgE sensitisation in male and females and discuss recent mechanistic studies casting further light on how the expression of sex hormones may influence the innate and adaptive immune system at mucosal surfaces and how sex hormones may be involved in translating IgE sensitisation into clinical manifestations. Full article
(This article belongs to the Special Issue Molecular Research on Mucosal Immunity)
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16 pages, 2728 KiB  
Article
Effect of Melatonin on Rat Heart Mitochondria in Acute Heart Failure in Aged Rats
by Irina Odinokova, Yulia Baburina, Alexey Kruglov, Irina Fadeeva, Alena Zvyagina, Linda Sotnikova, Vladimir Akatov and Olga Krestinina
Int. J. Mol. Sci. 2018, 19(6), 1555; https://doi.org/10.3390/ijms19061555 - 23 May 2018
Cited by 37 | Viewed by 8435
Abstract
Excessive generation of reactive oxygen species (ROS) in mitochondria and the opening of the nonselective mitochondrial permeability transition pore are important factors that promote cardiac pathologies and dysfunction. The hormone melatonin (MEL) is known to improve the functional state of mitochondria via an [...] Read more.
Excessive generation of reactive oxygen species (ROS) in mitochondria and the opening of the nonselective mitochondrial permeability transition pore are important factors that promote cardiac pathologies and dysfunction. The hormone melatonin (MEL) is known to improve the functional state of mitochondria via an antioxidant effect. Here, the effect of MEL administration on heart mitochondria from aged rats with acute cardiac failure caused by isoprenaline hydrochloride (ISO) was studied. A histological analysis revealed that chronic intake of MEL diminished the age-dependent changes in the structure of muscle fibers of the left ventricle, muscle fiber swelling, and injury zones characteristic of acute cardiac failure caused by ISO. In acute heart failure, the respiratory control index (RCI) and the Ca2+ retention capacity in isolated rat heart mitochondria (RHM) were reduced by 30% and 40%, respectively, and mitochondrial swelling increased by 34%. MEL administration abolished the effect of ISO. MEL partially prevented ISO-induced changes at the subunit level of respiratory complexes III and V and drastically decreased the expression of complex I subunit NDUFB8 both in control RHM and in RHM treated with ISO, which led to the inhibition of ROS production. MEL prevents the mitochondrial dysfunction associated with heart failure caused by ISO. It was shown that the level of 2′,3′-cyclicnucleotide-3′-phosphodiasterase (CNPase), which is capable of protecting cells in aging, increased in acute heart failure. MEL also retained the CNPase content in RHM both in control experiments and after ISO-induced heart damage. We concluded that an increase in the CNPase level promotes cardioprotection. Full article
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17 pages, 5920 KiB  
Article
Isoviolanthin Extracted from Dendrobium officinale Reverses TGF-β1-Mediated Epithelial–Mesenchymal Transition in Hepatocellular Carcinoma Cells via Deactivating the TGF-β/Smad and PI3K/Akt/mTOR Signaling Pathways
by Shangping Xing, Wenxia Yu, Xiaofeng Zhang, Yingyi Luo, Zhouxi Lei, Dandan Huang, Ji Lin, Yuechun Huang, Shaowei Huang, Feifei Nong, Chunhua Zhou and Gang Wei
Int. J. Mol. Sci. 2018, 19(6), 1556; https://doi.org/10.3390/ijms19061556 - 23 May 2018
Cited by 77 | Viewed by 7824
Abstract
Dendrobium officinale is a precious medicinal herb and health food, and its pharmacological actions have been studied and proved. However, the mechanisms by which its active flavonoid glycosides affect epithelial–mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells, such as HepG2 and Bel-7402 cells, [...] Read more.
Dendrobium officinale is a precious medicinal herb and health food, and its pharmacological actions have been studied and proved. However, the mechanisms by which its active flavonoid glycosides affect epithelial–mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) cells, such as HepG2 and Bel-7402 cells, have not been previously investigated. Therefore, we investigated whether isoviolanthin extracted from the leaves of Dendrobium officinale inhibits transforming growth factor (TGF)-β1-induced EMT in HCC cells. In this study, the physicochemical properties and structure of isoviolanthin were identified by HPLC, UV, ESIMS, and NMR and were compared with literature data. HCC cells were pretreated with 10 ng/mL TGF-β1 to induce EMT and then treated with isoviolanthin. Herein, we found that isoviolanthin exhibited no cytotoxic effects on normal liver LO2 cells but notably reduced the migratory and invasive capacities of TGF-β1-treated HCC cells. Additionally, isoviolanthin treatment decreased matrix metalloproteinase (MMP)-2 and -9 levels, and remarkably altered the expression of EMT markers via regulating the TGF-β/Smad and PI3K/Akt/mTOR signaling pathways; Western blot analysis confirmed that the effects of the inhibitors SB431542 and LY294002 were consistent with those of isoviolanthin. These findings demonstrate the potential of isoviolanthin as a therapeutic agent for the treatment of advanced-stage metastatic HCC. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT))
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12 pages, 2334 KiB  
Article
Supplementation with IL-6 and Muscle Cell Culture Conditioned Media Enhances Myogenic Differentiation of Adipose Tissue-Derived Stem Cells through STAT3 Activation
by Eunhui Seo, Hwansu Kang, Oh-Kyung Lim and Hee-Sook Jun
Int. J. Mol. Sci. 2018, 19(6), 1557; https://doi.org/10.3390/ijms19061557 - 24 May 2018
Cited by 16 | Viewed by 5837
Abstract
Mature skeletal muscle cells cannot be expanded in culture systems. Therefore, it is difficult to construct an in vitro model for muscle diseases. To establish an efficient protocol for myogenic differentiation of human adipose tissue-derived stem cells (hADSCs), we investigated whether addition of [...] Read more.
Mature skeletal muscle cells cannot be expanded in culture systems. Therefore, it is difficult to construct an in vitro model for muscle diseases. To establish an efficient protocol for myogenic differentiation of human adipose tissue-derived stem cells (hADSCs), we investigated whether addition of IL-6 and/or myocyte-conditioned media (CM) to conventional differentiation media can shorten the differentiation period. hADSCs were differentiated to myocytes using the conventional protocol or modified with the addition of 25 pg/mL IL-6 and/or C2C12 CM (25% v/v). The expression of MyoD and myogenine mRNA was significantly higher at 5–6 days after differentiation using the modified protocol than with the conventional protocol. mRNA and protein expression of myosin heavy chain, a marker of myotubes, was significantly upregulated at 28 and 42 days of differentiation using the modified protocol, and the level achieved after a 4-week differentiation period was similar to that achieved at 6 weeks using the conventional protocol. The expression of p-STAT3 was significantly increased when the modified protocol was used. Similarly, addition of colivelin, a STAT3 activator, instead of IL-6 and C2C12 CM, promoted the myogenic differentiation of ADSCs. The modified protocol improved differentiation efficiency and reduced the time required for differentiation of myocytes. It might be helpful to save cost and time when preparing myocytes for cell therapies and drug discovery. Full article
(This article belongs to the Special Issue Adipose Stem Cells)
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14 pages, 2278 KiB  
Article
Pannexin-1 in Human Lymphatic Endothelial Cells Regulates Lymphangiogenesis
by Jonathan Boucher, Claire Simonneau, Golthlay Denet, Jonathan Clarhaut, Annie-Claire Balandre, Marc Mesnil, Laurent Cronier and Arnaud Monvoisin
Int. J. Mol. Sci. 2018, 19(6), 1558; https://doi.org/10.3390/ijms19061558 - 24 May 2018
Cited by 11 | Viewed by 5656
Abstract
The molecular mechanisms governing the formation of lymphatic vasculature are not yet well understood. Pannexins are transmembrane proteins that form channels which allow for diffusion of ions and small molecules (<1 kDa) between the extracellular space and the cytosol. The expression and function [...] Read more.
The molecular mechanisms governing the formation of lymphatic vasculature are not yet well understood. Pannexins are transmembrane proteins that form channels which allow for diffusion of ions and small molecules (<1 kDa) between the extracellular space and the cytosol. The expression and function of pannexins in blood vessels have been studied in the last few decades. Meanwhile, no studies have been conducted to evaluate the role of pannexins during human lymphatic vessel formation. Here we show, using primary human dermal lymphatic endothelial cells (HDLECs), pharmacological tools (probenecid, Brilliant Blue FCF, mimetic peptides [10Panx]) and siRNA-mediated knockdown that Pannexin-1 is necessary for capillary tube formation on Matrigel and for VEGF-C-induced invasion. These results newly identify Pannexin-1 as a protein highly expressed in HDLECs and its requirement during in vitro lymphangiogenesis. Full article
(This article belongs to the Special Issue Interplay of Connexins and Pannexins in Tissue Function and Disease)
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16 pages, 1625 KiB  
Article
Distinct DNA Methylation Profiles in Ovarian Tumors: Opportunities for Novel Biomarkers
by Lorena Losi, Sergio Fonda, Sara Saponaro, Sonia T. Chelbi, Cesare Lancellotti, Gaia Gozzi, Loredana Alberti, Luca Fabbiani, Laura Botticelli and Jean Benhattar
Int. J. Mol. Sci. 2018, 19(6), 1559; https://doi.org/10.3390/ijms19061559 - 24 May 2018
Cited by 26 | Viewed by 4728
Abstract
Aberrant methylation of multiple promoter CpG islands could be related to the biology of ovarian tumors and its determination could help to improve treatment strategies. DNA methylation profiling was performed using the Methylation Ligation-dependent Macroarray (MLM), an array-based analysis. Promoter regions of 41 [...] Read more.
Aberrant methylation of multiple promoter CpG islands could be related to the biology of ovarian tumors and its determination could help to improve treatment strategies. DNA methylation profiling was performed using the Methylation Ligation-dependent Macroarray (MLM), an array-based analysis. Promoter regions of 41 genes were analyzed in 102 ovarian tumors and 17 normal ovarian samples. An average of 29% of hypermethylated promoter genes was observed in normal ovarian tissues. This percentage increased slightly in serous, endometrioid, and mucinous carcinomas (32%, 34%, and 45%, respectively), but decreased in germ cell tumors (20%). Ovarian tumors had methylation profiles that were more heterogeneous than other epithelial cancers. Unsupervised hierarchical clustering identified four groups that are very close to the histological subtypes of ovarian tumors. Aberrant methylation of three genes (BRCA1, MGMT, and MLH1), playing important roles in the different DNA repair mechanisms, were dependent on the tumor subtype and represent powerful biomarkers for precision therapy. Furthermore, a promising relationship between hypermethylation of MGMT, OSMR, ESR1, and FOXL2 and overall survival was observed. Our study of DNA methylation profiling indicates that the different histotypes of ovarian cancer should be treated as separate diseases both clinically and in research for the development of targeted therapies. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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11 pages, 912 KiB  
Communication
Comparison of Three Extraction Approaches for the Isolation of Neurotransmitters from Rat Brain Samples
by Natalia Miękus, Ilona Olędzka, Darya Harshkova, Ivan Liakh, Alina Plenis, Piotr Kowalski and Tomasz Bączek
Int. J. Mol. Sci. 2018, 19(6), 1560; https://doi.org/10.3390/ijms19061560 - 24 May 2018
Cited by 8 | Viewed by 5190
Abstract
The determination of neurotransmitters (NTs) as relevant potential biomarkers in the study of various central nervous system (CNS) pathologies has been demonstrated. Knowing that NTs-related diseases mostly occupy individual regions of the nervous system, as observed, for instance, in neurodegenerative diseases (Alzheimer’s and [...] Read more.
The determination of neurotransmitters (NTs) as relevant potential biomarkers in the study of various central nervous system (CNS) pathologies has been demonstrated. Knowing that NTs-related diseases mostly occupy individual regions of the nervous system, as observed, for instance, in neurodegenerative diseases (Alzheimer’s and Parkinson’s Diseases), the analysis of brain slices is preferred to whole-brain analysis. In this report, we present sample preparation approaches, such as solid-phase extraction, solid-phase microextraction, and dispersive liquid–liquid microextraction, and discuss the pitfalls and advantages of each extraction method. The ionic liquid (1-ethyl-3-methylimidazolium tetrafluoroborate)-assisted solid-phase microextraction (IL-SPME) is found to be, in our research, the relevant step towards the simultaneous determination of six NTs, namely, dopamine (DA), adrenaline (A), noradrenaline (NA), serotonin (5-HT), l-tryptophan (l-Trp), l-tyrosine (l-Tyr) in rat brain samples. The development of a novel bioanalytical technique for the evaluation of biomarkers in the context of green chemistry might be accelerated just with the use of IL, and this approach can be considered an advantageous strategy. Full article
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23 pages, 2294 KiB  
Article
Enhancement of Recombinant Protein Production in Transgenic Nicotiana benthamiana Plant Cell Suspension Cultures with Co-Cultivation of Agrobacterium Containing Silencing Suppressors
by Ting-Kuo Huang, Bryce W. Falk, Abhaya M. Dandekar and Karen A. McDonald
Int. J. Mol. Sci. 2018, 19(6), 1561; https://doi.org/10.3390/ijms19061561 - 24 May 2018
Cited by 12 | Viewed by 9947
Abstract
We have previously demonstrated that the inducible plant viral vector (CMViva) in transgenic plant cell cultures can significantly improve the productivity of extracellular functional recombinant human alpha-1-antiryspin (rAAT) compared with either a common plant constitutive promoter (Cauliflower mosaic virus (CaMV) 35S) or [...] Read more.
We have previously demonstrated that the inducible plant viral vector (CMViva) in transgenic plant cell cultures can significantly improve the productivity of extracellular functional recombinant human alpha-1-antiryspin (rAAT) compared with either a common plant constitutive promoter (Cauliflower mosaic virus (CaMV) 35S) or a chemically inducible promoter (estrogen receptor-based XVE) system. For a transgenic plant host system, however, viral or transgene-induced post-transcriptional gene silencing (PTGS) has been identified as a host response mechanism that may dramatically reduce the expression of a foreign gene. Previous studies have suggested that viral gene silencing suppressors encoded by a virus can block or interfere with the pathways of transgene-induced PTGS in plant cells. In this study, the capability of nine different viral gene silencing suppressors were evaluated for improving the production of rAAT protein in transgenic plant cell cultures (CMViva, XVE or 35S system) using an Agrobacterium-mediated transient expression co-cultivation process in which transgenic plant cells and recombinant Agrobacterium carrying the viral gene silencing suppressor were grown together in suspension cultures. Through the co-cultivation process, the impacts of gene silencing suppressors on the rAAT production were elucidated, and promising gene silencing suppressors were identified. Furthermore, the combinations of gene silencing suppressors were optimized using design of experiments methodology. The results have shown that in transgenic CMViva cell cultures, the functional rAAT as a percentage of total soluble protein is increased 5.7 fold with the expression of P19, and 17.2 fold with the co-expression of CP, P19 and P24. Full article
(This article belongs to the Special Issue Recombinant Proteins)
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12 pages, 1929 KiB  
Article
Connexin43 Carboxyl-Terminal Domain Directly Interacts with β-Catenin
by Gaelle Spagnol, Andrew J. Trease, Li Zheng, Mirtha Gutierrez, Ishika Basu, Cleofes Sarmiento, Gabriella Moore, Matthew Cervantes and Paul L. Sorgen
Int. J. Mol. Sci. 2018, 19(6), 1562; https://doi.org/10.3390/ijms19061562 - 24 May 2018
Cited by 32 | Viewed by 4973
Abstract
Activation of Wnt signaling induces Connexin43 (Cx43) expression via the transcriptional activity of β-catenin, and results in the enhanced accumulation of the Cx43 protein and the formation of gap junction channels. In response to Wnt signaling, β-catenin co-localizes with the Cx43 protein itself [...] Read more.
Activation of Wnt signaling induces Connexin43 (Cx43) expression via the transcriptional activity of β-catenin, and results in the enhanced accumulation of the Cx43 protein and the formation of gap junction channels. In response to Wnt signaling, β-catenin co-localizes with the Cx43 protein itself as part of a complex at the gap junction plaque. Work from several labs have also shown indirect evidence of this interaction via reciprocal co-immunoprecipitation. Our goal for the current study was to identify whether β-catenin directly interacts with Cx43, and if so, the location of that direct interaction. Identifying residues involved in direct protein–protein interaction is of importance when they are correlated to the phosphorylation of Cx43, as phosphorylation can modify the binding affinities of Cx43 regulatory protein partners. Therefore, combining the location of a protein partner interaction on Cx43 along with the phosphorylation pattern under different homeostatic and pathological conditions will be crucial information for any potential therapeutic intervention. Here, we identified that β-catenin directly interacts with the Cx43 carboxyl-terminal domain, and that this interaction would be inhibited by the Src phosphorylation of Cx43CT residues Y265 and Y313. Full article
(This article belongs to the Special Issue Interplay of Connexins and Pannexins in Tissue Function and Disease)
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15 pages, 2603 KiB  
Review
Recent Advances in Laser-Ablative Synthesis of Bare Au and Si Nanoparticles and Assessment of Their Prospects for Tissue Engineering Applications
by Ahmed Al-Kattan, Viraj P. Nirwan, Anton Popov, Yury V. Ryabchikov, Gleb Tselikov, Marc Sentis, Amir Fahmi and Andrei V. Kabashin
Int. J. Mol. Sci. 2018, 19(6), 1563; https://doi.org/10.3390/ijms19061563 - 24 May 2018
Cited by 38 | Viewed by 6580
Abstract
Driven by surface cleanness and unique physical, optical and chemical properties, bare (ligand-free) laser-synthesized nanoparticles (NPs) are now in the focus of interest as promising materials for the development of advanced biomedical platforms related to biosensing, bioimaging and therapeutic drug delivery. We recently [...] Read more.
Driven by surface cleanness and unique physical, optical and chemical properties, bare (ligand-free) laser-synthesized nanoparticles (NPs) are now in the focus of interest as promising materials for the development of advanced biomedical platforms related to biosensing, bioimaging and therapeutic drug delivery. We recently achieved significant progress in the synthesis of bare gold (Au) and silicon (Si) NPs and their testing in biomedical tasks, including cancer imaging and therapy, biofuel cells, etc. We also showed that these nanomaterials can be excellent candidates for tissue engineering applications. This review is aimed at the description of our recent progress in laser synthesis of bare Si and Au NPs and their testing as functional modules (additives) in innovative scaffold platforms intended for tissue engineering tasks. Full article
(This article belongs to the Special Issue Novel Biomaterials for Tissue Engineering 2018)
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11 pages, 5056 KiB  
Article
DsSWEET17, a Tonoplast-Localized Sugar Transporter from Dianthus spiculifolius, Affects Sugar Metabolism and Confers Multiple Stress Tolerance in Arabidopsis
by Aimin Zhou, Hongping Ma, Shuang Feng, Shufang Gong and Jingang Wang
Int. J. Mol. Sci. 2018, 19(6), 1564; https://doi.org/10.3390/ijms19061564 - 24 May 2018
Cited by 49 | Viewed by 4670
Abstract
Plant SWEETs (Sugars Will Eventually be Exported Transporters) affect the growth of plants by regulating the transport of sugar from source to sink and its intracellular transport between different organelles. In this study, DsSWEET17 from Dianthus spiculifolius was identified and characterized. Real-time quantitative [...] Read more.
Plant SWEETs (Sugars Will Eventually be Exported Transporters) affect the growth of plants by regulating the transport of sugar from source to sink and its intracellular transport between different organelles. In this study, DsSWEET17 from Dianthus spiculifolius was identified and characterized. Real-time quantitative PCR analysis revealed that the expression of DsSWEET17 was affected by exogenous application of fructose and glucose as well as under salt, osmotic, and oxidation stress. Colocalization experiments showed that the DsSWEET17-GFP (green fluorescent protein) fusion protein was localized to the FM4-64-labeled tonoplasts in Arabidopsis. Compared to the wild type, the transgenic Arabidopsis seedlings overexpressing DsSWEET17 had longer roots, greater fresh weight, and a faster root growth upon exogenous application of fructose. Furthermore, transgenic Arabidopsis seedlings had significantly higher fructose accumulation than was observed for the wild-type seedlings. The analysis of root length revealed that transgenic Arabidopsis had higher tolerance to salt, osmotic, and oxidative stresses. Taken together, our results suggest that DsSWEET17 may be a tonoplast sugar transporter, and its overexpression affects sugar metabolism and confers multiple stress tolerance in Arabidopsis. Full article
(This article belongs to the Section Molecular Plant Sciences)
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18 pages, 3183 KiB  
Article
Anti-Metastatic Effects of Antrodan with and without Cisplatin on Lewis Lung Carcinomas in a Mouse Xenograft Model
by Pei-Chun Chen, Chin-Chu Chen, Yaw-Bee Ker, Chi-Huang Chang, Charng-Cherng Chyau and Miao-Lin Hu
Int. J. Mol. Sci. 2018, 19(6), 1565; https://doi.org/10.3390/ijms19061565 - 24 May 2018
Cited by 15 | Viewed by 4888
Abstract
Antrodan, a unique protein-bound polysaccharide derived from the fungal mycelia of Antrodia cinnamomea, has been reported to exhibit antitumor and anti-metastatic effects on Lewis lung carcinoma (LLC) cells through direct action and immunomodulation in vitro. In this study, we investigated the combined [...] Read more.
Antrodan, a unique protein-bound polysaccharide derived from the fungal mycelia of Antrodia cinnamomea, has been reported to exhibit antitumor and anti-metastatic effects on Lewis lung carcinoma (LLC) cells through direct action and immunomodulation in vitro. In this study, we investigated the combined treatment of antrodan with an anti-cancer drug—cisplatin—and its underlying molecular mechanisms of action in a mouse xenograft tumor model. C57BL/6 mice were implanted (s.c.) with LLCs for nine days, before administration with only antrodan (20 mg/kg and 40 mg/kg; p.o.) daily, only cisplatin (1 mg/kg; i.p.) twice per week, or a combination of both for an additional 28 days. As expected, antrodan on its own significantly inhibited metastasis of lung and liver tissues, while treatment with cisplatin only merely inhibited metastasis of the liver. Antrodan exhibited efficient adjuvant therapy in combination with cisplatin, by inhibiting the activities of the plasma urokinase plasminogen activator (uPA) and the liver matrix metalloproteinase 9 (MMP-9), as well as by inhibiting the phosphorylation of p38 and extracellular signal-regulated kinase 2 (ERK2) in lung and liver tissues. In addition, antrodan effectively ameliorated cisplatin-induced kidney dysfunction when treated combinatorially, as evidenced by a decrease in cisplatin-induced blood urea nitrogen (BUN) levels in plasma and in the level of p38 phosphorylation in the kidney. Mechanistically, the actions of antrodan on its own involved (i) reducing the activities of uPA and MMP-2 and -9 in plasma; (ii) reducing protein expression of MMP-2/9, and the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38 in lung and liver tissues; and (iii) enhancing immune system functions resulting in the promotion of an anti-metastatic response through immunomodulation, by increasing interferon-γ (IFN-γ) levels and decreasing interleukin-6 (IL-6) levels in plasma. These results demonstrated that antrodan provides a novel, complementary therapeutic strategy against cancer metastasis, by attenuating the activities of MMP-2 and -9 through the modulation of STAT3/MAPK/ERK/JNK signaling pathways, and of the host’s immune system. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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18 pages, 615 KiB  
Review
Cutaneous Melanoma—A Long Road from Experimental Models to Clinical Outcome: A Review
by Dorina Coricovac, Cristina Dehelean, Elena-Alina Moaca, Iulia Pinzaru, Tiberiu Bratu, Dan Navolan and Ovidiu Boruga
Int. J. Mol. Sci. 2018, 19(6), 1566; https://doi.org/10.3390/ijms19061566 - 24 May 2018
Cited by 67 | Viewed by 8207
Abstract
Cutaneous melanoma is a complex disorder characterized by an elevated degree of heterogeneity, features that place it among the most aggressive types of cancer. Although significant progress was recorded in both the understanding of melanoma biology and genetics, and in therapeutic approaches, this [...] Read more.
Cutaneous melanoma is a complex disorder characterized by an elevated degree of heterogeneity, features that place it among the most aggressive types of cancer. Although significant progress was recorded in both the understanding of melanoma biology and genetics, and in therapeutic approaches, this malignancy still represents a major problem worldwide due to its high incidence and the lack of a curative treatment for advanced stages. This review offers a survey of the most recent information available regarding the melanoma epidemiology, etiology, and genetic profile. Also discussed was the topic of cutaneous melanoma murine models outlining the role of these models in understanding the molecular pathways involved in melanoma initiation, progression, and metastasis. Full article
(This article belongs to the Special Issue Animal Models of Melanoma)
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13 pages, 2810 KiB  
Article
Luteolin-Mediated Inhibition of Hepatic Stellate Cell Activation via Suppression of the STAT3 Pathway
by Claire B. Cummins, Xiaofu Wang, Omar Nunez Lopez, Gabriel Graham, Hong-Yan Tie, Jia Zhou and Ravi S. Radhakrishnan
Int. J. Mol. Sci. 2018, 19(6), 1567; https://doi.org/10.3390/ijms19061567 - 24 May 2018
Cited by 33 | Viewed by 6034
Abstract
Hepatic stellate cell (HSC) activation is responsible for hepatic fibrogenesis and is associated with an overexpression of transcription 3 (STAT3). Luteolin, a common dietary flavonoid with potent anti-inflammatory properties, has previously demonstrated antifibrogenic properties in HSCs but the mechanism has not been fully [...] Read more.
Hepatic stellate cell (HSC) activation is responsible for hepatic fibrogenesis and is associated with an overexpression of transcription 3 (STAT3). Luteolin, a common dietary flavonoid with potent anti-inflammatory properties, has previously demonstrated antifibrogenic properties in HSCs but the mechanism has not been fully elucidated. Activated human and rat hepatic stellate cell lines LX-2 and HSC-T6 were used to study the effects of luteolin on HSCs. Cellular proteins were determined by western blot and immunofluorescence. Cell proliferation was assessed with Alamar Blue assay. Luteolin significantly decreased LX-2 and HSC-T6 cell viability in a time-and-dose-dependent manner, as well as decreased HSC end-products α-smooth muscle actin (α-SMA), collagen I, and fibronectin. Luteolin decreased levels of total and phosphorylated STAT3, suppressed STAT3 nuclear translocation and transcriptional activity, and attenuated expression of STAT3-regulated proteins c-myc and cyclin D1. STAT3 specific inhibitors stattic and SH-4-54 demonstrated similar effects on HSC viability and α-SMA production. In LX-2 and HSC-T6 cells, luteolin demonstrates a potent ability to inhibit hepatic fibrogenesis via suppression of the STAT3 pathway. These results further elucidate the mechanism of luteolin as well as the effect of the STAT3 pathway on HSC activation. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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15 pages, 275 KiB  
Review
Signaling Crosstalk of TGF-β/ALK5 and PAR2/PAR1: A Complex Regulatory Network Controlling Fibrosis and Cancer
by Hendrik Ungefroren, Frank Gieseler, Roland Kaufmann, Utz Settmacher, Hendrik Lehnert and Bernhard H. Rauch
Int. J. Mol. Sci. 2018, 19(6), 1568; https://doi.org/10.3390/ijms19061568 - 24 May 2018
Cited by 46 | Viewed by 8560
Abstract
Both signaling by transforming growth factor-β (TGF-β) and agonists of the G Protein-coupled receptors proteinase-activated receptor-1 (PAR1) and -2 (PAR2) have been linked to tissue fibrosis and cancer. Intriguingly, TGF-β and PAR signaling either converge on the regulation of certain matrix genes overexpressed [...] Read more.
Both signaling by transforming growth factor-β (TGF-β) and agonists of the G Protein-coupled receptors proteinase-activated receptor-1 (PAR1) and -2 (PAR2) have been linked to tissue fibrosis and cancer. Intriguingly, TGF-β and PAR signaling either converge on the regulation of certain matrix genes overexpressed in these pathologies or display mutual regulation of their signaling components, which is mediated in part through sphingosine kinases and sphingosine-1-phosphate and indicative of an intimate signaling crosstalk between the two pathways. In the first part of this review, we summarize the various regulatory interactions that have been discovered so far according to the organ/tissue in which they were described. In the second part, we highlight the types of signaling crosstalk between TGF-β on the one hand and PAR2/PAR1 on the other hand. Both ligand–receptor systems interact at various levels and by several mechanisms including mutual regulation of ligand–ligand, ligand–receptor, and receptor–receptor at the transcriptional, post-transcriptional, and receptor transactivation levels. These mutual interactions between PAR2/PAR1 and TGF-β signaling components eventually result in feed-forward loops/vicious cycles of matrix deposition and malignant traits that exacerbate fibrosis and oncogenesis, respectively. Given the crucial role of PAR2 and PAR1 in controlling TGF-β receptor activation, signaling, TGF-β synthesis and bioactivation, combining PAR inhibitors with TGF-β blocking agents may turn out to be more efficient than targeting TGF-β alone in alleviating unwanted TGF-β-dependent responses but retaining the beneficial ones. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)
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11 pages, 255 KiB  
Review
Recent Insights into Mucinous Ovarian Carcinoma
by Francesca Ricci, Roberta Affatato, Laura Carrassa and Giovanna Damia
Int. J. Mol. Sci. 2018, 19(6), 1569; https://doi.org/10.3390/ijms19061569 - 24 May 2018
Cited by 53 | Viewed by 7450
Abstract
Ovarian mucinous tumors represent a group of rare neoplasms with a still undefined cell of origin but with an apparent progression from benign to borderline to carcinoma. Even though these tumors are different from the other histological subtypes of epithelial ovarian neoplasms, they [...] Read more.
Ovarian mucinous tumors represent a group of rare neoplasms with a still undefined cell of origin but with an apparent progression from benign to borderline to carcinoma. Even though these tumors are different from the other histological subtypes of epithelial ovarian neoplasms, they are still treated with a similar chemotherapeutic approach. Here, we review its pathogenesis, molecular alterations, (differential) diagnosis, clinical presentation and current treatment, and how recent molecular and biological information on this tumor might lead to better and more specific clinical management of patients with mucinous ovarian carcinoma. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
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13 pages, 1498 KiB  
Article
Na+-Dependent High-Affinity Nitrate, Phosphate and Amino Acids Transport in Leaf Cells of the Seagrass Posidonia oceanica (L.) Delile
by Lourdes Rubio, Delia García-Pérez, María Jesús García-Sánchez and José A. Fernández
Int. J. Mol. Sci. 2018, 19(6), 1570; https://doi.org/10.3390/ijms19061570 - 24 May 2018
Cited by 13 | Viewed by 3988
Abstract
Posidonia oceanica (L.) Delile is a seagrass, the only group of vascular plants to colonize the marine environment. Seawater is an extreme yet stable environment characterized by high salinity, alkaline pH and low availability of essential nutrients, such as nitrate and phosphate. Classical [...] Read more.
Posidonia oceanica (L.) Delile is a seagrass, the only group of vascular plants to colonize the marine environment. Seawater is an extreme yet stable environment characterized by high salinity, alkaline pH and low availability of essential nutrients, such as nitrate and phosphate. Classical depletion experiments, membrane potential and cytosolic sodium measurements were used to characterize the high-affinity NO3, Pi and amino acids uptake mechanisms in this species. Net uptake rates of both NO3 and Pi were reduced by more than 70% in the absence of Na+. Micromolar concentrations of NO3 depolarized mesophyll leaf cells plasma membrane. Depolarizations showed saturation kinetics (Km = 8.7 ± 1 μM NO3), which were not observed in the absence of Na+. NO3 induced depolarizations at increasing Na+ also showed saturation kinetics (Km = 7.2 ± 2 mM Na+). Cytosolic Na+ measured in P. oceanica leaf cells (17 ± 2 mM Na+) increased by 0.4 ± 0.2 mM Na+ upon the addition of 100 μM NO3. Na+-dependence was also observed for high-affinity l-ala and l-cys uptake and high-affinity Pi transport. All together, these results strongly suggest that NO3, amino acids and Pi uptake in P. oceanica leaf cells are mediated by high-affinity Na+-dependent transport systems. This mechanism seems to be a key step in the process of adaptation of seagrasses to the marine environment. Full article
(This article belongs to the Special Issue Plasma-Membrane Transport)
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12 pages, 1468 KiB  
Article
The Crystal Structure of a hCA VII Variant Provides Insights into the Molecular Determinants Responsible for Its Catalytic Behavior
by Martina Buonanno, Anna Di Fiore, Emma Langella, Katia D’Ambrosio, Claudiu T. Supuran, Simona Maria Monti and Giuseppina De Simone
Int. J. Mol. Sci. 2018, 19(6), 1571; https://doi.org/10.3390/ijms19061571 - 24 May 2018
Cited by 27 | Viewed by 4407
Abstract
Although important progress has been achieved in understanding the catalytic mechanism of Carbonic Anhydrases, a detailed picture of all factors influencing the catalytic efficiency of the various human isoforms is still missing. In this paper we report a detailed structural study and theoretical [...] Read more.
Although important progress has been achieved in understanding the catalytic mechanism of Carbonic Anhydrases, a detailed picture of all factors influencing the catalytic efficiency of the various human isoforms is still missing. In this paper we report a detailed structural study and theoretical pKa calculations on a hCA VII variant. The obtained data were compared with those already known for another thoroughly investigated cytosolic isoform, hCA II. Our structural studies show that in hCA VII the network of ordered water molecules, which connects the zinc bound solvent molecule to the proton shuttle His64, is altered compared to hCA II, causing a reduction of the catalytic efficiency. Theoretical calculations suggest that changes in solvent network are related to the difference in pKa of the proton shuttle in the two enzymes. The residue that plays a major role in determining the diverse pKa values of the proton shuttle is the one in position four, namely His for hCA II and Gly for hCA VII. This residue is located on the protein surface, outside of the active site cavity. These findings are in agreement with our previous studies that highlighted the importance of histidines on the protein surface of hCA II (among which His4) as crucial residues for the high catalytic efficiency of this isoform. Full article
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20 pages, 4290 KiB  
Article
Sirt1 Protects against Oxidative Stress-Induced Apoptosis in Fibroblasts from Psoriatic Patients: A New Insight into the Pathogenetic Mechanisms of Psoriasis
by Matteo Becatti, Victoria Barygina, Amanda Mannucci, Giacomo Emmi, Domenico Prisco, Torello Lotti, Claudia Fiorillo and Niccolò Taddei
Int. J. Mol. Sci. 2018, 19(6), 1572; https://doi.org/10.3390/ijms19061572 - 25 May 2018
Cited by 62 | Viewed by 6286
Abstract
Psoriasis, a multisystem chronic disease characterized by abnormal keratinocyte proliferation, has an unclear pathogenesis where systemic inflammation and oxidative stress play mutual roles. Dermal fibroblasts, which are known to provide a crucial microenvironment for epidermal keratinocyte function, represented the selected experimental model in [...] Read more.
Psoriasis, a multisystem chronic disease characterized by abnormal keratinocyte proliferation, has an unclear pathogenesis where systemic inflammation and oxidative stress play mutual roles. Dermal fibroblasts, which are known to provide a crucial microenvironment for epidermal keratinocyte function, represented the selected experimental model in our study which aimed to clarify the potential role of SIRT1 in the pathogenetic mechanisms of the disease. We firstly detected the presence of oxidative stress (lipid peroxidation and total antioxidant capacity), significantly reduced SIRT1 expression level and activity, mitochondrial damage and apoptosis (caspase-3, -8 and -9 activities) in psoriatic fibroblasts. Upon SIRT1 activation, redox balance was re-established, mitochondrial function was restored and apoptosis was no longer evident. Furthermore, we examined p38, ERK and JNK activation, which was strongly altered in psoriatic fibroblasts, in response to SIRT1 activation and we measured caspase-3 activity in the presence of specific MAPK inhibitors demonstrating the key role of the SIRT1 pathway against apoptotic cell death via MAPK modulation. Our results clearly demonstrate the involvement of SIRT1 in the protective mechanisms related to fibroblast injury in psoriasis. SIRT1 activation exerts an active role in restoring both mitochondrial function and redox balance via modulation of MAPK signaling. Hence, SIRT1 can be proposed as a specific tool for the treatment of psoriasis. Full article
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16 pages, 1086 KiB  
Review
Bioactivities of Phenolics by Focusing on Suppression of Chronic Diseases: A Review
by Fereidoon Shahidi and JuDong Yeo
Int. J. Mol. Sci. 2018, 19(6), 1573; https://doi.org/10.3390/ijms19061573 - 25 May 2018
Cited by 354 | Viewed by 12841
Abstract
Phenolics, which are secondary metabolites of plants, exhibit remarkable bioactivities. In this contribution, we have focused on their protective effect against chronic diseases rather than their antioxidant activities, which have been widely discussed in the literature. A large body of epidemiological studies has [...] Read more.
Phenolics, which are secondary metabolites of plants, exhibit remarkable bioactivities. In this contribution, we have focused on their protective effect against chronic diseases rather than their antioxidant activities, which have been widely discussed in the literature. A large body of epidemiological studies has proven the bioactivities of phenolics in both standard compounds and natural extracts: namely, anticancer, anti-inflammatory, and antibacterial activities as well as reducing diabetes, cardiovascular disease, and neurodegenerative disease. Phenolics also display anti-analgesic, anti-allergic, and anti-Alzheimer’s properties. Thus, this review provides crucial information for better understanding the bioactivities of phenolics in foods and fills a gap in the existing collective and overall knowledge in the field. Full article
(This article belongs to the Special Issue Bioactive Phenolics and Polyphenols 2018)
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15 pages, 3985 KiB  
Article
The Extracts and Major Compounds Derived from Astragali Radix Alter Mitochondrial Bioenergetics in Cultured Cardiomyocytes: Comparison of Various Polar Solvents and Compounds
by Yun Huang, Kenneth Kin Leung Kwan, Ka Wing Leung, Huaiyou Wang, Xiang Peng Kong, Tina Ting Xia Dong and Karl Wah Keung Tsim
Int. J. Mol. Sci. 2018, 19(6), 1574; https://doi.org/10.3390/ijms19061574 - 25 May 2018
Cited by 22 | Viewed by 4862
Abstract
Astragali Radix (AR) is a widely used “Qi-invigorating” herb in China for its tonic effects in strengthening biological tissues. The extract of AR contains abundant antioxidants, including astragalosides and isoflavonoids. However, very few reports have systematically measured the effects of the major components [...] Read more.
Astragali Radix (AR) is a widely used “Qi-invigorating” herb in China for its tonic effects in strengthening biological tissues. The extract of AR contains abundant antioxidants, including astragalosides and isoflavonoids. However, very few reports have systematically measured the effects of the major components of AR on cell mitochondrial bioenergetics. Here, a systemic approach employing an extracellular flux analyzer was developed to evaluate mitochondrial respiration in cultured cardiomyocyte cells H9C2. The effects of different polar extractives, as well as of the major compounds of AR, were compared. The contents of astragaloside IV, calycosin, formononetin, and genistein in the AR extracts obtained by using water, 50% ethanol, and 90% ethanol were measured by liquid chromatograph-mass spectrometer (LC–MS). The antioxidant activities of the AR extracts, as well as of their major compounds, were determined by measuring the free radical scavenging activity and protective effects in tert-butyl hydroperoxide (tBHP)-treated H9C2 cells. By monitoring the real-time oxygen consumption rate (OCR) in tBHP-treated cardiomyocytes with a Seahorse extracellular flux analyzer, the tonic effects of the AR extracts and of their main compounds on mitochondrial bioenergetics were evaluated. AR water extracts possessed the strongest antioxidant activity and protective effects in cardiomyocytes exposed to oxidative stress. The protection was proposed to be mediated via increasing the spare respiratory capacity and mitochondrial ATP production in the stressed cells. The major compounds of AR, astragaloside IV and genistein, showed opposite effects in regulating mitochondrial bioenergetics. These results demonstrate that highly polar extracts of AR, especially astragaloside-enriched extracts, possess better tonic effects on mitochondrial bioenergetics of cultured cardiomyocytes than extracts with a lower polarity. Full article
(This article belongs to the Special Issue Plant Natural Products for Human Health)
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16 pages, 877 KiB  
Review
Regulation of Immune Cell Function by PPARs and the Connection with Metabolic and Neurodegenerative Diseases
by Gwenaëlle Le Menn and Jaap G. Neels
Int. J. Mol. Sci. 2018, 19(6), 1575; https://doi.org/10.3390/ijms19061575 - 25 May 2018
Cited by 51 | Viewed by 5954
Abstract
Increasing evidence points towards the existence of a bidirectional interconnection between metabolic disease and neurodegenerative disorders, in which inflammation is linking both together. Activation of members of the peroxisome proliferator-activated receptor (PPAR) family has been shown to have beneficial effects in these interlinked [...] Read more.
Increasing evidence points towards the existence of a bidirectional interconnection between metabolic disease and neurodegenerative disorders, in which inflammation is linking both together. Activation of members of the peroxisome proliferator-activated receptor (PPAR) family has been shown to have beneficial effects in these interlinked pathologies, and these improvements are often attributed to anti-inflammatory effects of PPAR activation. In this review, we summarize the role of PPARs in immune cell function, with a focus on macrophages and T cells, and how this was shown to contribute to obesity-associated inflammation and insulin resistance, atherosclerosis, and neurodegenerative disorders. We address gender differences as a potential explanation in observed contradictory results, and we highlight PPAR-induced metabolic changes as a potential mechanism of regulation of immune cell function through these nuclear receptors. Together, immune cell-specific activation of PPARs present a promising therapeutic approach to treat both metabolic and neurodegenerative diseases. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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17 pages, 3123 KiB  
Article
Novel Safranin-Tinted Candida rugosa Lipase Nanoconjugates Reagent for Visualizing Latent Fingerprints on Stainless Steel Knives Immersed in a Natural Outdoor Pond
by Aida Rasyidah Azman, Naji Arafat Mahat, Roswanira Abdul Wahab, Fazira Ilyana Abdul Razak and Hafezul Helmi Hamzah
Int. J. Mol. Sci. 2018, 19(6), 1576; https://doi.org/10.3390/ijms19061576 - 25 May 2018
Cited by 17 | Viewed by 5803
Abstract
Waterways are popular locations for the disposition of criminal evidence because the recovery of latent fingerprints from such evidence is difficult. Currently, small particle reagent is a method often used to visualize latent fingerprints containing carcinogenic and hazardous compounds. This study proposes an [...] Read more.
Waterways are popular locations for the disposition of criminal evidence because the recovery of latent fingerprints from such evidence is difficult. Currently, small particle reagent is a method often used to visualize latent fingerprints containing carcinogenic and hazardous compounds. This study proposes an eco-friendly, safranin-tinted Candida rugosa lipase (triacylglycerol ester hydrolysis EC 3.1.1.3) with functionalized carbon nanotubes (CRL-MWCNTS/GA/SAF) as an alternative reagent to the small particle reagent. The CRL-MWCNTS/GA/SAF reagent was compared with the small particle reagent to visualize groomed, full fingerprints deposited on stainless steel knives which were immersed in a natural outdoor pond for 30 days. The quality of visualized fingerprints using the new reagent was similar (modified-Centre for Applied Science and Technology grade: 4; p > 0.05) to small particle reagent, even after 15 days of immersion. Despite the slight decrease in quality of visualized fingerprints using the CRL-MWCNTS/GA/SAF on the last three immersion periods, the fingerprints remained forensically identifiable (modified-Centre for Applied Science and Technology grade: 3). The possible chemical interactions that enabled successful visualization is also discussed. Thus, this novel reagent may provide a relatively greener alternative for the visualization of latent fingerprints on immersed non-porous objects. Full article
(This article belongs to the Section Biochemistry)
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17 pages, 4220 KiB  
Article
Structural Basis for Mutations of Human Aquaporins Associated to Genetic Diseases
by Luisa Calvanese, Gabriella D’Auria, Anna Vangone, Lucia Falcigno and Romina Oliva
Int. J. Mol. Sci. 2018, 19(6), 1577; https://doi.org/10.3390/ijms19061577 - 25 May 2018
Cited by 21 | Viewed by 5462
Abstract
Aquaporins (AQPs) are among the best structural-characterized membrane proteins, fulfilling the role of allowing water flux across cellular membranes. Thus far, 34 single amino acid polymorphisms have been reported in HUMSAVAR for human aquaporins as disease-related. They affect AQP2, AQP5 and AQP8, where [...] Read more.
Aquaporins (AQPs) are among the best structural-characterized membrane proteins, fulfilling the role of allowing water flux across cellular membranes. Thus far, 34 single amino acid polymorphisms have been reported in HUMSAVAR for human aquaporins as disease-related. They affect AQP2, AQP5 and AQP8, where they are associated with nephrogenic diabetes insipidus, keratoderma and colorectal cancer, respectively. For half of these mutations, although they are mostly experimentally characterized in their dysfunctional phenotypes, a structural characterization at a molecular level is still missing. In this work, we focus on such mutations and discuss what the structural defects are that they appear to cause. To achieve this aim, we built a 3D molecular model for each mutant and explored the effect of the mutation on all of their structural features. Based on these analyses, we could collect the structural defects of all the pathogenic mutations (here or previously analysed) under few main categories, that we found to nicely correlate with the experimental phenotypes reported for several of the analysed mutants. Some of the structural analyses we present here provide a rationale for previously experimentally observed phenotypes. Furthermore, our comprehensive overview can be used as a reference frame for the interpretation, on a structural basis, of defective phenotypes of other aquaporin pathogenic mutants. Full article
(This article belongs to the Special Issue Aquaporins: Water Channels Essential for Living Organisms)
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29 pages, 2234 KiB  
Review
Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery
by Nicholas Ekow Thomford, Dimakatso Alice Senthebane, Arielle Rowe, Daniella Munro, Palesa Seele, Alfred Maroyi and Kevin Dzobo
Int. J. Mol. Sci. 2018, 19(6), 1578; https://doi.org/10.3390/ijms19061578 - 25 May 2018
Cited by 973 | Viewed by 57666
Abstract
The therapeutic properties of plants have been recognised since time immemorial. Many pathological conditions have been treated using plant-derived medicines. These medicines are used as concoctions or concentrated plant extracts without isolation of active compounds. Modern medicine however, requires the isolation and purification [...] Read more.
The therapeutic properties of plants have been recognised since time immemorial. Many pathological conditions have been treated using plant-derived medicines. These medicines are used as concoctions or concentrated plant extracts without isolation of active compounds. Modern medicine however, requires the isolation and purification of one or two active compounds. There are however a lot of global health challenges with diseases such as cancer, degenerative diseases, HIV/AIDS and diabetes, of which modern medicine is struggling to provide cures. Many times the isolation of “active compound” has made the compound ineffective. Drug discovery is a multidimensional problem requiring several parameters of both natural and synthetic compounds such as safety, pharmacokinetics and efficacy to be evaluated during drug candidate selection. The advent of latest technologies that enhance drug design hypotheses such as Artificial Intelligence, the use of ‘organ-on chip’ and microfluidics technologies, means that automation has become part of drug discovery. This has resulted in increased speed in drug discovery and evaluation of the safety, pharmacokinetics and efficacy of candidate compounds whilst allowing novel ways of drug design and synthesis based on natural compounds. Recent advances in analytical and computational techniques have opened new avenues to process complex natural products and to use their structures to derive new and innovative drugs. Indeed, we are in the era of computational molecular design, as applied to natural products. Predictive computational softwares have contributed to the discovery of molecular targets of natural products and their derivatives. In future the use of quantum computing, computational softwares and databases in modelling molecular interactions and predicting features and parameters needed for drug development, such as pharmacokinetic and pharmacodynamics, will result in few false positive leads in drug development. This review discusses plant-based natural product drug discovery and how innovative technologies play a role in next-generation drug discovery. Full article
(This article belongs to the Special Issue Plant Natural Products for Human Health)
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13 pages, 1043 KiB  
Review
Nanomotors for Nucleic Acid, Proteins, Pollutants and Cells Detection
by Alejandro Baeza and María Vallet-Regí
Int. J. Mol. Sci. 2018, 19(6), 1579; https://doi.org/10.3390/ijms19061579 - 25 May 2018
Cited by 15 | Viewed by 4718
Abstract
The development of nanomachines able to operate at the nanoscale, performing complex tasks such as drug delivery, precision surgery, or cell detection, constitutes one of the most important challenges in nanotechnology. The principles that rule the nanoscale are completely different from the ones [...] Read more.
The development of nanomachines able to operate at the nanoscale, performing complex tasks such as drug delivery, precision surgery, or cell detection, constitutes one of the most important challenges in nanotechnology. The principles that rule the nanoscale are completely different from the ones which govern the macroscopic world and, therefore, the collaboration of scientists with expertise in different fields is required for the effective fabrication of these tiny machines. In this review, the most recent advances carried out in the synthesis and application of nanomachines for diagnosis applications will be presented in order to provide a picture of their potential in the detection of important biomolecules or pathogens in a selective and controlled manner. Full article
(This article belongs to the Special Issue Nucleic Acid Nanotechnology)
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14 pages, 1917 KiB  
Article
Increased Phenacetin Oxidation upon the L382V Substitution in Cytochrome P450 1A2 is Associated with Altered Substrate Binding Orientation
by Qingbiao Huang and Grazyna D. Szklarz
Int. J. Mol. Sci. 2018, 19(6), 1580; https://doi.org/10.3390/ijms19061580 - 25 May 2018
Cited by 3 | Viewed by 4309
Abstract
Leucine382 of cytochrome P450 1A2 (CYP1A2) plays an important role in binding and O-dealkylation of phenacetin, with the L382V mutation increasing substrate oxidation (Huang and Szklarz, 2010, Drug Metab. Dispos. 38:1039–1045). This was attributed to altered substrate binding orientation, but no [...] Read more.
Leucine382 of cytochrome P450 1A2 (CYP1A2) plays an important role in binding and O-dealkylation of phenacetin, with the L382V mutation increasing substrate oxidation (Huang and Szklarz, 2010, Drug Metab. Dispos. 38:1039–1045). This was attributed to altered substrate binding orientation, but no direct experimental evidence had been available. Therefore, in the current studies, we employed nuclear magnetic resonance (NMR) longitudinal (T1) relaxation measurements to investigate phenacetin binding orientations within the active site of CYP1A2 wild type (WT) and mutants. Paramagnetic relaxation time (T1P) for each proton of phenacetin was calculated from the T1 value obtained from the enzymes in ferric and ferrous-CO state in the presence of phenacetin, and used to model the orientation of phenacetin in the active site. All aromatic protons of phenacetin were nearly equidistant from the heme iron (6.34–8.03 Å). In contrast, the distance between the proton of the –OCH2– group, which is abstracted during phenacetin oxidation, and the heme iron, was much shorter in the L382V (5.93 Å) and L382V/N312L (5.96 Å) mutants compared to the N312L mutant (7.84 Å) and the wild type enzyme (6.55 Å), consistent with modeling results. These studies provide direct evidence for the molecular mechanism underlying increased oxidation of phenacetin upon the L382V mutation. Full article
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism and Bioactivation)
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12 pages, 2693 KiB  
Article
Stimulatory Effects of Melatonin on Porcine In Vitro Maturation Are Mediated by MT2 Receptor
by Sanghoon Lee, Jun-Xue Jin, Anukul Taweechaipaisankul, Geon-A Kim and Byeong-Chun Lee
Int. J. Mol. Sci. 2018, 19(6), 1581; https://doi.org/10.3390/ijms19061581 - 26 May 2018
Cited by 31 | Viewed by 5037
Abstract
Melatonin is a multifunctional molecule with numerous biological activities. The fact that melatonin modulates the functions of porcine granulosa cells via the MT2 receptor suggests the possibility of MT2 receptor-mediation for melatonin to promote cumulus expansion of porcine cumulus-oocyte complexes (COCs). Therefore, we [...] Read more.
Melatonin is a multifunctional molecule with numerous biological activities. The fact that melatonin modulates the functions of porcine granulosa cells via the MT2 receptor suggests the possibility of MT2 receptor-mediation for melatonin to promote cumulus expansion of porcine cumulus-oocyte complexes (COCs). Therefore, we investigated the presence of MT2 in porcine COCs, and the effects of melatonin with or without selective MT2 antagonists (luzindole and 4-P-PDOT) on this process; COCs underwent in vitro maturation culturing with six different conditions (control, melatonin, luzindole, 4-P-PDOT, melatonin + luzindole or melatonin + 4-P-PDOT). Cumulus expansion, oocyte nuclear maturation, and subsequent embryo development after parthenogenetic activation (PA) were evaluated. In experiment 1, MT2 was expressed in both oocytes and cumulus cells. In experiment 2, melatonin significantly increased the proportion of complete cumulus expansion (degree 4), which was inhibited by simultaneous addition of either luzindole or 4-P-PDOT. A similar pattern was observed in the expression of genes related to cumulus expansion, apoptosis, and MT2. In experiment 3, no significant difference was observed in immature, degenerate, and MII oocyte rates among the groups. In experiment 4, melatonin significantly increased blastocyst formation rates and total blastocyst cell numbers after PA, but these effects were abolished when either luzindole or 4-P-PDOT was added concomitantly. In conclusion, our results indicate that the MT2 receptor mediated the stimulatory effects of melatonin on porcine cumulus expansion and subsequent embryo development. Full article
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18 pages, 2754 KiB  
Article
The Organization of Mitochondrial Supercomplexes is Modulated by Oxidative Stress In Vivo in Mouse Models of Mitochondrial Encephalopathy
by Mir R. Anwar, Amy Saldana-Caboverde, Sofia Garcia and Francisca Diaz
Int. J. Mol. Sci. 2018, 19(6), 1582; https://doi.org/10.3390/ijms19061582 - 26 May 2018
Cited by 19 | Viewed by 5577
Abstract
We examine the effect of oxidative stress on the stability of mitochondrial respiratory complexes and their association into supercomplexes (SCs) in the neuron-specific Rieske iron sulfur protein (RISP) and COX10 knockout (KO) mice. Previously we reported that these two models display different grades [...] Read more.
We examine the effect of oxidative stress on the stability of mitochondrial respiratory complexes and their association into supercomplexes (SCs) in the neuron-specific Rieske iron sulfur protein (RISP) and COX10 knockout (KO) mice. Previously we reported that these two models display different grades of oxidative stress in distinct brain regions. Using blue native gel electrophoresis, we observed a redistribution of the architecture of SCs in KO mice. Brain regions with moderate levels of oxidative stress (cingulate cortex of both COX10 and RISP KO and hippocampus of the RISP KO) showed a significant increase in the levels of high molecular weight (HMW) SCs. High levels of oxidative stress in the piriform cortex of the RISP KO negatively impacted the stability of CI, CIII and SCs. Treatment of the RISP KO with the mitochondrial targeted antioxidant mitoTEMPO preserved the stability of respiratory complexes and formation of SCs in the piriform cortex and increased the levels of glutathione peroxidase. These results suggest that mild to moderate levels of oxidative stress can modulate SCs into a more favorable architecture of HMW SCs to cope with rising levels of free radicals and cover the energetic needs. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases)
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21 pages, 7396 KiB  
Article
Genome-Wide Identification and Expression Analysis of the UGlcAE Gene Family in Tomato
by Xing Ding, Jinhua Li, Yu Pan, Yue Zhang, Lei Ni, Yaling Wang and Xingguo Zhang
Int. J. Mol. Sci. 2018, 19(6), 1583; https://doi.org/10.3390/ijms19061583 - 27 May 2018
Cited by 27 | Viewed by 5185
Abstract
The UGlcAE has the capability of interconverting UDP-d-galacturonic acid and UDP-d-glucuronic acid, and UDP-d-galacturonic acid is an activated precursor for the synthesis of pectins in plants. In this study, we identified nine UGlcAE protein-encoding genes in tomato. [...] Read more.
The UGlcAE has the capability of interconverting UDP-d-galacturonic acid and UDP-d-glucuronic acid, and UDP-d-galacturonic acid is an activated precursor for the synthesis of pectins in plants. In this study, we identified nine UGlcAE protein-encoding genes in tomato. The nine UGlcAE genes that were distributed on eight chromosomes in tomato, and the corresponding proteins contained one or two trans-membrane domains. The phylogenetic analysis showed that SlUGlcAE genes could be divided into seven groups, designated UGlcAE1 to UGlcAE6, of which the UGlcAE2 were classified into two groups. Expression profile analysis revealed that the SlUGlcAE genes display diverse expression patterns in various tomato tissues. Selective pressure analysis indicated that all of the amino acid sites of SlUGlcAE proteins are undergoing purifying selection. Fifteen stress-, hormone-, and development-related elements were identified in the upstream regions (0.5 kb) of these SlUGlcAE genes. Furthermore, we investigated the expression patterns of SlUGlcAE genes in response to three hormones (indole-3-acetic acid (IAA), gibberellin (GA), and salicylic acid (SA)). We detected firmness, pectin contents, and expression levels of UGlcAE family genes during the development of tomato fruit. Here, we systematically summarize the general characteristics of the SlUGlcAE genes in tomato, which could provide a basis for further function studies of tomato UGlcAE genes. Full article
(This article belongs to the Special Issue Plant Genomics)
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26 pages, 2301 KiB  
Review
Prioritization of Variants Detected by Next Generation Sequencing According to the Mutation Tolerance and Mutational Architecture of the Corresponding Genes
by Iria Roca, Ana Fernández-Marmiesse, Sofía Gouveia, Marta Segovia and María L. Couce
Int. J. Mol. Sci. 2018, 19(6), 1584; https://doi.org/10.3390/ijms19061584 - 27 May 2018
Cited by 17 | Viewed by 6439
Abstract
The biggest challenge geneticists face when applying next-generation sequencing technology to the diagnosis of rare diseases is determining which rare variants, from the dozens or hundreds detected, are potentially implicated in the patient’s phenotype. Thus, variant prioritization is an essential step in the [...] Read more.
The biggest challenge geneticists face when applying next-generation sequencing technology to the diagnosis of rare diseases is determining which rare variants, from the dozens or hundreds detected, are potentially implicated in the patient’s phenotype. Thus, variant prioritization is an essential step in the process of rare disease diagnosis. In addition to conducting the usual in-silico analyses to predict variant pathogenicity (based on nucleotide/amino-acid conservation and the differences between the physicochemical features of the amino-acid change), three important concepts should be borne in mind. The first is the “mutation tolerance” of the genes in which variants are located. This describes the susceptibility of a given gene to any functional mutation and depends on the strength of purifying selection acting against it. The second is the “mutational architecture” of each gene. This describes the type and location of mutations previously identified in the gene, and their association with different phenotypes or degrees of severity. The third is the mode of inheritance (inherited vs. de novo) of the variants detected. Here, we discuss the importance of each of these concepts for variant prioritization in the diagnosis of rare diseases. Using real data, we show how genes, rather than variants, can be prioritized by calculating a gene-specific mutation tolerance score. We also illustrate the influence of mutational architecture on variant prioritization using five paradigmatic examples. Finally, we discuss the importance of familial variant analysis as final step in variant prioritization. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies)
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36 pages, 3770 KiB  
Article
Src Cooperates with Oncogenic Ras in Tumourigenesis via the JNK and PI3K Pathways in Drosophila epithelial Tissue
by Carole L.C. Poon, Anthony M. Brumby and Helena E. Richardson
Int. J. Mol. Sci. 2018, 19(6), 1585; https://doi.org/10.3390/ijms19061585 - 27 May 2018
Cited by 13 | Viewed by 7546
Abstract
The Ras oncogene (Rat Sarcoma oncogene, a small GTPase) is a key driver of human cancer, however alone it is insufficient to produce malignancy, due to the induction of cell cycle arrest or senescence. In a Drosophila melanogaster genetic screen for genes that [...] Read more.
The Ras oncogene (Rat Sarcoma oncogene, a small GTPase) is a key driver of human cancer, however alone it is insufficient to produce malignancy, due to the induction of cell cycle arrest or senescence. In a Drosophila melanogaster genetic screen for genes that cooperate with oncogenic Ras (bearing the RasV12 mutation, or RasACT), we identified the Drosophila Src (Sarcoma virus oncogene) family non-receptor tyrosine protein kinase genes, Src42A and Src64B, as promoting increased hyperplasia in a whole epithelial tissue context in the Drosophila eye. Moreover, overexpression of Src cooperated with RasACT in epithelial cell clones to drive neoplastic tumourigenesis. We found that Src overexpression alone activated the Jun N-terminal Kinase (JNK) signalling pathway to promote actin cytoskeletal and cell polarity defects and drive apoptosis, whereas, in cooperation with RasACT, JNK led to a loss of differentiation and an invasive phenotype. Src + RasACT cooperative tumourigenesis was dependent on JNK as well as Phosphoinositide 3-Kinase (PI3K) signalling, suggesting that targeting these pathways might provide novel therapeutic opportunities in cancers dependent on Src and Ras signalling. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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11 pages, 26427 KiB  
Article
Prognostic Value of RNASEH2A-, CDK1-, and CD151-Related Pathway Gene Profiling for Kidney Cancers
by Chin-An Yang, Hsi-Yuan Huang, Ju-Chen Yen and Jan-Gowth Chang
Int. J. Mol. Sci. 2018, 19(6), 1586; https://doi.org/10.3390/ijms19061586 - 28 May 2018
Cited by 16 | Viewed by 4419
Abstract
The nucleotide degrading enzyme gene RNASEH2A (ribonuclease H2 subunit A) has been found to be overexpressed in cancers. Our aim was to understand the role of RNASEH2A in cancer prognostication and to establish a scoring system based on the expressions of genes interacting [...] Read more.
The nucleotide degrading enzyme gene RNASEH2A (ribonuclease H2 subunit A) has been found to be overexpressed in cancers. Our aim was to understand the role of RNASEH2A in cancer prognostication and to establish a scoring system based on the expressions of genes interacting with RNASEH2A. We screened the nucleotide degrading enzyme gene expression in RNAseq data of 14 cancer types derived from The Cancer Genome Atlas (TCGA) and found that RNASEH2A overexpression was associated with poor patient survival only in renal cell carcinomas (RCCs). Further cluster analyses of samples with poor outcomes revealed that cluster of differentiation 151 (CD151) upregulation correlated with low cyclin dependent kinase 1 (CDK1) and high RNASEH2A expression. The combination of low CD151 expression and high RNASEH2A expression resulted in impaired proliferation in four kidney cancer cell lines, suggesting potential synthetic dosage lethality (SDL) interactions between the two genes. A prognostication scoring system was established based on the expression levels of RNASEH2A-, CDK1-, and CD151-related genes, which could effectively predict the overall survival in a TCGA clear cell RCC cohort (n = 533, 995.3 versus 2242.2 days, p < 0.0001), in another clear cell renal cell carcinoma (ccRCC) cohort E-GEOD-22541 (n = 44, 390.0 versus 1889.2 days, p = 0.0007), and in a TCGA papillary RCC (pRCC) cohort (n = 287, 741.6 versus 1623.7 days, p < 0.0001). Our results provide a clinically applicable prognostication scoring system for renal cancers. Full article
(This article belongs to the Special Issue Precision Medicine—From Bench to Bedside)
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15 pages, 2147 KiB  
Article
DNA Damage-Response Pathway Heterogeneity of Human Lung Cancer A549 and H1299 Cells Determines Sensitivity to 8-Chloro-Adenosine
by Sheng-Yong Yang, Yi Li, Guo-Shun An, Ju-Hua Ni, Hong-Ti Jia and Shu-Yan Li
Int. J. Mol. Sci. 2018, 19(6), 1587; https://doi.org/10.3390/ijms19061587 - 28 May 2018
Cited by 16 | Viewed by 5971
Abstract
Human lung cancer H1299 (p53-null) cells often display enhanced susceptibility to chemotherapeutics comparing to A549 (p53-wt) cells. However, little is known regarding to the association of DNA damage-response (DDR) pathway heterogeneity with drug sensitivity in these two cells. We investigated the DDR pathway [...] Read more.
Human lung cancer H1299 (p53-null) cells often display enhanced susceptibility to chemotherapeutics comparing to A549 (p53-wt) cells. However, little is known regarding to the association of DNA damage-response (DDR) pathway heterogeneity with drug sensitivity in these two cells. We investigated the DDR pathway differences between A549 and H1299 cells exposed to 8-chloro-adenosine (8-Cl-Ado), a potential anticancer drug that can induce DNA double-strand breaks (DSBs), and found that the hypersensitivity of H1299 cells to 8-Cl-Ado is associated with its DSB overaccumulation. The major causes of excessive DSBs in H1299 cells are as follows: First, defect of p53-p21 signal and phosphorylation of SMC1 increase S phase cells, where replication of DNA containing single-strand DNA break (SSB) produces more DSBs in H1299 cells. Second, p53 defect and no available induction of DNA repair protein p53R2 impair DNA repair activity in H1299 cells more severely than A549 cells. Third, cleavage of PARP-1 inhibits topoisomerase I and/or topoisomerase I-like activity of PARP-1, aggravates DNA DSBs and DNA repair mechanism impairment in H1299 cells. Together, DDR pathway heterogeneity of cancer cells is linked to cancer susceptibility to DNA damage-based chemotherapeutics, which may provide aid in design of chemotherapy strategy to improve treatment outcomes. Full article
(This article belongs to the Special Issue DNA Replication Stress)
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11 pages, 1364 KiB  
Article
Palladacyclic Conjugate Group Promotes Hybridization of Short Oligonucleotides
by Madhuri Hande, Sajal Maity and Tuomas Lönnberg
Int. J. Mol. Sci. 2018, 19(6), 1588; https://doi.org/10.3390/ijms19061588 - 28 May 2018
Cited by 11 | Viewed by 4654
Abstract
Short oligonucleotides with cyclopalladated benzylamine moieties at their 5′-termini have been prepared to test the possibility of conferring palladacyclic anticancer agents sequence-selectivity by conjugation with a guiding oligonucleotide. Hybridization of these oligonucleotides with natural counterparts was studied by UV and CD (circular dichroism) [...] Read more.
Short oligonucleotides with cyclopalladated benzylamine moieties at their 5′-termini have been prepared to test the possibility of conferring palladacyclic anticancer agents sequence-selectivity by conjugation with a guiding oligonucleotide. Hybridization of these oligonucleotides with natural counterparts was studied by UV and CD (circular dichroism) melting experiments in the absence and presence of a competing ligand (2-mercaptoethanol). Cyclopalladated benzylamine proved to be strongly stabilizing relative to unmetalated benzylamine and modestly stabilizing relative to an extra A•T base pair. The stabilization was largely abolished in the presence of 2-mercaptoethanol, suggesting direct coordination of Pd(II) to a nucleobase of the complementary strand. In all cases, fidelity of Watson-Crick base pairing between the two strands was retained. Hybridization of the cyclopalladated oligonucleotides was characterized by relatively large negative enthalpy and entropy, consistent with stabilizing Pd(II) coordination partially offset by the entropic penalty of imposing conformational constraints on the flexible diethylene glycol linker between the oligonucleotide and the palladacyclic moiety. Full article
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22 pages, 4778 KiB  
Review
Therapeutics for Inflammatory-Related Diseases Based on Plasmon-Activated Water: A Review
by Chih-Ping Yang and Yu-Chuan Liu
Int. J. Mol. Sci. 2018, 19(6), 1589; https://doi.org/10.3390/ijms19061589 - 28 May 2018
Cited by 5 | Viewed by 5129
Abstract
It is recognized that the properties of liquid water can be markedly different from those of bulk one when it is in contact with hydrophobic surfaces or is confined in nano-environments. Because our knowledge regarding water structure on the molecular level of dynamic [...] Read more.
It is recognized that the properties of liquid water can be markedly different from those of bulk one when it is in contact with hydrophobic surfaces or is confined in nano-environments. Because our knowledge regarding water structure on the molecular level of dynamic equilibrium within a picosecond time scale is far from completeness all of water’s conventionally known properties are based on inert “bulk liquid water” with a tetrahedral hydrogen-bonded structure. Actually, the strength of water’s hydrogen bonds (HBs) decides its properties and activities. In this review, an innovative idea on preparation of metastable plasmon-activated water (PAW) with intrinsically reduced HBs, by letting deionized (DI) water flow through gold-supported nanoparticles (AuNPs) under resonant illumination at room temperature, is reported. Compared to DI water, the created stable PAW can scavenge free hydroxyl and 2,2-diphenyl-1-picrylhydrazyl radicals and effectively reduce NO release from lipopolysaccharide-induced inflammatory cells. Moreover, PAW can dramatically induce a major antioxidative Nrf2 gene in human gingival fibroblasts. This further confirms its cellular antioxidative and anti-inflammatory properties. In addition, innovatively therapeutic strategy of daily drinking PAW on inflammatory-related diseases based on animal disease models is demonstrated, examples being chronic kidney disease (CKD), chronic sleep deprivation (CSD), and lung cancer. Full article
(This article belongs to the Special Issue Translating Gold Nanoparticles to Diagnostics and Therapeutics)
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21 pages, 4848 KiB  
Article
Red to Far-Red Light Ratio Modulates Hormonal and Genetic Control of Axillary bud Outgrowth in Chrysanthemum (Dendranthema grandiflorum ‘Jinba’)
by Cunquan Yuan, Sagheer Ahmad, Tangren Cheng, Jia Wang, Huitang Pan, Liangjun Zhao and Qixiang Zhang
Int. J. Mol. Sci. 2018, 19(6), 1590; https://doi.org/10.3390/ijms19061590 - 28 May 2018
Cited by 27 | Viewed by 4942
Abstract
Single-flower cut Chrysanthemum (Dendranthema grandiflorum ‘Jinba’) holds a unique status in global floriculture industry. However, the extensive axillary bud outgrowth presents a major drawback. Shade is an environment cue that inhibits shoot branching. Present study was aimed at investigating the effect of [...] Read more.
Single-flower cut Chrysanthemum (Dendranthema grandiflorum ‘Jinba’) holds a unique status in global floriculture industry. However, the extensive axillary bud outgrowth presents a major drawback. Shade is an environment cue that inhibits shoot branching. Present study was aimed at investigating the effect of ratio of red to far-red light (R:FR) in regulating the lateral bud outgrowth of Chrysanthemum and the detailed mechanism. Results showed that the fate of axillary buds at specific positions in stem exhibited difference in response to R:FR. Decreasing R:FR resulted in elevation of abscisic acid (ABA) accumulation in axillary buds. Expression of ABA, indole-3-acetic acid (IAA) and strigolactones (SL) -related metabolism and signal transduction genes was significantly changed in response to low R:FR. In addition, low R:FR caused the re-distribution of sucrose across the whole plant, driving more sucrose towards bottom buds. Our results indicate that low R:FR not always inhibits bud outgrowth, rather its influence depends on the bud position in the stem. ABA, SL and auxin pathways were involved in the process. Interestingly, sucrose also appears to be involved in the process which is necessary to pay attention in the further studies. The present study also lays the foundation for developing methods to regulate axillary bud outgrowth in Chrysanthemum. Full article
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14 pages, 2449 KiB  
Review
Structural Biology of STAT3 and Its Implications for Anticancer Therapies Development
by Jacopo Sgrignani, Maura Garofalo, Milos Matkovic, Jessica Merulla, Carlo V. Catapano and Andrea Cavalli
Int. J. Mol. Sci. 2018, 19(6), 1591; https://doi.org/10.3390/ijms19061591 - 28 May 2018
Cited by 121 | Viewed by 10659
Abstract
Transcription factors are proteins able to bind DNA and induce the transcription of specific genes. Consequently, they play a pivotal role in multiple cellular pathways and are frequently over-expressed or dysregulated in cancer. Here, we will focus on a specific “signal transducer and [...] Read more.
Transcription factors are proteins able to bind DNA and induce the transcription of specific genes. Consequently, they play a pivotal role in multiple cellular pathways and are frequently over-expressed or dysregulated in cancer. Here, we will focus on a specific “signal transducer and activator of transcription” (STAT3) factor that is involved in several pathologies, including cancer. For long time, the mechanism by which STAT3 exerts its cellular functions has been summarized by a three steps process: (1) Protein phosphorylation by specific kinases, (2) dimerization promoted by phosphorylation, (3) activation of gene expression by the phosphorylated dimer. Consequently, most of the inhibitors reported in literature aimed at blocking phosphorylation and dimerization. However, recent observations reopened the debate and the entire functional mechanism has been revisited stimulating the scientific community to pursue new inhibition strategies. In particular, the dimerization of the unphosphorylated species has been experimentally demonstrated and specific roles proposed also for these dimers. Despite difficulties in the expression and purification of the full length STAT3, structural biology investigations allowed the determination of atomistic structures of STAT3 dimers and several protein domains. Starting from this information, computational methods have been used both to improve the understanding of the STAT3 functional mechanism and to design new inhibitors to be used as anticancer drugs. In this review, we will focus on the contribution of structural biology to understand the roles of STAT3, to design new inhibitors and to suggest new strategies of pharmacological intervention. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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16 pages, 459 KiB  
Review
Recognizing Depression from the Microbiota–Gut–Brain Axis
by Shan Liang, Xiaoli Wu, Xu Hu, Tao Wang and Feng Jin
Int. J. Mol. Sci. 2018, 19(6), 1592; https://doi.org/10.3390/ijms19061592 - 29 May 2018
Cited by 262 | Viewed by 51203
Abstract
Major depression is one of the leading causes of disability, morbidity, and mortality worldwide. The brain–gut axis functions are disturbed, revealed by a dysfunction of the brain, immune system, endocrine system, and gut. Traditional depression treatments all target the brain, with different drugs [...] Read more.
Major depression is one of the leading causes of disability, morbidity, and mortality worldwide. The brain–gut axis functions are disturbed, revealed by a dysfunction of the brain, immune system, endocrine system, and gut. Traditional depression treatments all target the brain, with different drugs and/or psychotherapy. Unfortunately, most of the patients have never received any treatment. Studies indicate that gut microbiota could be a direct cause for the disorder. Abnormal microbiota and the microbiota–gut–brain dysfunction may cause mental disorders, while correcting these disturbance could alleviate depression. Nowadays, the gut microbiota modulation has become a hot topic in treatment research of mental disorders. Depression is closely related with the health condition of the brain–gut axis, and maintaining/restoring the normal condition of gut microbiota helps in the prevention/therapy of mental disorders. Full article
(This article belongs to the Special Issue The (Microbiota)–Gut–Brain Axis: Hype or Revolution?)
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17 pages, 3226 KiB  
Article
Transcriptional Profiles of SmWRKY Family Genes and Their Putative Roles in the Biosynthesis of Tanshinone and Phenolic Acids in Salvia miltiorrhiza
by Haizheng Yu, Wanli Guo, Dongfeng Yang, Zhuoni Hou and Zongsuo Liang
Int. J. Mol. Sci. 2018, 19(6), 1593; https://doi.org/10.3390/ijms19061593 - 29 May 2018
Cited by 52 | Viewed by 4784
Abstract
Salvia miltiorrhiza Bunge is a Chinese traditional herb for treating cardiovascular and cerebrovascular diseases, and tanshinones and phenolic acids are the dominated medicinal and secondary metabolism constituents of this plant. WRKY transcription factors (TFs) can function as regulators of secondary metabolites biosynthesis in [...] Read more.
Salvia miltiorrhiza Bunge is a Chinese traditional herb for treating cardiovascular and cerebrovascular diseases, and tanshinones and phenolic acids are the dominated medicinal and secondary metabolism constituents of this plant. WRKY transcription factors (TFs) can function as regulators of secondary metabolites biosynthesis in many plants. However, studies on the WRKY that regulate tanshinones and phenolics biosynthesis are limited. In this study, 69 SmWRKYs were identified in the transcriptome database of S. miltiorrhiza, and phylogenetic analysis indicated that some SmWRKYs had closer genetic relationships with other plant WRKYs, which were involved in secondary metabolism. Hairy roots of S. miltiorrhiza were treated by methyl jasmonate (MeJA) to detect the dynamic change trend of SmWRKY, biosynthetic genes, and medicinal ingredients accumulation. Base on those date, a correlation analysis using Pearson’s correlation coefficient was performed to construct gene-to-metabolite network and identify 9 SmWRKYs (SmWRKY1, 7, 19, 29, 45, 52, 56, 58, and 68), which were most likely to be involved in tanshinones and phenolic acids biosynthesis. Taken together, this study has provided a significant resource that could be used for further research on SmWRKY in S. miltiorrhiza and especially could be used as a cue for further investigating SmWRKY functions in secondary metabolite accumulation. Full article
(This article belongs to the Section Molecular Plant Sciences)
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26 pages, 4657 KiB  
Article
Candidate Genes for Yellow Leaf Color in Common Wheat (Triticum aestivum L.) and Major Related Metabolic Pathways according to Transcriptome Profiling
by Huiyu Wu, Narong Shi, Xuyao An, Cong Liu, Hongfei Fu, Li Cao, Yi Feng, Daojie Sun and Lingli Zhang
Int. J. Mol. Sci. 2018, 19(6), 1594; https://doi.org/10.3390/ijms19061594 - 29 May 2018
Cited by 79 | Viewed by 7578
Abstract
The photosynthetic capacity and efficiency of a crop depends on the biosynthesis of photosynthetic pigments and chloroplast development. However, little is known about the molecular mechanisms of chloroplast development and chlorophyll (Chl) biosynthesis in common wheat because of its huge and complex genome. [...] Read more.
The photosynthetic capacity and efficiency of a crop depends on the biosynthesis of photosynthetic pigments and chloroplast development. However, little is known about the molecular mechanisms of chloroplast development and chlorophyll (Chl) biosynthesis in common wheat because of its huge and complex genome. Ygm, a spontaneous yellow-green leaf color mutant of winter wheat, exhibits reduced Chl contents and abnormal chloroplast development. Thus, we searched for candidate genes associated with this phenotype. Comparative transcriptome profiling was performed using leaves from the yellow leaf color type (Y) and normal green color type (G) of the Ygm mutant progeny. We identified 1227 differentially expressed genes (DEGs) in Y compared with G (i.e., 689 upregulated genes and 538 downregulated genes). Gene ontology and pathway enrichment analyses indicated that the DEGs were involved in Chl biosynthesis (i.e., magnesium chelatase subunit H (CHLH) and protochlorophyllide oxidoreductase (POR) genes), carotenoid biosynthesis (i.e., β-carotene hydroxylase (BCH) genes), photosynthesis, and carbon fixation in photosynthetic organisms. We also identified heat shock protein (HSP) genes (sHSP, HSP70, HSP90, and DnaJ) and heat shock transcription factor genes that might have vital roles in chloroplast development. Quantitative RT-PCR analysis of the relevant DEGs confirmed the RNA-Seq results. Moreover, measurements of seven intermediate products involved in Chl biosynthesis and five carotenoid compounds involved in carotenoid-xanthophyll biosynthesis confirmed that CHLH and BCH are vital enzymes for the unusual leaf color phenotype in Y type. These results provide insights into leaf color variation in wheat at the transcriptional level. Full article
(This article belongs to the Special Issue Chloroplast)
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16 pages, 3012 KiB  
Article
Deciphering RNA-Recognition Patterns of Intrinsically Disordered Proteins
by Ambuj Srivastava, Shandar Ahmad and M. Michael Gromiha
Int. J. Mol. Sci. 2018, 19(6), 1595; https://doi.org/10.3390/ijms19061595 - 29 May 2018
Cited by 18 | Viewed by 4909
Abstract
Intrinsically disordered regions (IDRs) and protein (IDPs) are highly flexible owing to their lack of well-defined structures. A subset of such proteins interacts with various substrates; including RNA; frequently adopting regular structures in the final complex. In this work; we have analysed a [...] Read more.
Intrinsically disordered regions (IDRs) and protein (IDPs) are highly flexible owing to their lack of well-defined structures. A subset of such proteins interacts with various substrates; including RNA; frequently adopting regular structures in the final complex. In this work; we have analysed a dataset of protein–RNA complexes undergoing disorder-to-order transition (DOT) upon binding. We found that DOT regions are generally small in size (less than 3 residues) for RNA binding proteins. Like structured proteins; positively charged residues are found to interact with RNA molecules; indicating the dominance of electrostatic and cation-π interactions. However, a comparison of binding frequency shows that interface hydrophobic and aromatic residues have more interactions in only DOT regions than in a protein. Further; DOT regions have significantly higher exposure to water than their structured counterparts. Interactions of DOT regions with RNA increase the sheet formation with minor changes in helix forming residues. We have computed the interaction energy for amino acids–nucleotide pairs; which showed the preference of His–G; Asn–U and Ser–U at for the interface of DOT regions. This study provides insights to understand protein–RNA interactions and the results could also be used for developing a tool for identifying DOT regions in RNA binding proteins. Full article
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17 pages, 4845 KiB  
Article
Tumor Size-Dependent Anticancer Efficacy of Chlorin Derivatives for Photodynamic Therapy
by Ji-Eun Chang, Yang Liu, Tae Heon Lee, Woo Kyoung Lee, Il Yoon and Kwhanmien Kim
Int. J. Mol. Sci. 2018, 19(6), 1596; https://doi.org/10.3390/ijms19061596 - 29 May 2018
Cited by 25 | Viewed by 4486
Abstract
Photodynamic therapy (PDT) with a suitable photosensitizer molecule is a promising anticancer treatment. We evaluated two chlorin molecules as potential photosensitizers, methyl pyropheophorbide a (MPPa) and N-methoxyl purpurinimide (NMPi), against A549 human lung adenocarcinoma cells in vitro as well as in A549 [...] Read more.
Photodynamic therapy (PDT) with a suitable photosensitizer molecule is a promising anticancer treatment. We evaluated two chlorin molecules as potential photosensitizers, methyl pyropheophorbide a (MPPa) and N-methoxyl purpurinimide (NMPi), against A549 human lung adenocarcinoma cells in vitro as well as in A549 tumor-bearing mice in vivo. Cell viability, microscopy, and fluorescence-activated cell sorting (FACS) analyses were performed for the in vitro studies. MPPa and NMPi showed high phototoxicity in vitro, which was dependent on the concentration of the photosensitizers as well as the light irradiation time. In the animal study, tumor volume change, tumor surface alterations, and hematoxylin & eosin (H&E) and terminal deoxyribonucleotidyl transferse-mediated dUTP nick-end labelling (TUNEL) staining analyses were performed and compared between small (tumor volume of <50 mm3) and large (tumor volume of >50 mm3) size of initial tumors. MPPa and NMPi showed high anticancer efficacy against small-size tumors, indicating that early treatment with PDT is effective. Especially, repeated two times PDT with NMPi allowed almost complete eradication against small-size tumors. However, MPPa and NMPi were not effective against large-size tumors. In conclusion, the two chlorin derivatives, MPPa and NMPi, show good anticancer efficacy as promising photosensitizers for PDT in vitro and in vivo. Moreover, their activity in vivo was significantly dependent on the initial tumor size in mice, which confirms the importance of early cancer treatment. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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12 pages, 1091 KiB  
Review
Human Fibrinogen: Molecular and Genetic Aspects of Congenital Disorders
by Giovanni Luca Tiscia and Maurizio Margaglione
Int. J. Mol. Sci. 2018, 19(6), 1597; https://doi.org/10.3390/ijms19061597 - 29 May 2018
Cited by 60 | Viewed by 8454
Abstract
Congenital fibrinogen disorders can be quantitative (afibrinogenemia, hypofibrinogenemia) or functional (dysfibrinognemia). To date, several genetic variants have been identified in individuals with fibrinogen disorders. The complexity of the fibrinogen molecules, formed by three non-identical chains and with a trinodal organization, renders the identification [...] Read more.
Congenital fibrinogen disorders can be quantitative (afibrinogenemia, hypofibrinogenemia) or functional (dysfibrinognemia). To date, several genetic variants have been identified in individuals with fibrinogen disorders. The complexity of the fibrinogen molecules, formed by three non-identical chains and with a trinodal organization, renders the identification of molecular causes and of clinical and biochemical phenotypes very challenging. However, the acknowledgement of the type of molecular defect is crucial for a safer therapy, which is going to improve the clinical management of these patients. In this review, some aspects concerning molecular and clinical findings available on congenital fibrinogen disorders will be discussed. Full article
(This article belongs to the Special Issue Genetic Basis of Fibrinogen Disorders)
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15 pages, 2484 KiB  
Article
Genome-Wide Screening and Characterization of the Dof Gene Family in Physic Nut (Jatropha curcas L.)
by Peipei Wang, Jing Li, Xiaoyang Gao, Di Zhang, Anlin Li and Changning Liu
Int. J. Mol. Sci. 2018, 19(6), 1598; https://doi.org/10.3390/ijms19061598 - 29 May 2018
Cited by 21 | Viewed by 5520
Abstract
Physic nut (Jatropha curcas L.) is a species of flowering plant with great potential for biofuel production and as an emerging model organism for functional genomic analysis, particularly in the Euphorbiaceae family. DNA binding with one finger (Dof) transcription factors play critical [...] Read more.
Physic nut (Jatropha curcas L.) is a species of flowering plant with great potential for biofuel production and as an emerging model organism for functional genomic analysis, particularly in the Euphorbiaceae family. DNA binding with one finger (Dof) transcription factors play critical roles in numerous biological processes in plants. Nevertheless, the knowledge about members, and the evolutionary and functional characteristics of the Dof gene family in physic nut is insufficient. Therefore, we performed a genome-wide screening and characterization of the Dof gene family within the physic nut draft genome. In total, 24 JcDof genes (encoding 33 JcDof proteins) were identified. All the JcDof genes were divided into three major groups based on phylogenetic inference, which was further validated by the subsequent gene structure and motif analysis. Genome comparison revealed that segmental duplication may have played crucial roles in the expansion of the JcDof gene family, and gene expansion was mainly subjected to positive selection. The expression profile demonstrated the broad involvement of JcDof genes in response to various abiotic stresses, hormonal treatments and functional divergence. This study provides valuable information for better understanding the evolution of JcDof genes, and lays a foundation for future functional exploration of JcDof genes. Full article
(This article belongs to the Special Issue Plant Genomics)
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18 pages, 4734 KiB  
Article
Effects of Periostracum Cicadae on Cytokines and Apoptosis Regulatory Proteins in an IgA Nephropathy Rat Model
by Lu Yang, Yan Wang, Aobulikasimu Nuerbiye, Ping Cheng, Jin-Hui Wang, Rena Kasimu and Hong Li
Int. J. Mol. Sci. 2018, 19(6), 1599; https://doi.org/10.3390/ijms19061599 - 29 May 2018
Cited by 26 | Viewed by 5087
Abstract
Periostracum cicadae, the cast-off shell of the cicada Cryptotympana pustulata Fabricius, is used in traditional Chinese medicine for its diaphoretic, anticonvulsive, sedative, antipyretic, and antiallergic effects. However, the exact pathogenesis of immunoglobulin A nephropathy (IgAN) remains unclear, thereby hindering investigations to identify novel [...] Read more.
Periostracum cicadae, the cast-off shell of the cicada Cryptotympana pustulata Fabricius, is used in traditional Chinese medicine for its diaphoretic, anticonvulsive, sedative, antipyretic, and antiallergic effects. However, the exact pathogenesis of immunoglobulin A nephropathy (IgAN) remains unclear, thereby hindering investigations to identify novel therapeutic agents. A rat IgAN model was established by administration of bovine serum albumin, lipopolysaccharide, and carbon tetrachloride, which simultaneously established blood stasis and a heat syndrome model. The animals were sacrificed to detect changes in protein levels in urine and blood. Immunofluorescence was performed to assess IgA deposition in the glomeruli. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin 6 (IL-6) levels were measured in bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assay. Hematology and eosin, periodic acid-Schiff, TUNEL (TdT-mediated dUTP Nick-End Labeling), and immunohistochemical staining were performed to evaluate histopathological changes in kidney tissues. Additionally, target-related proteins were measured by Western blotting. Periostracum cicadae resulted in a reduction in blood and urine protein levels. Serum TNF-α, IL-1β, and IL-6 levels significantly decreased in the periostracum cicadae-treated groups compared to the IgAN group. Furthermore, a reduction in MCP-1 (Monocyte Chemotactic Protein-1), TLR4 ((Toll-Like Receptor 4)), and IgA expression levels and a dose-dependent increase in caspase 3 expression were observed in response to periostracum cicadae treatment. TGF-β1(Transforming Growth Factor-β) levels decreased, whereas that of Fas increased in the kidney tissues of the periostracum cicadae-treated groups. The findings of the present study indicate that periostracum cicadae induces apoptosis and improves kidney inflammation and fibrosis in IgA nephropathy rat models. Full article
(This article belongs to the Section Biochemistry)
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11 pages, 1713 KiB  
Article
UDP-Glucose 4-Epimerase and β-1,4-Galactosyltransferase from the Oyster Magallana gigas as Valuable Biocatalysts for the Production of Galactosylated Products
by Hui-Bo Song, Meng He, Zhi-Peng Cai, Kun Huang, Sabine L. Flitsch, Li Liu and Josef Voglmeir
Int. J. Mol. Sci. 2018, 19(6), 1600; https://doi.org/10.3390/ijms19061600 - 29 May 2018
Cited by 12 | Viewed by 7855
Abstract
Uridine diphosphate galactose (UDP-galactose) is a valuable building block in the enzymatic synthesis of galactose-containing glycoconjugates. UDP-glucose 4-epimerase (UGE) is an enzyme which catalyzes the reversible conversion of abundantly available UDP-glucose to UDP-galactose. Herein, we described the cloning, expression, purification, and biochemical characterization [...] Read more.
Uridine diphosphate galactose (UDP-galactose) is a valuable building block in the enzymatic synthesis of galactose-containing glycoconjugates. UDP-glucose 4-epimerase (UGE) is an enzyme which catalyzes the reversible conversion of abundantly available UDP-glucose to UDP-galactose. Herein, we described the cloning, expression, purification, and biochemical characterization of an unstudied UGE from the oyster Magallana gigas (MgUGE). Activity tests of recombinantly expressed MgUGE, using HPLC (high-performance liquid chromatography), mass spectrometry, and photometric assays, showed an optimal temperature of 16 °C, and reasonable thermal stability up to 37 °C. No metal ions were required for enzymatic activity. The simple nickel-affinity-purification procedure makes MgUGE a valuable biocatalyst for the synthesis of UDP-galactose from UDP-glucose. The biosynthetic potential of MgUGE was further exemplified in a coupled enzymatic reaction with an oyster-derived β-1,4-galactosyltransferase (MgGalT7), allowing the galactosylation of the model substrate para-nitrophenol xylose (pNP-xylose) using UDP-glucose as the starting material. Full article
(This article belongs to the Special Issue Molecular Transformations of Natural Products)
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12 pages, 3168 KiB  
Article
In Vitro Antifungal Activity of New and Known Geranylated Phenols against Phytophthora cinnamomi Rands
by María I. Chavez, Mauricio Soto, Franco A. Cimino, Andrés F. Olea, Luis Espinoza, Katy Díaz and Lautaro Taborga
Int. J. Mol. Sci. 2018, 19(6), 1601; https://doi.org/10.3390/ijms19061601 - 29 May 2018
Cited by 10 | Viewed by 3336
Abstract
A series of new and known geranylated phenol/methoxyphenol derivatives has been tested in vitro as inhibitor agents of mycelial growth of Phytophthora cinnamomi. The activity of tested compounds is correlated with the nature, number, and position of the substituent group on the [...] Read more.
A series of new and known geranylated phenol/methoxyphenol derivatives has been tested in vitro as inhibitor agents of mycelial growth of Phytophthora cinnamomi. The activity of tested compounds is correlated with the nature, number, and position of the substituent group on the aromatic ring. Results indicate that the most active geranylated derivatives are those having two hydroxyl groups (or one –OH and one –OCH3) attached to the aromatic ring. Interestingly, these derivatives are as active as Metalaxil®, a commonly used commercial fungicide. Thus, our results suggest that some of these compounds might be of agricultural interest due to their potential use as fungicides against P. cinnamomi. The effect of structure on fungicide activity is discussed in terms of electronic distribution on both the aromatic ring and side geranyl chain. All tested compounds have been synthesized by direct coupling of geraniol and the respective phenol. Interestingly, new digeranylated derivatives were obtained by increasing the reaction time. Full article
(This article belongs to the Section Materials Science)
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24 pages, 1167 KiB  
Review
Immunotherapy for Gastric Cancer: Time for a Personalized Approach?
by Riccardo Dolcetti, Valli De Re and Vincenzo Canzonieri
Int. J. Mol. Sci. 2018, 19(6), 1602; https://doi.org/10.3390/ijms19061602 - 29 May 2018
Cited by 55 | Viewed by 11144
Abstract
Over the last decade, our understanding of the mechanisms underlying immune modulation has greatly improved, allowing for the development of multiple therapeutic approaches that are revolutionizing the treatment of cancer. Immunotherapy for gastric cancer (GC) is still in the early phases but is [...] Read more.
Over the last decade, our understanding of the mechanisms underlying immune modulation has greatly improved, allowing for the development of multiple therapeutic approaches that are revolutionizing the treatment of cancer. Immunotherapy for gastric cancer (GC) is still in the early phases but is rapidly evolving. Recently, multi-platform molecular analyses of GC have proposed a new classification of this heterogeneous group of tumors, highlighting subset-specific features that may more reliably inform therapeutic choices, including the use of new immunotherapeutic drugs. The clinical benefit and improved survival observed in GC patients treated with immunotherapeutic strategies and their combination with conventional therapies highlighted the importance of the immune environment surrounding the tumor. A thorough investigation of the tumor microenvironment and the complex and dynamic interaction between immune cells and tumor cells is a fundamental requirement for the rational design of novel and more effective immunotherapeutic approaches. This review summarizes the pre-clinical and clinical results obtained so far with immunomodulatory and immunotherapeutic treatments for GC and discusses the novel combination strategies that are being investigated to improve the personalization and efficacy of GC immunotherapy. Full article
(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)
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14 pages, 782 KiB  
Review
Heterogeneity in Malignant Pleural Mesothelioma
by Kathrin Oehl, Bart Vrugt, Isabelle Opitz and Mayura Meerang
Int. J. Mol. Sci. 2018, 19(6), 1603; https://doi.org/10.3390/ijms19061603 - 30 May 2018
Cited by 43 | Viewed by 5589
Abstract
Despite advances in malignant pleural mesothelioma therapy, life expectancy of affected patients remains short. The limited efficiency of treatment options is mainly caused by inter- and intra-tumor heterogeneity of mesotheliomas. This diversity can be observed at the morphological and molecular levels. Molecular analyses [...] Read more.
Despite advances in malignant pleural mesothelioma therapy, life expectancy of affected patients remains short. The limited efficiency of treatment options is mainly caused by inter- and intra-tumor heterogeneity of mesotheliomas. This diversity can be observed at the morphological and molecular levels. Molecular analyses reveal a high heterogeneity (i) between patients; (ii) within different areas of a given tumor in terms of different clonal compositions; and (iii) during treatment over time. The aim of the present review is to highlight this diversity and its therapeutic implications. Full article
(This article belongs to the Special Issue Mesothelioma Heterogeneity: Potential Mechanisms)
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13 pages, 1205 KiB  
Article
Targeting the Bacterial Cytoskeleton of the Burkholderia cepacia Complex for Antimicrobial Development: A Cautionary Tale
by Sonya C. Carnell, John D. Perry, Lee Borthwick, Daniela Vollmer, Jacob Biboy, Marcella Facchini, Alessandra Bragonzi, Alba Silipo, Annette C. Vergunst, Waldemar Vollmer, Anjam C. M. Khan and Anthony De Soyza
Int. J. Mol. Sci. 2018, 19(6), 1604; https://doi.org/10.3390/ijms19061604 - 30 May 2018
Cited by 4 | Viewed by 5397
Abstract
Burkholderia cepacia complex (BCC) bacteria are a group of opportunistic pathogens that cause severe lung infections in cystic fibrosis (CF). Treatment of BCC infections is difficult, due to the inherent and acquired multidrug resistance of BCC. There is a pressing need to find [...] Read more.
Burkholderia cepacia complex (BCC) bacteria are a group of opportunistic pathogens that cause severe lung infections in cystic fibrosis (CF). Treatment of BCC infections is difficult, due to the inherent and acquired multidrug resistance of BCC. There is a pressing need to find new bacterial targets for antimicrobials. Here, we demonstrate that the novel compound Q22, which is related to the bacterial cytoskeleton destabilising compound A22, can reduce the growth rate and inhibit growth of BCC bacteria. We further analysed the phenotypic effects of Q22 treatment on BCC virulence traits, to assess its feasibility as an antimicrobial. BCC bacteria were grown in the presence of Q22 with a broad phenotypic analysis, including resistance to H2O2-induced oxidative stress, changes in the inflammatory potential of cell surface components, and in-vivo drug toxicity studies. The influence of the Q22 treatment on inflammatory potential was measured by monitoring the cytokine responses of BCC whole cell lysates, purified lipopolysaccharide, and purified peptidoglycan extracted from bacterial cultures grown in the presence or absence of Q22 in differentiated THP-1 cells. BCC bacteria grown in the presence of Q22 displayed varying levels of resistance to H2O2-induced oxidative stress, with some strains showing increased resistance after treatment. There was strain-to-strain variation in the pro-inflammatory ability of bacterial lysates to elicit TNFα and IL-1β from human myeloid cells. Despite minimal toxicity previously shown in vitro with primary CF cell lines, in-vivo studies demonstrated Q22 toxicity in both zebrafish and mouse infection models. In summary, destabilisation of the bacterial cytoskeleton in BCC, using compounds such as Q22, led to increased virulence-related traits in vitro. These changes appear to vary depending on strain and BCC species. Future development of antimicrobials targeting the BCC bacterial cytoskeleton may be hampered if such effects translate into the in-vivo environment of the CF infection. Full article
(This article belongs to the Special Issue Lung Diseases: Chronic Respiratory Infections)
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15 pages, 2014 KiB  
Article
Quinolones Modulate Ghrelin Receptor Signaling: Potential for a Novel Small Molecule Scaffold in the Treatment of Cachexia
by Cristina Torres-Fuentes, Elena Pastor-Cavada, Rafael Cano, Dalia Kandil, Rachel Shanahan, Rocio Juan, Hamdy Shaban, Gerard P. McGlacken and Harriët Schellekens
Int. J. Mol. Sci. 2018, 19(6), 1605; https://doi.org/10.3390/ijms19061605 - 30 May 2018
Cited by 11 | Viewed by 7867
Abstract
Cachexia is a metabolic wasting disorder characterized by progressive weight loss, muscle atrophy, fatigue, weakness, and appetite loss. Cachexia is associated with almost all major chronic illnesses including cancer, heart failure, obstructive pulmonary disease, and kidney disease and significantly impedes treatment outcome and [...] Read more.
Cachexia is a metabolic wasting disorder characterized by progressive weight loss, muscle atrophy, fatigue, weakness, and appetite loss. Cachexia is associated with almost all major chronic illnesses including cancer, heart failure, obstructive pulmonary disease, and kidney disease and significantly impedes treatment outcome and therapy tolerance, reducing physical function and increasing mortality. Current cachexia treatments are limited and new pharmacological strategies are needed. Agonists for the growth hormone secretagogue (GHS-R1a), or ghrelin receptor, prospectively regulate the central regulation of appetite and growth hormone secretion, and therefore have tremendous potential as cachexia therapeutics. Non-peptide GHS-R1a agonists are of particular interest, especially given the high gastrointestinal degradation of peptide-based structures, including that of the endogenous ligand, ghrelin, which has a half-life of only 30 min. However, few compounds have been reported in the literature as non-peptide GHS-R1a agonists. In this paper, we investigate the in vitro potential of quinolone compounds to modulate the GHS-R1a in both transfected human cells and mouse hypothalamic cells. These chemically synthesized compounds demonstrate a promising potential as GHS-R1a agonists, shown by an increased intracellular calcium influx. Further studies are now warranted to substantiate and exploit the potential of these novel quinolone-based compounds as orexigenic therapeutics in conditions of cachexia and other metabolic and eating disorders. Full article
(This article belongs to the Special Issue Integrative Physiology of Ghrelin and Synthetic GH Secretagogues)
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13 pages, 5249 KiB  
Article
Preparation of Biodegradable Oligo(lactide)s-Grafted Dextran Nanogels for Efficient Drug Delivery by Controlling Intracellular Traffic
by Yuichi Ohya, Akihiro Takahashi and Akinori Kuzuya
Int. J. Mol. Sci. 2018, 19(6), 1606; https://doi.org/10.3390/ijms19061606 - 30 May 2018
Cited by 9 | Viewed by 6135
Abstract
Nanogels, nanometer-sized hydrogel particles, have great potential as drug delivery carriers. To achieve effective drug delivery to the active sites in a cell, control of intracellular traffic is important. In this study, we prepared nanogels composed of dextran with oligolactide (OLA) chains attached [...] Read more.
Nanogels, nanometer-sized hydrogel particles, have great potential as drug delivery carriers. To achieve effective drug delivery to the active sites in a cell, control of intracellular traffic is important. In this study, we prepared nanogels composed of dextran with oligolactide (OLA) chains attached via disulfide bonds (Dex-g-SS-OLA) that collapse under the reductive conditions of the cytosol to achieve efficient drug delivery. In addition, we introduced galactose (Gal) residues on the nanogels, to enhance cellular uptake by receptor-mediated endocytosis, and secondary oligo-amine (tetraethylenepentamine) groups, to aid in escape from endosomes via proton sponge effects. The obtained Dex-g-SS-OLA with attached Gal residues and tetraethylenepentamine (EI4) groups, EI4/Gal-Dex-g-SS-OLA, formed a nanogel with a hydrodynamic diameter of ca. 203 nm in phosphate-buffered solution. The collapse of the EI4/Gal-Dex-g-SS-OLA nanogels under reductive conditions was confirmed by a decrease in the hydrodynamic diameter in the presence of reductive agents. The specific uptake of the hydrogels into HepG2 cells and their intercellular behavior were investigated by flow cytometry and confocal laser scanning microscopy using fluorescence dye-labeled nanogels. Escape from the endosome and subsequent collapse in the cytosol of the EI4/Gal-Dex-g-SS-OLA were observed. These biodegradable nanogels that collapse under reductive conditions in the cytosol should have great potential as efficient drug carriers in, for example, cancer chemotherapy. Full article
(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)
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14 pages, 15004 KiB  
Review
The Role of Endoplasmic Reticulum Stress-Glycogen Synthase Kinase-3 Signaling in Atherogenesis
by Aric Huang, Sarvatit Patel, Cameron S. McAlpine and Geoff H. Werstuck
Int. J. Mol. Sci. 2018, 19(6), 1607; https://doi.org/10.3390/ijms19061607 - 30 May 2018
Cited by 22 | Viewed by 6565
Abstract
Cardiovascular disease (CVD) is the number one cause of global mortality and atherosclerosis is the underlying cause of most CVD. However, the molecular mechanisms by which cardiovascular risk factors promote the development of atherosclerosis are not well understood. The development of new efficient [...] Read more.
Cardiovascular disease (CVD) is the number one cause of global mortality and atherosclerosis is the underlying cause of most CVD. However, the molecular mechanisms by which cardiovascular risk factors promote the development of atherosclerosis are not well understood. The development of new efficient therapies to directly block or slow disease progression will require a better understanding of these mechanisms. Accumulating evidence supports a role for endoplasmic reticulum (ER) stress in all stages of the developing atherosclerotic lesion however, it was not clear how ER stress may contribute to disease progression. Recent findings have shown that ER stress signaling through glycogen synthase kinase (GSK)-3α may significantly contribute to macrophage lipid accumulation, inflammatory cytokine production and M1macrophage polarization. In this review we summarize our knowledge of the potential role of ER stress-GSK3 signaling in the development and progression of atherosclerosis as well as the possible therapeutic implications of this pathway. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part I)
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11 pages, 1424 KiB  
Article
Biochemical Properties of a Decoy Oligodeoxynucleotide Inhibitor of STAT3 Transcription Factor
by David S. Lee, Rachel A. O’Keefe, Patrick K. Ha, Jennifer R. Grandis and Daniel E. Johnson
Int. J. Mol. Sci. 2018, 19(6), 1608; https://doi.org/10.3390/ijms19061608 - 30 May 2018
Cited by 12 | Viewed by 4630
Abstract
Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of [...] Read more.
Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of proteins that promote cellular proliferation and survival. Previous studies have demonstrated antitumor activity of CS3D in preclinical models of solid tumors. However, prior to entering human clinical trials, the efficiency of generating the CS3D molecule and its stability in biological fluids should be determined. CS3D is synthesized as a single-stranded ODN and must have its free ends ligated to generate the final cyclic form. In this study, we report a ligation efficiency of nearly 95 percent. The ligated CS3D demonstrated a half-life of 7.9 h in human serum, indicating adequate stability for intravenous delivery. These results provide requisite biochemical characterization of CS3D that will inform upcoming clinical trials. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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13 pages, 2942 KiB  
Article
Ru(II)-Thymine Complex Causes Cell Growth Inhibition and Induction of Caspase-Mediated Apoptosis in Human Promyelocytic Leukemia HL-60 Cells
by Maiara De Souza Oliveira, Ádila Angélica Dantas De Santana, Rodrigo S. Correa, Milena Botelho Pereira Soares, Alzir Azevedo Batista and Daniel Pereira Bezerra
Int. J. Mol. Sci. 2018, 19(6), 1609; https://doi.org/10.3390/ijms19061609 - 30 May 2018
Cited by 15 | Viewed by 4361
Abstract
Ruthenium-based compounds represent a class of potential antineoplastic drugs. Recently, we designed, synthesized, and identified the Ru(II)-thymine complex [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh = triphenylphosphine, Thy = thymine and bipy = 2,2′-bipyridine) as a potent cytotoxic agent with the ability [...] Read more.
Ruthenium-based compounds represent a class of potential antineoplastic drugs. Recently, we designed, synthesized, and identified the Ru(II)-thymine complex [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh = triphenylphosphine, Thy = thymine and bipy = 2,2′-bipyridine) as a potent cytotoxic agent with the ability to bind to DNA and human and bovine serum albumins. In this study, the underlying cytotoxic mechanism of the [Ru(PPh3)2(Thy)(bipy)]PF6 complex was assessed. This complex displayed potent cytotoxicity in different cancer cell lines; the morphology that is associated with apoptotic cell death, increased internucleosomal DNA fragmentation without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization, and caspase-3 activation were observed in human promyelocytic leukemia HL-60 cells that were treated with the complex. Moreover, pretreatment of HL-60 cells with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, partially reduced the apoptosis that was induced by the complex, indicating that the apoptotic cell death occurred through a caspase-mediated pathway. In conclusion, the [Ru(PPh3)2(Thy)(bipy)]PF6 complex displays potent cytotoxicity to different cancer cells and induces caspase-mediated apoptosis in HL-60 cells. Full article
(This article belongs to the Section Bioinorganic Chemistry)
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12 pages, 1528 KiB  
Article
Circulating Cell-Free DNA as a Prognostic and Molecular Marker for Patients with Brain Tumors under Perillyl Alcohol-Based Therapy
by Giselle Faria, Emanuelle Silva, Clovis Da Fonseca and Thereza Quirico-Santos
Int. J. Mol. Sci. 2018, 19(6), 1610; https://doi.org/10.3390/ijms19061610 - 30 May 2018
Cited by 28 | Viewed by 5452
Abstract
Tumor infiltration into brain tissue usually remains undetected even by high-resolution imaging. Molecular markers are used to increase diagnostic accuracy, but with limited continuous monitoring application. We evaluated the potential of circulating cell-free DNA (cfDNA) as a molecular indicator of the response to [...] Read more.
Tumor infiltration into brain tissue usually remains undetected even by high-resolution imaging. Molecular markers are used to increase diagnostic accuracy, but with limited continuous monitoring application. We evaluated the potential of circulating cell-free DNA (cfDNA) as a molecular indicator of the response to therapy by the intranasal administration (ITN) of perillyl alcohol (POH) in brain tumors. The cohort included 130 healthy subjects arranged as control-paired groups and patients at terminal stages with glioblastoma (GBM, n = 122) or brain metastasis (BM, n = 55) from stage IV adenocarcinomas. Serum cfDNA was isolated and quantified by fluorimetry. Compared with the controls (40 ng/mL), patients with brain tumors before ITN-POH treatment had increased (p < 0.0001) cfDNA median levels: GBM (286 ng/mL) and BM (588 ng/mL). ITN-POH treatment was significantly correlated (rho = −0.225; p = 0.024) with survival of >6 months at a concentration of 599 ± 221 ng/mL and of <6 months at 1626 ± 505 ng/mL, but a sharp and abrupt increase of cfDNA and tumor recurrence occurred after ITN-POH discontinuation. Patients under continuous ITN-POH treatment and checked with brain magnetic resonance imaging (MRI) compatible with complete response had cfDNA levels similar to the controls. cfDNA may be used as a noninvasive prognostic and molecular marker for POH-based therapy in brain tumors and as an accurate screening tool for the early detection of tumor progression. Full article
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14 pages, 70804 KiB  
Communication
Dopamine Transporter/α-Synuclein Complexes Are Altered in the Post Mortem Caudate Putamen of Parkinson’s Disease: An In Situ Proximity Ligation Assay Study
by Francesca Longhena, Gaia Faustini, Cristina Missale, Marina Pizzi and Arianna Bellucci
Int. J. Mol. Sci. 2018, 19(6), 1611; https://doi.org/10.3390/ijms19061611 - 30 May 2018
Cited by 22 | Viewed by 5561
Abstract
Parkinson’s disease (PD) is characterized by the degeneration of the dopaminergic nigrostriatal neurons and the presence of Lewy bodies (LB) and Lewy neurites (LN) mainly composed of α-synuclein. By using the in situ proximity ligation assay (PLA), which allows for the visualization of [...] Read more.
Parkinson’s disease (PD) is characterized by the degeneration of the dopaminergic nigrostriatal neurons and the presence of Lewy bodies (LB) and Lewy neurites (LN) mainly composed of α-synuclein. By using the in situ proximity ligation assay (PLA), which allows for the visualization of protein-protein interactions in tissues to detect dopamine transporter (DAT)/α-synuclein complexes, we previously described that these are markedly redistributed in the striatum of human α-synuclein transgenic mice at the phenotypic stage, showing dopamine (DA) release impairment without a DAT drop and motor symptoms. Here, we used the in situ PLA to investigate DAT/α-synuclein complexes in the caudate putamen of PD patients and age-matched controls. They were found to be redistributed and showed an increased size in PD patients, where we observed several neuropil-like and neuritic-like PLA-positive structures. In the PD brains, DAT immunolabeling showed a pattern similar to that of in situ PLA in areas with abundant α-synuclein neuropathology. This notwithstanding, the in situ PLA signal was only partially retracing DAT or α-synuclein immunolabeling, suggesting that a large amount of complexes may have been lost along with the degeneration process. These findings reveal a DAT/α-synuclein neuropathological signature in PD and hint that synaptic alterations involving striatal DAT may derive from α-synuclein aggregation. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases)
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16 pages, 2858 KiB  
Article
Synthesis and Biological Evaluation of Zeise’s Salt Derivatives with Acetylsalicylic Acid Substructure
by Alexander Weninger, Daniel Baecker, Victoria Obermoser, Dorothea Egger, Klaus Wurst and Ronald Gust
Int. J. Mol. Sci. 2018, 19(6), 1612; https://doi.org/10.3390/ijms19061612 - 30 May 2018
Cited by 17 | Viewed by 8102
Abstract
The development of novel biologically active organometallic compounds bearing an acetylsalicylic acid (ASA) substructure led to the synthesis of analogical Zeise-type salts that accordingly inhibit cyclooxygenase (COX) enzymes. In order to determine the influence of the length of the alkyl chain between the [...] Read more.
The development of novel biologically active organometallic compounds bearing an acetylsalicylic acid (ASA) substructure led to the synthesis of analogical Zeise-type salts that accordingly inhibit cyclooxygenase (COX) enzymes. In order to determine the influence of the length of the alkyl chain between the platinum(II) center and the ASA moiety, compounds with varying methylene groups (n = 1–4) were synthesized and characterized. For the propene derivative structural elucidation by X-ray crystallography was possible. Prior to evaluation of biological activity, the complexes were investigated regarding their stability in different media, such as water, physiological sodium chloride, and phosphate buffered saline. Therefore, an analytical method based on capillary electrophoresis was established. All of the compounds were tested for their COX inhibitory potential. In general, complexes with longer alkyl chains caused higher inhibition of COX enzymes and the inhibitory potential towards COX enzymes was enhanced when compared to Zeise’s salt. The growth inhibitory effects of the synthesized substances were investigated in vitro against colon carcinoma (HT-29) and breast cancer (MCF-7) cells. The IC50 values of the new derivatives ranged from 30 to 50 µM, whereas neither Zeise’s salt itself nor ASA showed any antiproliferative activity at the used concentrations. Full article
(This article belongs to the Special Issue Platinum-Based Anti-Tumor Drugs)
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12 pages, 1881 KiB  
Article
Effects of PTEN Loss and Activated KRAS Overexpression on Mechanical Properties of Breast Epithelial Cells
by Will Linthicum, Minh-Tri Ho Thanh, Michele I. Vitolo and Qi Wen
Int. J. Mol. Sci. 2018, 19(6), 1613; https://doi.org/10.3390/ijms19061613 - 30 May 2018
Cited by 12 | Viewed by 4970
Abstract
It has previously been shown that the simultaneous activation of PI3K (phosphatidylinositol 3-kinase) and Ras/MAPK (mitogen-activated protein kinases) pathways facilitate tumor growth despite only inducing cancer cell dormancy individually. Determining the impacts on cellular mechanics each pathway incites alone and in unison is [...] Read more.
It has previously been shown that the simultaneous activation of PI3K (phosphatidylinositol 3-kinase) and Ras/MAPK (mitogen-activated protein kinases) pathways facilitate tumor growth despite only inducing cancer cell dormancy individually. Determining the impacts on cellular mechanics each pathway incites alone and in unison is critical to developing non-toxic cancer therapies for triple-negative breast cancers. PTEN (phosphatase and tensin homolog) knockout and activated KRAS (Kristen rat sarcoma viral oncogene homolog) overexpression in healthy MCF-10A human breast epithelial cells activated the PI3K and Ras/MAPK pathways, respectively. Cell stiffness and fluidity were simultaneously measured using atomic force microscopy. Results suggest that PTEN knockout reduced cell stiffness and increased cell fluidity independent of PI3K activation. Effects of activated KRAS overexpression on cell stiffness depends on rigidity of cell culture substrate. Activated KRAS overexpression also counteracts the effects of PTEN knockout. Full article
(This article belongs to the Special Issue Atomic Force Microscopy for Biological Applications)
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32 pages, 3546 KiB  
Article
GBS Mapping and Analysis of Genes Conserved between Gossypium tomentosum and Gossypium hirsutum Cotton Cultivars that Respond to Drought Stress at the Seedling Stage of the BC2F2 Generation
by Richard Odongo Magwanga, Pu Lu, Joy Nyangasi Kirungu, Latyr Diouf, Qi Dong, Yangguang Hu, Xiaoyan Cai, Yanchao Xu, Yuqing Hou, Zhongli Zhou, Xingxing Wang, Kunbo Wang and Fang Liu
Int. J. Mol. Sci. 2018, 19(6), 1614; https://doi.org/10.3390/ijms19061614 - 30 May 2018
Cited by 37 | Viewed by 6417
Abstract
Cotton production is on the decline due to ever-changing environmental conditions. Drought and salinity stress contribute to over 30% of total loss in cotton production, the situation has worsened more due to the narrow genetic base of the cultivated upland cotton. The genetic [...] Read more.
Cotton production is on the decline due to ever-changing environmental conditions. Drought and salinity stress contribute to over 30% of total loss in cotton production, the situation has worsened more due to the narrow genetic base of the cultivated upland cotton. The genetic diversity of upland cotton has been eroded over the years due to intense selection and inbreeding. To break the bottleneck, the wild cotton progenitors offer unique traits which can be introgressed into the cultivated cotton, thereby improving their performance. In this research, we developed a BC2F2 population between wild male parent, G. tomentosum as the donor, known for its high tolerance to drought and the elite female parent, G. hirsutum as the recurrent parent, which is high yielding but sensitive to drought stress. The population was genotyped through the genotyping by sequencing (GBS) method, in which 10,888 single-nucleotide polymorphism (SNP) s were generated and used to construct a genetic map. The map spanned 4191.3 cM, with average marker distance of 0.3849 cM. The map size of the two sub genomes had a narrow range, 2149 cM and 2042.3 cM for At and Dt_sub genomes respectively. A total of 66,434 genes were mined, with 32,032 (48.2%) and 34,402 (51.8%) genes being obtained within the At and Dt_sub genomes respectively. Pkinase (PF00069) was found to be the dominant domain, with 1069 genes. Analysis of the main sub family, serine threonine protein kinases through gene ontology (GO), cis element and miRNA targets analysis revealed that most of the genes were involved in various functions aimed at enhancing abiotic stress tolerance. Further analysis of the RNA sequence data and qRT-PCR validation revealed 16 putative genes, which were highly up regulated under drought stress condition, and were found to be targeted by ghr-miR169a and ghr-miR164, previously associated with NAC(NAM, ATAF1/2 and CUC2) and myeloblastosis (MYB), the top rank drought stress tolerance genes. These genes can be exploited further to aid in development of more drought tolerant cotton genotypes. Full article
(This article belongs to the Section Molecular Plant Sciences)
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19 pages, 4500 KiB  
Article
Preparation and Characterization of Electrostatically Crosslinked Polymer–Liposomes in Anticancer Therapy
by Yi-Ting Chiang, Sih-Ying Lyu, Yu-Han Wen and Chun-Liang Lo
Int. J. Mol. Sci. 2018, 19(6), 1615; https://doi.org/10.3390/ijms19061615 - 30 May 2018
Cited by 16 | Viewed by 4968
Abstract
pH-sensitive polymer–liposomes can rapidly release their payloads. However, it is difficult to simultaneously achieve stability and pH-responsiveness in the polymer–liposomes. In this study, stable and pH-sensitive crosslinked polymer–liposomes were fabricated through electrostatic interactions. The pH-sensitive copolymer methoxy poly(ethylene glycol)-block-poly(methacrylic acid)-cholesterol (mPEG- [...] Read more.
pH-sensitive polymer–liposomes can rapidly release their payloads. However, it is difficult to simultaneously achieve stability and pH-responsiveness in the polymer–liposomes. In this study, stable and pH-sensitive crosslinked polymer–liposomes were fabricated through electrostatic interactions. The pH-sensitive copolymer methoxy poly(ethylene glycol)-block-poly(methacrylic acid)-cholesterol (mPEG-b-P(MAAc)-chol) and crosslinking reagent poly(ethylene glycol) with end-capped with lysine (PEG-Lys2) were synthesized and characterized. At physiological conditions, the pH-sensitive copolymers were anionic and interacted electrostatically with the cationic crosslinker PEG-Lys2, forming the electrostatically-crosslinked polymer–liposomes and stabilizing the liposomal structure. At pH 5.0, the carboxylic groups in mPEG-b-P(MAAc)-chol were neutralized, and the liposomal structure was destroyed. The particle size of the crosslinked polymer–liposomes was approximately 140 nm and the polymer–liposomes were loaded with the anticancer drug doxorubicin. At pH 7.4, the crosslinked polymer–liposomes exhibited good stability with steady particle size and low drug leakage, even in the presence of fetal bovine serum. At pH 5.0, the architecture of the crosslinked polymer–liposomes was damaged following rapid drug release, as observed by using transmission electron microscopy and their apparent size variation. The crosslinked polymer–liposomes were pH-sensitive within the endosome and in the human breast cancer cells MDA-MB-231, as determined by using confocal laser scanning microscopy. The intracellular drug release profiles indicated cytotoxicity in cancer cells. These results indicated that the highly-stable and pH-sensitive electrostatically-crosslinked polymer–liposomes offered a potent drug-delivery system for use in anticancer therapies. Full article
(This article belongs to the Special Issue Nanotechnology in Drug Delivery)
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15 pages, 1602 KiB  
Article
Persistent Infiltration and Impaired Response of Peripherally-Derived Monocytes after Traumatic Brain Injury in the Aged Brain
by Austin Chou, Karen Krukowski, Josh M. Morganti, Lara-Kirstie Riparip and Susanna Rosi
Int. J. Mol. Sci. 2018, 19(6), 1616; https://doi.org/10.3390/ijms19061616 - 30 May 2018
Cited by 56 | Viewed by 6029
Abstract
Traumatic brain injury (TBI) is a leading cause for neurological disabilities world-wide. TBI occurs most frequently among the elderly population, and elderly TBI survivors suffer from reduced recovery and poorer quality of life. The effect of age on the pathophysiology of TBI is [...] Read more.
Traumatic brain injury (TBI) is a leading cause for neurological disabilities world-wide. TBI occurs most frequently among the elderly population, and elderly TBI survivors suffer from reduced recovery and poorer quality of life. The effect of age on the pathophysiology of TBI is still poorly understood. We previously established that peripherally-derived monocytes (CCR2+) infiltrate the injured brain and contribute to chronic TBI-induced cognitive deficits in young animals. Furthermore, age was shown to amplify monocyte infiltration acutely after injury. In the current study, we investigated the impact of age on the subchronic response of peripherally-derived monocytes (CD45hi; CCR2+) and their role in the development of chronic cognitive deficits. In the aged brain, there was a significant increase in the number of peripherally-derived monocytes after injury compared to young, injured animals. The infiltration rate of peripherally-derived monocytes remained elevated subchronically and corresponded with enhanced expression of CCR2 chemotactic ligands. Interestingly, the myeloid cell populations observed in injured aged brains had impaired anti-inflammatory responses compared to those in young animals. Additionally, in the aged animals, there was an expansion of the blood CCR2+ monocyte population after injury that was not present in the young animals. Importantly, knocking out CCR2 to inhibit infiltration of peripherally-derived monocytes prevented chronic TBI-induced spatial memory deficits in the aged mice. Altogether, these results demonstrate the critical effects of age on the peripherally-derived monocyte response during the progression of TBI pathophysiology. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases)
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21 pages, 2503 KiB  
Review
Ligand Access Channels in Cytochrome P450 Enzymes: A Review
by Philippe Urban, Thomas Lautier, Denis Pompon and Gilles Truan
Int. J. Mol. Sci. 2018, 19(6), 1617; https://doi.org/10.3390/ijms19061617 - 30 May 2018
Cited by 78 | Viewed by 10465
Abstract
Quantitative structure-activity relationships may bring invaluable information on structural elements of both enzymes and substrates that, together, govern substrate specificity. Buried active sites in cytochrome P450 enzymes are connected to the solvent by a network of channels exiting at the distal surface of [...] Read more.
Quantitative structure-activity relationships may bring invaluable information on structural elements of both enzymes and substrates that, together, govern substrate specificity. Buried active sites in cytochrome P450 enzymes are connected to the solvent by a network of channels exiting at the distal surface of the protein. This review presents different in silico tools that were developed to uncover such channels in P450 crystal structures. It also lists some of the experimental evidence that actually suggest that these predicted channels might indeed play a critical role in modulating P450 functions. Amino acid residues at the entrance of the channels may participate to a first global ligand recognition of ligands by P450 enzymes before they reach the buried active site. Moreover, different P450 enzymes show different networks of predicted channels. The plasticity of P450 structures is also important to take into account when looking at how channels might play their role. Full article
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism and Bioactivation)
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28 pages, 331 KiB  
Review
Role of Vitamin D Beyond the Skeletal Function: A Review of the Molecular and Clinical Studies
by Meenakshi Umar, Konduru S. Sastry and Aouatef I. Chouchane
Int. J. Mol. Sci. 2018, 19(6), 1618; https://doi.org/10.3390/ijms19061618 - 30 May 2018
Cited by 179 | Viewed by 20248
Abstract
The classical function of Vitamin D, which involves mineral balance and skeletal maintenance, has been known for many years. With the discovery of vitamin D receptors in various tissues, several other biological functions of vitamin D are increasingly recognized and its role in [...] Read more.
The classical function of Vitamin D, which involves mineral balance and skeletal maintenance, has been known for many years. With the discovery of vitamin D receptors in various tissues, several other biological functions of vitamin D are increasingly recognized and its role in many human diseases like cancer, diabetes, hypertension, cardiovascular, and autoimmune and dermatological diseases is being extensively explored. The non-classical function of vitamin D involves regulation of cellular proliferation, differentiation, apoptosis, and innate and adaptive immunity. In this review, we discuss and summarize the latest findings on the non-classical functions of vitamin D at the cellular/molecular level and its role in complex human diseases. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
21 pages, 4552 KiB  
Article
The Influence of Selective Laser Melting (SLM) Process Parameters on In-Vitro Cell Response
by Bartłomiej Wysocki, Joanna Idaszek, Joanna Zdunek, Krzysztof Rożniatowski, Marcin Pisarek, Akiko Yamamoto and Wojciech Święszkowski
Int. J. Mol. Sci. 2018, 19(6), 1619; https://doi.org/10.3390/ijms19061619 - 30 May 2018
Cited by 57 | Viewed by 8808
Abstract
The use of laser 3D printers is very perspective in the fabrication of solid and porous implants made of various polymers, metals, and its alloys. The Selective Laser Melting (SLM) process, in which consolidated powders are fully melted on each layer, gives the [...] Read more.
The use of laser 3D printers is very perspective in the fabrication of solid and porous implants made of various polymers, metals, and its alloys. The Selective Laser Melting (SLM) process, in which consolidated powders are fully melted on each layer, gives the possibility of fabrication personalized implants based on the Computer Aid Design (CAD) model. During SLM fabrication on a 3D printer, depending on the system applied, there is a possibility for setting the amount of energy density (J/mm3) transferred to the consolidated powders, thus controlling its porosity, contact angle and roughness. In this study, we have controlled energy density in a range 8–45 J/mm3 delivered to titanium powder by setting various levels of laser power (25–45 W), exposure time (20–80 µs) and distance between exposure points (20–60 µm). The growing energy density within studied range increased from 63 to 90% and decreased from 31 to 13 µm samples density and Ra parameter, respectively. The surface energy 55–466 mN/m was achieved with contact angles in range 72–128° and 53–105° for water and formamide, respectively. The human mesenchymal stem cells (hMSCs) adhesion after 4 h decreased with increasing energy density delivered during processing within each parameter group. The differences in cells proliferation were clearly seen after a 7-day incubation. We have observed that proliferation was decreasing with increasing density of energy delivered to the samples. This phenomenon was explained by chemical composition of oxide layers affecting surface energy and internal stresses. We have noticed that TiO2, which is the main oxide of raw titanium powder, disintegrated during selective laser melting process and oxygen was transferred into metallic titanium. The typical for 3D printed parts post-processing methods such as chemical polishing in hydrofluoric (HF) or hydrofluoric/nitric (HF/HNO3) acid solutions and thermal treatments were used to restore surface chemistry of raw powders and improve surface. Full article
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16 pages, 2518 KiB  
Article
Decoding the Divergent Subcellular Location of Two Highly Similar Paralogous LEA Proteins
by Marie-Hélène Avelange-Macherel, Adrien Candat, Martine Neveu, Dimitri Tolleter and David Macherel
Int. J. Mol. Sci. 2018, 19(6), 1620; https://doi.org/10.3390/ijms19061620 - 31 May 2018
Cited by 10 | Viewed by 5352
Abstract
Many mitochondrial proteins are synthesized as precursors in the cytosol with an N-terminal mitochondrial targeting sequence (MTS) which is cleaved off upon import. Although much is known about import mechanisms and MTS structural features, the variability of MTS still hampers robust sub-cellular software [...] Read more.
Many mitochondrial proteins are synthesized as precursors in the cytosol with an N-terminal mitochondrial targeting sequence (MTS) which is cleaved off upon import. Although much is known about import mechanisms and MTS structural features, the variability of MTS still hampers robust sub-cellular software predictions. Here, we took advantage of two paralogous late embryogenesis abundant proteins (LEA) from Arabidopsis with different subcellular locations to investigate structural determinants of mitochondrial import and gain insight into the evolution of the LEA genes. LEA38 and LEA2 are short proteins of the LEA_3 family, which are very similar along their whole sequence, but LEA38 is targeted to mitochondria while LEA2 is cytosolic. Differences in the N-terminal protein sequences were used to generate a series of mutated LEA2 which were expressed as GFP-fusion proteins in leaf protoplasts. By combining three types of mutation (substitution, charge inversion, and segment replacement), we were able to redirect the mutated LEA2 to mitochondria. Analysis of the effect of the mutations and determination of the LEA38 MTS cleavage site highlighted important structural features within and beyond the MTS. Overall, these results provide an explanation for the likely loss of mitochondrial location after duplication of the ancestral gene. Full article
(This article belongs to the Special Issue Plant Mitochondria)
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11 pages, 223 KiB  
Review
Presenilins as Drug Targets for Alzheimer’s Disease—Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development
by R. Scott Duncan, Bob Song and Peter Koulen
Int. J. Mol. Sci. 2018, 19(6), 1621; https://doi.org/10.3390/ijms19061621 - 31 May 2018
Cited by 20 | Viewed by 4791
Abstract
A major cause underlying familial Alzheimer’s disease (AD) are mutations in presenilin proteins, presenilin 1 (PS1) and presenilin 2 (PS2). Presenilins are components of the γ-secretase complex which, when mutated, can affect amyloid precursor protein (APP) processing to toxic forms of amyloid beta [...] Read more.
A major cause underlying familial Alzheimer’s disease (AD) are mutations in presenilin proteins, presenilin 1 (PS1) and presenilin 2 (PS2). Presenilins are components of the γ-secretase complex which, when mutated, can affect amyloid precursor protein (APP) processing to toxic forms of amyloid beta (Aβ). Consequently, presenilins have been the target of numerous and varied research efforts to develop therapeutic strategies for AD. The presenilin 1 gene harbors the largest number of AD-causing mutations resulting in the late onset familial form of AD. As a result, the majority of efforts for drug development focused on PS1 and Aβ. Soon after the discovery of the major involvement of PS1 and PS2 in γ-secretase activity, it became clear that neuronal signaling, particularly calcium ion (Ca2+) signaling, is regulated by presenilins and impacted by mutations in presenilin genes. Intracellular Ca2+ signaling not only controls the activity of neurons, but also gene expression patterns, structural functionality of the cytoskeleton, synaptic connectivity and viability. Here, we will briefly review the role of presenilins in γ-secretase activity, then focus on the regulation of Ca2+ signaling, oxidative stress, and cellular viability by presenilins within the context of AD and discuss the relevance of presenilins in AD drug development efforts. Full article
(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)
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12 pages, 1674 KiB  
Article
Diagnostic and Prognostic Potential of MicroRNA Maturation Regulators Drosha, AGO1 and AGO2 in Urothelial Carcinomas of the Bladder
by Anja Rabien, Nadine Ratert, Anica Högner, Andreas Erbersdobler, Klaus Jung, Thorsten H. Ecke and Ergin Kilic
Int. J. Mol. Sci. 2018, 19(6), 1622; https://doi.org/10.3390/ijms19061622 - 31 May 2018
Cited by 7 | Viewed by 3884
Abstract
Bladder cancer still requires improvements in diagnosis and prognosis, because many of the cases will recur and/or metastasize with bad outcomes. Despite ongoing research on bladder biomarkers, the clinicopathological impact and diagnostic function of miRNA maturation regulators Drosha and Argonaute proteins AGO1 and [...] Read more.
Bladder cancer still requires improvements in diagnosis and prognosis, because many of the cases will recur and/or metastasize with bad outcomes. Despite ongoing research on bladder biomarkers, the clinicopathological impact and diagnostic function of miRNA maturation regulators Drosha and Argonaute proteins AGO1 and AGO2 in urothelial bladder carcinoma remain unclear. Therefore, we conducted immunohistochemical investigations of a tissue microarray composed of 112 urothelial bladder carcinomas from therapy-naïve patients who underwent radical cystectomy or transurethral resection and compared the staining signal with adjacent normal bladder tissue. The correlations of protein expression of Drosha, AGO1 and AGO2 with sex, age, tumor stage, histological grading and overall survival were evaluated in order to identify their diagnostic and prognostic potential in urothelial cancer. Our results show an upregulation of AGO1, AGO2 and Drosha in non-muscle-invasive bladder carcinomas, while there was increased protein expression of only AGO2 in muscle-invasive bladder carcinomas. Moreover, we were able to differentiate between non-muscle-invasive and muscle-invasive bladder carcinoma according to AGO1 and Drosha expression. Finally, despite Drosha being a discriminating factor that can predict the probability of overall survival in the Kaplan–Meier analysis, AGO1 turned out to be independent of all clinicopathological parameters according to Cox regression. In conclusion, we assumed that the miRNA processing factors have clinical relevance as potential diagnostic and prognostic tools for bladder cancer. Full article
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17 pages, 4352 KiB  
Article
Alteration of Transcripts of Stress-Protective Genes and Transcriptional Factors by γ-Aminobutyric Acid (GABA) Associated with Improved Heat and Drought Tolerance in Creeping Bentgrass (Agrostis stolonifera)
by Zhou Li, Yan Peng and Bingru Huang
Int. J. Mol. Sci. 2018, 19(6), 1623; https://doi.org/10.3390/ijms19061623 - 31 May 2018
Cited by 67 | Viewed by 5147
Abstract
Gamma-aminobutyric acid (GABA) may play a positive role in regulating plant tolerance to drought or heat stress. The objectives of this study were to investigate the physiological effects of GABA on tolerance of creeping bentgrass (Agrostis stolonifera) to heat and drought [...] Read more.
Gamma-aminobutyric acid (GABA) may play a positive role in regulating plant tolerance to drought or heat stress. The objectives of this study were to investigate the physiological effects of GABA on tolerance of creeping bentgrass (Agrostis stolonifera) to heat and drought stress and to determine whether enhanced heat and drought tolerance due to GABA treatment was associated with the up-regulation of selected genes and transcriptional factors involved in stress protection. Creeping bentgrass (cultivar “Penncross”) plants were treated with 0.5 mM GABA or water (untreated control) as a foliar spray and were subsequently exposed to heat stress (35/30 °C, day/night), drought stress by withholding irrigation, or non-stress conditions in controlled-environment growth chambers. Exogenous application of GABA significantly improved plant tolerance to heat and drought stress, as reflected by increased leaf water content, cell membrane stability, and chlorophyll content. The analysis of gene transcript level revealed that exogenous GABA up-regulated the expression of ABF3, POD, APX, HSP90, DHN3, and MT1 during heat stress and the expression of CDPK26, MAPK1, ABF3, WRKY75, MYB13, HSP70, MT1, 14-3-3, and genes (SOD, CAT, POD, APX, MDHAR, DHAR, and GR) encoding antioxidant enzymes during drought stress. The up-regulation of the aforementioned stress-protective genes and transcriptional factors could contribute to improved heat and drought tolerance in creeping bentgrass. Full article
(This article belongs to the Section Molecular Plant Sciences)
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14 pages, 11075 KiB  
Article
3D Bioprinted Artificial Trachea with Epithelial Cells and Chondrogenic-Differentiated Bone Marrow-Derived Mesenchymal Stem Cells
by Sang-Woo Bae, Kang-Woog Lee, Jae-Hyun Park, JunHee Lee, Cho-Rok Jung, JunJie Yu, Hwi-Yool Kim and Dae-Hyun Kim
Int. J. Mol. Sci. 2018, 19(6), 1624; https://doi.org/10.3390/ijms19061624 - 31 May 2018
Cited by 98 | Viewed by 10249
Abstract
Tracheal resection has limited applicability. Although various tracheal replacement strategies were performed using artificial prosthesis, synthetic stents and tissue transplantation, the best method in tracheal reconstruction remains to be identified. Recent advances in tissue engineering enabled 3D bioprinting using various biocompatible materials including [...] Read more.
Tracheal resection has limited applicability. Although various tracheal replacement strategies were performed using artificial prosthesis, synthetic stents and tissue transplantation, the best method in tracheal reconstruction remains to be identified. Recent advances in tissue engineering enabled 3D bioprinting using various biocompatible materials including living cells, thereby making the product clinically applicable. Moreover, clinical interest in mesenchymal stem cell has dramatically increased. Here, rabbit bone marrow-derived mesenchymal stem cells (bMSC) and rabbit respiratory epithelial cells were cultured. The chondrogenic differentiation level of bMSC cultured in regular media (MSC) and that in chondrogenic media (d-MSC) were compared. Dual cell-containing artificial trachea were manufactured using a 3D bioprinting method with epithelial cells and undifferentiated bMSC (MSC group, n = 6) or with epithelial cells and chondrogenic-differentiated bMSC (d-MSC group, n = 6). d-MSC showed a relatively higher level of glycosaminoglycan (GAG) accumulation and chondrogenic marker gene expression than MSC in vitro. Neo-epithelialization and neo-vascularization were observed in all groups in vivo but neo-cartilage formation was only noted in d-MSC. The epithelial cells in the 3D bioprinted artificial trachea were effective in respiratory epithelium regeneration. Chondrogenic-differentiated bMSC had more neo-cartilage formation potential in a short period. Nevertheless, the cartilage formation was observed only in a localized area. Full article
(This article belongs to the Special Issue Novel Biomaterials for Tissue Engineering 2018)
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15 pages, 6616 KiB  
Article
NSC 95397 Suppresses Proliferation and Induces Apoptosis in Colon Cancer Cells through MKP-1 and the ERK1/2 Pathway
by Navneet Kumar Dubey, Bou-Yue Peng, Chien-Min Lin, Peter D. Wang, Joseph R. Wang, Chun-Hao Chan, Hong-Jian Wei and Win-Ping Deng
Int. J. Mol. Sci. 2018, 19(6), 1625; https://doi.org/10.3390/ijms19061625 - 31 May 2018
Cited by 25 | Viewed by 7339
Abstract
NSC 95397, a quinone-based small molecule compound, has been identified as an inhibitor for dual-specificity phosphatases, including mitogen-activated protein kinase phosphatase-1 (MKP-1). MKP-1 is known to inactivate mitogen-activated protein kinases by dephosphorylating both of their threonine and tyrosine residues. Moreover, owing to their [...] Read more.
NSC 95397, a quinone-based small molecule compound, has been identified as an inhibitor for dual-specificity phosphatases, including mitogen-activated protein kinase phosphatase-1 (MKP-1). MKP-1 is known to inactivate mitogen-activated protein kinases by dephosphorylating both of their threonine and tyrosine residues. Moreover, owing to their participation in tumorigenesis and drug resistance in colon cancer cells, MKP-1 is an attractive therapeutic target for colon cancer treatment. We therefore investigated the inhibitory activity of NSC 95397 against three colon cancer cell lines including SW480, SW620, and DLD-1, and their underlying mechanisms. The results demonstrated that NSC 95397 reduced cell viability and anchorage-independent growth of all the three colon cancer cell lines through inhibited proliferation and induced apoptosis via regulating cell-cycle-related proteins, including p21, cyclin-dependent kinases, and caspases. Besides, by using mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor U0126, we provided mechanistic evidence that the antineoplastic effects of NSC 95397 were achieved via inhibiting MKP-1 activity followed by ERK1/2 phosphorylation. Conclusively, our results indicated that NSC 95397 might serve as an effective therapeutic intervention for colon cancer through regulating MKP-1 and ERK1/2 pathway. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)
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15 pages, 3548 KiB  
Article
Oxaloacetate Ameliorates Chemical Liver Injury via Oxidative Stress Reduction and Enhancement of Bioenergetic Fluxes
by Ye Kuang, Xiaoyun Han, Mu Xu, Yue Wang, Yuxiang Zhao and Qing Yang
Int. J. Mol. Sci. 2018, 19(6), 1626; https://doi.org/10.3390/ijms19061626 - 31 May 2018
Cited by 30 | Viewed by 6587
Abstract
Chemical injury is partly due to free radical lipid peroxidation, which can induce oxidative stress and produce a large number of reactive oxygen species (ROS). Oxaloacetic acid is an important intermediary in the tricarboxylic acid cycle (TCA cycle) and participates in metabolism and [...] Read more.
Chemical injury is partly due to free radical lipid peroxidation, which can induce oxidative stress and produce a large number of reactive oxygen species (ROS). Oxaloacetic acid is an important intermediary in the tricarboxylic acid cycle (TCA cycle) and participates in metabolism and energy production. In our study, we found that oxaloacetate (OA) effectively alleviated liver injury which was induced by hydrogen peroxide (H2O2) in vitro and carbon tetrachloride (CCl4) in vivo. OA scavenged ROS, prevented oxidative damage and maintained the normal structure of mitochondria. We further confirmed that OA increased adenosine triphosphate (ATP) by promoting the TCA production cycle and oxidative phosphorylation (OXPHOS). Finally, OA inhibited the mitogen-activated protein kinase (MAPK) and apoptotic pathways by suppressing tumor necrosis factor-α (TNF-α). Our findings reveal a mechanism for OA ameliorating chemical liver injury and suggest a possible implementation for preventing the chemical liver injury. Full article
(This article belongs to the Special Issue Liver Damage and Repair)
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28 pages, 1720 KiB  
Review
Nanoparticles for Signaling in Biodiagnosis and Treatment of Infectious Diseases
by Clara I. Colino, Carmen Gutiérrez Millán and José M. Lanao
Int. J. Mol. Sci. 2018, 19(6), 1627; https://doi.org/10.3390/ijms19061627 - 31 May 2018
Cited by 54 | Viewed by 7904
Abstract
Advances in nanoparticle-based systems constitute a promising research area with important implications for the treatment of bacterial infections, especially against multidrug resistant strains and bacterial biofilms. Nanosystems may be useful for the diagnosis and treatment of viral and fungal infections. Commercial diagnostic tests [...] Read more.
Advances in nanoparticle-based systems constitute a promising research area with important implications for the treatment of bacterial infections, especially against multidrug resistant strains and bacterial biofilms. Nanosystems may be useful for the diagnosis and treatment of viral and fungal infections. Commercial diagnostic tests based on nanosystems are currently available. Different methodologies based on nanoparticles (NPs) have been developed to detect specific agents or to distinguish between Gram-positive and Gram-negative microorganisms. Also, biosensors based on nanoparticles have been applied in viral detection to improve available analytical techniques. Several point-of-care (POC) assays have been proposed that can offer results faster, easier and at lower cost than conventional techniques and can even be used in remote regions for viral diagnosis. Nanoparticles functionalized with specific molecules may modulate pharmacokinetic targeting recognition and increase anti-infective efficacy. Quorum sensing is a stimuli-response chemical communication process correlated with population density that bacteria use to regulate biofilm formation. Disabling it is an emerging approach for combating its pathogenicity. Natural or synthetic inhibitors may act as antibiofilm agents and be useful for treating multi-drug resistant bacteria. Nanostructured materials that interfere with signal molecules involved in biofilm growth have been developed for the control of infections associated with biofilm-associated infections. Full article
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28 pages, 1998 KiB  
Review
Fascinating Fasciclins: A Surprisingly Widespread Family of Proteins that Mediate Interactions between the Cell Exterior and the Cell Surface
by Georg J. Seifert
Int. J. Mol. Sci. 2018, 19(6), 1628; https://doi.org/10.3390/ijms19061628 - 31 May 2018
Cited by 72 | Viewed by 10232
Abstract
The Fasciclin 1 (FAS1) domain is an ancient structural motif in extracellular proteins present in all kingdoms of life and particularly abundant in plants. The FAS1 domain accommodates multiple interaction surfaces, enabling it to bind different ligands. The frequently observed tandem FAS1 arrangement [...] Read more.
The Fasciclin 1 (FAS1) domain is an ancient structural motif in extracellular proteins present in all kingdoms of life and particularly abundant in plants. The FAS1 domain accommodates multiple interaction surfaces, enabling it to bind different ligands. The frequently observed tandem FAS1 arrangement might both positively and negatively regulate ligand binding. Additional protein domains and post-translational modifications are partially conserved between different evolutionary clades. Human FAS1 family members are associated with multiple aspects of health and disease. At the cellular level, mammalian FAS1 proteins are implicated in extracellular matrix structure, cell to extracellular matrix and cell to cell adhesion, paracrine signaling, intracellular trafficking and endocytosis. Mammalian FAS1 proteins bind to the integrin family of receptors and to protein and carbohydrate components of the extracellular matrix. FAS1 protein encoding plant genes exert effects on cellulosic and non-cellulosic cell wall structure and cellular signaling but to establish the modes of action for any plant FAS1 protein still requires biochemical experimentation. In fungi, eubacteria and archaea, the differential presence of FAS1 proteins in closely related organisms and isolated biochemical data suggest functions in pathogenicity and symbiosis. The inter-kingdom comparison of FAS1 proteins suggests that molecular mechanisms mediating interactions between cells and their environment may have evolved at the earliest known stages of evolution. Full article
(This article belongs to the Special Issue Plant Cell Wall Proteins and Development)
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13 pages, 3750 KiB  
Article
Furosine Induced Apoptosis by the Regulation of STAT1/STAT2 and UBA7/UBE2L6 Genes in HepG2 Cells
by Huiying Li, Lei Xing, Nan Zhao, Jiaqi Wang and Nan Zheng
Int. J. Mol. Sci. 2018, 19(6), 1629; https://doi.org/10.3390/ijms19061629 - 31 May 2018
Cited by 11 | Viewed by 4549
Abstract
As a typical product in the Miallard reaction, research on the quantitative detection of furosine is abundant, while its bioactivities and toxic effects are still unclear. Our own work recently demonstrated the induction of furosine on apoptosis in HepG2 cells, while the related [...] Read more.
As a typical product in the Miallard reaction, research on the quantitative detection of furosine is abundant, while its bioactivities and toxic effects are still unclear. Our own work recently demonstrated the induction of furosine on apoptosis in HepG2 cells, while the related mechanism remained elusive. In this study, the effects of furosine on cell viability and apoptosis were detected to select the proper dosage, and transcriptomics detection and data analysis were performed to screen out the special genes. Additionally, SiRNA fragments of the selected genes were designed and transfected into HepG2 cells to validate the role of these genes in inducing apoptosis. Results showed that furosine inhibited cell viability and induced cell apoptosis in a dose-dependent manner, as well as activated expressions of the selected genes STAT1 (signal transducer and activator of transcription 1), STAT2 (signal transducer and activator of transcription 2), UBA7 (ubiquitin-like modifier activating enzyme 7), and UBE2L6 (ubiquitin-conjugating enzyme E2L6), which significantly affected downstream apoptosis factors Caspase-3 (cysteinyl aspartate specific proteinase-3), Bcl-2 (B-cell lymphoma gene-2), Bax (BCL2-Associated gene X), and Caspase-9 (cysteinyl aspartate specific proteinase-9). For the first time, we revealed furosine induced apoptosis through two transcriptional regulators (STAT1 and STAT2) and two ubiquitination-related enzymes (UBA7 and UBE2L6). Full article
(This article belongs to the Section Biochemistry)
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10 pages, 1805 KiB  
Article
Downregulations of AKT/mTOR Signaling Pathway for Salmonella-Mediated Suppression of Matrix Metalloproteinases-9 Expression in Mouse Tumor Models
by Yu-Tzu Tsao, Chun-Yu Kuo, Shun-Ping Cheng and Che-Hsin Lee
Int. J. Mol. Sci. 2018, 19(6), 1630; https://doi.org/10.3390/ijms19061630 - 31 May 2018
Cited by 33 | Viewed by 4369
Abstract
The roles of Matrix MetalloProteinases (MMPs), such as MMP-9, in tumor metastasis are well studied, and this in turns stimulates the development of MMP inhibitors as antitumor agents. Previously, Salmonella accumulation was observed in the metastatic nodules of the lungs after systemic administration. [...] Read more.
The roles of Matrix MetalloProteinases (MMPs), such as MMP-9, in tumor metastasis are well studied, and this in turns stimulates the development of MMP inhibitors as antitumor agents. Previously, Salmonella accumulation was observed in the metastatic nodules of the lungs after systemic administration. Salmonella significantly enhanced the survival of the pulmonary metastatic tumor-bearing mice. Based on our previous observation, we hypothesized that Salmonella could affect metastasis-related protein expression. The treatment of Salmonella clearly reduced the expression of MMP-9. Meanwhile, the MMP-9 related signaling pathways, including Phosph-Protein Kinase B (P-AKT) and Phosph-mammalian Targets Of Rapamycin (P-mTOR) were decreased after a Salmonella treatment. The Salmonella inhibited tumor cell migration by wound-healing and Transwell assay. The anti-metastatic effects of Salmonella were evaluated in mice bearing experimental metastasis tumor models. Consequently, Salmonella inhibited the expression of MMP-9 by reducing the AKT/mTOR pathway and metastatic nodules in vivo. Full article
(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing 2018)
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14 pages, 1894 KiB  
Article
Mir-34a-5p Mediates Cross-Talk between M2 Muscarinic Receptors and Notch-1/EGFR Pathways in U87MG Glioblastoma Cells: Implication in Cell Proliferation
by Maria Di Bari, Valeria Bevilacqua, Antonella De Jaco, Pietro Laneve, Roberta Piovesana, Laura Trobiani, Claudio Talora, Elisa Caffarelli and Ada Maria Tata
Int. J. Mol. Sci. 2018, 19(6), 1631; https://doi.org/10.3390/ijms19061631 - 31 May 2018
Cited by 27 | Viewed by 4554
Abstract
Glioblastoma (GBM) is the most aggressive human brain tumor. The high growth potential and decreased susceptibility to apoptosis of the glioma cells is mainly dependent on genetic amplifications or mutations of oncogenic or pro-apoptotic genes, respectively. We have previously shown that the activation [...] Read more.
Glioblastoma (GBM) is the most aggressive human brain tumor. The high growth potential and decreased susceptibility to apoptosis of the glioma cells is mainly dependent on genetic amplifications or mutations of oncogenic or pro-apoptotic genes, respectively. We have previously shown that the activation of the M2 acetylcholine muscarinic receptors inhibited cell proliferation and induced apoptosis in two GBM cell lines and cancer stem cells. The aim of this study was to delve into the molecular mechanisms underlying the M2-mediated cell proliferation arrest. Exploiting U87MG and U251MG cell lines as model systems, we evaluated the ability of M2 receptors to interfere with Notch-1 and EGFR pathways, whose activation promotes GBM proliferation. We demonstrated that the activation of M2 receptors, by agonist treatment, counteracted Notch and EGFR signaling, through different regulatory cascades depending, at least in part, on p53 status. Only in U87MG cells, which mimic p53-wild type GBMs, did M2 activation trigger a molecular circuitry involving p53, Notch-1, and the tumor suppressor mir-34a-5p. This regulatory module negatively controls Notch-1, which affects cell proliferation mainly through the Notch-1/EGFR axis. Our data highlighted, for the first time, a molecular circuitry that is deregulated in the p53 wild type GBM, based on the cross-talk between M2 receptor and the Notch-1/EGFR pathways, mediated by mir-34a-5p. Full article
(This article belongs to the Special Issue The Role of MicroRNAs in Human Diseases)
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13 pages, 1510 KiB  
Review
Bacterial Toxins and Targeted Brain Therapy: New Insights from Cytotoxic Necrotizing Factor 1 (CNF1)
by Elena Tantillo, Antonella Colistra, Eleonora Vannini, Chiara Cerri, Laura Pancrazi, Laura Baroncelli, Mario Costa and Matteo Caleo
Int. J. Mol. Sci. 2018, 19(6), 1632; https://doi.org/10.3390/ijms19061632 - 31 May 2018
Cited by 14 | Viewed by 4606
Abstract
Pathogenic bacteria produce toxins to promote host invasion and, therefore, their survival. The extreme potency and specificity of these toxins confer to this category of proteins an exceptionally strong potential for therapeutic exploitation. In this review, we deal with cytotoxic necrotizing factor (CNF1), [...] Read more.
Pathogenic bacteria produce toxins to promote host invasion and, therefore, their survival. The extreme potency and specificity of these toxins confer to this category of proteins an exceptionally strong potential for therapeutic exploitation. In this review, we deal with cytotoxic necrotizing factor (CNF1), a cytotoxin produced by Escherichia coli affecting fundamental cellular processes, including cytoskeletal dynamics, cell cycle progression, transcriptional regulation, cell survival and migration. First, we provide an overview of the mechanisms of action of CNF1 in target cells. Next, we focus on the potential use of CNF1 as a pharmacological treatment in central nervous system’s diseases. CNF1 appears to impact neuronal morphology, physiology, and plasticity and displays an antineoplastic activity on brain tumors. The ability to preserve neural functionality and, at the same time, to trigger senescence and death of proliferating glioma cells, makes CNF1 an encouraging new strategy for the treatment of brain tumors. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins: Enemies within or Unexpected Friends)
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10 pages, 1515 KiB  
Communication
Tuning the Mechanical Properties of a DNA Hydrogel in Three Phases Based on ATP Aptamer
by Hengyuan Liu, Tianyang Cao, Yun Xu, Yuanchen Dong and Dongsheng Liu
Int. J. Mol. Sci. 2018, 19(6), 1633; https://doi.org/10.3390/ijms19061633 - 31 May 2018
Cited by 38 | Viewed by 9135
Abstract
By integrating ATP aptamer into the linker DNA, a novel DNA hydrogel was designed, with mechanical properties that could be tuned into three phases. Based on the unique interaction between ATP and its aptamer, the mechanical strength of the hydrogel increased from 204 [...] Read more.
By integrating ATP aptamer into the linker DNA, a novel DNA hydrogel was designed, with mechanical properties that could be tuned into three phases. Based on the unique interaction between ATP and its aptamer, the mechanical strength of the hydrogel increased from 204 Pa to 380 Pa after adding ATP. Furthermore, with the addition of the complementary sequence to the ATP aptamer, the mechanical strength could be increased to 570 Pa. Full article
(This article belongs to the Special Issue Nucleic Acid Nanotechnology)
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29 pages, 1257 KiB  
Review
Revisiting the Role of Plant Transcription Factors in the Battle against Abiotic Stress
by Sardar-Ali Khan, Meng-Zhan Li, Suo-Min Wang and Hong-Ju Yin
Int. J. Mol. Sci. 2018, 19(6), 1634; https://doi.org/10.3390/ijms19061634 - 31 May 2018
Cited by 225 | Viewed by 17002
Abstract
Owing to diverse abiotic stresses and global climate deterioration, the agricultural production worldwide is suffering serious losses. Breeding stress-resilient crops with higher quality and yield against multiple environmental stresses via application of transgenic technologies is currently the most promising approach. Deciphering molecular principles [...] Read more.
Owing to diverse abiotic stresses and global climate deterioration, the agricultural production worldwide is suffering serious losses. Breeding stress-resilient crops with higher quality and yield against multiple environmental stresses via application of transgenic technologies is currently the most promising approach. Deciphering molecular principles and mining stress-associate genes that govern plant responses against abiotic stresses is one of the prerequisites to develop stress-resistant crop varieties. As molecular switches in controlling stress-responsive genes expression, transcription factors (TFs) play crucial roles in regulating various abiotic stress responses. Hence, functional analysis of TFs and their interaction partners during abiotic stresses is crucial to perceive their role in diverse signaling cascades that many researchers have continued to undertake. Here, we review current developments in understanding TFs, with particular emphasis on their functions in orchestrating plant abiotic stress responses. Further, we discuss novel molecular mechanisms of their action under abiotic stress conditions. This will provide valuable information for understanding regulatory mechanisms to engineer stress-tolerant crops. Full article
(This article belongs to the Section Molecular Plant Sciences)
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12 pages, 2314 KiB  
Article
Extension of Tissue Plasminogen Activator Treatment Window by Granulocyte-Colony Stimulating Factor in a Thromboembolic Rat Model of Stroke
by Ike C. Dela Peña, Samuel Yang, Guofang Shen, Hsiao Fang Liang, Sara Solak and Cesar V. Borlongan
Int. J. Mol. Sci. 2018, 19(6), 1635; https://doi.org/10.3390/ijms19061635 - 31 May 2018
Cited by 11 | Viewed by 4341
Abstract
When given beyond 4.5 h of stroke onset, tissue plasminogen activator (tPA) induces deleterious side effects in the ischemic brain, notably, hemorrhagic transformation (HT). We examined the efficacy of granulocyte-colony stimulating factor (G-CSF) in reducing delayed tPA-induced HT, cerebral infarction, and neurological deficits [...] Read more.
When given beyond 4.5 h of stroke onset, tissue plasminogen activator (tPA) induces deleterious side effects in the ischemic brain, notably, hemorrhagic transformation (HT). We examined the efficacy of granulocyte-colony stimulating factor (G-CSF) in reducing delayed tPA-induced HT, cerebral infarction, and neurological deficits in a thromboembolic (TE) stroke model, and whether the effects of G-CSF were sustained for longer periods of recovery. After stroke induction, rats were given intravenous saline (control), tPA (10 mg/kg), or G-CSF (300 μg/kg) + tPA 6 h after stroke. We found that G-CSF reduced delayed tPA-associated HT by 47%, decreased infarct volumes by 33%, and improved motor and neurological deficits by 15% and 25%, respectively. It also prevented delayed tPA treatment-induced mortality by 46%. Immunohistochemistry showed 1.5- and 1.8-fold enrichment of the endothelial progenitor cell (EPC) markers CD34+ and VEGFR2 in the ischemic cortex and striatum, respectively, and 1.7- and 2.8-fold increases in the expression of the vasculogenesis marker von Willebrand factor (vWF) in the ischemic cortex and striatum, respectively, in G-CSF-treated rats compared with tPA-treated animals. Flow cytometry revealed increased mobilization of CD34+ cells in the peripheral blood of rats given G-CSF. These results corroborate the efficacy of G-CSF in enhancing the therapeutic time window of tPA for stroke treatment via EPC mobilization and enhancement of vasculogenesis. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases)
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19 pages, 1707 KiB  
Article
Fewer Functional Deficits and Reduced Cell Death after Ranibizumab Treatment in a Retinal Ischemia Model
by Marina Palmhof, Stephanie Lohmann, Dustin Schulte, Gesa Stute, Natalie Wagner, H. Burkhard Dick and Stephanie C. Joachim
Int. J. Mol. Sci. 2018, 19(6), 1636; https://doi.org/10.3390/ijms19061636 - 31 May 2018
Cited by 28 | Viewed by 4378
Abstract
Retinal ischemia is an important factor in several eye disorders. To investigate the impact of VEGF inhibitors, as a therapeutic option, we studied these in a retinal ischemia animal model. Therefore, animals received bevacizumab or ranibizumab intravitreally one day after ischemia induction. Via [...] Read more.
Retinal ischemia is an important factor in several eye disorders. To investigate the impact of VEGF inhibitors, as a therapeutic option, we studied these in a retinal ischemia animal model. Therefore, animals received bevacizumab or ranibizumab intravitreally one day after ischemia induction. Via electroretinography, a significant decrease in a- and b-wave amplitudes was detected fourteen days after ischemia, but they were reduced to a lesser extent in the ranibizumab group. Ischemic and bevacizumab retinae displayed fewer retinal ganglion cells (RGCs), while no significant cell loss was noted in the ranibizumab group. Apoptosis was reduced after therapy. More autophagocytotic cells were observed in ischemic and bevacizumab eyes, but not in ranibizumab eyes. Additionally, more microglia, as well as active ones, were revealed in all ischemic groups, but the increase was less prominent under ranibizumab treatment. Fewer cone bipolar cells were detected in ischemic eyes, in contrast to bevacizumab and ranibizumab-treated ones. Our results demonstrate a reduced apoptosis and autophagocytosis rate after ranibizumab treatment. Furthermore, a certain protection was seen regarding functionality, RGC, and bipolar cell availability, as well as microglia activation by ranibizumab treatment after ischemic damage. Thus, ranibizumab could be an option for treatment of retinal ischemic injury. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases)
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42 pages, 21548 KiB  
Review
Use of Curcumin, a Natural Polyphenol for Targeting Molecular Pathways in Treating Age-Related Neurodegenerative Diseases
by Panchanan Maiti and Gary L. Dunbar
Int. J. Mol. Sci. 2018, 19(6), 1637; https://doi.org/10.3390/ijms19061637 - 31 May 2018
Cited by 192 | Viewed by 21769
Abstract
Progressive accumulation of misfolded amyloid proteins in intracellular and extracellular spaces is one of the principal reasons for synaptic damage and impairment of neuronal communication in several neurodegenerative diseases. Effective treatments for these diseases are still lacking but remain the focus of much [...] Read more.
Progressive accumulation of misfolded amyloid proteins in intracellular and extracellular spaces is one of the principal reasons for synaptic damage and impairment of neuronal communication in several neurodegenerative diseases. Effective treatments for these diseases are still lacking but remain the focus of much active investigation. Despite testing several synthesized compounds, small molecules, and drugs over the past few decades, very few of them can inhibit aggregation of amyloid proteins and lessen their neurotoxic effects. Recently, the natural polyphenol curcumin (Cur) has been shown to be a promising anti-amyloid, anti-inflammatory and neuroprotective agent for several neurodegenerative diseases. Because of its pleotropic actions on the central nervous system, including preferential binding to amyloid proteins, Cur is being touted as a promising treatment for age-related brain diseases. Here, we focus on molecular targeting of Cur to reduce amyloid burden, rescue neuronal damage, and restore normal cognitive and sensory motor functions in different animal models of neurodegenerative diseases. We specifically highlight Cur as a potential treatment for Alzheimer’s, Parkinson’s, Huntington’s, and prion diseases. In addition, we discuss the major issues and limitations of using Cur for treating these diseases, along with ways of circumventing those shortcomings. Finally, we provide specific recommendations for optimal dosing with Cur for treating neurological diseases. Full article
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13 pages, 3631 KiB  
Article
Anti-Apoptosis and Anti-Fibrosis Effects of Eriobotrya Japonica in Spontaneously Hypertensive Rat Hearts
by Jui-Ting Chiang, Khan Farheen Badrealam, Marthandam Asokan Shibu, Sue-Fei Cheng, Chia-Yao Shen, Chih-Feng Chang, Yueh-Min Lin, Vijaya Padma Viswanadha, Shih-Chieh Liao and Chih-Yang Huang
Int. J. Mol. Sci. 2018, 19(6), 1638; https://doi.org/10.3390/ijms19061638 - 31 May 2018
Cited by 28 | Viewed by 4885
Abstract
Myocardial apoptosis and fibrosis represent important contributing factors for development of hypertension-induced heart failure. The present study aims to investigate the potential effects of Eriobotrya japonica leaf extract (EJLE) against hypertension-induced cardiac apoptosis and fibrosis in spontaneously hypertensive rats (SHRs). Twelve-week-old male rats [...] Read more.
Myocardial apoptosis and fibrosis represent important contributing factors for development of hypertension-induced heart failure. The present study aims to investigate the potential effects of Eriobotrya japonica leaf extract (EJLE) against hypertension-induced cardiac apoptosis and fibrosis in spontaneously hypertensive rats (SHRs). Twelve-week-old male rats were randomly divided into four different groups; control Wistar Kyoto (WKY) rats, hypertensive SHR rats, SHR rats treated with a low dose (100 mg/kg body weight) of EJLE and SHR rats treated with a high dose (300 mg/kg body weight) of EJLE. Animals were acclimatized for 4 weeks and thereafter were gastric fed for 8 weeks with two doses of EJLE per week. The rats were then euthanized following cardiac functional analysis by echocardiography. The cardiac tissue sections were examined by Terminal Deoxynucleotidyl Transferase-Mediated Deoxyuridine Triphosphate (dUTP) Nick End-Labeling (TUNEL) assay, histological staining and Western blotting to assess the cardio-protective effects of EJ in SHR animals. Echocardiographic measurements provided convincing evidence to support the ability of EJ to ameliorate crucial cardiac functional characteristics. Furthermore, our results reveal that supplementation of EJLE effectively attenuated cardiac apoptosis and fibrosis and also enhanced cell survival in hypertensive SHR hearts. Thus, the present study concludes that EJLE potentially provides cardio-protective effects against hypertension-induced cardiac apoptosis and fibrosis in SHR animals. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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25 pages, 544 KiB  
Review
Metabolic Dysfunction and Peroxisome Proliferator-Activated Receptors (PPAR) in Multiple Sclerosis
by Véronique Ferret-Sena, Carlos Capela and Armando Sena
Int. J. Mol. Sci. 2018, 19(6), 1639; https://doi.org/10.3390/ijms19061639 - 1 Jun 2018
Cited by 22 | Viewed by 6943
Abstract
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS) probably caused, in most cases, by the interaction of genetic and environmental factors. This review first summarizes some clinical, epidemiological and pathological characteristics of MS. Then, the involvement [...] Read more.
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS) probably caused, in most cases, by the interaction of genetic and environmental factors. This review first summarizes some clinical, epidemiological and pathological characteristics of MS. Then, the involvement of biochemical pathways is discussed in the development and repair of the CNS lesions and the immune dysfunction in the disease. Finally, the potential roles of peroxisome proliferator-activated receptors (PPAR) in MS are discussed. It is suggested that metabolic mechanisms modulated by PPAR provide a window to integrate the systemic and neurological events underlying the pathogenesis of the disease. In conclusion, the reviewed data highlight molecular avenues of understanding MS that may open new targets for improved therapies and preventive strategies for the disease. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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14 pages, 2194 KiB  
Article
Downregulation of α-Melanocyte-Stimulating Hormone-Induced Activation of the Pax3-MITF-Tyrosinase Axis by Sorghum Ethanolic Extract in B16F10 Melanoma Cells
by Da Hyun Lee, Sung Shin Ahn, Jung-Bong Kim, Yoongho Lim, Young Han Lee and Soon Young Shin
Int. J. Mol. Sci. 2018, 19(6), 1640; https://doi.org/10.3390/ijms19061640 - 1 Jun 2018
Cited by 18 | Viewed by 6315
Abstract
Ultraviolet irradiation-induced hyperpigmentation of the skin is associated with excessive melanin production in melanocytes. Tyrosinase (TYR) is a key enzyme catalyzing the rate-limiting step in melanogenesis. TYR expression is controlled by microphthalmia-associated transcription factor (MITF) expression. Sorghum is a cereal crop widely used [...] Read more.
Ultraviolet irradiation-induced hyperpigmentation of the skin is associated with excessive melanin production in melanocytes. Tyrosinase (TYR) is a key enzyme catalyzing the rate-limiting step in melanogenesis. TYR expression is controlled by microphthalmia-associated transcription factor (MITF) expression. Sorghum is a cereal crop widely used in a variety of foods worldwide. Sorghum contains many bioactive compounds and is beneficial to human health. However, the effects of sorghum in anti-melanogenesis have not been well characterized. In this study, the biological activity of sorghum ethanolic extract (SEE) on α-melanocyte-stimulating hormone (α-MSH)-induced TYR expression was evaluated in B16F10 melanoma cells. SEE attenuated α-MSH-induced TYR gene promoter activity through the downregulation of the transcription factor MITF. We found that paired box gene 3 (Pax3) contributes to the maximal induction of MITF gene promoter activity. Further analysis demonstrated that SEE inhibited α-MSH-induced Pax3 expression. The collective results indicate that SEE attenuates α-MSH-induced TYR expression through the suppression of Pax3-mediated MITF gene promoter activity. Targeting the Pax3-MITF axis pathway could be considered a potential strategy to increase the efficacy of anti-melanogenesis. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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20 pages, 91191 KiB  
Review
Biomimetic Layer-by-Layer Self-Assembly of Nanofilms, Nanocoatings, and 3D Scaffolds for Tissue Engineering
by Shichao Zhang, Malcolm Xing and Bingyun Li
Int. J. Mol. Sci. 2018, 19(6), 1641; https://doi.org/10.3390/ijms19061641 - 1 Jun 2018
Cited by 83 | Viewed by 13717
Abstract
Achieving surface design and control of biomaterial scaffolds with nanometer- or micrometer-scaled functional films is critical to mimic the unique features of native extracellular matrices, which has significant technological implications for tissue engineering including cell-seeded scaffolds, microbioreactors, cell assembly, tissue regeneration, etc. Compared [...] Read more.
Achieving surface design and control of biomaterial scaffolds with nanometer- or micrometer-scaled functional films is critical to mimic the unique features of native extracellular matrices, which has significant technological implications for tissue engineering including cell-seeded scaffolds, microbioreactors, cell assembly, tissue regeneration, etc. Compared with other techniques available for surface design, layer-by-layer (LbL) self-assembly technology has attracted extensive attention because of its integrated features of simplicity, versatility, and nanoscale control. Here we present a brief overview of current state-of-the-art research related to the LbL self-assembly technique and its assembled biomaterials as scaffolds for tissue engineering. An overview of the LbL self-assembly technique, with a focus on issues associated with distinct routes and driving forces of self-assembly, is described briefly. Then, we highlight the controllable fabrication, properties, and applications of LbL self-assembly biomaterials in the forms of multilayer nanofilms, scaffold nanocoatings, and three-dimensional scaffolds to systematically demonstrate advances in LbL self-assembly in the field of tissue engineering. LbL self-assembly not only provides advances for molecular deposition but also opens avenues for the design and development of innovative biomaterials for tissue engineering. Full article
(This article belongs to the Special Issue Novel Biomaterials for Tissue Engineering 2018)
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18 pages, 470 KiB  
Review
VEGF Upregulation in Viral Infections and Its Possible Therapeutic Implications
by Khaled R. Alkharsah
Int. J. Mol. Sci. 2018, 19(6), 1642; https://doi.org/10.3390/ijms19061642 - 1 Jun 2018
Cited by 70 | Viewed by 9359
Abstract
Several viruses are recognized as the direct or indirect causative agents of human tumors and other severe human diseases. Vascular endothelial growth factor (VEGF) is identified as a principal proangiogenic factor that enhances the production of new blood vessels from existing vascular network. [...] Read more.
Several viruses are recognized as the direct or indirect causative agents of human tumors and other severe human diseases. Vascular endothelial growth factor (VEGF) is identified as a principal proangiogenic factor that enhances the production of new blood vessels from existing vascular network. Therefore, oncogenic viruses such as Kaposi’s sarcoma herpesvirus (KSHV) and Epstein-Barr virus (EBV) and non-oncogenic viruses such as herpes simplex virus (HSV-1) and dengue virus, which lack their own angiogenic factors, rely on the recruitment of cellular genes for angiogenesis in tumor progression or disease pathogenesis. This review summarizes how human viruses exploit the cellular signaling machinery to upregulate the expression of VEGF and benefit from its physiological functions for their own pathogenesis. Understanding the interplay between viruses and VEGF upregulation will pave the way to design targeted and effective therapeutic approaches for viral oncogenesis and severe diseases. Full article
(This article belongs to the Special Issue Vascular Endothelial Growth Factor)
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17 pages, 5671 KiB  
Article
Treatment with Obestatin—A Ghrelin Gene-Encoded Peptide—Reduces the Severity of Experimental Colitis Evoked by Trinitrobenzene Sulfonic Acid
by Katarzyna Konarska, Jakub Cieszkowski, Zygmunt Warzecha, Piotr Ceranowicz, Anna Chmura, Beata Kuśnierz-Cabala, Krystyna Gałązka, Paweł Kowalczyk, Andrzej Miskiewicz, Thomas Jan Konturek, Michał Pędziwiatr and Artur Dembiński
Int. J. Mol. Sci. 2018, 19(6), 1643; https://doi.org/10.3390/ijms19061643 - 1 Jun 2018
Cited by 29 | Viewed by 4877
Abstract
Obestatin is a 23-amino acid peptide derived from proghrelin, a common prohormone for ghrelin and obestatin. Previous studies showed that obestatin exhibited some protective and therapeutic effects in the gut. The aim of our presented study was to examine the effect of treatment [...] Read more.
Obestatin is a 23-amino acid peptide derived from proghrelin, a common prohormone for ghrelin and obestatin. Previous studies showed that obestatin exhibited some protective and therapeutic effects in the gut. The aim of our presented study was to examine the effect of treatment with obestatin on trinitrobenzene sulfonic acid (TNBS)-induced colitis. In rats anesthetized with ketamine, colitis was induced through intrarectal administration of 25 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Obestatin was administered intraperitoneally at doses of 4, 8, or 16 nmol/kg, twice per day for four consecutive days. The first dose of obestatin was given one day before the induction of colitis, and the last one was given two days after administration of TNBS. Fourteen days after the induction of colitis, rats were anesthetized again with ketamine, and the severity of colitis was determined. The administration of obestatin had no effect on the parameters tested in rats without the induction of colitis. In rats with colitis, administration of obestatin at doses of 8 or 16 nmol/kg reduced the area of colonic damage, and improved mucosal blood flow in the colon. These effects were accompanied by a reduction in the colitis-evoked increase in the level of blood leukocytes, and mucosal concentration of pro-inflammatory interleukin-1β. Moreover, obestatin administered at doses of 8 or 16 nmol/kg reduced histological signs of colonic damage. The administration of obestatin at a dose of 4 nmol/kg failed to significantly affect the parameters tested. Overall, treatment with obestatin reduced the severity of TNBS-induced colitis in rats. This effect was associated with an improvement in mucosal blood flow in the colon, and a decrease in local and systemic inflammatory processes. Full article
(This article belongs to the Special Issue Integrative Physiology of Ghrelin and Synthetic GH Secretagogues)
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15 pages, 4070 KiB  
Article
Butterbur Leaves Attenuate Memory Impairment and Neuronal Cell Damage in Amyloid Beta-Induced Alzheimer’s Disease Models
by Namkwon Kim, Jin Gyu Choi, Sangsu Park, Jong Kil Lee and Myung Sook Oh
Int. J. Mol. Sci. 2018, 19(6), 1644; https://doi.org/10.3390/ijms19061644 - 1 Jun 2018
Cited by 14 | Viewed by 5603
Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, and is characterized by the accumulation of amyloid beta (Aβ) as a pathological hallmark. Aβ plays a central role in neuronal degeneration and synaptic dysfunction through the generation of excessive oxidative stress. In the [...] Read more.
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, and is characterized by the accumulation of amyloid beta (Aβ) as a pathological hallmark. Aβ plays a central role in neuronal degeneration and synaptic dysfunction through the generation of excessive oxidative stress. In the present study, we explored whether leaves of Petasites japonicus (Siebold & Zucc.) Maxim. (PL), called butterbur and traditionally used in folk medicine, show neuroprotective action against Aβ25–35 plaque neurotoxicity in vitro and in vivo. We found that PL protected Aβ25–35 plaque-induced neuronal cell death and intracellular reactive oxygen species generation in HT22 cells by elevating expression levels of phosphorylated cyclic AMP response element-binding protein, heme oxygenase-1, and NAD(P)H quinine dehydrogenase 1. These neuroprotective effects of PL were also observed in Aβ25–35 plaque-injected AD mouse models. Moreover, administration of PL diminished Aβ25–35 plaque-induced synaptic dysfunction and memory impairment in mice. These findings lead us to suggest that PL can protect neurons against Aβ25–35 plaque-induced neurotoxicity and thus may be a potential candidate to regulate the progression of AD. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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27 pages, 1540 KiB  
Review
Connexins and Pannexins: Important Players in Tumorigenesis, Metastasis and Potential Therapeutics
by Sheila V. Graham, Jean X. Jiang and Marc Mesnil
Int. J. Mol. Sci. 2018, 19(6), 1645; https://doi.org/10.3390/ijms19061645 - 1 Jun 2018
Cited by 43 | Viewed by 7647
Abstract
Since their characterization more than five decades ago, gap junctions and their structural proteins—the connexins—have been associated with cancer cell growth. During that period, the accumulation of data and molecular knowledge about this association revealed an apparent contradictory relationship between them and cancer. [...] Read more.
Since their characterization more than five decades ago, gap junctions and their structural proteins—the connexins—have been associated with cancer cell growth. During that period, the accumulation of data and molecular knowledge about this association revealed an apparent contradictory relationship between them and cancer. It appeared that if gap junctions or connexins can down regulate cancer cell growth they can be also implied in the migration, invasion and metastatic dissemination of cancer cells. Interestingly, in all these situations, connexins seem to be involved through various mechanisms in which they can act either as gap-junctional intercellular communication mediators, modulators of signalling pathways through their interactome, or as hemichannels, which mediate autocrine/paracrine communication. This complex involvement of connexins in cancer progression is even more complicated by the fact that their hemichannel function may overlap with other gap junction-related proteins, the pannexins. Despite this complexity, the possible involvements of connexins and pannexins in cancer progression and the elucidation of the mechanisms they control may lead to use them as new targets to control cancer progression. In this review, the involvements of connexins and pannexins in these different topics (cancer cell growth, invasion/metastasis process, possible cancer therapeutic targets) are discussed. Full article
(This article belongs to the Special Issue Interplay of Connexins and Pannexins in Tissue Function and Disease)
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15 pages, 4577 KiB  
Article
LAT1-Targeting Thermoresponsive Fluorescent Polymer Probes for Cancer Cell Imaging
by Minami Matsuura, Mariko Ohshima, Yuki Hiruta, Tomohiro Nishimura, Kenichi Nagase and Hideko Kanazawa
Int. J. Mol. Sci. 2018, 19(6), 1646; https://doi.org/10.3390/ijms19061646 - 1 Jun 2018
Cited by 41 | Viewed by 6882
Abstract
L-type amino acid transporter 1 (LAT1) is more highly expressed in cancer cells compared with normal cells. LAT1 targeting probes would therefore be a promising tool for cancer cell imaging. In this study, LAT1-targeting thermoresponsive fluorescent polymer probes based on poly(N-isopropylacrylamide- [...] Read more.
L-type amino acid transporter 1 (LAT1) is more highly expressed in cancer cells compared with normal cells. LAT1 targeting probes would therefore be a promising tool for cancer cell imaging. In this study, LAT1-targeting thermoresponsive fluorescent polymer probes based on poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (P(NIPAAm-co-DMAAm)) were synthesized and their affinity for LAT1 was evaluated. The synthesized polymer probes interacted with LAT1 on HeLa cells, and inhibition of l-[3H]-leucine, one of the substrates for LAT1 uptake, was investigated. l-Tyrosine-conjugated P(NIPAAm-co-DMAAm) inhibited the uptake of l-[3H]-leucine, while P(NIPAAm-co-DMAAm) and l-phenylalanine-conjugated P(NIPAAm-co-DMAAm) did not. This result indicated that l-tyrosine-conjugated polymer has a high affinity for LAT1. The fluorescent polymer probes were prepared by modification of a terminal polymer group with fluorescein-5-maleimide (FL). Above the polymer transition temperature, cellular uptake of the polymer probes was observed because the polymers became hydrophobic, which enhanced the interaction with the cell membrane. Furthermore, quantitative analysis of the fluorescent probe using flow cytometry indicated that l-tyrosine-conjugated P(NIPAAm-co-DMAAm)-FL shows higher fluorescence intensity earlier than P(NIPAAm-co-DMAAm)-FL. The result suggested that cellular uptake was promoted by the LAT1 affinity site. The developed LAT1-targeting thermoresponsive fluorescent polymer probes are expected to be useful for cancer cell imaging. Full article
(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)
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44 pages, 3779 KiB  
Review
Current Knowledge on Endocrine Disrupting Chemicals (EDCs) from Animal Biology to Humans, from Pregnancy to Adulthood: Highlights from a National Italian Meeting
by Maria Elisabeth Street, Sabrina Angelini, Sergio Bernasconi, Ernesto Burgio, Alessandra Cassio, Cecilia Catellani, Francesca Cirillo, Annalisa Deodati, Enrica Fabbrizi, Vassilios Fanos, Giancarlo Gargano, Enzo Grossi, Lorenzo Iughetti, Pietro Lazzeroni, Alberto Mantovani, Lucia Migliore, Paola Palanza, Giancarlo Panzica, Anna Maria Papini, Stefano Parmigiani, Barbara Predieri, Chiara Sartori, Gabriele Tridenti and Sergio Amarriadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2018, 19(6), 1647; https://doi.org/10.3390/ijms19061647 - 2 Jun 2018
Cited by 205 | Viewed by 24799
Abstract
Wildlife has often presented and suggested the effects of endocrine disrupting chemicals (EDCs). Animal studies have given us an important opportunity to understand the mechanisms of action of many chemicals on the endocrine system and on neurodevelopment and behaviour, and to evaluate the [...] Read more.
Wildlife has often presented and suggested the effects of endocrine disrupting chemicals (EDCs). Animal studies have given us an important opportunity to understand the mechanisms of action of many chemicals on the endocrine system and on neurodevelopment and behaviour, and to evaluate the effects of doses, time and duration of exposure. Although results are sometimes conflicting because of confounding factors, epidemiological studies in humans suggest effects of EDCs on prenatal growth, thyroid function, glucose metabolism and obesity, puberty, fertility, and on carcinogenesis mainly through epigenetic mechanisms. This manuscript reviews the reports of a multidisciplinary national meeting on this topic. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals)
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18 pages, 1270 KiB  
Review
Signal Transduction in Plant–Nematode Interactions
by Muhammad Amjad Ali, Muhammad Shahzad Anjam, Muhammad Amjad Nawaz, Hon-Ming Lam and Gyuhwa Chung
Int. J. Mol. Sci. 2018, 19(6), 1648; https://doi.org/10.3390/ijms19061648 - 2 Jun 2018
Cited by 56 | Viewed by 13290
Abstract
To successfully invade and infect their host plants, plant parasitic nematodes (PPNs) need to evolve molecular mechanisms to overcome the defense responses from the plants. Nematode-associated molecular patterns (NAMPs), including ascarosides and certain proteins, while instrumental in enabling the infection, can be perceived [...] Read more.
To successfully invade and infect their host plants, plant parasitic nematodes (PPNs) need to evolve molecular mechanisms to overcome the defense responses from the plants. Nematode-associated molecular patterns (NAMPs), including ascarosides and certain proteins, while instrumental in enabling the infection, can be perceived by the host plants, which then initiate a signaling cascade leading to the induction of basal defense responses. To combat host resistance, some nematodes can inject effectors into the cells of susceptible hosts to reprogram the basal resistance signaling and also modulate the hosts’ gene expression patterns to facilitate the establishment of nematode feeding sites (NFSs). In this review, we summarized all the known signaling pathways involved in plant–nematode interactions. Specifically, we placed particular focus on the effector proteins from PPNs that mimic the signaling of the defense responses in host plants. Furthermore, we gave an updated overview of the regulation by PPNs of different host defense pathways such as salicylic acid (SA)/jasmonic acid (JA), auxin, and cytokinin and reactive oxygen species (ROS) signaling to facilitate their parasitic successes in plants. This review will enhance the understanding of the molecular signaling pathways involved in both compatible and incompatible plant–nematode interactions. Full article
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12 pages, 2982 KiB  
Article
Effects of Cyclic Mechanical Stretch on the Proliferation of L6 Myoblasts and Its Mechanisms: PI3K/Akt and MAPK Signal Pathways Regulated by IGF-1 Receptor
by Shaoting Fu, Lijun Yin, Xiaojing Lin, Jianqiang Lu and Xiaohui Wang
Int. J. Mol. Sci. 2018, 19(6), 1649; https://doi.org/10.3390/ijms19061649 - 2 Jun 2018
Cited by 42 | Viewed by 5544
Abstract
Myoblast proliferation is crucial to skeletal muscle hypertrophy and regeneration. Our previous study indicated that mechanical stretch altered the proliferation of C2C12 myoblasts, associated with insulin growth factor 1 (IGF-1)-mediated phosphoinositide 3-kinase (PI3K)/Akt (also known as protein kinase B) and mitogen-activated protein kinase [...] Read more.
Myoblast proliferation is crucial to skeletal muscle hypertrophy and regeneration. Our previous study indicated that mechanical stretch altered the proliferation of C2C12 myoblasts, associated with insulin growth factor 1 (IGF-1)-mediated phosphoinositide 3-kinase (PI3K)/Akt (also known as protein kinase B) and mitogen-activated protein kinase (MAPK) pathways through IGF-1 receptor (IGF-1R). The purpose of this study was to explore the same stretches on the proliferation of L6 myoblasts and its association with IGF-1-regulated PI3K/Akt and MAPK activations. L6 myoblasts were divided into three groups: control, 15% stretch, and 20% stretch. Stretches were achieved using FlexCell Strain Unit. Cell proliferation and IGF-1 concentration were detected by CCK8 and ELISA, respectively. IGF-1R expression, and expressions and activities of PI3K, Akt, and MAPKs (including extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38) were determined by Western blot. We found that 15% stretch promoted, while 20% stretch inhibited L6 myoblast proliferation. A 15% stretch increased IGF-1R level, although had no effect on IGF-1 secretion of L6 myoblasts, and PI3K/Akt and ERK1/2 (not p38) inhibitors attenuated 15% stretch-induced pro-proliferation. Exogenous IGF-1 reversed 20% stretch-induced anti-proliferation, accompanied with increases in IGF-1R level as well as PI3K/Akt and MAPK (ERK1/2 and p38) activations. In conclusion, stretch regulated L6 myoblasts proliferation, which may be mediated by the changes in PI3K/Akt and MAPK activations regulated by IGF-1R, despite no detectable IGF-1 from stretched L6 myoblasts. Full article
(This article belongs to the Special Issue Signaling Promiscuity of PI3K)
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17 pages, 5474 KiB  
Article
Differential Effects of Statins on Inflammatory Interleukin-8 and Antimicrobial Peptide Human Β-Defensin 2 Responses in Salmonella-Infected Intestinal Epithelial Cells
by Fu-Chen Huang and Shun-Chen Huang
Int. J. Mol. Sci. 2018, 19(6), 1650; https://doi.org/10.3390/ijms19061650 - 2 Jun 2018
Cited by 17 | Viewed by 3867
Abstract
Alternative therapies are needed to reduce the use of antibiotics and incidence of drug-resistant Salmonellosis. Previous studies have revealed important roles of statins in regulating innate immunity. Therefore, we investigated the effects of statins on innate immunity in Salmonella-infected intestinal epithelial [...] Read more.
Alternative therapies are needed to reduce the use of antibiotics and incidence of drug-resistant Salmonellosis. Previous studies have revealed important roles of statins in regulating innate immunity. Therefore, we investigated the effects of statins on innate immunity in Salmonella-infected intestinal epithelial cells (IECs), which are involved in mucosal innate immunity. SW480 cells and Akt siRNA- or vitamin D receptor (VDR) siRNA-transfected SW480 cells were infected by wild-type S. Typhimurium strain SL1344 in the presence or absence of statins. The mRNA or protein expression was analyzed by real-time quantitative PCR or western blot analysis, respectively. Simvastatin or fluvastatin caused IL-8 (interleukin-8) suppression, but increased hBD-2 mRNA expression in Salmonella-infected SW480 cells. Both statins enhanced phosphorylated Akt and VDR expressions. Akt or VDR knockdown by siRNA counteracted the suppressive effect of simvastatin on IL-8 expression, whereas VDR knockdown diminished the enhanced hBD-2 expression in Salmonella-infected SW480 cells. Therefore, we observed differential regulation of statins on inflammatory IL-8 and anti-microbial hBD-2 expressions in Salmonella-infected IECs via PI3K/Akt signaling and VDR protein expression, respectively. The enhanced activity of antimicrobial peptides by statins in Salmonella-infected IECs could protect the host against infection, and modulation of pro-inflammatory responses could prevent the detrimental effects of overwhelming inflammation in the host. Full article
(This article belongs to the Section Biochemistry)
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13 pages, 2964 KiB  
Article
Impaired Photic Entrainment of Spontaneous Locomotor Activity in Mice Overexpressing Human Mutant α-Synuclein
by Martina Pfeffer, Zuzana Zimmermann, Suzana Gispert, Georg Auburger, Horst-Werner Korf and Charlotte Von Gall
Int. J. Mol. Sci. 2018, 19(6), 1651; https://doi.org/10.3390/ijms19061651 - 3 Jun 2018
Cited by 18 | Viewed by 5329
Abstract
Parkinson’s disease (PD) is characterized by distinct motor and non-motor symptoms. Sleep disorders are the most frequent and challenging non-motor symptoms in PD patients, and there is growing evidence that they are a consequence of disruptions within the circadian system. PD is characterized [...] Read more.
Parkinson’s disease (PD) is characterized by distinct motor and non-motor symptoms. Sleep disorders are the most frequent and challenging non-motor symptoms in PD patients, and there is growing evidence that they are a consequence of disruptions within the circadian system. PD is characterized by a progressive degeneration of the dorsal vagal nucleus and midbrain dopaminergic neurons together with an imbalance of many other neurotransmitters. Mutations in α-synuclein (SNCA), a protein modulating SNARE complex-dependent neurotransmission, trigger dominantly inherited PD variants and sporadic cases of PD. The A53T SNCA missense mutation is associated with an autosomal dominant early-onset familial PD. To test whether this missense mutation affects the circadian system, we analyzed the spontaneous locomotor behavior of non-transgenic wildtype mice and transgenic mice overexpressing mutant human A53T α-synuclein (A53T). The mice were subjected to entrained- and free-running conditions as well as to experimental jet lag. Furthermore, the vesicular glutamate transporter 2 (VGLUT2) in the suprachiasmatic nucleus (SCN) was analyzed by immunohistochemistry. Free-running circadian rhythm and, thus, circadian rhythm generation, were not affected in A53T mice. A53T mice entrained to the light–dark cycle, however, with an advanced phase angle of 2.65 ± 0.5 h before lights off. Moreover, re-entrainment after experimental jet lag was impaired in A53T mice. Finally, VGLUT2 immunoreaction was reduced in the SCN of A53T mice. These data suggest an impaired light entrainment of the circadian system in A53T mice. Full article
(This article belongs to the Special Issue Circadian Rhythms: Molecular and Physiological Mechanisms)
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24 pages, 3856 KiB  
Article
Mechanism of Salt-Induced Self-Compatibility Dissected by Comparative Proteomic Analysis in Brassica napus L.
by Yong Yang, Zhiquan Liu, Tong Zhang, Guilong Zhou, Zhiqiang Duan, Bing Li, Shengwei Dou, Xiaomei Liang, Jinxing Tu, Jinxiong Shen, Bin Yi, Tingdong Fu, Cheng Dai and Chaozhi Ma
Int. J. Mol. Sci. 2018, 19(6), 1652; https://doi.org/10.3390/ijms19061652 - 3 Jun 2018
Cited by 18 | Viewed by 6401
Abstract
Self-incompatibility (SI) in plants genetically prevents self-fertilization to promote outcrossing and genetic diversity. Its hybrids in Brassica have been widely cultivated due to the propagation of SI lines by spraying a salt solution. We demonstrated that suppression of Brassica napus SI from edible [...] Read more.
Self-incompatibility (SI) in plants genetically prevents self-fertilization to promote outcrossing and genetic diversity. Its hybrids in Brassica have been widely cultivated due to the propagation of SI lines by spraying a salt solution. We demonstrated that suppression of Brassica napus SI from edible salt solution treatment was ascribed to sodium chloride and independent of S haplotypes, but it did not obviously change the expression of SI-related genes. Using the isobaric tags for relative and absolute quantitation (iTRAQ) technique, we identified 885 differentially accumulated proteins (DAPs) in Brassica napus stigmas of un-pollinated (UP), pollinated with compatible pollen (PC), pollinated with incompatible pollen (PI), and pollinated with incompatible pollen after edible salt solution treatment (NA). Of the 307 DAPs in NA/UP, 134 were unique and 94 were shared only with PC/UP. In PC and NA, some salt stress protein species, such as glyoxalase I, were induced, and these protein species were likely to participate in the self-compatibility (SC) pathway. Most of the identified protein species were related to metabolic pathways, biosynthesis of secondary metabolites, ribosome, and so on. A systematic analysis implied that salt treatment-overcoming SI in B. napus was likely conferred by at least five different physiological mechanisms: (i) the use of Ca2+ as signal molecule; (ii) loosening of the cell wall to allow pollen tube penetration; (iii) synthesis of compatibility factor protein species for pollen tube growth; (iv) depolymerization of microtubule networks to facilitate pollen tube movement; and (v) inhibition of protein degradation pathways to restrain the SI response. Full article
(This article belongs to the Special Issue Advances in Proteomic Research)
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13 pages, 2679 KiB  
Article
Treadmill Running Ameliorates Destruction of Articular Cartilage and Subchondral Bone, Not Only Synovitis, in a Rheumatoid Arthritis Rat Model
by Seiji Shimomura, Hiroaki Inoue, Yuji Arai, Shuji Nakagawa, Yuta Fujii, Tsunao Kishida, Shohei Ichimaru, Shinji Tsuchida, Toshiharu Shirai, Kazuya Ikoma, Osam Mazda and Toshikazu Kubo
Int. J. Mol. Sci. 2018, 19(6), 1653; https://doi.org/10.3390/ijms19061653 - 3 Jun 2018
Cited by 26 | Viewed by 6115
Abstract
We analyzed the influence of treadmill running on rheumatoid arthritis (RA) joints using a collagen-induced arthritis (CIA) rat model. Eight-week-old male Dark Agouti rats were randomly divided into four groups: The control group, treadmill group (30 min/day for 4 weeks from 10-weeks-old), CIA [...] Read more.
We analyzed the influence of treadmill running on rheumatoid arthritis (RA) joints using a collagen-induced arthritis (CIA) rat model. Eight-week-old male Dark Agouti rats were randomly divided into four groups: The control group, treadmill group (30 min/day for 4 weeks from 10-weeks-old), CIA group (induced CIA at 8-weeks-old), and CIA + treadmill group. Destruction of the ankle joint was evaluated by histological analyses. Morphological changes of subchondral bone were analyzed by μ-CT. CIA treatment-induced synovial membrane invasion, articular cartilage destruction, and bone erosion. Treadmill running improved these changes. The synovial membrane in CIA rats produced a large amount of tumor necrosis factor-α and Connexin 43; production was significantly suppressed by treadmill running. On μ-CT of the talus, bone volume fraction (BV/TV) was significantly decreased in the CIA group. Marrow star volume (MSV), an index of bone loss, was significantly increased. These changes were significantly improved by treadmill running. Bone destruction in the talus was significantly increased with CIA and was suppressed by treadmill running. On tartrate-resistant acid phosphate and alkaline phosphatase (TRAP/ALP) staining, the number of osteoclasts around the pannus was decreased by treadmill running. These findings indicate that treadmill running in CIA rats inhibited synovial hyperplasia and joint destruction. Full article
(This article belongs to the Section Biochemistry)
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12 pages, 1435 KiB  
Article
Upregulation of FLG, LOR, and IVL Expression by Rhodiola crenulata Root Extract via Aryl Hydrocarbon Receptor: Differential Involvement of OVOL1
by Akiko Hashimoto-Hachiya, Gaku Tsuji, Mika Murai, Xianghong Yan and Masutaka Furue
Int. J. Mol. Sci. 2018, 19(6), 1654; https://doi.org/10.3390/ijms19061654 - 4 Jun 2018
Cited by 51 | Viewed by 6698
Abstract
Rhodiola species are antioxidative, salubrious plants that are known to inhibit oxidative stress induced by ultraviolet and γ-radiation in epidermal keratinocytes. As certain phytochemicals activate aryl hydrocarbon receptors (AHR) or OVO-like 1 (OVOL1) to upregulate the expression of epidermal barrier proteins such as [...] Read more.
Rhodiola species are antioxidative, salubrious plants that are known to inhibit oxidative stress induced by ultraviolet and γ-radiation in epidermal keratinocytes. As certain phytochemicals activate aryl hydrocarbon receptors (AHR) or OVO-like 1 (OVOL1) to upregulate the expression of epidermal barrier proteins such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL), we investigated such regulation by Rhodiola crenulata root extract (RCE). We demonstrated that RCE induced FLG and LOR upregulation in an AHR-OVOL1-dependent fashion. However, RCE-mediated IVL upregulation was AHR-dependent but OVOL1-independent. Coordinated upregulation of skin barrier proteins by RCE via AHR may be beneficial in the management of barrier-disrupted inflammatory skin diseases such as atopic dermatitis. Full article
(This article belongs to the Special Issue Novel Aspects of Toxicity Mechanisms of Dioxins and Related Compounds)
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3 pages, 154 KiB  
Editorial
Biological Basis of Tumor Angiogenesis and Therapeutic Intervention: Past, Present, and Future
by Girolamo Ranieri
Int. J. Mol. Sci. 2018, 19(6), 1655; https://doi.org/10.3390/ijms19061655 - 4 Jun 2018
Cited by 5 | Viewed by 2855
14 pages, 598 KiB  
Review
A New Perspective: Mitochondrial Stat3 as a Regulator for Lymphocyte Function
by Mercedes Rincon and Felipe Valença Pereira
Int. J. Mol. Sci. 2018, 19(6), 1656; https://doi.org/10.3390/ijms19061656 - 4 Jun 2018
Cited by 43 | Viewed by 10003
Abstract
Stat3 as a transcription factor regulating gene expression in lymphocytes during the immune response is well known. However, since the pioneering studies discovering the presence of Stat3 in mitochondria and its role in regulating mitochondrial metabolism, only a few studies have investigated this [...] Read more.
Stat3 as a transcription factor regulating gene expression in lymphocytes during the immune response is well known. However, since the pioneering studies discovering the presence of Stat3 in mitochondria and its role in regulating mitochondrial metabolism, only a few studies have investigated this non-conventional function of Stat3 in lymphocytes. From this perspective, we review what is known about Stat3 as a transcription factor and what is known and unknown about mitochondrial Stat3 (mitoStat3) in lymphocytes. We also provide a framework to consider how some of the functions previously assigned to Stat3 as regulator of gene transcription could be mediated by mitoStat3 in lymphocytes. The goal of this review is to stimulate interest for future studies investigating mitoStat3 in the immune response that could lead to the generation of alternative pharmacological inhibitors of mitoStat3 for the treatment of chronic inflammatory diseases. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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14 pages, 2478 KiB  
Review
Some Biological Consequences of the Inhibition of Na,K-ATPase by Translationally Controlled Tumor Protein (TCTP)
by Jiwon Jung, Seonhyung Ryu, In A Ki, Hyun Ae Woo and Kyunglim Lee
Int. J. Mol. Sci. 2018, 19(6), 1657; https://doi.org/10.3390/ijms19061657 - 4 Jun 2018
Cited by 16 | Viewed by 6021
Abstract
Na,K-ATPase is an ionic pump that regulates the osmotic equilibrium and membrane potential of cells and also functions as a signal transducer. The interaction of Na,K-ATPase with translationally controlled tumor protein (TCTP) results, among others, in the inhibition of the former’s pump activity [...] Read more.
Na,K-ATPase is an ionic pump that regulates the osmotic equilibrium and membrane potential of cells and also functions as a signal transducer. The interaction of Na,K-ATPase with translationally controlled tumor protein (TCTP) results, among others, in the inhibition of the former’s pump activity and in the initiation of manifold biological and pathological phenomena. These phenomena include hypertension and cataract development in TCTP-overexpressing transgenic mice, as well as the induction of tumorigenesis signaling pathways and the activation of Src that ultimately leads to cell proliferation and migration. This review attempts to collate the biological effects of Na,K-ATPase and TCTP interaction and suggests that this interaction has the potential to serve as a possible therapeutic target for selected diseases. Full article
(This article belongs to the Section Biochemistry)
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19 pages, 479 KiB  
Review
The Pattern of Signatures in Gastric Cancer Prognosis
by Julita Machlowska, Ryszard Maciejewski and Robert Sitarz
Int. J. Mol. Sci. 2018, 19(6), 1658; https://doi.org/10.3390/ijms19061658 - 4 Jun 2018
Cited by 66 | Viewed by 7105
Abstract
Gastric cancer is one of the most common malignancies worldwide and it is a fourth leading cause of cancer-related death. Carcinogenesis is a multistage disease process specified by the gradual procurement of mutations and epigenetic alterations in the expression of different genes, which [...] Read more.
Gastric cancer is one of the most common malignancies worldwide and it is a fourth leading cause of cancer-related death. Carcinogenesis is a multistage disease process specified by the gradual procurement of mutations and epigenetic alterations in the expression of different genes, which finally lead to the occurrence of a malignancy. These genes have diversified roles regarding cancer development. Intracellular pathways are assigned to the expression of different genes, signal transduction, cell-cycle supervision, genomic stability, DNA repair, and cell-fate destination, like apoptosis, senescence. Extracellular pathways embrace tumour invasion, metastasis, angiogenesis. Altered expression patterns, leading the different clinical responses. This review highlights the list of molecular biomarkers that can be used for prognostic purposes and provide information on the likely outcome of the cancer disease in an untreated individual. Full article
(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)
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19 pages, 1997 KiB  
Article
Cx43 Channel Gating and Permeation: Multiple Phosphorylation-Dependent Roles of the Carboxyl Terminus
by José F. Ek-Vitorín, Tasha K. Pontifex and Janis M. Burt
Int. J. Mol. Sci. 2018, 19(6), 1659; https://doi.org/10.3390/ijms19061659 - 4 Jun 2018
Cited by 30 | Viewed by 4425
Abstract
Connexin 43 (Cx43), a gap junction protein seemingly fit to support cardiac impulse propagation and synchronic contraction, is phosphorylated in normoxia by casein kinase 1 (CK1). However, during cardiac ischemia or pressure overload hypertrophy, this phosphorylation fades, Cx43 abundance decreases at intercalated disks [...] Read more.
Connexin 43 (Cx43), a gap junction protein seemingly fit to support cardiac impulse propagation and synchronic contraction, is phosphorylated in normoxia by casein kinase 1 (CK1). However, during cardiac ischemia or pressure overload hypertrophy, this phosphorylation fades, Cx43 abundance decreases at intercalated disks and increases at myocytes’ lateral borders, and the risk of arrhythmia rises. Studies in wild-type and transgenic mice indicate that enhanced CK1-phosphorylation of Cx43 protects from arrhythmia, while dephosphorylation precedes arrhythmia vulnerability. The mechanistic bases of these Cx43 (de)phosphoform-linked cardiac phenotypes are unknown. We used patch-clamp and dye injection techniques to study the channel function (gating, permeability) of Cx43 mutants wherein CK1-targeted serines were replaced by aspartate (Cx43-CK1-D) or alanine (Cx43-CK1-A) to emulate phosphorylation and dephosphorylation, respectively. Cx43-CK1-D, but not Cx43-CK1-A, displayed high Voltage-sensitivity and variable permselectivity. Both mutants showed multiple channel open states with overall increased conductivity, resistance to acidification-induced junctional uncoupling, and hemichannel openings in normal external calcium. Modest differences in the mutant channels’ function and regulation imply the involvement of dissimilar structural conformations of the interacting domains of Cx43 in electrical and chemical gating that may contribute to the divergent phenotypes of CK1-(de)phospho-mimicking Cx43 transgenic mice and that may bear significance in arrhythmogenesis. Full article
(This article belongs to the Special Issue Interplay of Connexins and Pannexins in Tissue Function and Disease)
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12 pages, 2585 KiB  
Article
Interaction of Nevirapine with the Peptide Binding Groove of HLA-DRB1*01:01 and Its Effect on the Conformation of HLA-Peptide Complex
by Makoto Hirasawa, Katsunobu Hagihara, Koji Abe, Osamu Ando and Noriaki Hirayama
Int. J. Mol. Sci. 2018, 19(6), 1660; https://doi.org/10.3390/ijms19061660 - 4 Jun 2018
Cited by 7 | Viewed by 4738
Abstract
Human leukocyte antigen (HLA)-DRB1*01:01 has been shown to be involved in nevirapine-induced hepatic hypersensitivity reactions. In the present study, in silico docking simulations and molecular dynamics simulations were performed to predict the interaction mode of nevirapine with the peptide binding groove of HLA-DRB1*01:01 [...] Read more.
Human leukocyte antigen (HLA)-DRB1*01:01 has been shown to be involved in nevirapine-induced hepatic hypersensitivity reactions. In the present study, in silico docking simulations and molecular dynamics simulations were performed to predict the interaction mode of nevirapine with the peptide binding groove of HLA-DRB1*01:01 and its possible effect on the position and orientation of the ligand peptide derived from hemagglutinin (HA). In silico analyses suggested that nevirapine interacts with HLA-DRB1*01:01 around the P4 pocket within the peptide binding groove and the HA peptide stably binds on top of nevirapine at the groove. The analyses also showed that binding of nevirapine at the groove will significantly change the inter-helical distances of the groove. An in vitro competitive assay showed that nevirapine (1000 μM) increases the binding of the HA peptide to HLA-DRB1*01:01 in an allele-specific manner. These results indicate that nevirapine might interact directly with the P4 pocket and modifies its structure, which could change the orientation of loaded peptides and the conformation of HLA-DRB1*01:01; these changes could be distinctively recognized by T-cell receptors. Through this molecular mechanism, nevirapine might stimulate the immune system, resulting in hepatic hypersensitivity reactions. Full article
(This article belongs to the Special Issue Hepatotoxicity: Molecular Mechanisms and Pathophysiology)
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15 pages, 2773 KiB  
Article
TRAIL/NF-κB/CX3CL1 Mediated Onco-Immuno Crosstalk Leading to TRAIL Resistance of Pancreatic Cancer Cell Lines
by Claudia Geismann, Wiebke Erhart, Frauke Grohmann, Stefan Schreiber, Günter Schneider, Heiner Schäfer and Alexander Arlt
Int. J. Mol. Sci. 2018, 19(6), 1661; https://doi.org/10.3390/ijms19061661 - 4 Jun 2018
Cited by 26 | Viewed by 5336
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant neoplasms and registers rising death rates in western countries. Due to its late detection in advanced stages, its extremely aggressive nature and the minimal effectiveness of currently available therapies, PDAC is a [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant neoplasms and registers rising death rates in western countries. Due to its late detection in advanced stages, its extremely aggressive nature and the minimal effectiveness of currently available therapies, PDAC is a challenging problem in the clinical field. One characteristic of PDAC is a distinct desmoplasia consisting of fibroblasts, endothelial and immune cells as well as non-cellular components, contributing to therapy resistance. It is well established that the NF-κB signaling pathway controls inflammation, cancer progression and apoptosis resistance in PDAC. This study attempts to identify NF-κB target genes mediating therapy resistance of humane PDAC cell lines towards death ligand induced apoptosis. By using a genome wide unbiased approach the chemokine CX3CL1 was established as a central NF-κB target gene mediating therapy resistance. While no direct impact of CX3CL1 expression on cancer cell apoptosis was identified in co-culture assays it became apparent that CX3CL1 is acting in a paracrine fashion, leading to an increased recruitment of inflammatory cells. These inflammatory cells in turn mediate apoptosis resistance of PDAC cells. Therefore, our data dissect a bifunctional cross-signaling pathway in PDAC between tumor and immune cells giving rise to therapy resistance. Full article
(This article belongs to the Special Issue NF-κB and Cancer)
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27 pages, 942 KiB  
Review
Regulation and Evolution of NLR Genes: A Close Interconnection for Plant Immunity
by Grazia M. Borrelli, Elisabetta Mazzucotelli, Daniela Marone, Cristina Crosatti, Vania Michelotti, Giampiero Valè and Anna M. Mastrangelo
Int. J. Mol. Sci. 2018, 19(6), 1662; https://doi.org/10.3390/ijms19061662 - 5 Jun 2018
Cited by 66 | Viewed by 9666
Abstract
NLR (NOD-like receptor) genes belong to one of the largest gene families in plants. Their role in plants’ resistance to pathogens has been clearly described for many members of this gene family, and dysregulation or overexpression of some of these genes has been [...] Read more.
NLR (NOD-like receptor) genes belong to one of the largest gene families in plants. Their role in plants’ resistance to pathogens has been clearly described for many members of this gene family, and dysregulation or overexpression of some of these genes has been shown to induce an autoimmunity state that strongly affects plant growth and yield. For this reason, these genes have to be tightly regulated in their expression and activity, and several regulatory mechanisms are described here that tune their gene expression and protein levels. This gene family is subjected to rapid evolution, and to maintain diversity at NLRs, a plethora of genetic mechanisms have been identified as sources of variation. Interestingly, regulation of gene expression and evolution of this gene family are two strictly interconnected aspects. Indeed, some examples have been reported in which mechanisms of gene expression regulation have roles in promotion of the evolution of this gene family. Moreover, co-evolution of the NLR gene family and other gene families devoted to their control has been recently demonstrated, as in the case of miRNAs. Full article
(This article belongs to the Special Issue Plant Defense Genes Against Biotic Stresses)
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23 pages, 761 KiB  
Review
Connexins and Pannexins in Vascular Function and Disease
by Filippo Molica, Xavier F. Figueroa, Brenda R. Kwak, Brant E. Isakson and Jonathan M. Gibbins
Int. J. Mol. Sci. 2018, 19(6), 1663; https://doi.org/10.3390/ijms19061663 - 5 Jun 2018
Cited by 43 | Viewed by 5460
Abstract
Connexins (Cxs) and pannexins (Panxs) are ubiquitous membrane channel forming proteins that are critically involved in many aspects of vascular physiology and pathology. The permeation of ions and small metabolites through Panx channels, Cx hemichannels and gap junction channels confers a crucial role [...] Read more.
Connexins (Cxs) and pannexins (Panxs) are ubiquitous membrane channel forming proteins that are critically involved in many aspects of vascular physiology and pathology. The permeation of ions and small metabolites through Panx channels, Cx hemichannels and gap junction channels confers a crucial role to these proteins in intercellular communication and in maintaining tissue homeostasis. This review provides an overview of current knowledge with respect to the pathophysiological role of these channels in large arteries, the microcirculation, veins, the lymphatic system and platelet function. The essential nature of these membrane proteins in vascular homeostasis is further emphasized by the pathologies that are linked to mutations and polymorphisms in Cx and Panx genes. Full article
(This article belongs to the Special Issue Interplay of Connexins and Pannexins in Tissue Function and Disease)
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19 pages, 7981 KiB  
Article
Luteoloside Inhibits Proliferation and Promotes Intrinsic and Extrinsic Pathway-Mediated Apoptosis Involving MAPK and mTOR Signaling Pathways in Human Cervical Cancer Cells
by Junli Shao, Chaoxi Wang, Linqiu Li, Hairong Liang, Juanxiu Dai, Xiaoxuan Ling and Huanwen Tang
Int. J. Mol. Sci. 2018, 19(6), 1664; https://doi.org/10.3390/ijms19061664 - 5 Jun 2018
Cited by 45 | Viewed by 5801
Abstract
Cervical cancer is a common gynecological malignancy with high incidence and mortality. Drugs commonly used in chemotherapy are often accompanied by strong side-effects. To find an anti-cervical cancer drug with high effects and low toxicity, luteoloside was used to treat the cervical cancer [...] Read more.
Cervical cancer is a common gynecological malignancy with high incidence and mortality. Drugs commonly used in chemotherapy are often accompanied by strong side-effects. To find an anti-cervical cancer drug with high effects and low toxicity, luteoloside was used to treat the cervical cancer cell line Hela to investigate its effects on cell morphology, proliferation, apoptosis, and related proteins. The study demonstrated that luteoloside could inhibit proliferation remarkably; promote apoptosis and cytochrome C release; decrease the mitochondrial membrane potential and reactive oxygen species level; upregulate the expression of Fas, Bax, p53, phospho-p38, phospho-JNK, and cleaved PARP; downregulate the expression of Bcl-2 and phospho-mTOR; activate caspase-3 and caspase-8; change the nuclear morphology, and fragmentate DNA in Hela cells. These results strongly suggest that luteoloside can significantly inhibit the proliferation and trigger apoptosis in Hela cells. In contrast, luteoloside had less proliferation inhibiting effects on the normal cell lines HUVEC12 and LO2, and minor apoptosis promoting effects on HUVEC12 cells. Furthermore, the luteoloside-induced apoptosis in Hela cells is mediated by both intrinsic and extrinsic pathways and the effects of luteoloside may be regulated by the mitogen-activated protein kinases and mTOR signaling pathways via p53. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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19 pages, 2594 KiB  
Article
Interleukin-34 Regulates Th1 and Th17 Cytokine Production by Activating Multiple Signaling Pathways through CSF-1R in Chicken Cell Lines
by Anh Duc Truong, Yeojin Hong, Janggeun Lee, Kyungbaek Lee, Dong Yong Kil, Hyun S. Lillehoj and Yeong Ho Hong
Int. J. Mol. Sci. 2018, 19(6), 1665; https://doi.org/10.3390/ijms19061665 - 5 Jun 2018
Cited by 18 | Viewed by 6425
Abstract
Interleukin-34 (IL-34) is a newly recognized cytokine with functions similar to macrophage colony-stimulating factor 1. It is expressed in macrophages and fibroblasts, where it induces cytokine production; however, the mechanism of chicken IL-34 (chIL-34) signaling has not been identified to date. The aim [...] Read more.
Interleukin-34 (IL-34) is a newly recognized cytokine with functions similar to macrophage colony-stimulating factor 1. It is expressed in macrophages and fibroblasts, where it induces cytokine production; however, the mechanism of chicken IL-34 (chIL-34) signaling has not been identified to date. The aim of this study was to analyze the signal transduction pathways and specific biological functions associated with chIL-34 in chicken macrophage (HD11) and fibroblast (OU2) cell lines. We found that IL-34 is a functional ligand for the colony-stimulating factor receptor (CSF-1R) in chicken cell lines. Treatment with chIL-34 increased the expression of Th1 and Th17 cytokines through phosphorylation of tyrosine and serine residues in Janus kinase (JAK) 2, tyrosine kinase 2 (TYK2), signal transducer and activator of transcription (STAT) 1, STAT3, and Src homology 2-containing tyrosine phosphatase 2 (SHP-2), which also led to phosphorylation of NF-κB1, p-mitogen-activated protein kinase kinase kinase 7 (TAK1), MyD88, suppressor of cytokine signaling 1 (SOCS1), and extracellular signal-regulated kinase 1 and 2 (ERK1/2). Taken together, these results suggest that chIL-34 functions by binding to CSF-1R and activating the JAK/STAT, nuclear factor κ B (NF-κB), and mitogen-activated protein kinase signaling pathways; these signaling events regulate cytokine expression and suggest roles for chIL-34 in innate and adaptive immunity. Full article
(This article belongs to the Special Issue Signaling Pathway of Immune Cells and Immune Disorder)
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19 pages, 5140 KiB  
Article
Wheat Gene TaATG8j Contributes to Stripe Rust Resistance
by Md. Abdullah-Al Mamun, Chunlei Tang, Yingchao Sun, Md. Nazrul Islam, Peng Liu, Xiaojie Wang and Zhensheng Kang
Int. J. Mol. Sci. 2018, 19(6), 1666; https://doi.org/10.3390/ijms19061666 - 5 Jun 2018
Cited by 13 | Viewed by 4354
Abstract
Autophagy-related 8 (ATG8) protein has been reported to be involved in plant’s innate immune response, but it is not clear whether such genes play a similar role in cereal crops against obligate biotrophic fungal pathogens. Here, we reported an ATG8 gene from wheat [...] Read more.
Autophagy-related 8 (ATG8) protein has been reported to be involved in plant’s innate immune response, but it is not clear whether such genes play a similar role in cereal crops against obligate biotrophic fungal pathogens. Here, we reported an ATG8 gene from wheat (Triticum aestivum), designated TaATG8j. This gene has three copies located in chromosomes 2AS, 2BS, and 2DS. The transcriptions of all three copies were upregulated in plants of the wheat cultivar Suwon 11, inoculated with an avirulent race (CYR23) of Puccinia striiformis f. sp. tritici (Pst), the causal fungal pathogen of stripe rust. The transient expression of TaATG8j in Nicotiana benthamiana showed that TaATG8j proteins were distributed throughout the cytoplasm, but mainly in the nucleus and plasma membrane. The overexpression of TaATG8j in N. benthamiana slightly delayed the cell death caused by the mouse apoptotic protein BAX (BCL2-associated X protein). However, the expression of TaATG8j in yeast (Schizosaccharomyces pombe) induced cell death. The virus-induced gene silencing of all TaATG8j copies rendered Suwon 11 susceptible to the avirulent Pst race CYR23, accompanied by an increased fungal biomass and a decreased necrotic area per infection site. These results indicate that TaATG8j contributes to wheat resistance against stripe rust fungus by regulating cell death, providing information for the understanding of the mechanisms of wheat resistance to the stripe rust pathogen. Full article
(This article belongs to the Section Molecular Plant Sciences)
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12 pages, 2159 KiB  
Article
Design of a Seed-Specific Chimeric Promoter with a Modified Expression Profile to Improve Seed Oil Content
by Toshihiro Aoyagi, Masaya Kobayashi and Akiko Kozaki
Int. J. Mol. Sci. 2018, 19(6), 1667; https://doi.org/10.3390/ijms19061667 - 5 Jun 2018
Cited by 6 | Viewed by 4253
Abstract
Increasing the yield of plant oil is an important objective to meet the demand for sustainable resources and energy. Some attempts to enhance the expression of genes involved in oil synthesis in seeds have succeeded in increasing oil content. In many cases, the [...] Read more.
Increasing the yield of plant oil is an important objective to meet the demand for sustainable resources and energy. Some attempts to enhance the expression of genes involved in oil synthesis in seeds have succeeded in increasing oil content. In many cases, the promoters of seed-storage protein genes have been used as seed-specific promoters. However, conventional promoters are developmentally regulated and their expression periods are limited. We constructed a chimeric promoter that starts to express in the early stage of seed development, and high-level expression is retained until the later stage by connecting the promoters of the biotin carboxyl carrier protein 2 (BCCP2) gene encoding the BCCP2 subunit of acetyl-CoA carboxylase and the fatty acid elongase 1 (FAE1) gene from Arabidopsis. The constructed promoter was ligated upstream of the TAG1 gene encoding diacylglycerol acyltransferase 1 and introduced into Arabidopsis. Seeds from transgenic plants carrying AtTAG1 under the control of the chimeric promoter showed increased oil content (up by 18–73%) compared with wild-type seeds. The novel expression profile of the chimeric promoter showed that this could be a promising strategy to manipulate the content of seed-storage oils and other compounds. Full article
(This article belongs to the Section Molecular Plant Sciences)
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22 pages, 1725 KiB  
Review
Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety
by Rute Moreira, David M. Pereira, Patrícia Valentão and Paula B. Andrade
Int. J. Mol. Sci. 2018, 19(6), 1668; https://doi.org/10.3390/ijms19061668 - 5 Jun 2018
Cited by 233 | Viewed by 18917
Abstract
Pyrrolizidine alkaloids (PA) are widely distributed in plants throughout the world, frequently in species relevant for human consumption. Apart from the toxicity that these molecules can cause in humans and livestock, PA are also known for their wide range of pharmacological properties, which [...] Read more.
Pyrrolizidine alkaloids (PA) are widely distributed in plants throughout the world, frequently in species relevant for human consumption. Apart from the toxicity that these molecules can cause in humans and livestock, PA are also known for their wide range of pharmacological properties, which can be exploited in drug discovery programs. In this work we review the current body of knowledge regarding the chemistry, toxicology, pharmacology and food safety of PA. Full article
(This article belongs to the Special Issue Natural and Semi-Synthetic Small Molecules in Drug Discovery)
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21 pages, 970 KiB  
Review
Pathophysiological Mechanisms of Chronic Venous Disease and Implications for Venoactive Drug Therapy
by Armando Mansilha and Joel Sousa
Int. J. Mol. Sci. 2018, 19(6), 1669; https://doi.org/10.3390/ijms19061669 - 5 Jun 2018
Cited by 170 | Viewed by 16281
Abstract
Chronic venous disease (CVD) is a common pathology, with significant physical and psychological impacts for patients and high economic costs for national healthcare systems. Throughout the last decades, several risk factors for this condition have been identified, but only recently, have the roles [...] Read more.
Chronic venous disease (CVD) is a common pathology, with significant physical and psychological impacts for patients and high economic costs for national healthcare systems. Throughout the last decades, several risk factors for this condition have been identified, but only recently, have the roles of inflammation and endothelial dysfunction been properly assessed. Although still incompletely understood, current knowledge of the pathophysiological mechanisms of CVD reveals several potential targets and strategies for therapeutic intervention, some of which are addressable by currently available venoactive drugs. The roles of these drugs in the clinical improvement of venous tone and contractility, reduction of edema and inflammation, as well as in improved microcirculation and venous ulcer healing have been studied extensively, with favorable results reported in the literature. Here, we aim to review these pathophysiological mechanisms and their implications regarding currently available venoactive drug therapies. Full article
(This article belongs to the Special Issue Molecular Research on Chronic Venous Disease)
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17 pages, 6290 KiB  
Article
Methyl 3,4-Dihydroxybenzoate Enhances Resistance to Oxidative Stressors and Lifespan in C. elegans Partially via daf-2/daf-16
by Xiang-Nan Mi, Li-Fang Wang, Yang Hu, Jun-Ping Pan, Yi-Rong Xin, Jia-Hui Wang, Hai-Ju Geng, Song-Hui Hu, Qin Gao and Huan-Min Luo
Int. J. Mol. Sci. 2018, 19(6), 1670; https://doi.org/10.3390/ijms19061670 - 5 Jun 2018
Cited by 15 | Viewed by 4610
Abstract
Genetic studies have elucidated mechanisms that regulate aging; however, there has been little progress in identifying drugs that retard ageing. Caenorhabditis elegans is among the classical model organisms in ageing research. Methyl 3,4-dihydroxybenzoate (MDHB) can prolong the life-span of C. elegans, but [...] Read more.
Genetic studies have elucidated mechanisms that regulate aging; however, there has been little progress in identifying drugs that retard ageing. Caenorhabditis elegans is among the classical model organisms in ageing research. Methyl 3,4-dihydroxybenzoate (MDHB) can prolong the life-span of C. elegans, but the underlying molecular mechanisms are not yet fully understood. Here, we report that MDHB prolongs the life-span of C. elegans and delays age-associated declines of physiological processes. Besides, MDHB can lengthen the life-span of eat-2 (ad1113) mutations, revealing that MDHB does not work via caloric restriction (CR). Surprisingly, the life-span–extending activity of MDHB is completely abolished in daf-2 (e1370) mutations, which suggests that daf-2 is crucial for a MDHB-induced pro-longevity effect in C. elegans. Moreover, MDHB enhances the nuclear localization of daf-16/FoxO, and then modulates the expressions of genes that positively correlate with defenses against stress and longevity in C. elegans. Therefore, our results indicate that MDHB at least partially acts as a modulator of the daf-2/daf-16 pathway to extend the lifespan of C. elegans, and MDHB might be a promising therapeutic agent for age-related diseases. Full article
(This article belongs to the Section Biochemistry)
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16 pages, 58979 KiB  
Review
DNA Nanotechnology for Cancer Diagnosis and Therapy
by Tianshu Chen, Lingjie Ren, Xiaohao Liu, Mengru Zhou, Lingling Li, Jingjing Xu and Xiaoli Zhu
Int. J. Mol. Sci. 2018, 19(6), 1671; https://doi.org/10.3390/ijms19061671 - 5 Jun 2018
Cited by 97 | Viewed by 16964
Abstract
Cancer is one of the leading causes of mortality worldwide, because of the lack of accurate diagnostic tools for the early stages of cancer. Thus, early diagnosis, which provides important information for a timely therapy of cancer, is of great significance for controlling [...] Read more.
Cancer is one of the leading causes of mortality worldwide, because of the lack of accurate diagnostic tools for the early stages of cancer. Thus, early diagnosis, which provides important information for a timely therapy of cancer, is of great significance for controlling the development of the disease and the proliferation of cancer cells and for improving the survival rates of patients. To achieve the goals of early diagnosis and timely therapy of cancer, DNA nanotechnology may be effective, since it has emerged as a valid technique for the fabrication of various nanoscale structures and devices. The resultant DNA-based nanoscale structures and devices show extraordinary performance in cancer diagnosis, owing to their predictable secondary structures, small sizes, and high biocompatibility and programmability. In particular, the rapid development of DNA nanotechnologies, such as molecular assembly technologies, endows DNA-based nanomaterials with more functionalization and intellectualization. Here, we summarize recent progress made in the development of DNA nanotechnology for the fabrication of functional and intelligent nanomaterials and highlight the prospects of this technology in cancer diagnosis and therapy. Full article
(This article belongs to the Special Issue Nucleic Acid Nanotechnology)
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12 pages, 1268 KiB  
Article
Vitamin D Receptor Is Necessary for Mitochondrial Function and Cell Health
by Chiara Ricca, Alessia Aillon, Loredana Bergandi, Daniela Alotto, Carlotta Castagnoli and Francesca Silvagno
Int. J. Mol. Sci. 2018, 19(6), 1672; https://doi.org/10.3390/ijms19061672 - 5 Jun 2018
Cited by 140 | Viewed by 10912
Abstract
Vitamin D receptor (VDR) mediates many genomic and non-genomic effects of vitamin D. Recently, the mitochondrial effects of vitamin D have been characterized in many cell types. In this article, we investigated the importance of VDR not only in mitochondrial activity and integrity [...] Read more.
Vitamin D receptor (VDR) mediates many genomic and non-genomic effects of vitamin D. Recently, the mitochondrial effects of vitamin D have been characterized in many cell types. In this article, we investigated the importance of VDR not only in mitochondrial activity and integrity but also in cell health. The silencing of the receptor in different healthy, non-transformed, and cancer cells initially decreased cell growth and modulated the cell cycle. We demonstrated that, in silenced cells, the increased respiratory activity was associated with elevated reactive oxygen species (ROS) production. In the long run, the absence of the receptor caused impairment of mitochondrial integrity and, finally, cell death. Our data reveal that VDR plays a central role in protecting cells from excessive respiration and production of ROS that leads to cell damage. Because we confirmed our observations in different models of both normal and cancer cells, we conclude that VDR is essential for the health of human tissues. Full article
(This article belongs to the Special Issue Vitamin D and Human Health)
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16 pages, 2706 KiB  
Article
Rv0613c/MSMEG_1285 Interacts with HBHA and Mediates Its Proper Cell-Surface Exposure in Mycobacteria
by Romain Veyron-Churlet, Vincent Dupres, Jean-Michel Saliou, Frank Lafont, Dominique Raze and Camille Locht
Int. J. Mol. Sci. 2018, 19(6), 1673; https://doi.org/10.3390/ijms19061673 - 5 Jun 2018
Cited by 9 | Viewed by 4044
Abstract
Heparin-binding haemagglutinin (HBHA) is a surface-exposed virulence factor of Mycobacterium tuberculosis and is involved in the binding of mycobacteria to non-phagocytic cells, allowing for extra-pulmonary dissemination of the bacilli. Despite its surface exposure, HBHA is not produced as a pre-protein containing a typical [...] Read more.
Heparin-binding haemagglutinin (HBHA) is a surface-exposed virulence factor of Mycobacterium tuberculosis and is involved in the binding of mycobacteria to non-phagocytic cells, allowing for extra-pulmonary dissemination of the bacilli. Despite its surface exposure, HBHA is not produced as a pre-protein containing a typical cleavable N-terminal signal peptide and is thus likely secreted by a Sec-independent, as of yet unknown mechanism. Here, we used the bacterial adenylate cyclase two-hybrid system to identify the proteins encoded by rv0613c and mmpL14 as being able to interact with HBHA. Our study was focused on Rv0613c, as it showed more consistent interactions with HBHA than MmpL14. Deletion of its orthologous gene MSMEG_1285 in recombinant Mycobacterium smegmatis producing HBHA from M. tuberculosis resulted in the loss of proper surface exposure of HBHA, as evidenced by atomic force microscopy. Furthermore, the lack of MSMEG_1285 also abolished the clumping phenotype and rough colony morphology of the recombinant M. smegmatis and reduced its adherence to A549 epithelial cells. These phenotypes have previously been associated with surface-exposed HBHA. Thus, MSMEG_1285 is directly involved in the proper cell-surface exposure of HBHA. These observations identify MSMEG_1285/Rv0613c as the first accessory protein involved in the cell surface exposure of HBHA. Full article
(This article belongs to the Section Biochemistry)
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15 pages, 1308 KiB  
Article
Insulin-Like Growth Factor-1 as a Possible Alternative to Bone Morphogenetic Protein-7 to Induce Osteogenic Differentiation of Human Mesenchymal Stem Cells in Vitro
by Bruno Reible, Gerhard Schmidmaier, Arash Moghaddam and Fabian Westhauser
Int. J. Mol. Sci. 2018, 19(6), 1674; https://doi.org/10.3390/ijms19061674 - 5 Jun 2018
Cited by 70 | Viewed by 5847
Abstract
Growth factors and mesenchymal stem cells (MSC) support consolidation of bone defects. Bone Morphogenetic Protein-7 (BMP-7) has been used clinically and experimentally, but the outcomes remain controversial. Increased systemic expression of Insulin-like Growth Factor-1 (IGF-1) significantly correlates with successful regeneration of bone healing [...] Read more.
Growth factors and mesenchymal stem cells (MSC) support consolidation of bone defects. Bone Morphogenetic Protein-7 (BMP-7) has been used clinically and experimentally, but the outcomes remain controversial. Increased systemic expression of Insulin-like Growth Factor-1 (IGF-1) significantly correlates with successful regeneration of bone healing disorders, making IGF-1 a promising alternative to BMP-7. There is no experimental data comparing the osteoinductive potential of IGF-1 and BMP-7. Therefore, in this study, the influence of IGF-1 and BMP-7 in different concentrations on the osteogenic differentiation of two human MSC-subtypes, isolated from reaming debris (RMSC) and iliac crest bone marrow (BMSC) has been assessed. A more sensitive reaction of BMSC towards stimulation with IGF-1 in concentrations of 400–800 ng/mL was found, leading to a significantly higher degree of osteogenic differentiation compared to stimulation with BMP-7. RMSC react more sensitively to stimulation with BMP-7 compared to BMSC. Lower concentrations of IGF-1 were necessary to significantly increase osteogenic differentiation of RMSC and BMSC compared to BMP-7. Therefore, IGF-1 should be considered as a valuable option to improve osteogenic differentiation of MSC and merits further experimental consideration. The MSC subtype and method of differentiation factor application also have to be considered, as they affect the outcome of osteogenic differentiation. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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13 pages, 4577 KiB  
Article
Role of Cryptochrome-1 and Cryptochrome-2 in Aldosterone-Producing Adenomas and Adrenocortical Cells
by Martina Tetti, Isabella Castellano, Francesca Veneziano, Corrado Magnino, Franco Veglio, Paolo Mulatero and Silvia Monticone
Int. J. Mol. Sci. 2018, 19(6), 1675; https://doi.org/10.3390/ijms19061675 - 5 Jun 2018
Cited by 7 | Viewed by 3873
Abstract
Mice lacking the core-clock components, cryptochrome-1 (CRY1) and cryptochrome-2 (CRY2) display a phenotype of hyperaldosteronism, due to the upregulation of type VI 3β-hydroxyl-steroid dehydrogenase (Hsd3b6), the murine counterpart to the human type I 3β-hydroxyl-steroid dehydrogenase (HSD3B1) gene. In the [...] Read more.
Mice lacking the core-clock components, cryptochrome-1 (CRY1) and cryptochrome-2 (CRY2) display a phenotype of hyperaldosteronism, due to the upregulation of type VI 3β-hydroxyl-steroid dehydrogenase (Hsd3b6), the murine counterpart to the human type I 3β-hydroxyl-steroid dehydrogenase (HSD3B1) gene. In the present study, we evaluated the role of CRY1 and CRY2 genes, and their potential interplay with HSD3B isoforms in adrenal pathophysiology in man. Forty-six sporadic aldosterone-producing adenomas (APAs) and 20 paired adrenal samples were included, with the human adrenocortical cells HAC15 used as the in vitro model. In our cohort of sporadic APAs, CRY1 expression was 1.7-fold [0.75–2.26] higher (p = 0.016), while CRY2 showed a 20% lower expression [0.80, 0.52–1.08] (p = 0.04) in APAs when compared with the corresponding adjacent adrenal cortex. Type II 3β-hydroxyl-steroid dehydrogenase (HSD3B2) was 317-fold [200–573] more expressed than HSD3B1, and is the main HSD3B isoform in APAs. Both dehydrogenases were more expressed in APAs when compared with the adjacent cortex (5.7-fold and 3.5-fold, respectively, p < 0.001 and p = 0.001) and HSD3B1 was significantly more expressed in APAs composed mainly of zona glomerulosa-like cells. Treatment with angiotensin II (AngII) resulted in a significant upregulation of CRY1 (1.7 ± 0.25-fold, p < 0.001) at 6 h, and downregulation of CRY2 at 12 h (0.6 ± 0.1-fold, p < 0.001), through activation of the AngII type 1 receptor. Independent silencing of CRY1 and CRY2 genes in HAC15 cells resulted in a mild upregulation of HSD3B2 without affecting HSD3B1 expression. In conclusion, our results support the hypothesis that CRY1 and CRY2, being AngII-regulated genes, and showing a differential expression in APAs when compared with the adjacent adrenal cortex, might be involved in adrenal cell function, and in the regulation of aldosterone production. Full article
(This article belongs to the Special Issue Role of Genomics in the Management of Hypertension)
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18 pages, 1454 KiB  
Review
Validation of LDLr Activity as a Tool to Improve Genetic Diagnosis of Familial Hypercholesterolemia: A Retrospective on Functional Characterization of LDLr Variants
by Asier Benito-Vicente, Kepa B. Uribe, Shifa Jebari, Unai Galicia-Garcia, Helena Ostolaza and Cesar Martin
Int. J. Mol. Sci. 2018, 19(6), 1676; https://doi.org/10.3390/ijms19061676 - 5 Jun 2018
Cited by 44 | Viewed by 16528
Abstract
Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by high blood-cholesterol levels mostly caused by mutations in the low-density lipoprotein receptor (LDLr). With a prevalence as high as 1/200 in some populations, genetic screening for pathogenic LDLr mutations is a cost-effective approach [...] Read more.
Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by high blood-cholesterol levels mostly caused by mutations in the low-density lipoprotein receptor (LDLr). With a prevalence as high as 1/200 in some populations, genetic screening for pathogenic LDLr mutations is a cost-effective approach in families classified as ‘definite’ or ‘probable’ FH and can help to early diagnosis. However, with over 2000 LDLr variants identified, distinguishing pathogenic mutations from benign mutations is a long-standing challenge in the field. In 1998, the World Health Organization (WHO) highlighted the importance of improving the diagnosis and prognosis of FH patients thus, identifying LDLr pathogenic variants is a longstanding challenge to provide an accurate genetic diagnosis and personalized treatments. In recent years, accessible methodologies have been developed to assess LDLr activity in vitro, providing experimental reproducibility between laboratories all over the world that ensures rigorous analysis of all functional studies. In this review we present a broad spectrum of functionally characterized missense LDLr variants identified in patients with FH, which is mandatory for a definite diagnosis of FH. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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23 pages, 3453 KiB  
Review
The Neuromuscular Junction and Wide Heterogeneity of Congenital Myasthenic Syndromes
by Pedro M. Rodríguez Cruz, Jacqueline Palace and David Beeson
Int. J. Mol. Sci. 2018, 19(6), 1677; https://doi.org/10.3390/ijms19061677 - 5 Jun 2018
Cited by 91 | Viewed by 17405
Abstract
Congenital myasthenic syndromes (CMS) are genetic disorders characterised by impaired neuromuscular transmission. This review provides an overview on CMS and highlights recent advances in the field, including novel CMS causative genes and improved therapeutic strategies. CMS due to mutations in SLC5A7 and SLC18A3 [...] Read more.
Congenital myasthenic syndromes (CMS) are genetic disorders characterised by impaired neuromuscular transmission. This review provides an overview on CMS and highlights recent advances in the field, including novel CMS causative genes and improved therapeutic strategies. CMS due to mutations in SLC5A7 and SLC18A3, impairing the synthesis and recycling of acetylcholine, have recently been described. In addition, a novel group of CMS due to mutations in SNAP25B, SYT2, VAMP1, and UNC13A1 encoding molecules implicated in synaptic vesicles exocytosis has been characterised. The increasing number of presynaptic CMS exhibiting CNS manifestations along with neuromuscular weakness demonstrate that the myasthenia can be only a small part of a much more extensive disease phenotype. Moreover, the spectrum of glycosylation abnormalities has been increased with the report that GMPPB mutations can cause CMS, thus bridging myasthenic disorders with dystroglycanopathies. Finally, the discovery of COL13A1 mutations and laminin α5 deficiency has helped to draw attention to the role of extracellular matrix proteins for the formation and maintenance of muscle endplates. The benefit of β2-adrenergic agonists alone or combined with pyridostigmine or 3,4-Dyaminopiridine is increasingly being reported for different subtypes of CMS including AChR-deficiency and glycosylation abnormalities, thus expanding the therapeutic repertoire available. Full article
(This article belongs to the Special Issue The Neuromuscular Synapse in Health and Disease)
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15 pages, 1976 KiB  
Article
Niemann-Pick Type C2 Protein Regulates Free Cholesterol Accumulation and Influences Hepatic Stellate Cell Proliferation and Mitochondrial Respiration Function
by Yuan-Hsi Wang, Yuh-Ching Twu, Chung-Kwe Wang, Fu-Zhen Lin, Chun-Ya Lee and Yi-Jen Liao
Int. J. Mol. Sci. 2018, 19(6), 1678; https://doi.org/10.3390/ijms19061678 - 5 Jun 2018
Cited by 23 | Viewed by 6018
Abstract
Liver fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. A high-cholesterol diet is associated with liver fibrosis via the accumulation of free cholesterol in hepatic stellate cells (HSCs). Niemann-Pick type C2 (NPC2) plays an important role [...] Read more.
Liver fibrosis is the first step toward the progression to cirrhosis, portal hypertension, and hepatocellular carcinoma. A high-cholesterol diet is associated with liver fibrosis via the accumulation of free cholesterol in hepatic stellate cells (HSCs). Niemann-Pick type C2 (NPC2) plays an important role in the regulation of intracellular free cholesterol homeostasis via direct binding with free cholesterol. Previously, we reported that NPC2 was downregulated in liver cirrhosis tissues. Loss of NPC2 enhanced the accumulation of free cholesterol in HSCs and made them more susceptible to transforming growth factor (TGF)-β1. In this study, we showed that knockdown of NPC2 resulted in marked increases in platelet-derived growth factor BB (PDGF-BB)-induced HSC proliferation through enhanced extracellular signal-regulated kinases (ERK), p38, c-Jun N-terminal kinases (JNK), and protein kinase B (AKT) phosphorylation. In contrast, NPC2 overexpression decreased PDGF-BB-induced cell proliferation by inhibiting p38, JNK, and AKT phosphorylation. Although NPC2 expression did not affect caspase-related apoptosis, the autophagy marker light chain 3β (LC3B) was decreased in NPC2 knockdown, and free cholesterol accumulated in the HSCs. The mitochondrial respiration functions (such as oxygen consumption rate, ATP production, and maximal respiratory capacity) were decreased in NPC2 knockdown, and free cholesterol accumulated in the HSCs, while NPC2-overexpressed cells remained normal. In addition, NPC2 expression did not affect the susceptibility of HSCs to lipopolysaccharides (LPS), and U18666A treatment induced free cholesterol accumulation, which enhanced LPS-induced Toll-like receptor 4 (TLR4), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 phosphorylation, interleukin (IL)-1 and IL-6 expression. Our study demonstrated that NPC2-mediated free cholesterol homeostasis controls HSC proliferation and mitochondrial function. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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10 pages, 1952 KiB  
Article
Polysialic Acid in Human Plasma Can Compensate the Cytotoxicity of Histones
by Kristina Zlatina, Max Saftenberger, Andrea Kühnle, Christina E. Galuska, Ulrich Gärtner, Alexander Rebl, Michael Oster, Andreas Vernunft and Sebastian P. Galuska
Int. J. Mol. Sci. 2018, 19(6), 1679; https://doi.org/10.3390/ijms19061679 - 5 Jun 2018
Cited by 26 | Viewed by 4336
Abstract
The innate immune system has numerous mechanisms to fight against pathogens, including the formation of neutrophil extracellular traps (NETs). By spreading out chromatin, antimicrobial peptides and enzymes, neutrophils efficiently trap pathogens like bacteria and facilitate their elimination. During this process, high concentrations of [...] Read more.
The innate immune system has numerous mechanisms to fight against pathogens, including the formation of neutrophil extracellular traps (NETs). By spreading out chromatin, antimicrobial peptides and enzymes, neutrophils efficiently trap pathogens like bacteria and facilitate their elimination. During this process, high concentrations of extracellular histones can be reached. Several researchers have demonstrated that the cytotoxic characteristics of these histones can trigger diseases like sepsis. Interestingly, the carbohydrate polysialic acid (polySia) can bind histones and reduce histone-mediated cytotoxicity in a chain length-dependent manner. In the present study, we examined the chain length of polySia in plasma and tested its ability to decrease the cytotoxic characteristics of extracellular histones. Remarkably, we detected polySia not only in the soluble fraction of plasma, but also on enriched extracellular vesicles (EVs). Chain length analysis revealed that polySia chains originating from human plasma can consists of more than 40 sialic acid residues and show a cytoprotective effect against extracellular histones. Intriguingly, polySia is not only present in human plasma but also in fish and other branches of vertebrates. Thus, polySia is a physiological element in plasma and may represent a natural buffer for extracellular histones. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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21 pages, 1833 KiB  
Review
The Role of High-Density Lipoproteins in Diabetes and Its Vascular Complications
by Nathan K. P. Wong, Stephen J. Nicholls, Joanne T. M. Tan and Christina A. Bursill
Int. J. Mol. Sci. 2018, 19(6), 1680; https://doi.org/10.3390/ijms19061680 - 5 Jun 2018
Cited by 53 | Viewed by 9174
Abstract
Almost 600 million people are predicted to have diabetes mellitus (DM) by 2035. Diabetic patients suffer from increased rates of microvascular and macrovascular complications, associated with dyslipidaemia, impaired angiogenic responses to ischaemia, accelerated atherosclerosis, and inflammation. Despite recent treatment advances, many diabetic patients [...] Read more.
Almost 600 million people are predicted to have diabetes mellitus (DM) by 2035. Diabetic patients suffer from increased rates of microvascular and macrovascular complications, associated with dyslipidaemia, impaired angiogenic responses to ischaemia, accelerated atherosclerosis, and inflammation. Despite recent treatment advances, many diabetic patients remain refractory to current approaches, highlighting the need for alternative agents. There is emerging evidence that high-density lipoproteins (HDL) are able to rescue diabetes-related vascular complications through diverse mechanisms. Such protective functions of HDL, however, can be rendered dysfunctional within the pathological milieu of DM, triggering the development of vascular complications. HDL-modifying therapies remain controversial as many have had limited benefits on cardiovascular risk, although more recent trials are showing promise. This review will discuss the latest data from epidemiological, clinical, and pre-clinical studies demonstrating various roles for HDL in diabetes and its vascular complications that have the potential to facilitate its successful translation. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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15 pages, 809 KiB  
Review
Morphological Complexity as a Floral Signal: From Perception by Insect Pollinators to Co-Evolutionary Implications
by Shivani Krishna and Tamar Keasar
Int. J. Mol. Sci. 2018, 19(6), 1681; https://doi.org/10.3390/ijms19061681 - 6 Jun 2018
Cited by 48 | Viewed by 7086
Abstract
Morphologically complex flowers are characterized by bilateral symmetry, tube-like shapes, deep corolla tubes, fused petals, and/or poricidal anthers, all of which constrain the access of insect visitors to floral nectar and pollen rewards. Only a subset of potential pollinators, mainly large bees, learn [...] Read more.
Morphologically complex flowers are characterized by bilateral symmetry, tube-like shapes, deep corolla tubes, fused petals, and/or poricidal anthers, all of which constrain the access of insect visitors to floral nectar and pollen rewards. Only a subset of potential pollinators, mainly large bees, learn to successfully forage on such flowers. Thus, complexity may comprise a morphological filter that restricts the range of visitors and thereby increases food intake for successful foragers. Such pollinator specialization, in turn, promotes flower constancy and reduces cross-species pollen transfer, providing fitness benefits to plants with complex flowers. Since visual signals associated with floral morphological complexity are generally honest (i.e., indicate food rewards), pollinators need to perceive and process them. Physiological studies show that bees detect distant flowers through long-wavelength sensitive photoreceptors. Bees effectively perceive complex shapes and learn the positions of contours based on their spatial frequencies. Complex flowers require long handling times by naive visitors, and become highly profitable only for experienced foragers. To explore possible pathways towards the evolution of floral complexity, we discuss cognitive mechanisms that potentially allow insects to persist on complex flowers despite low initial foraging gains, suggest experiments to test these mechanisms, and speculate on their adaptive value. Full article
(This article belongs to the Special Issue Plant-Insect Interactions 2018)
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12 pages, 2263 KiB  
Article
Molecular and Pathological Features of Gastric Cancer in Lynch Syndrome and Familial Adenomatous Polyposis
by Mara Fornasarig, Raffaella Magris, Valli De Re, Ettore Bidoli, Vincenzo Canzonieri, Stefania Maiero, Alessandra Viel and Renato Cannizzaro
Int. J. Mol. Sci. 2018, 19(6), 1682; https://doi.org/10.3390/ijms19061682 - 6 Jun 2018
Cited by 31 | Viewed by 7760
Abstract
Lynch syndrome (LS) and familial adenomatous polyposis (FAP) are autosomal dominant hereditary diseases caused by germline mutations leading to the development of colorectal cancer. Moreover, these mutations result in the development of a spectrum of different tumors, including gastric cancers (GCs). Since the [...] Read more.
Lynch syndrome (LS) and familial adenomatous polyposis (FAP) are autosomal dominant hereditary diseases caused by germline mutations leading to the development of colorectal cancer. Moreover, these mutations result in the development of a spectrum of different tumors, including gastric cancers (GCs). Since the clinical characteristics of GCs associated with LS and FAP are not well known, we investigated clinical and molecular features of GCs occurring in patients with LS and FAP attending our Institution. The Hereditary Tumor Registry was established in 1994 at the Department of Oncologic Gastroenterology, CRO Aviano National Cancer Institute, Italy. It includes 139 patients with LS and 86 patients with FAP. Patients were recruited locally for prospective surveillance. Out of 139 LS patients, 4 developed GC—3 in the presence of helicobacter pylori infection and 1 on the background of autoimmune diseases. All GCs displayed a high microsatellite instability (MSI-H) and loss of related mismatch repair (MMR) protein. One of the FAP patients developed a flat adenoma, displaying low-grade dysplasia at the gastric body, and another poorly differentiated adenocarcinoma with signet ring cells like Krukenberg without HP infection. LS carriers displayed a risk of GC. The recognition of HP infection and autoimmune diseases would indicate those at higher risk for an endoscopic surveillance. Regarding FAP, the data suggested the need of suitable endoscopic surveillance in long survivals with diffuse fundic gland polyps. Full article
(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)
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20 pages, 899 KiB  
Review
Proposed Molecular and miRNA Classification of Gastric Cancer
by Lara Alessandrini, Melissa Manchi, Valli De Re, Riccardo Dolcetti and Vincenzo Canzonieri
Int. J. Mol. Sci. 2018, 19(6), 1683; https://doi.org/10.3390/ijms19061683 - 6 Jun 2018
Cited by 77 | Viewed by 11733
Abstract
Gastric cancer (GC) is a common malignant neoplasm worldwide and one of the main cause of cancer-related deaths. Despite some advances in therapies, long-term survival of patients with advanced disease remains poor. Different types of classification have been used to stratify patients with [...] Read more.
Gastric cancer (GC) is a common malignant neoplasm worldwide and one of the main cause of cancer-related deaths. Despite some advances in therapies, long-term survival of patients with advanced disease remains poor. Different types of classification have been used to stratify patients with GC for shaping prognosis and treatment planning. Based on new knowledge of molecular pathways associated with different aspect of GC, new pathogenetic classifications for GC have been and continue to be proposed. These novel classifications create a new paradigm in the definition of cancer biology and allow the identification of relevant GC genomic subsets by using different techniques such as genomic screenings, functional studies and molecular or epigenetic characterization. An improved prognostic classification for GC is essential for the development of a proper therapy for a proper patient population. The aim of this review is to discuss the state-of-the-art on combining histological and molecular classifications of GC to give an overview of the emerging therapeutic possibilities connected to the latest discoveries regarding GC. Full article
(This article belongs to the Special Issue Molecular Features Distinguishing Gastric Cancer Subtypes)
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13 pages, 1738 KiB  
Article
Radioprotective Effects of Dermatan Sulfate in a Preclinical Model of Oral Mucositis—Targeting Inflammation, Hypoxia and Junction Proteins without Stimulating Proliferation
by Sylvia Gruber, Marlene Arnold, Nilsu Cini, Victoria Gernedl, Sabine Hetzendorfer, Lisa-Marie Kowald, Peter Kuess, Julia Mayer, Susanne Morava, Stephanie Pfaffinger, Andreas Rohorzka and Wolfgang Dörr
Int. J. Mol. Sci. 2018, 19(6), 1684; https://doi.org/10.3390/ijms19061684 - 6 Jun 2018
Cited by 3 | Viewed by 3662
Abstract
Oral mucositis is the most frequently occurring early side effect of head-and-neck cancer radiotherapy. Systemic dermatan sulfate (DS) treatment revealed a significant radioprotective potential in a preclinical model of oral mucositis. This study was initiated to elucidate the mechanistic effects of DS in [...] Read more.
Oral mucositis is the most frequently occurring early side effect of head-and-neck cancer radiotherapy. Systemic dermatan sulfate (DS) treatment revealed a significant radioprotective potential in a preclinical model of oral mucositis. This study was initiated to elucidate the mechanistic effects of DS in the same model. Irradiation comprised daily fractionated irradiation (5 × 3 Gy/week) over two weeks, either alone (IR) or in combination with daily dermatan sulfate treatment of 4 mg/kg (IR + DS). Groups of mice (n = 5) were sacrificed every second day over the course of 14 days in both experimental arms, their tongues excised and evaluated. The response to irradiation with and without DS was analyzed on a morphological (cell numbers, epithelial thickness) as well as on a functional (proliferation and expression of inflammation, hypoxia and epithelial junction markers) level. The mucoprotective activity of DS can be attributed to a combination of various effects, comprising increased expression of epithelial junctions, reduced inflammation and reduced hypoxia. No DS-mediated effect on proliferation was observed. DS demonstrated a significant mucositis-ameliorating activity and could provide a promising strategy for mucositis treatment, based on targeting specific, radiation-induced, mucositis-associated signaling without stimulating proliferation. Full article
(This article belongs to the Special Issue Advances and Challenges in Biomolecular Radiation Research)
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12 pages, 3608 KiB  
Article
Influence of Bacterial Biofilm Polysaccharide Structure on Interactions with Antimicrobial Peptides: A Study on Klebsiella pneumoniae
by Barbara Bellich, Cristina Lagatolla, Alessandro Tossi, Monica Benincasa, Paola Cescutti and Roberto Rizzo
Int. J. Mol. Sci. 2018, 19(6), 1685; https://doi.org/10.3390/ijms19061685 - 6 Jun 2018
Cited by 18 | Viewed by 4196
Abstract
Biofilms are complex systems produced by bacteria and constituted by macromolecular matrix embedding cells. They provide advantages to bacteria including protection against antimicrobials. The protection given by biofilms produced by Klebsiella pneumoniae strains towards antimicrobial peptides of the innate immune system was investigated. [...] Read more.
Biofilms are complex systems produced by bacteria and constituted by macromolecular matrix embedding cells. They provide advantages to bacteria including protection against antimicrobials. The protection given by biofilms produced by Klebsiella pneumoniae strains towards antimicrobial peptides of the innate immune system was investigated. In particular, the role of matrix bacterial exopolysaccharides was explored. Three clinical strains producing exopolysaccharides with different chemistry were selected and the interaction of purified biofilm polysaccharides with two bovine cathelicidins was studied by circular dichroism spectroscopy and microbiological assays to establish their influence on the peptide’s antimicrobial activity. The spectroscopic data indicated a different extent of interaction with the two peptides, in a manner dependent on their sugar composition, and in particular the presence of rhamnose residues correlated with a lower interaction. The extent of interaction was then related to the protection towards antimicrobial peptides, conferred by the addition of the different exopolysaccharides, in minimum inhibitory concentration (MIC) assays against a reference Escherichia coli strain. Microbiological results were in very good agreement with spectroscopic data, confirming the active role of matrix polysaccharides in determining a biofilm’s protective capacity and indicating lower protection levels afforded by rhamnose containing exopolysaccharides. Full article
(This article belongs to the Section Biochemistry)
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15 pages, 3607 KiB  
Article
A WD40 Repeat Protein from Camellia sinensis Regulates Anthocyanin and Proanthocyanidin Accumulation through the Formation of MYB–bHLH–WD40 Ternary Complexes
by Yajun Liu, Hua Hou, Xiaolan Jiang, Peiqiang Wang, Xinlong Dai, Wei Chen, Liping Gao and Tao Xia
Int. J. Mol. Sci. 2018, 19(6), 1686; https://doi.org/10.3390/ijms19061686 - 6 Jun 2018
Cited by 114 | Viewed by 6795
Abstract
Flavan-3-ols and oligomeric proanthocyanidins (PAs) are the main nutritional polyphenols in green tea (Camellia sinensis), which provide numerous benefits to human health. To date, the regulatory mechanism of flavan-3-ol biosynthesis in green tea remains open to study. Herein, we report the [...] Read more.
Flavan-3-ols and oligomeric proanthocyanidins (PAs) are the main nutritional polyphenols in green tea (Camellia sinensis), which provide numerous benefits to human health. To date, the regulatory mechanism of flavan-3-ol biosynthesis in green tea remains open to study. Herein, we report the characterization of a C. sinensis tryptophan-aspartic acid repeat protein (CsWD40) that interacts with myeloblastosis (MYB) and basic helix-loop-helix (bHLH) transcription factors (TFs) to regulate the biosynthesis of flavan-3-ols. Full length CsWD40 cDNA was cloned from leaves and was deduced to encode 342 amino acids. An in vitro yeast two-hybrid assay demonstrated that CsWD40 interacted with two bHLH TFs (CsGL3 and CsTT8) and two MYB TFs (CsAN2 and CsMYB5e). The overexpression of CsWD40 in Arabidopsis thaliana transparent testa glabra 1 (ttg1) restored normal trichome and seed coat development. Ectopic expression of CsWD40 alone in tobacco resulted in a significant increase in the anthocyanins of transgenic petals. CsWD40 was then coexpressed with CsMYB5e in tobacco plants to increase levels of both anthocyanins and PAs. Furthermore, gene expression analysis revealed that CsWD40 expression in tea plants could be induced by several abiotic stresses. Taken together, these data provide solid evidence that CsWD40 partners with bHLH and MYB TFs to form ternary WBM complexes to regulate anthocyanin, PA biosynthesis, and trichome development. Full article
(This article belongs to the Section Biochemistry)
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19 pages, 558 KiB  
Review
Balneotherapy, Immune System, and Stress Response: A Hormetic Strategy?
by Isabel Gálvez, Silvia Torres-Piles and Eduardo Ortega-Rincón
Int. J. Mol. Sci. 2018, 19(6), 1687; https://doi.org/10.3390/ijms19061687 - 6 Jun 2018
Cited by 137 | Viewed by 19616
Abstract
Balneotherapy is a clinically effective complementary approach in the treatment of low-grade inflammation- and stress-related pathologies. The biological mechanisms by which immersion in mineral-medicinal water and the application of mud alleviate symptoms of several pathologies are still not completely understood, but it is [...] Read more.
Balneotherapy is a clinically effective complementary approach in the treatment of low-grade inflammation- and stress-related pathologies. The biological mechanisms by which immersion in mineral-medicinal water and the application of mud alleviate symptoms of several pathologies are still not completely understood, but it is known that neuroendocrine and immunological responses—including both humoral and cell-mediated immunity—to balneotherapy are involved in these mechanisms of effectiveness; leading to anti-inflammatory, analgesic, antioxidant, chondroprotective, and anabolic effects together with neuroendocrine-immune regulation in different conditions. Hormesis can play a critical role in all these biological effects and mechanisms of effectiveness. The hormetic effects of balneotherapy can be related to non-specific factors such as heat—which induces the heat shock response, and therefore the synthesis and release of heat shock proteins—and also to specific biochemical components such as hydrogen sulfide (H2S) in sulfurous water and radon in radioactive water. Results from several investigations suggest that the beneficial effects of balneotherapy and hydrotherapy are consistent with the concept of hormesis, and thus support a role for hormesis in hydrothermal treatments. Full article
(This article belongs to the Special Issue The Day Break of Hormesis)
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16 pages, 2418 KiB  
Article
Physiological and Proteomics Analyses Reveal Low-Phosphorus Stress Affected the Regulation of Photosynthesis in Soybean
by Shanshan Chu, Hongyan Li, Xiangqian Zhang, Kaiye Yu, Maoni Chao, Suoyi Han and Dan Zhang
Int. J. Mol. Sci. 2018, 19(6), 1688; https://doi.org/10.3390/ijms19061688 - 6 Jun 2018
Cited by 45 | Viewed by 5449
Abstract
Previous studies have revealed a significant genetic relationship between phosphorus (P)-efficiency and photosynthesis-related traits in soybean. In this study, we used proteome profiling in combination with expression analysis, biochemical investigations, and leaf ultrastructural analysis to identify the underlying physiological and molecular responses. The [...] Read more.
Previous studies have revealed a significant genetic relationship between phosphorus (P)-efficiency and photosynthesis-related traits in soybean. In this study, we used proteome profiling in combination with expression analysis, biochemical investigations, and leaf ultrastructural analysis to identify the underlying physiological and molecular responses. The expression analysis and ultrastructural analysis showed that the photosynthesis key genes were decreased at transcript levels and the leaf mesophyll and chloroplast were severely damaged after low-P stress. Approximately 55 protein spots showed changes under low-P condition by mass spectrometry, of which 17 were involved in various photosynthetic processes. Further analysis revealed the depression of photosynthesis caused by low-P stress mainly involves the regulation of leaf structure, adenosine triphosphate (ATP) synthesis, absorption and transportation of CO2, photosynthetic electron transport, production of assimilatory power, and levels of enzymes related to the Calvin cycle. In summary, our findings indicated that the existence of a stringent relationship between P supply and the genomic control of photosynthesis in soybean. As an important strategy to protect soybean photosynthesis, P could maintain the stability of cell structure, up-regulate the enzymes’ activities, recover the process of photosystem II (PSII), and induce the expression of low-P responsive genes and proteins. Full article
(This article belongs to the Special Issue Ion Transporters and Abiotic Stress Tolerance in Plants)
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19 pages, 275 KiB  
Review
Microbiome-Gut-Brain Axis and Toll-Like Receptors in Parkinson’s Disease
by Valentina Caputi and Maria Cecilia Giron
Int. J. Mol. Sci. 2018, 19(6), 1689; https://doi.org/10.3390/ijms19061689 - 6 Jun 2018
Cited by 277 | Viewed by 29807
Abstract
Parkinson’s disease (PD) is a progressively debilitating neurodegenerative disease characterized by α-synucleinopathy, which involves all districts of the brain-gut axis, including the central, autonomic and enteric nervous systems. The highly bidirectional communication between the brain and the gut is markedly influenced by the [...] Read more.
Parkinson’s disease (PD) is a progressively debilitating neurodegenerative disease characterized by α-synucleinopathy, which involves all districts of the brain-gut axis, including the central, autonomic and enteric nervous systems. The highly bidirectional communication between the brain and the gut is markedly influenced by the microbiome through integrated immunological, neuroendocrine and neurological processes. The gut microbiota and its relevant metabolites interact with the host via a series of biochemical and functional inputs, thereby affecting host homeostasis and health. Indeed, a dysregulated microbiota-gut-brain axis in PD might lie at the basis of gastrointestinal dysfunctions which predominantly emerge many years prior to the diagnosis, corroborating the theory that the pathological process is spread from the gut to the brain. Toll-like receptors (TLRs) play a crucial role in innate immunity by recognizing conserved motifs primarily found in microorganisms and a dysregulation in their signaling may be implicated in α-synucleinopathy, such as PD. An overstimulation of the innate immune system due to gut dysbiosis and/or small intestinal bacterial overgrowth, together with higher intestinal barrier permeability, may provoke local and systemic inflammation as well as enteric neuroglial activation, ultimately triggering the development of alpha-synuclein pathology. In this review, we provide the current knowledge regarding the relationship between the microbiota-gut–brain axis and TLRs in PD. A better understanding of the dialogue sustained by the microbiota-gut-brain axis and innate immunity via TLR signaling should bring interesting insights in the pathophysiology of PD and provide novel dietary and/or therapeutic measures aimed at shaping the gut microbiota composition, improving the intestinal epithelial barrier function and balancing the innate immune response in PD patients, in order to influence the early phases of the following neurodegenerative cascade. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases)
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32 pages, 767 KiB  
Review
Pharmacological Targeting of Cell Cycle, Apoptotic and Cell Adhesion Signaling Pathways Implicated in Chemoresistance of Cancer Cells
by Dauren Alimbetov, Sholpan Askarova, Bauyrzhan Umbayev, Terence Davis and David Kipling
Int. J. Mol. Sci. 2018, 19(6), 1690; https://doi.org/10.3390/ijms19061690 - 6 Jun 2018
Cited by 120 | Viewed by 15898
Abstract
Chemotherapeutic drugs target a physiological differentiating feature of cancer cells as they tend to actively proliferate more than normal cells. They have well-known side-effects resulting from the death of highly proliferative normal cells in the gut and immune system. Cancer treatment has changed [...] Read more.
Chemotherapeutic drugs target a physiological differentiating feature of cancer cells as they tend to actively proliferate more than normal cells. They have well-known side-effects resulting from the death of highly proliferative normal cells in the gut and immune system. Cancer treatment has changed dramatically over the years owing to rapid advances in oncology research. Developments in cancer therapies, namely surgery, radiotherapy, cytotoxic chemotherapy and selective treatment methods due to better understanding of tumor characteristics, have significantly increased cancer survival. However, many chemotherapeutic regimes still fail, with 90% of the drug failures in metastatic cancer treatment due to chemoresistance, as cancer cells eventually develop resistance to chemotherapeutic drugs. Chemoresistance is caused through genetic mutations in various proteins involved in cellular mechanisms such as cell cycle, apoptosis and cell adhesion, and targeting those mechanisms could improve outcomes of cancer therapy. Recent developments in cancer treatment are focused on combination therapy, whereby cells are sensitized to chemotherapeutic agents using inhibitors of target pathways inducing chemoresistance thus, hopefully, overcoming the problems of drug resistance. In this review, we discuss the role of cell cycle, apoptosis and cell adhesion in cancer chemoresistance mechanisms, possible drugs to target these pathways and, thus, novel therapeutic approaches for cancer treatment. Full article
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14 pages, 3574 KiB  
Article
Berberine Protects against NEFA-Induced Impairment of Mitochondrial Respiratory Chain Function and Insulin Signaling in Bovine Hepatocytes
by Zhen Shi, Xiao-Bing Li, Zhi-Cheng Peng, Shou-Peng Fu, Chen-Xu Zhao, Xi-Liang Du, Zhi-Yuan Fang, Zhe Wang, Guo-Wen Liu and Xin-Wei Li
Int. J. Mol. Sci. 2018, 19(6), 1691; https://doi.org/10.3390/ijms19061691 - 6 Jun 2018
Cited by 27 | Viewed by 4811
Abstract
Fatty liver is a major lipid metabolic disease in perinatal dairy cows and is characterized by high blood levels of non-esterified fatty acid (NEFA) and insulin resistance. Berberine (BBR) has been reported to improve insulin sensitivity in mice with hepatic steatosis. Mitochondrial dysfunction [...] Read more.
Fatty liver is a major lipid metabolic disease in perinatal dairy cows and is characterized by high blood levels of non-esterified fatty acid (NEFA) and insulin resistance. Berberine (BBR) has been reported to improve insulin sensitivity in mice with hepatic steatosis. Mitochondrial dysfunction is considered a causal factor that induces insulin resistance. This study investigates the underlying mechanism and the beneficial effects of BBR on mitochondrial and insulin signaling in bovine hepatocytes. Revised quantitative insulin sensitivity check index (RQUICKI) of cows with fatty liver was significantly lower than that of healthy cows. Importantly, the Akt and GSK3β phosphorylation levels, protein levels of PGC-1α and four of the five representative subunits of oxidative phosphorylation (OXPHOS) were significantly decreased in cows with fatty liver using Western Blot analysis. In bovine hepatocytes, 1.2 mmol/L NEFA reduced insulin signaling and mitochondrial respiratory chain function, and 10 and 20 umol/L BBR restored these changes. Furthermore, activation of PGC-1α played the same beneficial effects of BBR on hepatocytes treated with NEFA. BBR treatment improves NEFA-impaired mitochondrial respiratory chain function and insulin signaling by increasing PGC-1α expression in hepatocytes, which provides a potential new strategy for the prevention and treatment of fatty liver in dairy cows. Full article
(This article belongs to the Special Issue Liver Damage and Repair)
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16 pages, 2118 KiB  
Article
Particle Bombardment of the cry2A Gene Cassette Induces Stem Borer Resistance in Sugarcane
by Shiwu Gao, Yingying Yang, Liping Xu, Jinlong Guo, Yachun Su, Qibin Wu, Chunfeng Wang and Youxiong Que
Int. J. Mol. Sci. 2018, 19(6), 1692; https://doi.org/10.3390/ijms19061692 - 6 Jun 2018
Cited by 26 | Viewed by 5423
Abstract
Sugarcane borer is the most common and harmful pest in Chinese sugarcane fields, and can cause damage to the whole plant during the entire growing season. To improve borer resistance in sugarcane, we constructed a plant expression vector pGcry2A0229 with the bar gene [...] Read more.
Sugarcane borer is the most common and harmful pest in Chinese sugarcane fields, and can cause damage to the whole plant during the entire growing season. To improve borer resistance in sugarcane, we constructed a plant expression vector pGcry2A0229 with the bar gene as the marker and the cry2A gene as the target, and introduced it into embryogenic calli of most widely cultivated sugarcane cultivar ROC22 by particle bombardment. After screening with phosphinothricin in vitro and Basta spray, 21 resistance-regenerated plants were obtained, and 10 positive transgenic lines harboring the cry2A gene were further confirmed by conventional PCR detection. Real-time quantitative PCR (RT-qPCR) analysis showed that the copy number of the cry2A gene varied among different transgenic lines but did not exceed four copies. Quantitative ELISA analysis showed that there was no linear relationship with copy number but negatively correlated with the percentage of borer-infested plants. The analysis of industrial and agronomic traits showed that the theoretical sugar yields of transgenic lines TR-4 and TR-10 were slightly lower than that of the control in both plant cane and ratoon cane; nevertheless, TR-4 and TR-10 lines exhibited markedly lower in frequency of borer-infested plants in plant cane and in the ratoon cane compared to the control. Our results indicate that the introduction of the cry2A gene via bombardment produces transgenic lines with obviously increased stem borer resistance and comparable sugar yield, providing a practical value in direct commercial cultivation and crossbreeding for ROC22 has been used as the most popular elite genitor in various breeding programs in China. Full article
(This article belongs to the Special Issue Plant Genetics and Molecular Breeding)
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15 pages, 2369 KiB  
Article
Isobavachalcone from Angelica keiskei Inhibits Adipogenesis and Prevents Lipid Accumulation
by Hyejin Lee, Hua Li, Minson Kweon, Youngsook Choi, Min Jung Kim and Jae-Ha Ryu
Int. J. Mol. Sci. 2018, 19(6), 1693; https://doi.org/10.3390/ijms19061693 - 6 Jun 2018
Cited by 39 | Viewed by 5399
Abstract
We isolated isobavachalcone (IBC) from Angelica keiskei (AK) as an anti-obesity component. IBC dose-dependently inhibited 3T3-L1 adipocyte differentiation by down-regulating adipogenic factors. At the mitotic clonal expansion stage (MCE), IBC caused cell cycle arrest in G0/G1 with decreased expression of cell cycle-regulating proteins. [...] Read more.
We isolated isobavachalcone (IBC) from Angelica keiskei (AK) as an anti-obesity component. IBC dose-dependently inhibited 3T3-L1 adipocyte differentiation by down-regulating adipogenic factors. At the mitotic clonal expansion stage (MCE), IBC caused cell cycle arrest in G0/G1 with decreased expression of cell cycle-regulating proteins. IBC also inhibited autophagic flux by inducing intracellular accumulation of LC3B and SQSTM1/p62 proteins while decreasing expression levels of regulating factors for autophagy initiation. In parallel with the inhibition of adipocyte differentiation, IBC decreased intrahepatic fat deposits and rescued the liver steatosis in high fat cholesterol diet-fed zebrafish. In this study, we found that IBC isolated from AK suppresses mitotic clonal expansion and autophagy flux of adipocytes and also shows anti-obesity activity in a high cholesterol-diet zebrafish model by decreasing intrahepatic fat deposits. These results suggest that IBC could be a leading pharmacological compound for the development of anti-obesity drugs. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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13 pages, 3317 KiB  
Review
TSPO: An Evolutionarily Conserved Protein with Elusive Functions
by Frederick Bonsack and Sangeetha Sukumari-Ramesh
Int. J. Mol. Sci. 2018, 19(6), 1694; https://doi.org/10.3390/ijms19061694 - 7 Jun 2018
Cited by 74 | Viewed by 6991
Abstract
TSPO (18 kDa translocator protein) was identified decades ago in a search for peripheral tissue binding sites for benzodiazepines, and was formerly called the peripheral benzodiazepine receptor. TSPO is a conserved protein throughout evolution and it is implicated in the regulation of many [...] Read more.
TSPO (18 kDa translocator protein) was identified decades ago in a search for peripheral tissue binding sites for benzodiazepines, and was formerly called the peripheral benzodiazepine receptor. TSPO is a conserved protein throughout evolution and it is implicated in the regulation of many cellular processes, including inflammatory responses, oxidative stress, and mitochondrial homeostasis. TSPO, apart from its broad expression in peripheral tissues, is highly expressed in neuroinflammatory cells, such as activated microglia. In addition, emerging studies employing the ligands of TSPO suggest that TSPO plays an important role in neuropathological settings as a biomarker and therapeutic target. However, the precise molecular function of this protein in normal physiology and neuropathology remains enigmatic. This review provides an overview of recent advances in our understanding of this multifaceted molecule and identifies the knowledge gap in the field for future functional studies. Full article
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14 pages, 17326 KiB  
Review
The Multifaceted Role of STAT3 in Mammary Gland Involution and Breast Cancer
by Katherine Hughes and Christine J. Watson
Int. J. Mol. Sci. 2018, 19(6), 1695; https://doi.org/10.3390/ijms19061695 - 7 Jun 2018
Cited by 62 | Viewed by 10825
Abstract
Since seminal descriptions of signal transducer and activator of transcription 3 (STAT3) as a signal transducer and transcriptional regulator, which is most usually activated by phosphorylation of a specific tyrosine residue, a staggering wealth of research has delineated the key role of this [...] Read more.
Since seminal descriptions of signal transducer and activator of transcription 3 (STAT3) as a signal transducer and transcriptional regulator, which is most usually activated by phosphorylation of a specific tyrosine residue, a staggering wealth of research has delineated the key role of this transcription factor as a mediator of mammary gland postlactational regression (involution), and paradoxically, a pro-survival factor in breast cancer and some breast cancer cell lines. STAT3 is a critical regulator of lysosomal-mediated programmed cell death (LM-PCD) during mammary gland involution, where uptake of milk fat globules, and consequent high levels of free fatty acids, cause permeabilisation of lysosomal vesicle membranes, in turn leading to cathepsin protease leakage and cell death. A recent proteomic screen of STAT3-induced changes in lysosomal membrane protein components has highlighted wide-ranging effects of STAT3, which may coordinate LM-PCD via the stimulation of endocytosis, intracellular trafficking, and lysosome biogenesis. In parallel, STAT3 regulates the acute phase response during the first phase of involution, and it contributes to shaping the pro-tumourigenic ‘wound healing’ signature of the gland during the second phase of this process. STAT3 activation during involution is important across species, although some differences exist in the progression of involution in dairy cows. In breast cancer, a number of upstream regulators can lead to STAT3 activation and the effects of phosphorylation of STAT3 are equally wide-ranging. Recent studies have implicated microRNAs in some regulatory pathways. In this review, we will examine the multifaceted role of STAT3 in mammary gland involution and tumourigenesis, incorporating a review of these fundamental processes in tandem with a discussion of recent developments in this field. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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12 pages, 2405 KiB  
Article
Graphene Quantum Dots and Enzyme-Coupled Biosensor for Highly Sensitive Determination of Hydrogen Peroxide and Glucose
by Bingdi Wang, Jing Shen, Yanjun Huang, Zhenning Liu and Hong Zhuang
Int. J. Mol. Sci. 2018, 19(6), 1696; https://doi.org/10.3390/ijms19061696 - 7 Jun 2018
Cited by 32 | Viewed by 5449
Abstract
In this paper, a simple and specific graphene quantum dots (GQDs)-based fluorescent biosensor adopted for the determination of glucose based on the combination of the enzyme-coupled method and fluorescence quenching mechanism is demonstrated. Glucose was oxidized by the enzyme glucose oxidase (GOx), forming [...] Read more.
In this paper, a simple and specific graphene quantum dots (GQDs)-based fluorescent biosensor adopted for the determination of glucose based on the combination of the enzyme-coupled method and fluorescence quenching mechanism is demonstrated. Glucose was oxidized by the enzyme glucose oxidase (GOx), forming hydrogen peroxide (H 2 O 2 ) via the catalysis by horseradish peroxidase (HRP). H 2 O 2 was then employed to oxidize phenol to quinone, which led to effective quenching effect in the GQDs–GOx–HRP–phenol system. By optimizing the reaction conditions of the GQDs-enzyme system, a linear relationship between the concentration of glucose and the fluorescence intensity over a range of 0.2–10 μ mol/L was obtained. The limit of detection for glucose is 0.08 μ mol/L. The present biosensor for the determination of glucose showed satisfactory reproducibility and accuracy in human serum samples. Since the enzymes have high specificity and unique affinity to the certain substance, the enzyme-coupled system promises a sensitive way for further detection of those chemicals which could be oxidized by enzymes and generated H 2 O 2 or glucose. GQDs and other fluorescent materials coupled with several enzymes can be applied to extensive sensing field. Full article
(This article belongs to the Section Biochemistry)
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22 pages, 2918 KiB  
Article
Comparative Analyses of Anatomical Structure, Phytohormone Levels, and Gene Expression Profiles Reveal Potential Dwarfing Mechanisms in Shengyin Bamboo (Phyllostachys edulis f. tubaeformis)
by Tao Wang, Lei Liu, Xiaojing Wang, Lixiong Liang, Jinjun Yue and Lubin Li
Int. J. Mol. Sci. 2018, 19(6), 1697; https://doi.org/10.3390/ijms19061697 - 7 Jun 2018
Cited by 27 | Viewed by 4597
Abstract
Moso bamboo (Phyllostachys edulis) is one of the most important bamboo species in China and the third most important plant species for timber production. However, the dwarf variant of moso bamboo, P. edulis f. tubaeformis (shengyin bamboo), which has shortened internodes, [...] Read more.
Moso bamboo (Phyllostachys edulis) is one of the most important bamboo species in China and the third most important plant species for timber production. However, the dwarf variant of moso bamboo, P. edulis f. tubaeformis (shengyin bamboo), which has shortened internodes, is not well studied. We used anatomical, hormonal, and transcriptomic approaches to study internode shortening and shoot growth in dwarf shengyin and wild moso bamboo. Phenotypic and anatomical observations showed that dwarfing in shengyin bamboo is due to reduced internode length, and the culm fibers in shengyin bamboo are significantly shorter and thicker than in wild moso bamboo. We measured the levels of endogenous hormones in the internodes and found that shengyin bamboo had lower levels of four hormones while two others were higher in wild moso bamboo. Comparative transcriptome analyses revealed a potential regulating mechanism for internode length involving genes for cell wall loosening-related enzymes and the cellulose and lignin biosynthesis pathways. Genes involved in hormone biosynthesis and signal transduction, especially those that showed significant differential expression in the internodes between shengyin and wild moso bamboo, may be important in determining the shortened internode phenotype. A hypothesis involving possible cross-talk between phytohormone signaling cues and cell wall expansion leading to dwarfism in shengyin bamboo is proposed. The results presented here provide a comprehensive exploration of the biological mechanisms that determine internode shortening in moso bamboo. Full article
(This article belongs to the Section Molecular Plant Sciences)
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15 pages, 4801 KiB  
Article
Identification of Differentially Expressed Genes Induced by Aberrant Methylation in Oral Squamous Cell Carcinomas Using Integrated Bioinformatic Analysis
by Xiaoqi Zhang, Hao Feng, Dongfang Li, Shanshan Liu, Norio Amizuka and Minqi Li
Int. J. Mol. Sci. 2018, 19(6), 1698; https://doi.org/10.3390/ijms19061698 - 7 Jun 2018
Cited by 31 | Viewed by 6825
Abstract
Oral squamous cell carcinoma (OSCC) is a malignant disease. Methylation plays a key role in the etiology and pathogenesis of OSCC. The goal of this study was to identify aberrantly methylated differentially expressed genes (DEGs) in OSCCs, and to explore the underlying mechanisms [...] Read more.
Oral squamous cell carcinoma (OSCC) is a malignant disease. Methylation plays a key role in the etiology and pathogenesis of OSCC. The goal of this study was to identify aberrantly methylated differentially expressed genes (DEGs) in OSCCs, and to explore the underlying mechanisms of tumorigenesis by using integrated bioinformatic analysis. Gene expression profiles (GSE30784 and GSE38532) were analyzed using the R software to obtain aberrantly methylated DEGs. Functional enrichment analysis of screened genes was performed using the DAVID software. Protein–protein interaction (PPI) networks were constructed using the STRING database. The cBioPortal software was used to exhibit the alterations of genes. Lastly, we validated the results with the Cancer Genome Atlas (TCGA) data. Twenty-eight upregulated hypomethylated genes and 24 downregulated hypermethylated genes were identified. These genes were enriched in the biological process of regulation in immune response, and were mainly involved in the PI3K-AKT and EMT pathways. Additionally, three upregulated hypomethylated oncogenes and four downregulated hypermethylated tumor suppressor genes (TSGs) were identified. In conclusion, our study indicated possible aberrantly methylated DEGs and pathways in OSCCs, which could improve the understanding of the underlying molecular mechanisms. Aberrantly methylated oncogenes and TSGs may also serve as biomarkers and therapeutic targets for the precise diagnosis and treatment of OSCCs in the future. Full article
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21 pages, 4743 KiB  
Article
A Crude 1-DNJ Extract from Home Made Bombyx Batryticatus Inhibits Diabetic Cardiomyopathy-Associated Fibrosis in db/db Mice and Reduces Protein N-Glycosylation Levels
by Qing Zhao, Tian Zhu Jia, Qi Chen Cao, Fang Tian and Wan Tao Ying
Int. J. Mol. Sci. 2018, 19(6), 1699; https://doi.org/10.3390/ijms19061699 - 7 Jun 2018
Cited by 24 | Viewed by 6521
Abstract
The traditional Chinese drug Bombyx Batryticatus (BB), which is also named the white stiff silkworm, has been widely used in Chinese clinics for thousands of years. It is famous for its antispasmodic and blood circulation-promoting effects. Cardiomyocyte hypertrophy, interstitial cell hyperplasia, and myocardial [...] Read more.
The traditional Chinese drug Bombyx Batryticatus (BB), which is also named the white stiff silkworm, has been widely used in Chinese clinics for thousands of years. It is famous for its antispasmodic and blood circulation-promoting effects. Cardiomyocyte hypertrophy, interstitial cell hyperplasia, and myocardial fibrosis are closely related to the N-glycosylation of key proteins. To examine the alterations of N-glycosylation that occur in diabetic myocardium during the early stage of the disease, and to clarify the therapeutic effect of 1-Deoxynojirimycin (1-DNJ) extracted from BB, we used the db/db (diabetic) mouse model and an approach based on hydrophilic chromatography solid-phase extraction integrated with an liquid Chromatograph Mass Spectrometer (LC-MS) identification strategy to perform a site-specific N-glycosylation analysis of left ventricular cardiomyocyte proteins. Advanced glycation end products (AGEs), hydroxyproline, connective tissue growth factor (CTGF), and other serum biochemical indicators were measured with enzyme-linked immunosorbent assays (ELISA). In addition, the α-1,6-fucosylation of N-glycans was profiled with lens culinaris agglutinin (LCA) lectin blots and fluorescein isothiocyanate (FITC)-labelled lectin affinity histochemistry. The results indicated that 1-DNJ administration obviously downregulated myocardium protein N-glycosylation in db/db mice. The expression levels of serum indicators and fibrosis-related cytokines were reduced significantly by 1-DNJ in a dose-dependent manner. The glycan α-1,6-fucosylation level of the db/db mouse myocardium was elevated, and the intervention effect of 1-DNJ administration on N-glycan α-1,6-fucosylation was significant. To verify this result, the well-known transforming growth factor-β (TGF-β)/Smad2/3 pathway was selected, and core α-1,6-fucosylated TGF-β receptor II (TGFR-βII) was analysed semi-quantitatively with western blotting. The result supported the conclusions obtained from LCA lectin affinity histochemistry and lectin blot analysis. The expression level of α-1,6-fucosyltransferase (FUT8) mRNA was also detected, and the results showed that 1-DNJ administration did not cause obvious inhibitory effects on FUT8 expression. Therefore, the mechanism of 1-DNJ for relieving diabetic cardiomyopathy (DCM)-associated fibrosis can be concluded as the inhibition of N-acetylglucosamine (N-GlcNAc) formation and the reduction of substrate concentration. Full article
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13 pages, 4437 KiB  
Article
Keratinocyte Motility Is Affected by UVA Radiation—A Comparison between Normal and Dysplastic Cells
by Cristina M. Niculiţe, Marina T. Nechifor, Andreea O. Urs, Laura Olariu, Laura C. Ceafalan and Mircea Leabu
Int. J. Mol. Sci. 2018, 19(6), 1700; https://doi.org/10.3390/ijms19061700 - 7 Jun 2018
Cited by 8 | Viewed by 3998
Abstract
UVA radiation induces multiple and complex changes in the skin, affecting epidermal cell behavior. This study reports the effects of UVA exposure on normal (HaCaT) and dysplastic (DOK) keratinocytes. The adherence, spreading and proliferation were investigated by time-lapse measurement of cell layer impedance [...] Read more.
UVA radiation induces multiple and complex changes in the skin, affecting epidermal cell behavior. This study reports the effects of UVA exposure on normal (HaCaT) and dysplastic (DOK) keratinocytes. The adherence, spreading and proliferation were investigated by time-lapse measurement of cell layer impedance on different matrix proteins. Prior to UVA exposure, the time required for adherence and spreading did not differ significantly for HaCaT and DOK cells, while spreading areas were larger for HaCaT cells. Under UVA exposure, HaCaT and DOK cells behavior differed in terms of movement and proliferation. The cells’ ability to cover the denuded surface and individual cell trajectories were recorded by time-lapse videomicroscopy, during wound healing experiments. Dysplastic keratinocytes showed more sensitivity to UVA, exhibiting transient deficiencies in directionality of movement and a delay in re-coating the denuded area. The actin cytoskeleton displayed a cortical organization immediately after irradiation, in both cell lines, similar to mock-irradiated cells. Post-irradiation, DOK cells displayed a better organization of stress fibers, persistent filopodia, and new, stronger focal contacts. In conclusion, after UVA exposure HaCaT and DOK cells showed a different behavior in terms of adherence, spreading, motility, proliferation, and actin cytoskeleton dynamics, with the dyplastic keratinocytes being more sensitive. Full article
(This article belongs to the Section Biochemistry)
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36 pages, 766 KiB  
Review
Activity-Based Physical Rehabilitation with Adjuvant Testosterone to Promote Neuromuscular Recovery after Spinal Cord Injury
by Dana M. Otzel, Jimmy Lee, Fan Ye, Stephen E. Borst and Joshua F. Yarrow
Int. J. Mol. Sci. 2018, 19(6), 1701; https://doi.org/10.3390/ijms19061701 - 7 Jun 2018
Cited by 33 | Viewed by 9433
Abstract
Neuromuscular impairment and reduced musculoskeletal integrity are hallmarks of spinal cord injury (SCI) that hinder locomotor recovery. These impairments are precipitated by the neurological insult and resulting disuse, which has stimulated interest in activity-based physical rehabilitation therapies (ABTs) that promote neuromuscular plasticity after [...] Read more.
Neuromuscular impairment and reduced musculoskeletal integrity are hallmarks of spinal cord injury (SCI) that hinder locomotor recovery. These impairments are precipitated by the neurological insult and resulting disuse, which has stimulated interest in activity-based physical rehabilitation therapies (ABTs) that promote neuromuscular plasticity after SCI. However, ABT efficacy declines as SCI severity increases. Additionally, many men with SCI exhibit low testosterone, which may exacerbate neuromusculoskeletal impairment. Incorporating testosterone adjuvant to ABTs may improve musculoskeletal recovery and neuroplasticity because androgens attenuate muscle loss and the slow-to-fast muscle fiber-type transition after SCI, in a manner independent from mechanical strain, and promote motoneuron survival. These neuromusculoskeletal benefits are promising, although testosterone alone produces only limited functional improvement in rodent SCI models. In this review, we discuss the (1) molecular deficits underlying muscle loss after SCI; (2) independent influences of testosterone and locomotor training on neuromuscular function and musculoskeletal integrity post-SCI; (3) hormonal and molecular mechanisms underlying the therapeutic efficacy of these strategies; and (4) evidence supporting a multimodal strategy involving ABT with adjuvant testosterone, as a potential means to promote more comprehensive neuromusculoskeletal recovery than either strategy alone. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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13 pages, 4109 KiB  
Review
The Interplay between Two Transcriptional Repressors and Chaperones Orchestrates Helicobacter pylori Heat-Shock Response
by Davide Roncarati and Vincenzo Scarlato
Int. J. Mol. Sci. 2018, 19(6), 1702; https://doi.org/10.3390/ijms19061702 - 7 Jun 2018
Cited by 10 | Viewed by 5996
Abstract
The ability to gauge the surroundings and modulate gene expression accordingly is a crucial feature for the survival bacterial pathogens. In this respect, the heat-shock response, a universally conserved mechanism of protection, allows bacterial cells to adapt rapidly to hostile conditions and to [...] Read more.
The ability to gauge the surroundings and modulate gene expression accordingly is a crucial feature for the survival bacterial pathogens. In this respect, the heat-shock response, a universally conserved mechanism of protection, allows bacterial cells to adapt rapidly to hostile conditions and to survive during environmental stresses. The important and widespread human pathogen Helicobacter pylori enrolls a collection of highly conserved heat-shock proteins to preserve cellular proteins and to maintain their homeostasis, allowing the pathogen to adapt and survive in the hostile niche of the human stomach. Moreover, various evidences suggest that some chaperones of H. pylori may play also non-canonical roles as, for example, in the interaction with the extracellular environment. In H. pylori, two dedicated transcriptional repressors, named HspR and HrcA, homologues to well-characterized regulators found in many other bacterial species, orchestrate the regulation of heat-shock proteins expression. Following twenty years of intense research, characterized by molecular, as well as genome-wide, approaches, it is nowadays possible to appreciate the complex picture representing the heat-shock regulation in H. pylori. Specifically, the HspR and HrcA repressors combine to control the transcription of target genes in a way that the HrcA regulon results embedded within the HspR regulon. Moreover, an additional level of control of heat-shock genes’ expression is exerted by a posttranscriptional feedback regulatory circuit in which chaperones interact and modulate HspR and HrcA DNA-binding activity. This review recapitulates our understanding of the roles and regulation of the most important heat-shock proteins of H. pylori, which represent a crucial virulence factor for bacterial infection and persistence in the human host. Full article
(This article belongs to the Special Issue Helicobacter pylori Research)
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13 pages, 3256 KiB  
Article
Inhibition and Inactivation of Uropathogenic Escherichia coli Biofilms on Urinary Catheters by Sodium Selenite
by Amoolya Narayanan, Meera S. Nair, Muhammed S. Muyyarikkandy and Mary Anne Amalaradjou
Int. J. Mol. Sci. 2018, 19(6), 1703; https://doi.org/10.3390/ijms19061703 - 7 Jun 2018
Cited by 22 | Viewed by 5860
Abstract
Urinary tract infections (UTI) are the most common hospital-acquired infections in humans and are caused primarily by uropathogenic Escherichia coli (UPEC). Indwelling urinary catheters become encrusted with UPEC biofilms that are resistant to common antibiotics, resulting in chronic infections. Therefore, it is important [...] Read more.
Urinary tract infections (UTI) are the most common hospital-acquired infections in humans and are caused primarily by uropathogenic Escherichia coli (UPEC). Indwelling urinary catheters become encrusted with UPEC biofilms that are resistant to common antibiotics, resulting in chronic infections. Therefore, it is important to control UPEC biofilms on catheters to reduce the risk for UTIs. This study investigated the efficacy of selenium for inhibiting and inactivating UPEC biofilms on urinary catheters. Urinary catheters were inoculated with UPEC and treated with 0 and 35 mM selenium at 37 °C for 5 days for the biofilm inhibition assay. In addition, catheters with preformed UPEC biofilms were treated with 0, 45, 60, and 85 mM selenium and incubated at 37 °C. Biofilm-associated UPEC counts on catheters were enumerated on days 0, 1, 3, and 5 of incubation. Additionally, the effect of selenium on exopolysacchride (EPS) production and expression of UPEC biofilm-associated genes was evaluated. Selenium at 35 mM concentration was effective in preventing UPEC biofilm formation on catheters compared to controls (p < 0.05). Further, this inhibitory effect was associated with a reduction in EPS production and UPEC gene expression. Moreover, at higher concentrations, selenium was effective in inactivating preformed UPEC biofilms on catheters as early as day 3 of incubation. Results suggest that selenium could be potentially used in the control of UPEC biofilms on urinary catheters. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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15 pages, 571 KiB  
Review
Liquid Biopsy in Oral Cancer
by Fatima Lousada-Fernandez, Oscar Rapado-Gonzalez, Jose-Luis Lopez-Cedrun, Rafael Lopez-Lopez, Laura Muinelo-Romay and Maria Mercedes Suarez-Cunqueiro
Int. J. Mol. Sci. 2018, 19(6), 1704; https://doi.org/10.3390/ijms19061704 - 8 Jun 2018
Cited by 94 | Viewed by 12002
Abstract
Oral cancer is one of the most prevalent forms of cancer worldwide. Carcinogenesis is a complex process, in which heterogeneity plays an important role in the development and progression of the disease. This review provides an overview of the current biological and clinical [...] Read more.
Oral cancer is one of the most prevalent forms of cancer worldwide. Carcinogenesis is a complex process, in which heterogeneity plays an important role in the development and progression of the disease. This review provides an overview of the current biological and clinical significance of circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), and exosomes for diagnosis and prognosis of oral cancer. We highlight the importance of liquid biopsy—using blood and saliva—which represents a potential alternative to solid biopsy for diagnosis and prognosis. Moreover, liquid biomarkers allow for the real-time monitoring of tumour evolution and therapeutic responses, initiating the era of personalized medicine. However, in oral cancer, the impact of liquid biopsies in clinical settings is still limited, requiring further studies to discover the best scenario for its clinical use. Full article
(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)
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15 pages, 7898 KiB  
Article
Amyloid Beta Peptide Is Released during Thrombosis in the Skin
by Lilia Y. Kucheryavykh, Yuriy V. Kucheryavykh, A. Valance Washington and Mikhail Y. Inyushin
Int. J. Mol. Sci. 2018, 19(6), 1705; https://doi.org/10.3390/ijms19061705 - 8 Jun 2018
Cited by 15 | Viewed by 6736
Abstract
While it is known that amyloid beta (Aβ) deposits are found in different tissues of both Alzheimer’s disease (AD) patients and healthy individuals, there remain questions about the physiological role of these deposits, the origin of the Aβ peptide, and the mechanisms of [...] Read more.
While it is known that amyloid beta (Aβ) deposits are found in different tissues of both Alzheimer’s disease (AD) patients and healthy individuals, there remain questions about the physiological role of these deposits, the origin of the Aβ peptide, and the mechanisms of its localization to the tissues. Using immunostaining with specific antibodies, as well as enzyme-linked immunosorbent assay, this study demonstrated Aβ40 peptide accumulation in the skin during local experimental photothrombosis in mice. Specifically, Aβ peptide accumulation was concentrated near the dermal blood vessels in thrombotic skin. It was also studied whether the released peptide affects microorganisms. Application of Aβ40 (4 µM) to the external membrane of yeast cells significantly increased membrane conductance with no visible effect on mouse host cells. The results suggest that Aβ release in the skin is related to skin injury and thrombosis, and occurs along with clotting whenever skin is damaged. These results support the proposition that Aβ release during thrombosis serves as part of a natural defense against infection. Full article
(This article belongs to the Special Issue Peptides for Health Benefits)
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27 pages, 1204 KiB  
Review
High-Risk Human Papillomaviral Oncogenes E6 and E7 Target Key Cellular Pathways to Achieve Oncogenesis
by Nicole S. L. Yeo-Teh, Yoshiaki Ito and Sudhakar Jha
Int. J. Mol. Sci. 2018, 19(6), 1706; https://doi.org/10.3390/ijms19061706 - 8 Jun 2018
Cited by 200 | Viewed by 14118
Abstract
Infection with high-risk human papillomavirus (HPV) has been linked to several human cancers, the most prominent of which is cervical cancer. The integration of the viral genome into the host genome is one of the manners in which the viral oncogenes E6 and [...] Read more.
Infection with high-risk human papillomavirus (HPV) has been linked to several human cancers, the most prominent of which is cervical cancer. The integration of the viral genome into the host genome is one of the manners in which the viral oncogenes E6 and E7 achieve persistent expression. The most well-studied cellular targets of the viral oncogenes E6 and E7 are p53 and pRb, respectively. However, recent research has demonstrated the ability of these two viral factors to target many more cellular factors, including proteins which regulate epigenetic marks and splicing changes in the cell. These have the ability to exert a global change, which eventually culminates to uncontrolled proliferation and carcinogenesis. Full article
(This article belongs to the Special Issue Human Polyomaviruses and Papillomaviruses)
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16 pages, 235 KiB  
Review
The Role of Genetic Polymorphisms in Chronic Pain Patients
by Nebojsa Nick Knezevic, Tatiana Tverdohleb, Ivana Knezevic and Kenneth D. Candido
Int. J. Mol. Sci. 2018, 19(6), 1707; https://doi.org/10.3390/ijms19061707 - 8 Jun 2018
Cited by 25 | Viewed by 8242
Abstract
It is estimated that the total annual financial cost for pain management in the U.S. exceeds 100 billion dollars. However, when indirect costs are included, such as functional disability and reduction in working hours, the cost can reach more than 300 billion dollars. [...] Read more.
It is estimated that the total annual financial cost for pain management in the U.S. exceeds 100 billion dollars. However, when indirect costs are included, such as functional disability and reduction in working hours, the cost can reach more than 300 billion dollars. In chronic pain patients, the role of pharmacogenetics is determined by genetic effects on various pain types, as well as the genetic effect on drug safety and efficacy. In this review article, we discuss genetic polymorphisms present in different types of chronic pain, such as fibromyalgia, low back pain, migraine, painful peripheral diabetic neuropathy and trigeminal neuralgia. Furthermore, we discuss the role of CYP450 enzymes involved in metabolism of drugs, which have been used for treatment of chronic pain (amitriptyline, duloxetine, opioids, etc.). We also discuss how pharmacogenetics can be applied towards improving drug efficacy, shortening the time required to achieve therapeutic outcomes, reducing risks of side effects, and reducing medical costs and reliance upon polypharmacy. Full article
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism and Bioactivation)
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18 pages, 57494 KiB  
Article
Tapetal-Delayed Programmed Cell Death (PCD) and Oxidative Stress-Induced Male Sterility of Aegilops uniaristata Cytoplasm in Wheat
by Zihan Liu, Xiaoyi Shi, Sha Li, Gan Hu, Lingli Zhang and Xiyue Song
Int. J. Mol. Sci. 2018, 19(6), 1708; https://doi.org/10.3390/ijms19061708 - 8 Jun 2018
Cited by 51 | Viewed by 5854
Abstract
Cytoplasmic male sterility (CMS) plays a crucial role in the utilization of hybrid vigor. Pollen development is often accompanied by oxidative metabolism responses and tapetal programmed cell death (PCD), and deficiency in these processes could lead to male sterility. Aegilops uniaristata cytoplasmic male [...] Read more.
Cytoplasmic male sterility (CMS) plays a crucial role in the utilization of hybrid vigor. Pollen development is often accompanied by oxidative metabolism responses and tapetal programmed cell death (PCD), and deficiency in these processes could lead to male sterility. Aegilops uniaristata cytoplasmic male sterility (Mu-CMS) wheat is a novel male-sterile line in wheat, which possess important potential in hybrid wheat breeding. However, its CMS mechanisms remain poorly understood. In our study, U87B1-706A, with the Aegilops uniaristata cytoplasm, and the maintainer line 706B were used to explore the abortive reason. Compared with 706B, histological analysis and PCD detection of the anther demonstrated that U87B1-706A appeared as delayed tapetal PCD as well as a disorganized organelle phenotype in the early uninucleate stage. Subsequently, a shrunken microspore and disordered exine structure were exhibited in the late uninucleate stage. While the activities of antioxidase increased markedly, the nonenzymatic antioxidant contents declined obviously following overacummulation of reactive oxygen species (ROS) during pollen development in U87B1-706A. Real-time quantitative PCR testified that the transcript levels of the superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APX) genes, encoding pivotal antioxidant enzymes, were up-regulated in early pollen development. Therefore, we deduce excess ROS as a signal may be related to the increased expression levels of enzyme genes, thereby breaking the antioxidative system balance, resulting in delayed tapetal PCD initiation, which finally led to pollen abortion and male sterility in U87B1-706A. These results provide evidence to further explore the mechanisms of abortive pollen in CMS wheat. Full article
(This article belongs to the Section Molecular Plant Sciences)
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12 pages, 228 KiB  
Review
Cellular and Molecular Mediators of Bone Metastatic Lesions
by Giulia Battafarano, Michela Rossi, Francesco Marampon and Andrea Del Fattore
Int. J. Mol. Sci. 2018, 19(6), 1709; https://doi.org/10.3390/ijms19061709 - 8 Jun 2018
Cited by 17 | Viewed by 4901
Abstract
Bone is the preferential site of metastasis for breast and prostate tumor. Cancer cells establish a tight relationship with the host tissue, secreting factors that stimulate or inhibit bone cells, receiving signals generated from the bone remodeling activity, and displaying some features of [...] Read more.
Bone is the preferential site of metastasis for breast and prostate tumor. Cancer cells establish a tight relationship with the host tissue, secreting factors that stimulate or inhibit bone cells, receiving signals generated from the bone remodeling activity, and displaying some features of bone cells. This interplay between tumor and bone cells alters the physiological bone remodeling, leading to the generation of a vicious cycle that promotes bone metastasis growth. To prevent the skeletal-related events (SRE) associated with bone metastasis, approaches to inhibit osteoclast bone resorption are reported. The bisphosphonates and Denosumab are currently used in the treatment of patients affected by bone lesions. They act to prevent or counteract the SRE, including pathologic fractures, spinal cord compression, and pain associated with bone metastasis. However, their primary effects on tumor cells still remain controversial. In this review, a description of the mechanisms leading to the onset of bone metastasis and clinical approaches to treat them are described. Full article
(This article belongs to the Special Issue Bone Metastasis: Pathophysiology and Molecular Mechanisms)
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9 pages, 2450 KiB  
Article
ARID1B as a Potential Therapeutic Target for ARID1A-Mutant Ovarian Clear Cell Carcinoma
by Emi Sato, Kentaro Nakayama, Sultana Razia, Kohei Nakamura, Masako Ishikawa, Toshiko Minamoto, Tomoka Ishibashi, Hitomi Yamashita, Kouji Iida and Satoru Kyo
Int. J. Mol. Sci. 2018, 19(6), 1710; https://doi.org/10.3390/ijms19061710 - 8 Jun 2018
Cited by 23 | Viewed by 6656
Abstract
AT-rich interactive domain 1A (ARID1A) and AT-rich interactive domain 1B (ARID1B) are subunits of the SWI/SNF chromatin complex. ARID1A is a tumor suppressor gene that is frequently mutated (46%) in ovarian clear cell carcinomas (OCCC). Loss of ARID1B in an ARID1A-deficient background eliminates [...] Read more.
AT-rich interactive domain 1A (ARID1A) and AT-rich interactive domain 1B (ARID1B) are subunits of the SWI/SNF chromatin complex. ARID1A is a tumor suppressor gene that is frequently mutated (46%) in ovarian clear cell carcinomas (OCCC). Loss of ARID1B in an ARID1A-deficient background eliminates the intact SWI/SNF complex, indicating that ARID1B is essential for the formation or stabilization of an intact SWI/SNF complex and, thus, the survival of ARID1A-mutant cancer cell lines. In this study, we investigated the clinicopathologic and prognostic relevance of ARID1B in OCCC by immunohistochemical analysis of 53 OCCC patient samples and loss-of-function experiments in OCCC cell lines. We also examined whether ARID1B could be a therapeutic target or prognostic biomarker in OCCC. siRNA-mediated knockdown of ARID1B in an ARID1A-mutant cell line significantly decreased cell growth, whereas concurrent depletion of both ARID1A and ARID1B was required to decrease wild type cell growth. In the immunohistochemical analyses, low ARID1B level was frequent in samples lacking ARID1A and was associated with shorter progression-free survival. This is the first report demonstrating that a low ARID1B level could be a marker of poor prognosis in OCCC. Moreover, the correlation between the loss of ARID1A immunoreactivity and reduced ARID1B levels indicates that ARID1B could be an attractive target for anti-cancer therapy. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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14 pages, 2965 KiB  
Article
Blooming of Unusual Cytochrome P450s by Tandem Duplication in the Pathogenic Fungus Conidiobolus coronatus
by Mathula Lancelot Ngwenya, Wanping Chen, Albert Kotze Basson, Jabulani Siyabonga Shandu, Jae-Hyuk Yu, David R. Nelson and Khajamohiddin Syed
Int. J. Mol. Sci. 2018, 19(6), 1711; https://doi.org/10.3390/ijms19061711 - 9 Jun 2018
Cited by 14 | Viewed by 4901
Abstract
While the Zygomycete fungus Conidiobolus coronatus primarily infects insects, it can be pathogenic to mammals as well, including humans. High variability in the treatment of this fungal infection with currently available drugs, including azole drugs is a very common phenomenon. Azoles bind to [...] Read more.
While the Zygomycete fungus Conidiobolus coronatus primarily infects insects, it can be pathogenic to mammals as well, including humans. High variability in the treatment of this fungal infection with currently available drugs, including azole drugs is a very common phenomenon. Azoles bind to the cytochrome P450 monooxygenases (P450s/CYP) including CYP51, a sterol 14-α-demethylase, inhibiting the synthesis of cell membrane ergosterol and thus leading to the elimination of infecting fungi. Despite P450’s role as a drug target, to date, no information on C. coronatus P450s has been reported. Genome-wide data mining has revealed the presence of 142 P450s grouped into 12 families and 21 subfamilies in C. coronatus. Except for CYP51, the remaining 11 P450 families are new (CYP5854-CYP5864). Despite having a large number of P450s among entomopathogenic fungi, C. coronatus has the lowest number of P450 families, which suggests blooming P450s. Further analysis has revealed that 79% of the same family P450s is tandemly positioned, suggesting that P450 tandem duplication led to the blooming of P450s. The results of this study; i.e., unravelling the C. coronatus P450 content, will certainly help in designing experiments to understand P450s’ role in C. coronatus physiology, including a highly variable response to azole drugs with respect to P450s. Full article
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism and Bioactivation)
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18 pages, 1725 KiB  
Review
The Impact of the Nitric Oxide (NO)/Soluble Guanylyl Cyclase (sGC) Signaling Cascade on Kidney Health and Disease: A Preclinical Perspective
by Shalini M. Krishnan, Jan R. Kraehling, Frank Eitner, Agnès Bénardeau and Peter Sandner
Int. J. Mol. Sci. 2018, 19(6), 1712; https://doi.org/10.3390/ijms19061712 - 9 Jun 2018
Cited by 74 | Viewed by 11807
Abstract
Chronic Kidney Disease (CKD) is a highly prevalent disease with a substantial medical need for new and more efficacious treatments. The Nitric Oxide (NO), soluble guanylyl cyclase (sGC), cyclic guanosine monophosphate (cGMP) signaling cascade regulates various kidney functions. cGMP directly influences renal blood [...] Read more.
Chronic Kidney Disease (CKD) is a highly prevalent disease with a substantial medical need for new and more efficacious treatments. The Nitric Oxide (NO), soluble guanylyl cyclase (sGC), cyclic guanosine monophosphate (cGMP) signaling cascade regulates various kidney functions. cGMP directly influences renal blood flow, renin secretion, glomerular function, and tubular exchange processes. Downregulation of NO/sGC/cGMP signaling results in severe kidney pathologies such as CKD. Therefore, treatment strategies aiming to maintain or increase cGMP might have beneficial effects for the treatment of progressive kidney diseases. Within this article, we review the NO/sGC/cGMP signaling cascade and its major pharmacological intervention sites. We specifically focus on the currently known effects of cGMP on kidney function parameters. Finally, we summarize the preclinical evidence for kidney protective effects of NO-donors, PDE inhibitors, sGC stimulators, and sGC activators. Full article
(This article belongs to the Special Issue cGMP-Signalling in Cells: Molecular and Functional Features)
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11 pages, 2394 KiB  
Communication
Responsiveness of Carnosine Homeostasis Genes in the Pancreas and Brain of Streptozotocin-Treated Mice Exposed to Dietary Carnosine
by Amilcare Barca, Francesca Gatti, Daniela Spagnolo, Stefania Ippati, Carla Vetrugno and Tiziano Verri
Int. J. Mol. Sci. 2018, 19(6), 1713; https://doi.org/10.3390/ijms19061713 - 9 Jun 2018
Cited by 17 | Viewed by 4572
Abstract
In excitable tissues, the endogenous dipeptide carnosine (CAR, β-Ala-l-His) sustains homeostatic responses to various challenges. By eliciting hypoglycemic effects via actions on the autonomic nervous system and protection of pancreatic beta-cells, CAR is also relevant in diabetes. We investigated the expression [...] Read more.
In excitable tissues, the endogenous dipeptide carnosine (CAR, β-Ala-l-His) sustains homeostatic responses to various challenges. By eliciting hypoglycemic effects via actions on the autonomic nervous system and protection of pancreatic beta-cells, CAR is also relevant in diabetes. We investigated the expression of genes involved in CAR biosynthesis, degradation, and membrane transport pathways, in the pancreas and brains of mice treated with streptozotocin (STZ) and then exposed to dietary CAR. We induced hyperglycemia by STZ intraperitoneal injections; then, STZ-treated mice received drinking water with or without CAR for two weeks. We report that CAR administration elicits beneficial effects on blood glucose levels and weight loss in STZ-treated mice and, remarkably, on the insulin gene products in the pancreas, preserving gene expression from STZ challenge. Also, we describe mRNA downregulation of the Slc15a2/Pept2 (dipeptide transporter) and Cndp2 (intracellular dipeptidase) genes in the pancreas of hyperglycemic mice, and dysregulation of Carns1 (CAR synthase), Pept2 and Cndp2 in brains; interestingly, dietary CAR elicits counteracting effects. These expression patterns associate with variations of CAR content in tissues of mice. Overall, our report suggests a direct role of CAR in the diabetes-affected pancreas and in the diabetes-targeted CNS, proposing (dys)regulation of CAR’s homeostasis as a marker condition. Full article
(This article belongs to the Special Issue Amino Acids Transport and Metabolism)
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14 pages, 768 KiB  
Review
Molecular Genetics of Frontotemporal Dementia Elucidated by Drosophila Models—Defects in Endosomal–Lysosomal Pathway
by Sarah E. Vandal, Xiaoyue Zheng and S. Tariq Ahmad
Int. J. Mol. Sci. 2018, 19(6), 1714; https://doi.org/10.3390/ijms19061714 - 9 Jun 2018
Cited by 8 | Viewed by 5645
Abstract
Frontotemporal dementia (FTD) is the second most common senile neurodegenerative disease. FTD is a heterogeneous disease that can be classified into several subtypes. A mutation in CHMP2B locus (CHMP2Bintron5), which encodes a component of endosomal sorting complex required for transport-III [...] Read more.
Frontotemporal dementia (FTD) is the second most common senile neurodegenerative disease. FTD is a heterogeneous disease that can be classified into several subtypes. A mutation in CHMP2B locus (CHMP2Bintron5), which encodes a component of endosomal sorting complex required for transport-III (ESCRT-III), is associated with a rare hereditary subtype of FTD linked to chromosome 3 (FTD-3). ESCRT is involved in critical cellular processes such as multivesicular body (MVB) formation during endosomal–lysosomal pathway and autophagy. ESCRT mutants causes diverse physiological defects primarily due to accumulation of endosomes and defective MVBs resulting in misregulation of signaling pathways. Charged multivesicular body protein 2B (CHMP2B) is important for neuronal physiology which especially rely on precise regulation of protein homeostasis due to their post-mitotic status. Drosophila has proven to be an excellent model for charaterization of mechanistic underpinning of neurodegenerative disorders including FTD. In this review, current understanding of various FTD-related mutations is discussed with a focus on Drosophila models of CHMP2Bintron5-associated FTD. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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18 pages, 22094 KiB  
Article
Exosomes Derived from Human Induced Pluripotent Stem Cells Ameliorate the Aging of Skin Fibroblasts
by Myeongsik Oh, Jinhee Lee, Yu Jin Kim, Won Jong Rhee and Ju Hyun Park
Int. J. Mol. Sci. 2018, 19(6), 1715; https://doi.org/10.3390/ijms19061715 - 9 Jun 2018
Cited by 185 | Viewed by 17421
Abstract
Stem cells and their paracrine factors have emerged as a resource for regenerative medicine. Many studies have shown the beneficial effects of paracrine factors secreted from adult stem cells, such as exosomes, on skin aging. However, to date, few reports have demonstrated the [...] Read more.
Stem cells and their paracrine factors have emerged as a resource for regenerative medicine. Many studies have shown the beneficial effects of paracrine factors secreted from adult stem cells, such as exosomes, on skin aging. However, to date, few reports have demonstrated the use of exosomes derived from human pluripotent stem cells for the treatment of skin aging. In this study, we collected exosomes from the conditioned medium of human induced pluripotent stem cells (iPSCs) and investigated the effect on aged human dermal fibroblasts (HDFs). Cell proliferation and viability were determined by an MTT assay and cell migration capacity was shown by a scratch wound assay and a transwell migration assay. To induce photoaging and natural senescence, HDFs were irradiated by UVB (315 nm) and subcultured for over 30 passages, respectively. The expression level of certain mRNAs was evaluated by quantitative real-time PCR (qPCR). Senescence-associated-β-galactosidase (SA-β-Gal) activity was assessed as a marker of natural senescence. As a result, we found that exosomes derived from human iPSCs (iPSCs-Exo) stimulated the proliferation and migration of HDFs under normal conditions. Pretreatment with iPSCs-Exo inhibited the damages of HDFs and overexpression of matrix-degrading enzymes (MMP-1/3) caused by UVB irradiation. The iPSCs-Exo also increased the expression level of collagen type I in the photo-aged HDFs. In addition, we demonstrated that iPSCs-Exo significantly reduced the expression level of SA-β-Gal and MMP-1/3 and restored the collagen type I expression in senescent HDFs. Taken together, it is anticipated that these results suggest a therapeutic potential of iPSCs-Exo for the treatment of skin aging. Full article
(This article belongs to the Special Issue Skin Aging and Gene Expression)
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18 pages, 17608 KiB  
Review
The Role of Curcumin in Prevention and Management of Metastatic Disease
by Beatrice E. Bachmeier, Peter H. Killian and Dieter Melchart
Int. J. Mol. Sci. 2018, 19(6), 1716; https://doi.org/10.3390/ijms19061716 - 9 Jun 2018
Cited by 72 | Viewed by 8117
Abstract
In the last two decades, targeted therapies have enhanced tumor patient care and treatment success, however, metastatic growth still cannot be stopped efficiently and, therefore, mortality rates remain high. Prevention strategies against formation of metastases are the most promising approach we have, however, [...] Read more.
In the last two decades, targeted therapies have enhanced tumor patient care and treatment success, however, metastatic growth still cannot be stopped efficiently and, therefore, mortality rates remain high. Prevention strategies against formation of metastases are the most promising approach we have, however, due to lack of clinical validation studies, they have not yet entered routine clinical care. In order to smooth the way for efficient prevention, further preclinical and large clinical studies are required. In this context, the underlying molecular mechanisms and factors that lead to metastatic growth have to be explored, and potential preventive agents have to be tested. Thereby, special attention has to be paid to natural bioactive compounds which do not exert major adverse effects, like the plant-derived polyphenol Curcumin, which is known to be a powerful antitumor agent. So far, most of the preclinical studies with Curcumin have focused on its effect on inhibiting tumor cell proliferation and invasion, although, it is known that it also inhibits metastatic spread in vivo. This review discusses the preventive potential of this natural compound not only against tumor onset, but also against formation of metastases. Full article
(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)
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20 pages, 2032 KiB  
Review
Protein Polymer-Based Nanoparticles: Fabrication and Medical Applications
by Kelsey DeFrates, Theodore Markiewicz, Pamela Gallo, Aaron Rack, Aubrie Weyhmiller, Brandon Jarmusik and Xiao Hu
Int. J. Mol. Sci. 2018, 19(6), 1717; https://doi.org/10.3390/ijms19061717 - 9 Jun 2018
Cited by 215 | Viewed by 14558
Abstract
Nanoparticles are particles that range in size from about 1–1000 nanometers in diameter, about one thousand times smaller than the average cell in a human body. Their small size, flexible fabrication, and high surface-area-to-volume ratio make them ideal systems for drug delivery. Nanoparticles [...] Read more.
Nanoparticles are particles that range in size from about 1–1000 nanometers in diameter, about one thousand times smaller than the average cell in a human body. Their small size, flexible fabrication, and high surface-area-to-volume ratio make them ideal systems for drug delivery. Nanoparticles can be made from a variety of materials including metals, polysaccharides, and proteins. Biological protein-based nanoparticles such as silk, keratin, collagen, elastin, corn zein, and soy protein-based nanoparticles are advantageous in having biodegradability, bioavailability, and relatively low cost. Many protein nanoparticles are easy to process and can be modified to achieve desired specifications such as size, morphology, and weight. Protein nanoparticles are used in a variety of settings and are replacing many materials that are not biocompatible and have a negative impact on the environment. Here we attempt to review the literature pertaining to protein-based nanoparticles with a focus on their application in drug delivery and biomedical fields. Additional detail on governing nanoparticle parameters, specific protein nanoparticle applications, and fabrication methods are also provided. Full article
(This article belongs to the Special Issue Nanotechnology in Drug Delivery)
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12 pages, 7540 KiB  
Article
Morphological Study of Chitosan/Poly (Vinyl Alcohol) Nanofibers Prepared by Electrospinning, Collected on Reticulated Vitreous Carbon
by Diana Isela Sanchez-Alvarado, Javier Guzmán-Pantoja, Ulises Páramo-García, Alfredo Maciel-Cerda, Reinaldo David Martínez-Orozco and Ricardo Vera-Graziano
Int. J. Mol. Sci. 2018, 19(6), 1718; https://doi.org/10.3390/ijms19061718 - 9 Jun 2018
Cited by 32 | Viewed by 5215
Abstract
In this work, chitosan (CS)/poly (vinyl alcohol) (PVA) nanofibers were prepared by using the electrospinning method. Different CS concentrations (0.5, 1, 2, and 3 wt %), maintaining the PVA concentration at 8 wt %, were tested. Likewise, the studied electrospinning experimental parameters were: [...] Read more.
In this work, chitosan (CS)/poly (vinyl alcohol) (PVA) nanofibers were prepared by using the electrospinning method. Different CS concentrations (0.5, 1, 2, and 3 wt %), maintaining the PVA concentration at 8 wt %, were tested. Likewise, the studied electrospinning experimental parameters were: syringe/collector distance, solution flow and voltage. Subsequently, the electrospun fibers were collected on a reticulated vitreous carbon (RVC) support for 0.25, 0.5, 1, 1.5, and 2 h. The morphology and diameter of the CS/PVA nanofibers were characterized by scanning electron microscopy (SEM), finding diameters in the order of 132 and 212 nm; the best results (uniform fibers) were obtained from the solution with 2 wt % of chitosan and a voltage, distance, and flow rate of 16 kV, 20 cm, and 0.13 mL/h, respectively. Afterwards, a treatment with an ethanolic NaOH solution was performed, observing a change in the fiber morphology and a diameter decrease (117 ± 9 nm). Full article
(This article belongs to the Special Issue Synthesis and Applications of Biopolymer Composites)
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13 pages, 3212 KiB  
Article
Effect of Different Preconditioning Regimens on the Expression Profile of Murine Adipose-Derived Stromal/Stem Cells
by Patrick C. Baer, Jürgen M. Overath, Anja Urbschat, Ralf Schubert, Benjamin Koch, Asanke A. Bohn and Helmut Geiger
Int. J. Mol. Sci. 2018, 19(6), 1719; https://doi.org/10.3390/ijms19061719 - 10 Jun 2018
Cited by 17 | Viewed by 4700
Abstract
Stem cell-based therapies require cells with a maximum regenerative capacity in order to support regeneration after tissue injury and organ failure. Optimization of this regenerative potential of mesenchymal stromal/stem cells (MSC) or their conditioned medium by in vitro preconditioning regimens are considered to [...] Read more.
Stem cell-based therapies require cells with a maximum regenerative capacity in order to support regeneration after tissue injury and organ failure. Optimization of this regenerative potential of mesenchymal stromal/stem cells (MSC) or their conditioned medium by in vitro preconditioning regimens are considered to be a promising strategy to improve the release of regenerative factors. In the present study, MSC were isolated from inguinal adipose tissue (mASC) from C57BL/6 mice, cultured, and characterized. Then, mASC were either preconditioned by incubation in a hypoxic environment (0.5% O2), or in normoxia in the presence of murine epidermal growth factor (EGF) or tumor necrosis factor α (TNFα) for 48 h. Protein expression was measured by a commercially available array. Selected factors were verified by PCR analysis. The expression of 83 out of 308 proteins (26.9%) assayed was found to be increased after preconditioning with TNFα, whereas the expression of 61 (19.8%) and 70 (22.7%) proteins was increased after incubation with EGF or in hypoxia, respectively. Furthermore, we showed the proliferation-promoting effects of the preconditioned culture supernatants on injured epithelial cells in vitro. Our findings indicate that each preconditioning regimen tested induced an individual expression profile with a wide variety of factors, including several growth factors and cytokines, and therefore may enhance the regenerative potential of mASC for cell-based therapies. Full article
(This article belongs to the Special Issue Adipose Stem Cells)
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15 pages, 5097 KiB  
Article
pSTAT3 Levels Have Divergent Expression Patterns and Associations with Survival in Squamous Cell Carcinoma and Adenocarcinoma of the Oesophagus
by Katie E. O’ Sullivan, Adriana J. Michielsen, Esther O’ Regan, Mary C. Cathcart, Gillian Moore, Eamon Breen, Ricardo Segurado, John V. Reynolds, Joanne Lysaght and Jacintha O’ Sullivan
Int. J. Mol. Sci. 2018, 19(6), 1720; https://doi.org/10.3390/ijms19061720 - 10 Jun 2018
Cited by 10 | Viewed by 4545
Abstract
Signal transducers and activator of transcription (STAT)-3 is activated in cancers, where it promotes growth, inflammation, angiogenesis, and inhibits apoptosis. Tissue microarrays were generated using tissues from 154 patients, with oesophageal adenocarcinoma (OAC) (n = 116) or squamous cell carcinoma (SCC) ( [...] Read more.
Signal transducers and activator of transcription (STAT)-3 is activated in cancers, where it promotes growth, inflammation, angiogenesis, and inhibits apoptosis. Tissue microarrays were generated using tissues from 154 patients, with oesophageal adenocarcinoma (OAC) (n = 116) or squamous cell carcinoma (SCC) (n = 38) tumours. The tissues were stained for pSTAT3 and IL-6R using immunohistochemistry. The OE33 (OAC) and OE21 (SCC) cell lines were treated with the STAT3 inhibitor, STATTIC. The Univariate cox regression analysis revealed that a positive pSTAT3 in SCC was adversely associated with survival (Hazard ratio (HR) 6.382, 95% CI 1.266–32.184), while a protective effect was demonstrated with the higher pSTAT3 levels in OAC epithelium (HR 0.74, 95% CI 0.574–0.953). The IL-6R intensity levels were higher in the SCC tumours compared with the OAC tumours for the core and leading edge tumour tissue. The pSTAT3 levels correlated positively with the IL-6R levels in both the OAC and SCC. The treatment of OE21 and OE33 cells with the STAT3 inhibitor STATTIC in vitro resulted in decreased survival, proliferation, migration, and increased apoptosis. The pSTAT3 expression was associated with adverse survival in SCC, but not in the OAC patients. The inhibition of STAT3 in both of the tumour subtypes resulted in alterations in the survival, proliferation, migration, and apoptosis, suggesting a potential role for therapeutically targeting STAT3. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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19 pages, 266 KiB  
Review
Potential Clinical Application of Genomics in Multiple Myeloma
by Cinnie Yentia Soekojo, Sanjay De Mel, Melissa Ooi, Benedict Yan and Wee Joo Chng
Int. J. Mol. Sci. 2018, 19(6), 1721; https://doi.org/10.3390/ijms19061721 - 10 Jun 2018
Cited by 8 | Viewed by 5173
Abstract
Multiple myeloma is a heterogeneous disease with different characteristics, and genetic aberrations play important roles in this heterogeneity. Studies have shown that these genetic aberrations are crucial in prognostication and response assessment; recent efforts have focused on their possible therapeutic implications. Despite many [...] Read more.
Multiple myeloma is a heterogeneous disease with different characteristics, and genetic aberrations play important roles in this heterogeneity. Studies have shown that these genetic aberrations are crucial in prognostication and response assessment; recent efforts have focused on their possible therapeutic implications. Despite many emerging studies being published, the best way to incorporate these results into clinical practice remains unclear. In this review paper we describe the different genomic techniques available, including the latest advancements, and discuss the potential clinical application of genomics in multiple myeloma. Full article
14 pages, 4295 KiB  
Article
Systematic Analysis of Long Non-Coding RNAs and mRNAs in the Ovaries of Duroc Pigs During Different Follicular Stages Using RNA Sequencing
by Yi Liu, Mengxun Li, Xinwen Bo, Tao Li, Lipeng Ma, Tenjiao Zhai and Tao Huang
Int. J. Mol. Sci. 2018, 19(6), 1722; https://doi.org/10.3390/ijms19061722 - 11 Jun 2018
Cited by 38 | Viewed by 4809
Abstract
The dynamic process involving the selection and maturation of follicles is regulated and controlled by a highly synchronized and exquisitely timed cascade of gene expression. Studies have shown that long non-coding RNA (lncRNA) is essential for the normal maintenance of animal reproductive function [...] Read more.
The dynamic process involving the selection and maturation of follicles is regulated and controlled by a highly synchronized and exquisitely timed cascade of gene expression. Studies have shown that long non-coding RNA (lncRNA) is essential for the normal maintenance of animal reproductive function and has an important regulatory function in ovarian development and hormone secretion. In this study, a total of 2076 lncRNAs (1362 known lncRNAs and 714 new lncRNAs) and 25,491 mRNAs were identified in libraries constructed from Duroc ovaries on days 0, 2 and 4 of follicle development. lncRNAs were shorter, had fewer exons, exhibited a shorter ORF (Open Reading Frame) length and lower expression levels, and were less conserved than mRNAs. Furthermore, 1694 transcripts (140 lncRNAs and 1554 mRNAs) were found to be differentially expressed in pairwise comparisons. A total of 6945 co-localized mRNAs were detected in cis in 2076 lncRNAs. The most enriched GO (Gene Ontology) terms were related to developmental processes. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis revealed that the differentially expressed lncRNAs targeted mRNAs, and the differentially expressed mRNAs were related to the TGF-β signaling pathway, the PI3K-Akt signaling pathway, the Retinol metabolic pathway and the Wnt signaling pathway. This study deepened our understanding of the genetic basis and molecular mechanisms of follicular development in pigs. Full article
(This article belongs to the Section Biochemistry)
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15 pages, 2943 KiB  
Article
Long Non-Coding RNA Malat1 Regulates Angiogenesis in Hindlimb Ischemia
by Xuejing Zhang, Xuelian Tang, Milton H. Hamblin and Ke-Jie Yin
Int. J. Mol. Sci. 2018, 19(6), 1723; https://doi.org/10.3390/ijms19061723 - 11 Jun 2018
Cited by 63 | Viewed by 6066
Abstract
Angiogenesis is a complex process that depends on the delicate regulation of gene expression. Dysregulation of transcription during angiogenesis often leads to various human diseases. Emerging evidence has recently begun to show that long non-coding RNAs (lncRNAs) may mediate angiogenesis in both physiological [...] Read more.
Angiogenesis is a complex process that depends on the delicate regulation of gene expression. Dysregulation of transcription during angiogenesis often leads to various human diseases. Emerging evidence has recently begun to show that long non-coding RNAs (lncRNAs) may mediate angiogenesis in both physiological and pathological conditions; concurrently, underlying molecular mechanisms are largely unexplored. Previously, our lab identified metastasis associates lung adenocarcinoma transcript 1 (Malat1) as an oxygen-glucose deprivation (OGD)-responsive endothelial lncRNA. Here we reported that genetic deficiency of Malat1 leads to reduced blood vessel formation and local blood flow perfusion in mouse hind limbs at one to four weeks after hindlimb ischemia. Malat1 and vascular endothelial growth factor receptor 2 (VEGFR2) levels were found to be increased in both cultured mouse primary skeletal muscle microvascular endothelial cells (SMMECs) after 16 h OGD followed by 24 h reperfusion and in mouse gastrocnemius muscle that underwent hindlimb ischemia followed by 28 days of reperfusion. Moreover, Malat1 silencing by locked nucleic acid (LNA)-GapmeRs significantly reduced tube formation, cell migration, and cell proliferation in SMMEC cultures. Mechanistically, RNA subcellular isolation and RNA-immunoprecipitation experiments demonstrate that Malat1 directly targets VEGFR2 to facilitate angiogenesis. The results suggest that Malat1 regulates cell-autonomous angiogenesis through direct regulation of VEGFR2. Full article
(This article belongs to the Collection Regulation by Non-coding RNAs)
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23 pages, 682 KiB  
Review
Role of Magnesium Deficiency in Promoting Atherosclerosis, Endothelial Dysfunction, and Arterial Stiffening as Risk Factors for Hypertension
by Krasimir Kostov and Lyudmila Halacheva
Int. J. Mol. Sci. 2018, 19(6), 1724; https://doi.org/10.3390/ijms19061724 - 11 Jun 2018
Cited by 165 | Viewed by 17749
Abstract
Arterial hypertension is a disease with a complex pathogenesis. Despite considerable knowledge about this socially significant disease, the role of magnesium deficiency (MgD) as a risk factor is not fully understood. Magnesium is a natural calcium antagonist. It potentiates the production of local [...] Read more.
Arterial hypertension is a disease with a complex pathogenesis. Despite considerable knowledge about this socially significant disease, the role of magnesium deficiency (MgD) as a risk factor is not fully understood. Magnesium is a natural calcium antagonist. It potentiates the production of local vasodilator mediators (prostacyclin and nitric oxide) and alters vascular responses to a variety of vasoactive substances (endothelin-1, angiotensin II, and catecholamines). MgD stimulates the production of aldosterone and potentiates vascular inflammatory response, while expression/activity of various antioxidant enzymes (glutathione peroxidase, superoxide dismutase, and catalase) and the levels of important antioxidants (vitamin C, vitamin E, and selenium) are decreased. Magnesium balances the effects of catecholamines in acute and chronic stress. MgD may be associated with the development of insulin resistance, hyperglycemia, and changes in lipid metabolism, which enhance atherosclerotic changes and arterial stiffness. Magnesium regulates collagen and elastin turnover in the vascular wall and matrix metalloproteinase activity. Magnesium helps to protect the elastic fibers from calcium deposition and maintains the elasticity of the vessels. Considering the numerous positive effects on a number of mechanisms related to arterial hypertension, consuming a healthy diet that provides the recommended amount of magnesium can be an appropriate strategy for helping control blood pressure. Full article
(This article belongs to the Special Issue Nutrition and Cardiovascular Health)
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23 pages, 3771 KiB  
Review
Cytotoxicity of Plant-Mediated Synthesis of Metallic Nanoparticles: A Systematic Review
by Nurul Akma Hanan, Hock Ing Chiu, Muggundha Raoov Ramachandran, Wai Hau Tung, Nur Nadhirah Mohamad Zain, Noorfatimah Yahaya and Vuanghao Lim
Int. J. Mol. Sci. 2018, 19(6), 1725; https://doi.org/10.3390/ijms19061725 - 11 Jun 2018
Cited by 86 | Viewed by 8487
Abstract
In the field of medicine, nanomaterials, especially those derived using the green method, offer promise as anti-cancer agents and drug carriers. However, the biosafety of metallic nanoparticles used as anti-cancer agents remains a concern. The goal of this systematic review was to compare [...] Read more.
In the field of medicine, nanomaterials, especially those derived using the green method, offer promise as anti-cancer agents and drug carriers. However, the biosafety of metallic nanoparticles used as anti-cancer agents remains a concern. The goal of this systematic review was to compare the cytotoxicity of different plant-mediated syntheses of metallic nanoparticles based on their potency, therapeutic index, and cancer cell type susceptibility in the hopes of identifying the most promising anti-cancer agents. A literature search of electronic databases including Science Direct, PubMed, Springer Link, Google Scholar, and ResearchGate, was conducted to obtain research articles. Keywords such as biosynthesis, plant synthesis, plant-mediated, metallic nanoparticle, cytotoxicity, and anticancer were used in the literature search. All types of research materials that met the inclusion criteria were included in the study regardless of whether the results were positive, negative, or null. The therapeutic index was used as a safety measure for the studied compound of interest. Data from 76 selected articles were extracted and synthesised. Seventy-two studies reported that the cytotoxicity of plant-mediated synthesis of metallic nanoparticles was time and/or dose-dependent. Biosynthesised silver nanoparticles demonstrated higher cytotoxicity potency compared to gold nanoparticles synthesised by the same plants (Plumbago zeylanica, Commelina nudiflora, and Cassia auriculata) irrespective of the cancer cell type tested. This review also identified a correlation between the nanoparticle size and morphology with the potency of cytotoxicity. Cytotoxicity was found to be inversely proportional to nanoparticle size. The plant-mediated syntheses of metallic nanoparticles were predominantly spherical or quasi-spherical, with the median lethal dose of 1–20 µg/mL. Nanoparticles with other shapes (triangular, hexagonal, and rods) were less potent. Metallic nanoparticles synthesised by Abutilon inducum, Butea monosperma, Gossypium hirsutum, Indoneesiella echioides, and Melia azedarach were acceptably safe as anti-cancer agents, as they had a therapeutic index of >2.0 when tested on both cancer cells and normal human cells. Most plant-mediated syntheses of metallic nanoparticles were found to be cytotoxic, although some were non-cytotoxic. The results from this study suggest a focus on a selected list of potential anti-cancer agents for further investigations of their pharmacodynamic/toxicodynamic and pharmacokinetic/toxicokinetic actions with the goal of reducing the Global Burden of Diseases and the second leading cause of mortality. Full article
(This article belongs to the Section Molecular Toxicology)
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13 pages, 865 KiB  
Review
Phoenixin—A Pleiotropic Gut-Brain Peptide
by Martha A. Schalla and Andreas Stengel
Int. J. Mol. Sci. 2018, 19(6), 1726; https://doi.org/10.3390/ijms19061726 - 11 Jun 2018
Cited by 32 | Viewed by 7630
Abstract
Phoenixin is a recently discovered brain peptide initially thought to be restricted to reproductive functions. The subsequent identification of phoenixin’s expression in peripheral tissues was accompanied by the description of several other actions of this hormone, such as effects on behavior, sensory perception, [...] Read more.
Phoenixin is a recently discovered brain peptide initially thought to be restricted to reproductive functions. The subsequent identification of phoenixin’s expression in peripheral tissues was accompanied by the description of several other actions of this hormone, such as effects on behavior, sensory perception, memory retention, the cardiovascular system as well as food intake, pointing towards a pleiotropic role of this peptide. The present review will discuss the present knowledge on phoenixin and the signaling involved as well as highlight gaps in knowledge to stimulate further research. Full article
(This article belongs to the Special Issue The (Microbiota)–Gut–Brain Axis: Hype or Revolution?)
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22 pages, 2512 KiB  
Article
Genome-Wide Identification and Characterization of Warming-Related Genes in Brassica rapa ssp. pekinensis
by Hayoung Song, Xiangshu Dong, Hankuil Yi, Ju Young Ahn, Keunho Yun, Myungchul Song, Ching-Tack Han and Yoonkang Hur
Int. J. Mol. Sci. 2018, 19(6), 1727; https://doi.org/10.3390/ijms19061727 - 11 Jun 2018
Cited by 3 | Viewed by 4882
Abstract
For sustainable crop cultivation in the face of global warming, it is important to unravel the genetic mechanisms underlying plant adaptation to a warming climate and apply this information to breeding. Thermomorphogenesis and ambient temperature signaling pathways have been well studied in model [...] Read more.
For sustainable crop cultivation in the face of global warming, it is important to unravel the genetic mechanisms underlying plant adaptation to a warming climate and apply this information to breeding. Thermomorphogenesis and ambient temperature signaling pathways have been well studied in model plants, but little information is available for vegetable crops. Here, we investigated genes responsive to warming conditions from two Brassica rapa inbred lines with different geographic origins: subtropical (Kenshin) and temperate (Chiifu). Genes in Gene Ontology categories “response to heat”, “heat acclimation”, “response to light intensity”, “response to oxidative stress”, and “response to temperature stimulus” were upregulated under warming treatment in both lines, but genes involved in “response to auxin stimulus” were upregulated only in Kenshin under both warming and minor-warming conditions. We identified 16 putative high temperature (HT) adaptation-related genes, including 10 heat-shock response genes, 2 transcription factor genes, 1 splicing factor gene, and 3 others. BrPIF4, BrROF2, and BrMPSR1 are candidate genes that might function in HT adaptation. Auxin response, alternative splicing of BrHSFA2, and heat shock memory appear to be indispensable for HT adaptation in B. rapa. These results lay the foundation for molecular breeding and marker development to improve warming tolerance in B. rapa. Full article
(This article belongs to the Special Issue Plant Genomics)
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19 pages, 5352 KiB  
Article
Gene Profiling in Late Blight Resistance in Potato Genotype SD20
by Xiaohui Yang, Xiao Guo, Yu Yang, Pei Ye, Xingyao Xiong, Jun Liu, Daofeng Dong and Guangcun Li
Int. J. Mol. Sci. 2018, 19(6), 1728; https://doi.org/10.3390/ijms19061728 - 11 Jun 2018
Cited by 36 | Viewed by 6773
Abstract
Late blight caused by the oomycete fungus Phytophthora infestans (Pi) is the most serious obstacle to potato (Solanum tuberosum) production in the world. A super race isolate, CN152, which was identified from Sichuan Province, China, could overcome nearly all [...] Read more.
Late blight caused by the oomycete fungus Phytophthora infestans (Pi) is the most serious obstacle to potato (Solanum tuberosum) production in the world. A super race isolate, CN152, which was identified from Sichuan Province, China, could overcome nearly all known late blight resistance genes and caused serious damage in China. The potato genotype SD20 was verified to be highly resistant to CN152; however, the molecular regulation network underlying late blight resistance pathway remains unclear in SD20. Here, we performed a time-course experiment to systematically profile the late blight resistance response genes using RNA-sequencing in SD20. We identified 3354 differentially expressed genes (DEGs), which mainly encoded transcription factors and protein kinases, and also included four NBS-LRR genes. The late blight responsive genes showed time-point-specific induction/repression. Multi-signaling pathways of salicylic acid, jasmonic acid, and ethylene signaling pathways involved in resistance and defense against Pi in SD20. Gene Ontology and KEGG analyses indicated that the DEGs were significantly enriched in metabolic process, protein serine/threonine kinase activity, and biosynthesis of secondary metabolites. Forty-three DEGs were involved in immune response, of which 19 were enriched in hypersensitive response reaction, which could play an important role in broad-spectrum resistance to Pi infection. Experimental verification confirmed the induced expression of the responsive genes in the late blight resistance signaling pathway, such as WRKY, ERF, MAPK, and NBS-LRR family genes. Our results provided valuable information for understanding late blight resistance mechanism of potato. Full article
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14 pages, 7653 KiB  
Article
Caveolin-1 Scaffolding Domain Peptides Alleviate Liver Fibrosis by Inhibiting TGF-β1/Smad Signaling in Mice
by Jing Lu, Jie Zhang, Yan Wang and Quan Sun
Int. J. Mol. Sci. 2018, 19(6), 1729; https://doi.org/10.3390/ijms19061729 (registering DOI) - 11 Jun 2018
Cited by 36 | Viewed by 5007 | Correction
Abstract
Liver fibrosis is the common pathological process characterized by activation of hepatic stellate cells (HSCs) and overproduction of extracellular matrix (ECM). Caveolin-1 (Cav1), the principal component of caveolae, is regarded as an important inhibitor of multiple signaling molecules including transforming growth factor β1(TGF-β1) [...] Read more.
Liver fibrosis is the common pathological process characterized by activation of hepatic stellate cells (HSCs) and overproduction of extracellular matrix (ECM). Caveolin-1 (Cav1), the principal component of caveolae, is regarded as an important inhibitor of multiple signaling molecules including transforming growth factor β1(TGF-β1) signaling. To evaluate the role of Cav1 in liver fibrosis, Cav1 deficient (Cav1−/−) and wild type (WT) mice were subjected to liver fibrosis induced by carbon tetrachloride (CCl4). Results indicated no significant difference between Cav1−/− and WT mice in inflammation or collagen content before CCl4 treatment. After CCl4 administration, Cav1−/− mice showed enhanced TGF-β1 signaling, as reflected by a significantly greater amount of phosphorylation of Smad2 and collagen deposition in livers over WT animals. Qualitative and quantitative analysis indicated that inflammatory injury to the liver was markedly aggravated, accompanied by increased degeneration and necrosis of hepatocytes, higher alanine aminotransferase (ALT)/aspartate aminotransferase (AST), TGF-α and IL-1β levels in Cav1−/− animals. The mRNA and protein levels of α-smooth muscle actin (α-SMA), Collagen α1(I), and Collagen α1(III) were further enhanced in Cav1−/− animals. We also observed a significant decrease in collagen content in Cav1−/− and WT animals administrated with Cav1 scaffolding domain peptides (CSD). In vitro study indicated that phosphorylation of Smad2 was inhibited after CSD treatment, accompanied by decreased protein levels of α-SMA, Collagen α1(I), and Collagen α1(III) in HSCs. We conclude that Cav1 is an important inhibitor of TGF-β1/Smad signaling in HSCs activation and collagen production, which might make it a promising target for therapy of liver fibrosis. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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16 pages, 1230 KiB  
Article
Dietary Conjugated Linoleic Acid-Enriched Cheeses Influence the Levels of Circulating n-3 Highly Unsaturated Fatty Acids in Humans
by Elisabetta Murru, Gianfranca Carta, Lina Cordeddu, Maria Paola Melis, Erika Desogus, Hastimansooreh Ansar, Yves Chilliard, Anne Ferlay, Catherine Stanton, Mairéad Coakley, R. Paul Ross, Giovanni Piredda, Margherita Addis, Maria Cristina Mele, Giorgio Cannelli, Sebastiano Banni and Claudia Manca
Int. J. Mol. Sci. 2018, 19(6), 1730; https://doi.org/10.3390/ijms19061730 - 11 Jun 2018
Cited by 28 | Viewed by 6432
Abstract
n-3 highly unsaturated fatty acids (n-3 HUFA) directly and indirectly regulate lipid metabolism, energy balance and the inflammatory response. We investigated changes to the n-3 HUFA score of healthy adults, induced by different types and amounts of conjugated linoleic acid (CLA)-enriched (ENCH) cheeses [...] Read more.
n-3 highly unsaturated fatty acids (n-3 HUFA) directly and indirectly regulate lipid metabolism, energy balance and the inflammatory response. We investigated changes to the n-3 HUFA score of healthy adults, induced by different types and amounts of conjugated linoleic acid (CLA)-enriched (ENCH) cheeses consumed for different periods of time, compared to dietary fish oil (FO) pills (500 mg, each containing 100 mg of eicosapentaenoic and docosahexaenoic acids—EPA+DHA) or α-linolenic acid (ALA)-rich linseed oil (4 g, containing 2 g of ALA). A significant increase in the n-3 HUFA score was observed, in a dose-dependent manner, after administration of the FO supplement. In terms of the impact on the n-3 HUFA score, the intake of ENCH cheese (90 g/day) for two or four weeks was equivalent to the administration of one or two FO pills, respectively. Conversely, the linseed oil intake did not significantly impact the n-3 HUFA score. Feeding ENCH cheeses from different sources (bovine, ovine and caprine) for two months improved the n-3 HUFA score by increasing plasma DHA, and the effect was proportional to the CLA content in the cheese. We suggest that the improved n-3 HUFA score resulting from ENCH cheese intake may be attributed to increased peroxisome proliferator-activated receptor alpha (PPAR-α) activity. This study demonstrates that natural ENCH cheese is an alternative nutritional source of n-3 HUFA in humans. Full article
(This article belongs to the Special Issue Omega-3 Fatty Acids in Health and Disease: New Knowledge)
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16 pages, 4650 KiB  
Article
Design, Synthesis, Cytotoxic Evaluation and Molecular Docking of New Fluoroquinazolinones as Potent Anticancer Agents with Dual EGFR Kinase and Tubulin Polymerization Inhibitory Effects
by Mohamed F. Zayed, Sahar Ahmed, Saleh Ihmaid, Hany E. A. Ahmed, Heba S. Rateb and Sabrin R. M. Ibrahim
Int. J. Mol. Sci. 2018, 19(6), 1731; https://doi.org/10.3390/ijms19061731 - 11 Jun 2018
Cited by 25 | Viewed by 4683
Abstract
A series of new fluoroquinazolinone 68 and 10ag derivatives was designed, prepared and screened for their in vitro cytotoxic activity against human cancer cell lines MCF-7 and MDA-MBA-231. Compounds 6 (IC50 = 0.35 ± 0.01 µM), 10f (IC [...] Read more.
A series of new fluoroquinazolinone 68 and 10ag derivatives was designed, prepared and screened for their in vitro cytotoxic activity against human cancer cell lines MCF-7 and MDA-MBA-231. Compounds 6 (IC50 = 0.35 ± 0.01 µM), 10f (IC50 = 0.71 ± 0.01 µM), 10d (IC50 = 0.89 ± 0.02 µM) and 10a (IC50 = 0.95 ± 0.01 µM) displayed broad spectrum anticancer activity better than the reference drug gefitinib (IC50 = 0.97 ± 0.02 µM) against MCF-7. Compounds 10e (IC50 = 0.28 ± 0.02 µM), 10d (IC50 = 0.38 ± 0.01 µM), 7 (IC50 = 0.94 ± 0.07 µM) and 10c (IC50 = 1.09 ± 0.01 µM) showed better activity than the reference gefitinib (IC50 = 1.30 ± 0.04 µM) against MDA-MBA-231. Moreover, EGFR and tubulin inhibition assays were performed for the highest active derivatives and showed remarkable results comparing to the reference drugs. In order to assess and explain their binding affinities, molecular docking simulation was studied against EGFR and tubulin binding sites. The results obtained from molecular docking study and those obtained from cytotoxic screening were correlated. Full article
(This article belongs to the Section Molecular Biophysics)
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15 pages, 5139 KiB  
Article
Anti-Atherogenic Effects of Vaspin on Human Aortic Smooth Muscle Cell/Macrophage Responses and Hyperlipidemic Mouse Plaque Phenotype
by Kengo Sato, Remina Shirai, Maho Yamaguchi, Tomoyuki Yamashita, Koichiro Shibata, Taisuke Okano, Yusaku Mori, Taka-aki Matsuyama, Hatsue Ishibashi-Ueda, Tsutomu Hirano and Takuya Watanabe
Int. J. Mol. Sci. 2018, 19(6), 1732; https://doi.org/10.3390/ijms19061732 - 11 Jun 2018
Cited by 26 | Viewed by 5219
Abstract
Vaspin (visceral adipose tissue-derived serine protease inhibitor) was recently identified as a novel adipocytokine with insulin-sensitizing effects. Serum vaspin levels are reported either increased or decreased in patients with coronary artery disease. Our translational research was performed to evaluate the expression of vaspin [...] Read more.
Vaspin (visceral adipose tissue-derived serine protease inhibitor) was recently identified as a novel adipocytokine with insulin-sensitizing effects. Serum vaspin levels are reported either increased or decreased in patients with coronary artery disease. Our translational research was performed to evaluate the expression of vaspin in human coronary atherosclerotic lesions, and its effects on atherogenic responses in human macrophages and human aortic smooth muscle cells (HASMC), as well as aortic atherosclerotic lesion development in spontaneously hyperlipidemic Apoe−/− mice, an animal model of atherosclerosis. Vaspin was expressed at high levels in macrophages/vascular smooth muscle cells (VSMCs) within human coronary atheromatous plaques. Vaspin significantly suppressed inflammatory phenotypes with nuclear factor κB down-regulation in human macrophages. Vaspin significantly suppressed oxidized low-density lipoprotein-induced foam cell formation with CD36 and acyl-coenzyme A: cholesterol acyltransferase-1 down-regulation and ATP-binding cassette transporters A1 and G1, and scavenger receptor class B type 1 up-regulation in human macrophages. Vaspin significantly suppressed angiotensin II-induced migration and proliferation with ERK1/2 and JNK down-regulation, and increased collagen production with phosphoinositide 3-kinase and Akt up-regulation in HASMCs. Chronic infusion of vaspin into Apoe−/− mice significantly suppressed the development of aortic atherosclerotic lesions, with significant reductions of intraplaque inflammation and the macrophage/VSMC ratio, a marker of plaque instability. Our study indicates that vaspin prevents atherosclerotic plaque formation and instability, and may serve as a novel therapeutic target in atherosclerotic cardiovascular diseases. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part I)
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22 pages, 4204 KiB  
Article
Overexpression of BraLTP2, a Lipid Transfer Protein of Brassica napus, Results in Increased Trichome Density and Altered Concentration of Secondary Metabolites
by Nini Tian, Fang Liu, Pandi Wang, Xiaohong Yan, Hongfei Gao, Xinhua Zeng and Gang Wu
Int. J. Mol. Sci. 2018, 19(6), 1733; https://doi.org/10.3390/ijms19061733 - 12 Jun 2018
Cited by 27 | Viewed by 5297
Abstract
Plant non-specific lipid transfer proteins (nsLTPs) belong to a large multigene family that possesses complex physiological functions. Trichomes are present on the aerial surfaces of most plants and include both glandular secretory hairs and non-glandular hairs. In this study, BraLTP2 was isolated from [...] Read more.
Plant non-specific lipid transfer proteins (nsLTPs) belong to a large multigene family that possesses complex physiological functions. Trichomes are present on the aerial surfaces of most plants and include both glandular secretory hairs and non-glandular hairs. In this study, BraLTP2 was isolated from Brassica rapa (B. rapa) and its function was characterized in the important oilseed crop Brassica napus (B. napus). B. rapa lipid transfer protein 2 (BraLTP2) belongs to the little-known Y class of nsLTPs and encodes a predicted secretory protein. In ProBraLTP2::GUS (β-glucuronidase) transgenic plants, strong GUS activity was observed in young leaves and roots, while low activity was observed in the anther. It is noteworthy that strong GUS activity was observed in trichomes of the first four leaves of 4-week-old and 8-week-old seedings, however, it disappeared in 12-week-old seedings. In transgenic plants expressing a BraLTP2::GFP (green fluorescent protein) fusion protein, GFP fluorescence localized in the extracellular space of epidermal cells and trichomes. Overexpression of BraLTP2 in B. napus caused an increase in trichome number and altered the accumulation of secondary metabolites in leaves, including 43 upregulated secondary metabolites. Moreover, transgenic plants showed significantly increased activities of antioxidant enzymes. These results suggest that BraLTP2, a new nsLTP gene, may play a role in trichome development and the accumulation of secondary metabolites. Full article
(This article belongs to the Section Molecular Plant Sciences)
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23 pages, 664 KiB  
Review
ALUminating the Path of Atherosclerosis Progression: Chaos Theory Suggests a Role for Alu Repeats in the Development of Atherosclerotic Vascular Disease
by Miguel Hueso, Josep M. Cruzado, Joan Torras and Estanislao Navarro
Int. J. Mol. Sci. 2018, 19(6), 1734; https://doi.org/10.3390/ijms19061734 - 12 Jun 2018
Cited by 21 | Viewed by 6976
Abstract
Atherosclerosis (ATH) and coronary artery disease (CAD) are chronic inflammatory diseases with an important genetic background; they derive from the cumulative effect of multiple common risk alleles, most of which are located in genomic noncoding regions. These complex diseases behave as nonlinear dynamical [...] Read more.
Atherosclerosis (ATH) and coronary artery disease (CAD) are chronic inflammatory diseases with an important genetic background; they derive from the cumulative effect of multiple common risk alleles, most of which are located in genomic noncoding regions. These complex diseases behave as nonlinear dynamical systems that show a high dependence on their initial conditions; thus, long-term predictions of disease progression are unreliable. One likely possibility is that the nonlinear nature of ATH could be dependent on nonlinear correlations in the structure of the human genome. In this review, we show how chaos theory analysis has highlighted genomic regions that have shared specific structural constraints, which could have a role in ATH progression. These regions were shown to be enriched with repetitive sequences of the Alu family, genomic parasites that have colonized the human genome, which show a particular secondary structure and are involved in the regulation of gene expression. Here, we show the impact of Alu elements on the mechanisms that regulate gene expression, especially highlighting the molecular mechanisms via which the Alu elements alter the inflammatory response. We devote special attention to their relationship with the long noncoding RNA (lncRNA); antisense noncoding RNA in the INK4 locus (ANRIL), a risk factor for ATH; their role as microRNA (miRNA) sponges; and their ability to interfere with the regulatory circuitry of the (nuclear factor kappa B) NF-κB response. We aim to characterize ATH as a nonlinear dynamic system, in which small initial alterations in the expression of a number of repetitive elements are somehow amplified to reach phenotypic significance. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part I)
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17 pages, 2217 KiB  
Review
Role of the DNA Damage Response in Human Papillomavirus RNA Splicing and Polyadenylation
by Kersti Nilsson, Chengjun Wu and Stefan Schwartz
Int. J. Mol. Sci. 2018, 19(6), 1735; https://doi.org/10.3390/ijms19061735 - 12 Jun 2018
Cited by 18 | Viewed by 6222
Abstract
Human papillomaviruses (HPVs) have evolved to use the DNA repair machinery to replicate its DNA genome in differentiated cells. HPV activates the DNA damage response (DDR) in infected cells. Cellular DDR factors are recruited to the HPV DNA genome and position the cellular [...] Read more.
Human papillomaviruses (HPVs) have evolved to use the DNA repair machinery to replicate its DNA genome in differentiated cells. HPV activates the DNA damage response (DDR) in infected cells. Cellular DDR factors are recruited to the HPV DNA genome and position the cellular DNA polymerase on the HPV DNA and progeny genomes are synthesized. Following HPV DNA replication, HPV late gene expression is activated. Recent research has shown that the DDR factors also interact with RNA binding proteins and affects RNA processing. DDR factors activated by DNA damage and that associate with HPV DNA can recruit splicing factors and RNA binding proteins to the HPV DNA and induce HPV late gene expression. This induction is the result of altered alternative polyadenylation and splicing of HPV messenger RNA (mRNA). HPV uses the DDR machinery to replicate its DNA genome and to activate HPV late gene expression at the level of RNA processing. Full article
(This article belongs to the Special Issue Human Polyomaviruses and Papillomaviruses)
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15 pages, 4492 KiB  
Article
Berberine Protects Human Retinal Pigment Epithelial Cells from Hydrogen Peroxide-Induced Oxidative Damage through Activation of AMPK
by Shuai Li, Uma Gaur, Cheong-Meng Chong, Shaofen Lin, Jiankang Fang, Zhiwen Zeng, Haitao Wang and Wenhua Zheng
Int. J. Mol. Sci. 2018, 19(6), 1736; https://doi.org/10.3390/ijms19061736 - 12 Jun 2018
Cited by 40 | Viewed by 6841
Abstract
Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly with less effective treatment, especially for dry AMD (90% of AMD). Although the etiology of this disease is not well elucidated, increasing evidences indicate that excessive reactive oxygen [...] Read more.
Age-related macular degeneration (AMD) is the leading cause of central vision loss in the elderly with less effective treatment, especially for dry AMD (90% of AMD). Although the etiology of this disease is not well elucidated, increasing evidences indicate that excessive reactive oxygen species (ROS) impairing the physiological functions of retinal pigment epithelium (RPE) cells may be one of the main causes. Therefore, it could be a great strategy to find some drugs that can effectively protect RPE cells from oxidative damage which is desired to treat and slow the process of AMD. In the present study, a well-known traditional Chinese medicine berberine (BBR) was found to suppress hydrogen peroxide (H2O2)-induced oxidative damage in D407 cells, a human RPE cell line. Pre-treatment of D407 cells with BBR significantly suppressed H2O2-induced cell apoptosis by restoring abnormal changes in nuclear morphology, preventing the decline of mitochondrial membrane potential, reducing lactate dehydrogenase release and inhibiting caspase 3/7 activities induced by H2O2. Western blot analysis showed that BBR was able to stimulate the phosphorylation/activation of AMPK in a time- and dose-dependent manner in D407 cells, while treatment of cells with AMPK pathway inhibitor Compound C, or knockdown of the AMPK by specific siRNA blocked the effect of BBR. Similar results were obtained in primary cultured human RPE cells. Taken together, these results demonstrated that BBR was able to protect RPE cells against oxidative stress via the activation of AMPK pathway. Our findings also indicate the potential application of BBR in AMD treatment. Full article
(This article belongs to the Section Biochemistry)
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12 pages, 2288 KiB  
Article
Generation of Human Breg-Like Phenotype with Regulatory Function In Vitro with Bacteria-Derived Oligodeoxynucleotides
by Jorge Gallego-Valle, Verónica Astrid Pérez-Fernández, Rafael Correa-Rocha and Marjorie Pion
Int. J. Mol. Sci. 2018, 19(6), 1737; https://doi.org/10.3390/ijms19061737 - 12 Jun 2018
Cited by 26 | Viewed by 4878
Abstract
Regulatory B cells (Bregs) participate in auto-tolerance maintenance and immune homeostasis. Despite their impact on many diseases and due to the difficulty to define them, knowledge about their origin and their physiological inducers is still unclear. The incomplete understanding about the generation of [...] Read more.
Regulatory B cells (Bregs) participate in auto-tolerance maintenance and immune homeostasis. Despite their impact on many diseases and due to the difficulty to define them, knowledge about their origin and their physiological inducers is still unclear. The incomplete understanding about the generation of Bregs and their limited numbers in periphery make it difficult to develop Breg-based therapy. Therefore, identifying factors that promote their development would allow their ex-vivo production in order to create new immunotherapy. This project aims to test the capacity of several cytokines (Interleukin 1-beta (IL-1β), Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF), and Cluster of differentiation 40 ligand (CD40L)) and bacteria-derived oligodeoxynucleotides (CpG-ODN), alone or in combination, to generate B cells with regulatory phenotype and function. We have demonstrated that the Breg-associated phenotypes were heterogeneous between one and other stimulation conditions. However, the expression of other markers related to Bregs such as IL-10, CD80, CD86, CD71, Programmed cell death-1 (PD-1), and Programmed death-ligand 1 (PD-L1) was increased when cells were stimulated with CpG alone or in combination. Moreover, stimulated B cells presented a suppressive function on autologous activated peripheral blood mononuclear cells (PBMC) proliferation. Therefore, this work is the first step to demonstrate the feasibility to induce functional Breg-like cells in vitro and will then facilitate the way to produce Breg-like cells as a potential future cellular therapy. Full article
(This article belongs to the Special Issue B Cells and Immunological Tolerance)
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16 pages, 1167 KiB  
Review
Functional Regulation of PPARs through Post-Translational Modifications
by Reinhard Brunmeir and Feng Xu
Int. J. Mol. Sci. 2018, 19(6), 1738; https://doi.org/10.3390/ijms19061738 - 12 Jun 2018
Cited by 181 | Viewed by 13326
Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and they are essential regulators of cell differentiation, tissue development, and energy metabolism. Given their central roles in sensing the cellular metabolic state and controlling metabolic homeostasis, PPARs became important targets of drug [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and they are essential regulators of cell differentiation, tissue development, and energy metabolism. Given their central roles in sensing the cellular metabolic state and controlling metabolic homeostasis, PPARs became important targets of drug development for the management of metabolic disorders. The function of PPARs is mainly regulated through ligand binding, which induces structural changes, further affecting the interactions with co-activators or co-repressors to stimulate or inhibit their functions. In addition, PPAR functions are also regulated by various Post-translational modifications (PTMs). These PTMs include phosphorylation, SUMOylation, ubiquitination, acetylation, and O-GlcNAcylation, which are found at numerous modification sites. The addition of these PTMs has a wide spectrum of consequences on protein stability, transactivation function, and co-factor interaction. Moreover, certain PTMs in PPAR proteins have been associated with the status of metabolic diseases. In this review, we summarize the PTMs found on the three PPAR isoforms PPARα, PPARβ/δ, and PPARγ, and their corresponding modifying enzymes. We also discuss the functional roles of these PTMs in regulating metabolic homeostasis and provide a perspective for future research in this intriguing field. Full article
(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)
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14 pages, 262 KiB  
Review
Bimodal Function of Anti-TNF Treatment: Shall We Be Concerned about Anti-TNF Treatment in Patients with Rheumatoid Arthritis and Heart Failure?
by Przemyslaw J. Kotyla
Int. J. Mol. Sci. 2018, 19(6), 1739; https://doi.org/10.3390/ijms19061739 - 12 Jun 2018
Cited by 39 | Viewed by 6719
Abstract
Treatment with anti-TNF-α (tumor necrosis factor), one of the pivotal cytokines, was introduced to clinical practice at the end of last century and revolutionized the treatment of rheumatoid arthritis (RA) as well as many other inflammatory conditions. Such a treatment may however bring [...] Read more.
Treatment with anti-TNF-α (tumor necrosis factor), one of the pivotal cytokines, was introduced to clinical practice at the end of last century and revolutionized the treatment of rheumatoid arthritis (RA) as well as many other inflammatory conditions. Such a treatment may however bring many safety issues regarding infections, tuberculosis, as well as cardiovascular diseases, including heart failure. Given the central role of proinflammatory cytokines in RA, atherosclerosis, and congestive heart failure (CHF), such a treatment might result in better control of the RA process on the one side and improvement of heart function on the other. Unfortunately, at the beginning of this century two randomized controlled trials failed to show any benefit of anti-TNF treatment in patients with heart failure (HF), suggesting direct negative impact of the treatment on morbidity and mortality in HF patients. As a result the anti-TNF treatment is contraindicated in all patients with heart failure and a substantial portion of patients with RA and impaired heart function are not able to benefit from the treatment. The role of TNF in CHF and RA differs substantially with regard to the source and pathophysiological function of the cytokine in both conditions, therefore negative data from CHF studies should be interpreted with caution. At least some of RA patients with heart failure may benefit from anti-TNF treatment, as it results not only in the reduction of inflammation but also contributes significantly to the improvement of cardiac function. The paper addresses the epidemiological data of safety of anti-TNF treatment in RA patients with the special emphasis to basic pathophysiological mechanisms via which TNF may act differently in both diseases. Full article
(This article belongs to the Special Issue Tumor Necrosis Factor (TNF))
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12 pages, 624 KiB  
Article
Classical Risk Factors and Inflammatory Biomarkers: One of the Missing Biological Links between Cardiovascular Disease and Major Depressive Disorder
by Thomas C. Baghai, Gabriella Varallo-Bedarida, Christoph Born, Sibylle Häfner, Cornelius Schüle, Daniela Eser, Peter Zill, André Manook, Johannes Weigl, Somayeh Jooyandeh, Caroline Nothdurfter, Clemens Von Schacky, Brigitta Bondy and Rainer Rupprecht
Int. J. Mol. Sci. 2018, 19(6), 1740; https://doi.org/10.3390/ijms19061740 - 12 Jun 2018
Cited by 48 | Viewed by 6105
Abstract
Background: Cardiovascular disorders (CVD) and major depressive disorder (MDD) are the most frequent diseases worldwide responsible for premature death and disability. Behavioral and immunological variables influence the pathophysiology of both disorders. We therefore determined frequency and severity of MDD in CVD and studied [...] Read more.
Background: Cardiovascular disorders (CVD) and major depressive disorder (MDD) are the most frequent diseases worldwide responsible for premature death and disability. Behavioral and immunological variables influence the pathophysiology of both disorders. We therefore determined frequency and severity of MDD in CVD and studied whether MDD without CVD or other somatic diseases influences classical and inflammatory biomarkers of cardiovascular risk. In addition, we investigated the influence of proinflammatory cytokines on antidepressant treatment outcome. Methods: In a case-control design, 310 adults (MDD patients without CVD, CVD patients, and cardiologically and psychiatrically healthy matched controls) were investigated. MDD patients were recruited after admission in a psychiatric university hospital. Primary outcome criteria were clinical depression ratings (HAM-D scale), vital signs, classical cardiovascular risk factors and inflammatory biomarkers which were compared between MDD patients and healthy controls. Results: We detected an enhanced cardiovascular risk in MDD. Untreated prehypertension and signs directing to a metabolic syndrome were detected in MDD. Significantly higher inflammatory biomarkers such as the high sensitivity C-reaktive protein (hsCRP) and proinflammatory acute phase cytokines interleukine-1β (IL-1β) and interleukine-6 (IL-6) underlined the higher cardiovascular risk in physically healthy MDD patients. Surprisingly, high inflammation markers before treatment were associated with better clinical outcome and faster remission. The rate of MDD in CVD patients was high. Conclusions: Patients suffering from MDD are at specific risk for CVD. Precise detection of cardiovascular risks in MDD beyond classical risk factors is warranted to allow effective prophylaxis and treatment of both conditions. Future studies of prophylactic interventions may help to provide a basis for prophylactic treatment of both MDD and CVD. In addition, the high risk for MDD in CVD patients was confirmed and underlines the requirement for clinical attention. Full article
(This article belongs to the Special Issue Molecular Psychiatry)
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25 pages, 7439 KiB  
Article
Characterization of the Complete Mitochondrial Genome Sequences of Three Croakers (Perciformes, Sciaenidae) and Novel Insights into the Phylogenetics
by Huirong Yang, Jun Xia, Jia-en Zhang, Jinzeng Yang, Huihong Zhao, Qing Wang, Jijia Sun, Huayi Xue, Yuanyuan Wu, Jiehu Chen, Jingchuan Huang and Li Liu
Int. J. Mol. Sci. 2018, 19(6), 1741; https://doi.org/10.3390/ijms19061741 - 12 Jun 2018
Cited by 34 | Viewed by 5050
Abstract
The three croakers (Nibea coibor, Protonibea diacanthus and Argyrosomus amoyensis, Perciformes, Sciaenidae) are important commercial species inhabiting the Eastern Indian Ocean and Western Pacific. Molecular data employed in previous research on phylogenetic reconstruction have not been adequate and complete, and [...] Read more.
The three croakers (Nibea coibor, Protonibea diacanthus and Argyrosomus amoyensis, Perciformes, Sciaenidae) are important commercial species inhabiting the Eastern Indian Ocean and Western Pacific. Molecular data employed in previous research on phylogenetic reconstruction have not been adequate and complete, and systematic and comprehensive phylogenetic relationships for these fish are unresolved. We sequenced the complete mitochondrial genomes of the three croakers using next-generation sequencing for the first time. We analyzed the composition and phylogenies between 19 species in the family Sciaenidae using the mitochondrial protein coding sequences of 204 species in the Series Eupercaria. We present the characterization of the complete mitochondrial genome sequences of the three croakers. Gene arrangement and distribution of the three croakers are canonically identical and consistent with other vertebrates. We found that the family Sciaenidae is an independent branch that is isolated from the order Perciformes and does not belong to any extant classification. Therefore, this family is expected to belong to a new classification at the order level and needs further analysis. The evolution of Sciaenidae has lagged far behind the Perciformes differentiation. This study presents a novel insight into the phylogenetics of the family Sciaenidae from the order Perciformes and facilitates additional studies on the evolution and phylogeny of Series Eupercaria. Full article
(This article belongs to the Section Biochemistry)
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21 pages, 3311 KiB  
Article
Effects of Melatonin and Its Underlying Mechanism on Ethanol-Stimulated Senescence and Osteoclastic Differentiation in Human Periodontal Ligament Cells and Cementoblasts
by Won-Jung Bae, Jae Suh Park, Soo-Kyung Kang, Il-Keun Kwon and Eun-Cheol Kim
Int. J. Mol. Sci. 2018, 19(6), 1742; https://doi.org/10.3390/ijms19061742 - 12 Jun 2018
Cited by 32 | Viewed by 6412
Abstract
The present study evaluated the protective effects of melatonin in ethanol (EtOH)-induced senescence and osteoclastic differentiation in human periodontal ligament cells (HPDLCs) and cementoblasts and the underlying mechanism. EtOH increased senescence activity, levels of reactive oxygen species (ROS) and the expression of cell [...] Read more.
The present study evaluated the protective effects of melatonin in ethanol (EtOH)-induced senescence and osteoclastic differentiation in human periodontal ligament cells (HPDLCs) and cementoblasts and the underlying mechanism. EtOH increased senescence activity, levels of reactive oxygen species (ROS) and the expression of cell cycle regulators (p53, p21 and p16) and senescence-associated secretory phenotype (SASP) genes (interleukin [IL]-1β, IL-6, IL-8 and tumor necrosis factor-α) in HPDLCs and cementoblasts. Melatonin inhibited EtOH-induced senescence and the production of ROS as well as the increased expression of cell cycle regulators and SASP genes. However, it recovered EtOH-suppressed osteoblastic/cementoblastic differentiation, as evidenced by alkaline phosphatase activity, alizarin staining and mRNA expression levels of Runt-related transcription factor 2 (Runx2) and osteoblastic and cementoblastic markers (glucose transporter 1 and cementum-derived protein-32) in HPDLCs and cementoblasts. Moreover, it inhibited EtOH-induced osteoclastic differentiation in mouse bone marrow–derived macrophages (BMMs). Inhibition of protein never in mitosis gene A interacting-1 (PIN1) by juglone or small interfering RNA reversed the effects of melatonin on EtOH-mediated senescence as well as osteoblastic and osteoclastic differentiation. Melatonin blocked EtOH-induced activation of mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK) and Nuclear factor of activated T-cells (NFAT) c-1 pathways, which was reversed by inhibition of PIN1. This is the first study to show the protective effects of melatonin on senescence-like phenotypes and osteoclastic differentiation induced by oxidative stress in HPDLCs and cementoblasts through the PIN1 pathway. Full article
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16 pages, 619 KiB  
Review
Molecular Mechanisms of Oligodendrocyte Regeneration in White Matter-Related Diseases
by Ryo Ohtomo, Atsushi Iwata and Ken Arai
Int. J. Mol. Sci. 2018, 19(6), 1743; https://doi.org/10.3390/ijms19061743 - 12 Jun 2018
Cited by 29 | Viewed by 6511
Abstract
Even in adult brains, restorative mechanisms are still retained to maintain the microenvironment. Under the pathological conditions of central nervous system (CNS) diseases, several immature cells in the brain would be activated as a compensative response. As the concept of the neurovascular unit [...] Read more.
Even in adult brains, restorative mechanisms are still retained to maintain the microenvironment. Under the pathological conditions of central nervous system (CNS) diseases, several immature cells in the brain would be activated as a compensative response. As the concept of the neurovascular unit emphasizes, cell-cell interactions play important roles in this restorative process. White matter damage and oligodendrocyte loss are representative characteristics for many neurodegenerative diseases. In response to oligodendrocyte damage, residual oligodendrocyte precursor cells (OPCs) initiate their proliferation and differentiation for the purpose of remyelination. Although mechanisms of oligodendrogenesis and remyelination in CNS diseases are still mostly unknown and understudied, accumulated evidence now suggests that support from neighboring cells is necessary for OPC proliferation and differentiation. In this review, we first overview basic mechanisms of interaction between oligodendrocyte lineage cells and neighboring cells, and then introduce how oligodendrogenesis occurs under the conditions of neurodegenerative diseases, focusing on vascular cognitive impairment syndrome, Alzheimer’s disease, and multiple sclerosis. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases)
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13 pages, 845 KiB  
Review
AMP-Activated Protein Kinase as a Reprogramming Strategy for Hypertension and Kidney Disease of Developmental Origin
by You-Lin Tain and Chien-Ning Hsu
Int. J. Mol. Sci. 2018, 19(6), 1744; https://doi.org/10.3390/ijms19061744 - 12 Jun 2018
Cited by 64 | Viewed by 5176
Abstract
Suboptimal early-life conditions affect the developing kidney, resulting in long-term programming effects, namely renal programming. Adverse renal programming increases the risk for developing hypertension and kidney disease in adulthood. Conversely, reprogramming is a strategy aimed at reversing the programming processes in early life. [...] Read more.
Suboptimal early-life conditions affect the developing kidney, resulting in long-term programming effects, namely renal programming. Adverse renal programming increases the risk for developing hypertension and kidney disease in adulthood. Conversely, reprogramming is a strategy aimed at reversing the programming processes in early life. AMP-activated protein kinase (AMPK) plays a key role in normal renal physiology and the pathogenesis of hypertension and kidney disease. This review discusses the regulation of AMPK in the kidney and provides hypothetical mechanisms linking AMPK to renal programming. This will be followed by studies targeting AMPK activators like metformin, resveratrol, thiazolidinediones, and polyphenols as reprogramming strategies to prevent hypertension and kidney disease. Further studies that broaden our understanding of AMPK isoform- and tissue-specific effects on renal programming are needed to ultimately develop reprogramming strategies. Despite the fact that animal models have provided interesting results with regard to reprogramming strategies targeting AMPK signaling to protect against hypertension and kidney disease with developmental origins, these results await further clinical translation. Full article
(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)
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16 pages, 1361 KiB  
Review
Peribiliary Glands as the Cellular Origin of Biliary Tract Cancer
by Hayato Nakagawa, Yuki Hayata, Tomoharu Yamada, Satoshi Kawamura, Nobumi Suzuki and Kazuhiko Koike
Int. J. Mol. Sci. 2018, 19(6), 1745; https://doi.org/10.3390/ijms19061745 - 12 Jun 2018
Cited by 20 | Viewed by 6643
Abstract
The identification of the cellular origin of cancer is important for our understanding of the mechanisms regulating carcinogenesis, thus the cellular origin of cholangiocarcinoma (CCA) is a current topic of interest. Although CCA has been considered to originate from biliary epithelial cells, recent [...] Read more.
The identification of the cellular origin of cancer is important for our understanding of the mechanisms regulating carcinogenesis, thus the cellular origin of cholangiocarcinoma (CCA) is a current topic of interest. Although CCA has been considered to originate from biliary epithelial cells, recent studies have suggested that multiple cell types can develop into CCA. With regard to the hilar and extrahepatic bile ducts, peribiliary glands (PBGs), a potential stem cell niche of biliary epithelial cells, have attracted attention as the cellular origin of biliary tract cancer. Recent histopathological and experimental studies have suggested that some kinds of inflammation-induced CCA and intraductal papillary neoplasms of the bile duct are more likely to originate from PBGs. During inflammation-mediated cholangiocarcinogenesis, the biliary epithelial injury-induced regenerative response by PBGs is considered a key process. Thus, in this review, we discuss recent advances in our understanding of cholangiocarcinogenesis from the viewpoint of inflammation and the cellular origin of CCA, especially focusing on PBGs. Full article
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15 pages, 3066 KiB  
Article
The “Magnesium Sacrifice” Strategy Enables PMMA Bone Cement Partial Biodegradability and Osseointegration Potential
by Qingpan Zhai, Fengxuan Han, Zhiwei He, Chen Shi, Pinghui Zhou, Caihong Zhu, Qianping Guo, Xuesong Zhu, Huilin Yang and Bin Li
Int. J. Mol. Sci. 2018, 19(6), 1746; https://doi.org/10.3390/ijms19061746 - 12 Jun 2018
Cited by 25 | Viewed by 5902
Abstract
Poly (methyl methacrylate) (PMMA)-based bone cements are the most commonly used injectable orthopedic materials due to their excellent injectability and mechanical properties. However, their poor biocompatibility and excessive stiffness may cause complications such as aseptic implant loosening and stress shielding. In this study, [...] Read more.
Poly (methyl methacrylate) (PMMA)-based bone cements are the most commonly used injectable orthopedic materials due to their excellent injectability and mechanical properties. However, their poor biocompatibility and excessive stiffness may cause complications such as aseptic implant loosening and stress shielding. In this study, we aimed to develop a new type of partially biodegradable composite bone cement by incorporating magnesium (Mg) microspheres, known as “Mg sacrifices” (MgSs), in the PMMA matrix. Being sensitive to the physiological environment, the MgSs in PMMA could gradually degrade to produce bioactive Mg ions and, meanwhile, result in an interconnected macroporous structure within the cement matrix. The mechanical properties, solidification, and biocompatibility, both in vitro and in vivo, of PMMA–Mg bone cement were characterized. Interestingly, the incorporation of Mg microspheres did not markedly affect the mechanical strength of bone cement. However, the maximum temperature upon setting of bone cement decreased. This partially biodegradable composite bone cement showed good biocompatibility in vitro. In the in vivo study, considerable bony ingrowth occurred in the pores upon MgS degradation. Together, the findings from this study indicate that such partially biodegradable PMMA–Mg composite may be ideal bone cement for minimally invasive orthopedic surgeries such as vertebroplasty and kyphoplasty. Full article
(This article belongs to the Section Materials Science)
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11 pages, 2567 KiB  
Article
Effect of Calcium on Absorption Properties and Thermal Stability of Milk during Microwave Heating
by Yejun Wu, Daming Fan, Feng Hang, Bowen Yan, Jianxin Zhao, Hao Zhang and Wei Chen
Int. J. Mol. Sci. 2018, 19(6), 1747; https://doi.org/10.3390/ijms19061747 - 13 Jun 2018
Cited by 15 | Viewed by 3953
Abstract
During heating, there are a lot of physical and chemical changes in milk components, which are mainly reflected in the changes of proteins. Calcium ions in milk react with proteins to precipitate or form gels, and the thermal stability of milk is affected [...] Read more.
During heating, there are a lot of physical and chemical changes in milk components, which are mainly reflected in the changes of proteins. Calcium ions in milk react with proteins to precipitate or form gels, and the thermal stability of milk is affected by the type and content of calcium. In this study, different calcium-fortified milk systems were treated by rapid conventional heating (RCV) and microwave heating (MV) to evaluate the effects of forms and concentration of calcium in liquid milk on microwave absorption properties and thermal stability of milk. It was found that the concentration of calcium ions on microwave energy absorption is not a significant influence, while the forms affected the systems dramatically. The thermal stability of milk during MV is remarkably affected by the forms of calcium ions. When adding ionized calcium, the calcium-fortified milk systems had poor thermal stability and severe agglomeration of protein, while the addition of milk calcium had little effect and was almost free from protein coagulation. It could be speculated that the metal ions in the microwave field could create a strong vibration that could trigger protein agglomeration through the combination of the surrounding casein phosphorylates. Full article
(This article belongs to the Section Molecular Biophysics)
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19 pages, 2485 KiB  
Review
Synchrotron Radiation X-ray Diffraction Techniques Applied to Insect Flight Muscle
by Hiroyuki Iwamoto
Int. J. Mol. Sci. 2018, 19(6), 1748; https://doi.org/10.3390/ijms19061748 - 13 Jun 2018
Cited by 12 | Viewed by 5749
Abstract
X-ray fiber diffraction is a powerful tool used for investigating the molecular structure of muscle and its dynamics during contraction. This technique has been successfully applied not only to skeletal and cardiac muscles of vertebrates but also to insect flight muscle. Generally, insect [...] Read more.
X-ray fiber diffraction is a powerful tool used for investigating the molecular structure of muscle and its dynamics during contraction. This technique has been successfully applied not only to skeletal and cardiac muscles of vertebrates but also to insect flight muscle. Generally, insect flight muscle has a highly ordered structure and is often capable of high-frequency oscillations. The X-ray diffraction studies on muscle have been accelerated by the advent of 3rd-generation synchrotron radiation facilities, which can generate brilliant and highly oriented X-ray beams. This review focuses on some of the novel experiments done on insect flight muscle by using synchrotron radiation X-rays. These include diffraction recordings from single myofibrils within a flight muscle fiber by using X-ray microbeams and high-speed diffraction recordings from the flight muscle during the wing-beat of live insects. These experiments have provided information about the molecular structure and dynamic function of flight muscle in unprecedented detail. Future directions of X-ray diffraction studies on muscle are also discussed. Full article
(This article belongs to the Special Issue The Actin-Myosin Interaction in Muscle)
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4 pages, 173 KiB  
Editorial
Recent Advances in Scar Biology
by Rei Ogawa
Int. J. Mol. Sci. 2018, 19(6), 1749; https://doi.org/10.3390/ijms19061749 - 13 Jun 2018
Cited by 20 | Viewed by 3799
(This article belongs to the Special Issue Recent Advances in Scar Biology)
21 pages, 724 KiB  
Review
Complement Activation in Liver Transplantation: Role of Donor Macrosteatosis and Implications in Delayed Graft Function
by Kelley Núñez, Paul Thevenot, Abeer Alfadhli and Ari Cohen
Int. J. Mol. Sci. 2018, 19(6), 1750; https://doi.org/10.3390/ijms19061750 - 13 Jun 2018
Cited by 15 | Viewed by 4681
Abstract
The complement system anchors the innate inflammatory response by triggering both cell-mediated and antibody-mediated immune responses against pathogens. The complement system also plays a critical role in sterile tissue injury by responding to damage-associated molecular patterns. The degree and duration of complement activation [...] Read more.
The complement system anchors the innate inflammatory response by triggering both cell-mediated and antibody-mediated immune responses against pathogens. The complement system also plays a critical role in sterile tissue injury by responding to damage-associated molecular patterns. The degree and duration of complement activation may be a critical variable controlling the balance between regenerative and destructive inflammation following sterile injury. Recent studies in kidney transplantation suggest that aberrant complement activation may play a significant role in delayed graft function following transplantation, confirming results obtained from rodent models of renal ischemia/reperfusion (I/R) injury. Deactivating the complement cascade through targeting anaphylatoxins (C3a/C5a) might be an effective clinical strategy to dampen reperfusion injury and reduce delayed graft function in liver transplantation. Targeting the complement cascade may be critical in donor livers with mild to moderate steatosis, where elevated lipid burden amplifies stress responses and increases hepatocyte turnover. Steatosis-driven complement activation in the donor liver may also have implications in rejection and thrombolytic complications following transplantation. This review focuses on the roles of complement activation in liver I/R injury, strategies to target complement activation in liver I/R, and potential opportunities to translate these strategies to transplanting donor livers with mild to moderate steatosis. Full article
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20 pages, 3356 KiB  
Article
Whole-Transcriptome Sequence Analysis of Verbena bonariensis in Response to Drought Stress
by Bei Wang, Xue-Qi Lv, Ling He, Qian Zhao, Mao-Sheng Xu, Lei Zhang, Yin Jia, Fan Zhang, Feng-Luan Liu and Qing-Lin Liu
Int. J. Mol. Sci. 2018, 19(6), 1751; https://doi.org/10.3390/ijms19061751 - 13 Jun 2018
Cited by 17 | Viewed by 4661
Abstract
Drought is an important abiotic factor that threatens the growth and development of plants. Verbena bonariensis is a widely used landscape plant with a very high ornamental value. We found that Verbena has drought tolerance in production practice, so in order to delve [...] Read more.
Drought is an important abiotic factor that threatens the growth and development of plants. Verbena bonariensis is a widely used landscape plant with a very high ornamental value. We found that Verbena has drought tolerance in production practice, so in order to delve into its mechanism of drought resistance and screen out its drought-resistance genes, we used the RNA-Seq platform to perform a de novo transcriptome assembly to analyze Verbena transcription response to drought stress. By high-throughput sequencing with Illumina Hiseq Xten, a total of 44.59 Gb clean data was obtained from T01 (control group) and T02 (drought experiment group). After assembly, 111,313 unigenes were obtained, and 53,757 of them were annotated by compared databases. In this study, 4829 differentially expressed genes were obtained, of which 4165 were annotated. We performed GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analyses, and explored a lot of differently expressed genes related to plant energy production, hormone synthesis, cell signal transduction, and metabolism to understand the stress response of Verbena in drought stress. In addition, we also found that a series of TFs related to drought-resistance of Verbena and provide excellent genetic resources for improving the drought tolerance of crops. Full article
(This article belongs to the Special Issue Plant Genomics)
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11 pages, 220 KiB  
Review
Regulation of von-Willebrand Factor Secretion from Endothelial Cells by the Annexin A2-S100A10 Complex
by Anna Holthenrich and Volker Gerke
Int. J. Mol. Sci. 2018, 19(6), 1752; https://doi.org/10.3390/ijms19061752 - 13 Jun 2018
Cited by 29 | Viewed by 4768
Abstract
Endothelial cells serve as gatekeepers of vascular hemostasis and local inflammatory reactions. They can rapidly respond to changes in the environment, caused, for example, by blood vessel injury, tissue damage or infection, by secreting in a strictly regulated manner factors regulating these processes. [...] Read more.
Endothelial cells serve as gatekeepers of vascular hemostasis and local inflammatory reactions. They can rapidly respond to changes in the environment, caused, for example, by blood vessel injury, tissue damage or infection, by secreting in a strictly regulated manner factors regulating these processes. These factors include adhesion receptors for circulating leukocytes and platelets, P-selectin and von-Willebrand factor (VWF) that are stored in specialized secretory granules of endothelial cells, the Weibel-Palade bodies (WPB). Acute exposure of these adhesion molecules converts the endothelial cell surface from an anti-adhesive state enabling unrestricted flow of circulating blood cells to an adhesive one capable of capturing leukocytes (through P-selectin) and platelets (through VWF). While these are important (patho)physiological responses, compromised or dysregulated WPB secretion can cause pathologies such as excessive bleeding or vascular occlusion. Several factors are involved in regulating the exocytosis of WPB and thus represent potential targets for therapeutic interventions in these pathologies. Among them, the annexin A2 (AnxA2)-S100A10 complex has been shown to participate in the tethering/docking of secretion-competent WPB at the plasma membrane, and interference with AnxA2/S100A10 expression or complex formation significantly reduces acute WPB exocytosis and VWF release. Thus, developing specific means to efficiently block AnxA2-S100A10 complex formation in endothelial cells could lead to novel avenues towards interfering with acute vascular thrombosis. Full article
16 pages, 1076 KiB  
Review
The Late Stages of Melanogenesis: Exploring the Chemical Facets and the Application Opportunities
by Lucia Panzella, Atsuko Ebato, Alessandra Napolitano and Kenzo Koike
Int. J. Mol. Sci. 2018, 19(6), 1753; https://doi.org/10.3390/ijms19061753 - 13 Jun 2018
Cited by 57 | Viewed by 8302
Abstract
In the last decade, the late stages of melanin biosynthesis involving the oxidative polymerization of 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) have been extensively investigated. Most of the information derived from a biomimetic approach in which the oxidation of melanogenic indoles was carried [...] Read more.
In the last decade, the late stages of melanin biosynthesis involving the oxidative polymerization of 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA) have been extensively investigated. Most of the information derived from a biomimetic approach in which the oxidation of melanogenic indoles was carried out under conditions mimicking those occurring in the biological environment. Characterization of the early oligomers allowed for drawing a structural picture of DHI and DHICA melanins, providing also an interpretative basis for the different properties exhibited by these pigments, e.g., the chromophore and the antioxidant ability. The improved knowledge has opened new perspectives toward the exploitation of the unique chemistry of melanins and its precursors in cosmetic and health care applications. A noticeable example is the development of an innovative hair dyeing system that is based on the marked ease of DHI to give rise to black melanin on air oxidation under slightly alkaline conditions. The advantage of this method for a step-wise coverage of gray hair with a natural shade pigmentation on repeated treatment with a DHI-based formulation with respect to traditional dyes is presented. A variant of DHICA melanin combining solubility in water-miscible organic solvents, an intense chromophore in the UltraViolet-A UV-A region, and a marked antioxidant potency was evaluated as an ingredient for cosmetic formulations. Full article
(This article belongs to the Special Issue Melanins and Melanogenesis: From Nature to Applications)
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22 pages, 3309 KiB  
Article
The Effects of Combinatorial Genistein and Sulforaphane in Breast Tumor Inhibition: Role in Epigenetic Regulation
by Bidisha Paul, Yuanyuan Li and Trygve O. Tollefsbol
Int. J. Mol. Sci. 2018, 19(6), 1754; https://doi.org/10.3390/ijms19061754 - 13 Jun 2018
Cited by 82 | Viewed by 12582
Abstract
Dietary compounds that possess the properties of altering epigenetic processes are gaining popularity as targets for cancer prevention studies. These compounds when administered at optimal concentrations and especially in combination can have enhanced effects in cancer prevention or therapy. It is important to [...] Read more.
Dietary compounds that possess the properties of altering epigenetic processes are gaining popularity as targets for cancer prevention studies. These compounds when administered at optimal concentrations and especially in combination can have enhanced effects in cancer prevention or therapy. It is important to study the interaction of two or more compounds in order to assess their role in enhancing prevention. Genistein (GEN), found in soy, has been extensively studied for its role as an epigenetic modifier especially as a DNA methyltransferase (DNMT) inhibitor and sulforaphane (SFN), found in cruciferous vegetables, is known as a histone deacetylase (HDAC) inhibitor. However, very little is known about the effects of these two compounds in conjunction in breast cancer prevention or therapy. In our current study, we determined that, at certain doses, the compounds have synergistic effects in decreasing cellular viability of breast cancer cell lines. Our results indicate that the combination of GEN and SFN is much more effective than their single doses in increasing the rate of apoptosis and lowering the colony forming potential of these cells. We determined that these compounds inhibit cell cycle progression to G2 phase in MDA-MB-231 and G1 phase in MCF-7 breast cancer cell lines. Additionally, we determined that the combination is effective as an HDAC and histone methyltransferase (HMT) inhibitor. Furthermore, we demonstrated that this combination downregulates the levels of HDAC2 and HDAC3 both at the mRNA and protein levels. We also found that these compounds have the potential to downregulate KLF4 levels, which plays an important role in stem cell formation. The combination of GEN and SFN is also effective in downregulating hTERT levels, which is known to be activated when KLF4 binds to its promoter region. Our hypothesis is further strengthened by in vivo studies, where the combination is administered to transgenic mice in the form of genistein and SFN-enriched broccoli sprouts. We have demonstrated that the combination is more effective in preventing or treating mammary cancer via extending tumor latency and reducing tumor volumes/sizes than either of these dietary components administered alone. These results are consistent with our in vitro study suggesting potential preventive and therapeutic effects of this novel dietary combinatorial approach against breast cancer. Full article
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17 pages, 2547 KiB  
Review
Recent Approaches to the Manufacturing of Biomimetic Multi-Phasic Scaffolds for Osteochondral Regeneration
by Ryan Longley, Ana Marina Ferreira and Piergiorgio Gentile
Int. J. Mol. Sci. 2018, 19(6), 1755; https://doi.org/10.3390/ijms19061755 - 13 Jun 2018
Cited by 53 | Viewed by 6356
Abstract
Cartilage lesions of the knee are common disorders affecting people of all ages; as the lesion progresses, it extends to the underlying subchondral bone and an osteochondral defect appears. Osteochondral (OC) tissue compromises soft cartilage over hard subchondral bone with a calcified cartilage [...] Read more.
Cartilage lesions of the knee are common disorders affecting people of all ages; as the lesion progresses, it extends to the underlying subchondral bone and an osteochondral defect appears. Osteochondral (OC) tissue compromises soft cartilage over hard subchondral bone with a calcified cartilage interface between these two tissues. Osteochondral defects can be caused by numerous factors such as trauma and arthritis. Tissue engineering offers the possibility of a sustainable and effective treatment against osteochondral defects, where the damaged tissue is replaced with a long-lasting bio-manufactured replacement tissue. This review evaluates both bi-phasic and multi-phasic scaffold-based approaches of osteochondral tissue regeneration, highlighting the importance of having an interface layer between the bone and cartilage layer. The significance of a biomimetic approach is also evidenced and shown to be more effective than the more homogenous design approach to osteochondral scaffold design. Recent scaffold materials and manufacturing techniques are reviewed as well as the current clinical progress with osteochondral regeneration scaffolds. Full article
(This article belongs to the Section Materials Science)
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20 pages, 1132 KiB  
Review
Macrophage MicroRNAs as Therapeutic Targets for Atherosclerosis, Metabolic Syndrome, and Cancer
by Yuanyuan Wei, Mengyu Zhu and Andreas Schober
Int. J. Mol. Sci. 2018, 19(6), 1756; https://doi.org/10.3390/ijms19061756 - 13 Jun 2018
Cited by 31 | Viewed by 8013
Abstract
Macrophages play a crucial role in the innate immune system and contribute to a broad spectrum of pathologies in chronic inflammatory diseases. MicroRNAs (miRNAs) have been demonstrated to play important roles in macrophage functions by regulating macrophage polarization, lipid metabolism and so on. [...] Read more.
Macrophages play a crucial role in the innate immune system and contribute to a broad spectrum of pathologies in chronic inflammatory diseases. MicroRNAs (miRNAs) have been demonstrated to play important roles in macrophage functions by regulating macrophage polarization, lipid metabolism and so on. Thus, miRNAs represent promising diagnostic and therapeutic targets in immune disorders. In this review, we will summarize the role of miRNAs in atherosclerosis, metabolic syndrome, and cancer by modulating macrophage phenotypes, which has been supported by in vivo evidence. Full article
(This article belongs to the Special Issue Macrophages in Inflammation)
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20 pages, 3047 KiB  
Article
Transcriptome Analysis Provides Insight into the Molecular Mechanisms Underlying gametophyte factor 2-Mediated Cross-Incompatibility in Maize
by Man Wang, Zhibin Chen, Huairen Zhang, Huabang Chen and Xiquan Gao
Int. J. Mol. Sci. 2018, 19(6), 1757; https://doi.org/10.3390/ijms19061757 - 13 Jun 2018
Cited by 12 | Viewed by 4737
Abstract
In maize (Zea mays L.), unilateral cross-incompatibility (UCI) is controlled by Gametophyte factors (Ga), including Ga1, Ga2, and Tcb1; however, the molecular mechanisms underpinning this process remain unexplored. Here, we report the pollination phenotype of an inbred [...] Read more.
In maize (Zea mays L.), unilateral cross-incompatibility (UCI) is controlled by Gametophyte factors (Ga), including Ga1, Ga2, and Tcb1; however, the molecular mechanisms underpinning this process remain unexplored. Here, we report the pollination phenotype of an inbred line, 511L, which carries a near-dominant Ga2-S allele. We performed a high-throughput RNA sequencing (RNA-Seq) analysis of the compatible and incompatible crosses between 511L and B73, to identify the transcriptomic differences associated with Ga2-mediated UCI. An in vivo kinetics analysis revealed that the growth of non-self pollen tubes was blocked at the early stages after pollination in 511L, maintaining the UCI barrier in Ga2. In total, 25,759 genes were expressed, of which, 2063 differentially expressed genes (DEGs) were induced by pollination (G_GG, G_GB, B_BB, B_BG). A gene ontology (GO) enrichment analysis revealed that these genes were specifically enriched in functions involved in cell wall strength and pectic product modification. Moreover, 1839, 4382, and 5041 genes were detected to differentially express under same pollination treatments, including B_G, BG_GG, and BB_GB, respectively. A total of 1467 DEGs were constitutively expressed between the two inbred lines following pollination treatments, which were enriched in metabolic processes, flavonoid biosynthesis, cysteine biosynthesis, and vacuole functions. Furthermore, we confirmed 14 DEGs related to cell wall modification and stress by qRT-PCR, which might be involved in Ga2-S-mediated UCI. Our results provide a comprehensive foundation for the molecular mechanisms involved in silks of UCI mediated by Ga2-S. Full article
(This article belongs to the Section Molecular Plant Sciences)
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8 pages, 6775 KiB  
Case Report
Molecular Mechanisms of Disease Progression in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type during Ibrutinib Therapy
by Lucy C. Fox, Costas K. Yannakou, Georgina Ryland, Stephen Lade, Michael Dickinson, Belinda A. Campbell and Henry Miles Prince
Int. J. Mol. Sci. 2018, 19(6), 1758; https://doi.org/10.3390/ijms19061758 - 13 Jun 2018
Cited by 21 | Viewed by 4456
Abstract
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton’s tyrosine kinase [...] Read more.
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor. An 80-year-old woman presented with multiply relapsed PCDLBCL-LT after multiple lines of chemoimmunotherapy and radiotherapy. Pre-treatment testing of the localized cutaneous tumor lesion on a lymphoid amplicon panel demonstrated an MYD88 p.L265P mutation. Ibrutinib therapy was subsequently commenced, resulting in complete resolution of the skin disease. Despite an ongoing skin response, the patient developed progressive nodal disease at two months. Genomic analysis of the cutaneous tumor sample at baseline was compared to that of the inguinal lymph node upon progression, and revealed the acquisition of multiple genomic changes. These included several aberrations expected to bypass BTK inhibition, including two CARD11-activating mutations, and a deleterious mutation in the nuclear factor kappa B (NF-κB) negative regulator, NFKBIE. In addition, an IgH-IRF8 translocation was detected (which brings the IRF8 transcription factor under control of the immunoglobulin heavy chain locus), representing a third plausible mechanism contributing to ibrutinib resistance. Several copy-number changes occurred in both samples, including an amplification of 18q, which encodes the anti-apoptotic protein BCL2. We describe the first case of novel genomic changes of PCDLBCL-LT that occurred while on ibrutinib, providing important mechanistic insights into both pathogenesis and drug resistance. Full article
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18 pages, 2218 KiB  
Review
Metabolomics in Plant Priming Research: The Way Forward?
by Fidele Tugizimana, Msizi I. Mhlongo, Lizelle A. Piater and Ian A. Dubery
Int. J. Mol. Sci. 2018, 19(6), 1759; https://doi.org/10.3390/ijms19061759 - 13 Jun 2018
Cited by 102 | Viewed by 9813
Abstract
A new era of plant biochemistry at the systems level is emerging, providing detailed descriptions of biochemical phenomena at the cellular and organismal level. This new era is marked by the advent of metabolomics—the qualitative and quantitative investigation of the entire metabolome (in [...] Read more.
A new era of plant biochemistry at the systems level is emerging, providing detailed descriptions of biochemical phenomena at the cellular and organismal level. This new era is marked by the advent of metabolomics—the qualitative and quantitative investigation of the entire metabolome (in a dynamic equilibrium) of a biological system. This field has developed as an indispensable methodological approach to study cellular biochemistry at a global level. For protection and survival in a constantly-changing environment, plants rely on a complex and multi-layered innate immune system. This involves surveillance of ‘self’ and ‘non-self,’ molecule-based systemic signalling and metabolic adaptations involving primary and secondary metabolites as well as epigenetic modulation mechanisms. Establishment of a pre-conditioned or primed state can sensitise or enhance aspects of innate immunity for faster and stronger responses. Comprehensive elucidation of the molecular and biochemical processes associated with the phenotypic defence state is vital for a better understanding of the molecular mechanisms that define the metabolism of plant–pathogen interactions. Such insights are essential for translational research and applications. Thus, this review highlights the prospects of metabolomics and addresses current challenges that hinder the realisation of the full potential of the field. Such limitations include partial coverage of the metabolome and maximising the value of metabolomics data (extraction of information and interpretation). Furthermore, the review points out key features that characterise both the plant innate immune system and enhancement of the latter, thus underlining insights from metabolomic studies in plant priming. Future perspectives in this inspiring area are included, with the aim of stimulating further studies leading to a better understanding of plant immunity at the metabolome level. Full article
(This article belongs to the Special Issue Plant Innate Immunity 2.0)
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17 pages, 4834 KiB  
Article
RNA-Seq Analysis Reveals a Positive Role of HTR2A in Adipogenesis in Yan Yellow Cattle
by Jinyan Yun, Haiguo Jin, Yang Cao, Lichun Zhang, Yumin Zhao, Xin Jin and Yongsheng Yu
Int. J. Mol. Sci. 2018, 19(6), 1760; https://doi.org/10.3390/ijms19061760 - 13 Jun 2018
Cited by 26 | Viewed by 4941
Abstract
In this study, we performed high throughput RNA sequencing at the primary bovine preadipocyte (Day-0), mid-differentiation (Day-4), and differentiated adipocyte (Day-9) stages in order to characterize the transcriptional events regulating differentiation and function. The preadipocytes were isolated from subcutaneous fetal bovine adipose tissues [...] Read more.
In this study, we performed high throughput RNA sequencing at the primary bovine preadipocyte (Day-0), mid-differentiation (Day-4), and differentiated adipocyte (Day-9) stages in order to characterize the transcriptional events regulating differentiation and function. The preadipocytes were isolated from subcutaneous fetal bovine adipose tissues and were differentiated into mature adipocytes. The adipogenic characteristics of the adipocytes were detected during various stages of adipogenesis (Day-0, Day-4, and Day-9). We used RNA sequencing (RNA-seq) to investigate a comprehensive transcriptome information of adipocytic differentiation. Compared to the pre-differentiation stage (Day-0), 2510 genes were identified as differentially expressed genes (DEGs) at the mid-differentiation stage (Day-4). We found 2446 DEGs in the mature adipocytic stage relative to the mid-differentiation stage. Some adipogenesis-related transcription factors, CCAAT-enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ) were differentially expressed at Day-0, Day-4, and Day-9. We further investigated the adipogenic function of 5-hydroxytryptamine receptor 2A (HTR2A) in adipogenesis. Overexpression of HTR2A stimulated the differentiation of preadipocytes, and knockdown of HTR2A had opposite effects. Furthermore, functional enrichment analysis of DEGs revealed that the PI3K-Akt signaling pathway was the significantly enriched pathway, and HTR2A regulated adipogenesis by activating or inhibiting phosphorylation of phospho-AKT (Ser473). In summary, the present study provides the first comparative transcription of various periods of adipocytes in cattle, which presents a solid foundation for further study into the molecular mechanism of fat deposition and the improvement of beef quality in cattle. Full article
(This article belongs to the Section Biochemistry)
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24 pages, 3878 KiB  
Article
Quality Assessment of Surgical Disc Samples Discriminates Human Annulus Fibrosus and Nucleus Pulposus on Tissue and Molecular Level
by Ann-Kathrin Schubert, Jeske J. Smink, Mirko Arp, Jochen Ringe, Aldemar A. Hegewald and Michael Sittinger
Int. J. Mol. Sci. 2018, 19(6), 1761; https://doi.org/10.3390/ijms19061761 - 13 Jun 2018
Cited by 19 | Viewed by 5466
Abstract
A discrimination of the highly specialised annulus fibrosus (AF) and nucleus pulposus (NP) cells in the mature human intervertebral disc (IVD) is thus far still not possible in a reliable way. The aim of this study was to identify molecular markers that distinguish [...] Read more.
A discrimination of the highly specialised annulus fibrosus (AF) and nucleus pulposus (NP) cells in the mature human intervertebral disc (IVD) is thus far still not possible in a reliable way. The aim of this study was to identify molecular markers that distinguish AF and NP cells in human disc tissue using microarray analysis as a screening tool. AF and NP samples were obtained from 28 cervical discs. First, all samples underwent quality sorting using two novel scoring systems for small-sized disc tissue samples including macroscopic, haptic and histological evaluation. Subsequently, samples with clear disc characteristics of either AF or NP that were free from impurities of foreign tissue (IVD score) and with low signs of disc degeneration on cellular level (DD score) were selected for GeneChip analysis (HGU1332P). The 11 AF and 9 NP samples showed distinctly different genome-wide transcriptomes. The majority of differentially expressed genes (DEGs) could be specifically assigned to the AF, whereas no DEG was exclusively expressed in the NP. Nevertheless, we identified 11 novel marker genes that clearly distinguished AF and NP, as confirmed by quantitative gene expression analysis. The novel established scoring systems and molecular markers showed the identity of AF and NP in disc starting material and are thus of great importance in the quality assurance of cell-based therapeutics in regenerative treatment of disc degeneration. Full article
(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)
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27 pages, 1402 KiB  
Review
Molecular Genetics and Breeding for Nutrient Use Efficiency in Rice
by Jauhar Ali, Zilhas Ahmed Jewel, Anumalla Mahender, Annamalai Anandan, Jose Hernandez and Zhikang Li
Int. J. Mol. Sci. 2018, 19(6), 1762; https://doi.org/10.3390/ijms19061762 - 14 Jun 2018
Cited by 59 | Viewed by 12105
Abstract
In the coming decades, rice production needs to be carried out sustainably to keep the balance between profitability margins and essential resource input costs. Many fertilizers, such as N, depend primarily on fossil fuels, whereas P comes from rock phosphates. How long these [...] Read more.
In the coming decades, rice production needs to be carried out sustainably to keep the balance between profitability margins and essential resource input costs. Many fertilizers, such as N, depend primarily on fossil fuels, whereas P comes from rock phosphates. How long these reserves will last and sustain agriculture remains to be seen. Therefore, current agricultural food production under such conditions remains an enormous and colossal challenge. Researchers have been trying to identify nutrient use-efficient varieties over the past few decades with limited success. The concept of nutrient use efficiency is being revisited to understand the molecular genetic basis, while much of it is not entirely understood yet. However, significant achievements have recently been observed at the molecular level in nitrogen and phosphorus use efficiency. Breeding teams are trying to incorporate these valuable QTLs and genes into their rice breeding programs. In this review, we seek to identify the achievements and the progress made so far in the fields of genetics, molecular breeding and biotechnology, especially for nutrient use efficiency in rice. Full article
(This article belongs to the Special Issue Plant Genetics and Molecular Breeding)
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12 pages, 3486 KiB  
Article
Chrysin Attenuates Cell Viability of Human Colorectal Cancer Cells through Autophagy Induction Unlike 5-Fluorouracil/Oxaliplatin
by Yueh-Ming Lin, Chih-I Chen, Yi-Ping Hsiang, Yung-Chia Hsu, Kung-Chuan Cheng, Pei-Hsuan Chien, Hsiao-Lin Pan, Chien-Chang Lu and Yun-Ju Chen
Int. J. Mol. Sci. 2018, 19(6), 1763; https://doi.org/10.3390/ijms19061763 - 14 Jun 2018
Cited by 43 | Viewed by 6673
Abstract
Chemotherapeutic 5-fluorouracil (5-FU) combined with oxaliplatin is often used as the standard treatment for colorectal cancer (CRC). The disturbing side effects and drug resistance commonly observed in chemotherapy motivate us to develop alternative optimal therapeutic options for CRC treatment. Chrysin, a natural and [...] Read more.
Chemotherapeutic 5-fluorouracil (5-FU) combined with oxaliplatin is often used as the standard treatment for colorectal cancer (CRC). The disturbing side effects and drug resistance commonly observed in chemotherapy motivate us to develop alternative optimal therapeutic options for CRC treatment. Chrysin, a natural and biologically active flavonoid abundant in propolis, is reported to have antitumor effects on a few CRCs. However, whether and how chrysin achieves similar effectiveness to the 5-FU combination is not clear. In this study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), western blotting, fluorescence microscopy, and reactive oxygen species (ROS) production were assayed. We found that chrysin exhibited similar inhibition of cell viability as the 5-FU combination in a panel of human CRC cells. Furthermore, the results showed that chrysin significantly increased the levels of LC3-II, an autophagy-related marker, in CRC cells, which was not observed with the 5-FU combination. More importantly, blockage of autophagy induction restored chrysin-attenuated CRC cell viability. Further mechanistic analysis revealed that chrysin, not the 5-FU combination, induced ROS generation, and in turn, inhibited the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR). Collectively, these results imply that chrysin may be a potential replacement for the 5-FU and oxaliplatin combination to achieve antitumor activity through autophagy for CRC treatment in the future. Full article
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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18 pages, 3654 KiB  
Article
Ca2+/Calmodulin-Dependent AtSR1/CAMTA3 Plays Critical Roles in Balancing Plant Growth and Immunity
by Peiguo Yuan, Liqun Du and B. W. Poovaiah
Int. J. Mol. Sci. 2018, 19(6), 1764; https://doi.org/10.3390/ijms19061764 - 14 Jun 2018
Cited by 43 | Viewed by 6500
Abstract
During plant-pathogen interactions, plants have to relocate their resources including energy to defend invading organisms; as a result, plant growth and development are usually reduced. Arabidopsis signal responsive1 (AtSR1) has been documented as a negative regulator of plant immune responses and could serve [...] Read more.
During plant-pathogen interactions, plants have to relocate their resources including energy to defend invading organisms; as a result, plant growth and development are usually reduced. Arabidopsis signal responsive1 (AtSR1) has been documented as a negative regulator of plant immune responses and could serve as a positive regulator of plant growth and development. However, the mechanism by which AtSR1 balances plant growth and immunity is poorly understood. Here, we performed a global gene expression profiling using Affymetrix microarrays to study how AtSR1 regulates defense- and growth-related genes in plants with and without bacterial pathogen infection. Results revealed that AtSR1 negatively regulates most of the immune-related genes involved in molecular pattern-triggered immunity (PTI), effector-triggered immunity (ETI), and in salicylic acid (SA)- and jasmonate (JA)-mediated signaling pathways. AtSR1 may rigidly regulate several steps of the SA-mediated pathway, from the activation of SA synthesis to the perception of SA signal. Furthermore, AtSR1 may also regulate plant growth through its involvement in regulating auxin- and BRs-related pathways. Although microarray data revealed that expression levels of defense-related genes induced by pathogens are higher in wild-type (WT) plants than that in atsr1 mutant plants, WT plants are more susceptible to the infection of virulent pathogen as compared to atsr1 mutant plants. These observations indicate that the AtSR1 functions in suppressing the expression of genes induced by pathogen attack and contributes to the rapid establishment of resistance in WT background. Results of electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP)-PCR assays suggest that AtSR1 acts as transcription factor in balancing plant growth and immunity, through interaction with the “CGCG” containing CG-box in the promotors of its target genes. Full article
(This article belongs to the Special Issue Calcium Signals in Plant Cells)
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23 pages, 930 KiB  
Review
Molecular Markers of Therapy-Resistant Glioblastoma and Potential Strategy to Combat Resistance
by Ha S. Nguyen, Saman Shabani, Ahmed J. Awad, Mayank Kaushal and Ninh Doan
Int. J. Mol. Sci. 2018, 19(6), 1765; https://doi.org/10.3390/ijms19061765 - 14 Jun 2018
Cited by 45 | Viewed by 5958
Abstract
Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system. With its overall dismal prognosis (the median survival is 14 months), GBMs demonstrate a resounding resilience against all current treatment modalities. The absence of a major progress in the [...] Read more.
Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system. With its overall dismal prognosis (the median survival is 14 months), GBMs demonstrate a resounding resilience against all current treatment modalities. The absence of a major progress in the treatment of GBM maybe a result of our poor understanding of both GBM tumor biology and the mechanisms underlying the acquirement of treatment resistance in recurrent GBMs. A comprehensive understanding of these markers is mandatory for the development of treatments against therapy-resistant GBMs. This review also provides an overview of a novel marker called acid ceramidase and its implication in the development of radioresistant GBMs. Multiple signaling pathways were found altered in radioresistant GBMs. Given these global alterations of multiple signaling pathways found in radioresistant GBMs, an effective treatment for radioresistant GBMs may require a cocktail containing multiple agents targeting multiple cancer-inducing pathways in order to have a chance to make a substantial impact on improving the overall GBM survival. Full article
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13 pages, 1570 KiB  
Article
IL-6 and IL-8 Serum Levels Predict Tumor Response and Overall Survival after TACE for Primary and Secondary Hepatic Malignancies
by Sven H. Loosen, Maximilian Schulze-Hagen, Catherine Leyh, Fabian Benz, Mihael Vucur, Christiane Kuhl, Christian Trautwein, Frank Tacke, Philipp Bruners, Christoph Roderburg and Tom Luedde
Int. J. Mol. Sci. 2018, 19(6), 1766; https://doi.org/10.3390/ijms19061766 - 14 Jun 2018
Cited by 44 | Viewed by 5103
Abstract
While surgical resection represents the standard potentially curative therapy for liver cancer, transarterial chemoembolization (TACE) has evolved as a standard therapy for intermediate-stage hepatocellular carcinoma (HCC) as well as liver metastases. However, it is still not fully understood which patients particularly benefit from [...] Read more.
While surgical resection represents the standard potentially curative therapy for liver cancer, transarterial chemoembolization (TACE) has evolved as a standard therapy for intermediate-stage hepatocellular carcinoma (HCC) as well as liver metastases. However, it is still not fully understood which patients particularly benefit from TACE. Cytokines represent a broad category of signaling molecules that might reflect concomitant inflammation as an adverse prognostic factor. Here, we evaluated the role of interleukin (IL)-6, IL-8, and CC-chemokine ligand (CCL)22 as biomarkers in the context of TACE treatment. Cytokine serum levels were analyzed by multiplex immunoassay in 54 patients (HCC: n = 44, liver metastases: n = 10) undergoing TACE as well as 51 healthy controls. Patients with primary and secondary liver cancer showed significantly elevated levels of IL-6 and IL-8 but not CCL22 compared to healthy controls. Interestingly, low pre-interventional levels of IL-6 and IL-8 were predictors for an objective response after TACE in binary logistic regression. In contrast, patients with high pre-interventional IL-6 and IL-8 serum levels not only poorly responded to TACE but had a significantly impaired overall survival. Serum levels of IL-6 and IL-8 represent promising biomarkers for patients undergoing TACE and might help to pre-interventionally identify patients who particularly benefit from TACE regarding objective treatment response and overall survival. Full article
(This article belongs to the Special Issue Inflammation and Cancer 2018)
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4 pages, 175 KiB  
Editorial
Chemically-Induced DNA Damage, Mutagenesis, and Cancer
by Ashis K. Basu and Takehiko Nohmi
Int. J. Mol. Sci. 2018, 19(6), 1767; https://doi.org/10.3390/ijms19061767 - 14 Jun 2018
Cited by 17 | Viewed by 4246
(This article belongs to the Special Issue Chemically-Induced DNA Damage, Mutagenesis, and Cancer)
15 pages, 4116 KiB  
Article
Overexpression of CBX3 in Pancreatic Adenocarcinoma Promotes Cell Cycle Transition-Associated Tumor Progression
by Lian-Yu Chen, Chien-Shan Cheng, Chao Qu, Peng Wang, Hao Chen, Zhi-Qiang Meng and Zhen Chen
Int. J. Mol. Sci. 2018, 19(6), 1768; https://doi.org/10.3390/ijms19061768 - 14 Jun 2018
Cited by 34 | Viewed by 5243
Abstract
Background: Previous studies showed that Chromobox protein homolog 3 (CBX3) was overexpressed in several types of human cancers, however its pattern and role in pancreatic adenocarcinoma (PAAD) has not yet been understood. The aim of this study was to identify the expression and [...] Read more.
Background: Previous studies showed that Chromobox protein homolog 3 (CBX3) was overexpressed in several types of human cancers, however its pattern and role in pancreatic adenocarcinoma (PAAD) has not yet been understood. The aim of this study was to identify the expression and function of CBX3 in PAAD. Methods: Data of transcriptomic and protein expression of CBX3 in PAAD were collected from different databases and analyzed. The in vitro and in vivo role of CBX3 in PAAD was examined. Results: CBX3 was overexpressed in human PAAD tissues, which was associated with poor prognosis of overall and disease-free survival of the patients. Overexpression of CBX3 induced the in vitro proliferation, anchorage-free growth, migration and invasion of the PAAD cells, and led to in vivo growth of orthotoptic PAAD tumors in mice. GO and KEGG pathway analysis, as well as experimental observation showed that CBX3 may be associated with cell cycle transition of PAAD cells, and cyclin-dependent kinase 1 (CDK1) and proliferating cell nuclear antigen (PCNA) may mediate the tumor-promoting action of CBX3. CDK1 knockdown attenuated the cell cycle transition, proliferation and invasion of CBX3-overexpressing PAAD cells. Conclusion: Our findings suggest the tumor-promoting role of CBX3 in PAAD to be targeted by novel therapeutic strategies. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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14 pages, 2345 KiB  
Article
Synergistic Antitumor Effect of Oligogalacturonides and Cisplatin on Human Lung Cancer A549 Cells
by Cian-Song Huang, Ai-Chun Huang, Ping-Hsiu Huang, Diana Lo, Yuh-Tai Wang and Ming-Chang Wu
Int. J. Mol. Sci. 2018, 19(6), 1769; https://doi.org/10.3390/ijms19061769 - 14 Jun 2018
Cited by 6 | Viewed by 6592
Abstract
Cisplatin (DPP), a clinically potent antineoplastic agent, is limited by its severe adverse effects. The aim of this study was to investigate the effect of oligogalacturonides (OGA) and DDP on human lung cancer A549 cells. The combined use of OGA and DDP had [...] Read more.
Cisplatin (DPP), a clinically potent antineoplastic agent, is limited by its severe adverse effects. The aim of this study was to investigate the effect of oligogalacturonides (OGA) and DDP on human lung cancer A549 cells. The combined use of OGA and DDP had a synergistic effect on the growth inhibition of A549 cells, changed the cell cycle distribution, and enhanced apoptotic response, especially in sequential combination treatment group of DDP 12 h + OGA 12 h. Western blot analyses showed that the combination treatment of OGA and DDP upregulated Bax, p53, and Caspase-3 and downregulated Bcl-2 proteins. More importantly, DDP-induced toxicity was attenuated by OGA and DDP combination treatment in normal HEK293 cells. Our data suggests that the combined use of OGA from natural sources and DDP could be an important new adjuvant therapy for lung cancer as well as offer important insights for reducing kidney toxicity of DDP and delaying the development of DDP resistance. Full article
(This article belongs to the Special Issue Natural Bioactives and Phytochemicals in Cancer Prevention)
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12 pages, 2713 KiB  
Article
Farrerol Relieve Lipopolysaccharide (LPS)-Induced Mastitis by Inhibiting AKT/NF-κB p65, ERK1/2 and P38 Signaling Pathway
by Yanwei Li, Qian Gong, Wenjin Guo, Xingchi Kan, Dianwen Xu, He Ma, Shoupeng Fu and Juxiong Liu
Int. J. Mol. Sci. 2018, 19(6), 1770; https://doi.org/10.3390/ijms19061770 - 14 Jun 2018
Cited by 33 | Viewed by 5536
Abstract
Farrerol has been proved to have an anti-inflammatory effect. However, the effects of farrerol on mastitis have not been investigated. This study was aimed to investigate the effect and mechanism of farrerol in lipopolysaccharide (LPS)-induced mouse mastitis and LPS-induced inflammatory response of mouse [...] Read more.
Farrerol has been proved to have an anti-inflammatory effect. However, the effects of farrerol on mastitis have not been investigated. This study was aimed to investigate the effect and mechanism of farrerol in lipopolysaccharide (LPS)-induced mouse mastitis and LPS-induced inflammatory response of mouse mammary epithelial cells (mMECs). In vivo, LPS were injected to the tetrad pair of nipples for establishing mouse mastitis, and then tested the effect of farrerol on histopathological changes, inflammatory response and activation degree of protein kinase B (AKT), nuclear factor-kappa B p65 (NF-κB p65), p38, extracellular regulated protein kinase (ERK1/2). In vitro, the mMECs were incubated by farrerol for 1 h following by stimulating with LPS, and then the inflammatory response and the related signaling pathways were detected. The in vivo results found that farrerol could improve pathological injury of mammary gland, attenuate the activity of myeloperoxidase (MPO), inhibit the production of pro-inflammatory mediators and the phosphorylation of AKT, NF-κB p65, p38 and ERK1/2. The in vitro results also found farrerol inhibited inflammatory response and the related signaling pathways. Collectively, this study revealed that farrerol inhibits the further development of LPS-induced mastitis by inhibiting inflammatory response via down regulating phosphorylation of AKT, NF-κB p65, p38, and ERK1/2. These findings suggest that farrerol may be used as an anti-inflammatory drug for mastitis. Full article
(This article belongs to the Special Issue Natural Anti-Inflammatory Agents 2018)
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23 pages, 4664 KiB  
Article
Nerve Growth Factor (NGF)—Receptor Survival Axis in Head and Neck Squamous Cell Carcinoma
by József Dudás, Wolfgang Dietl, Angela Romani, Susanne Reinold, Rudolf Glueckert, Anneliese Schrott-Fischer, Daniel Dejaco, Lejo Johnson Chacko, Raphaela Tuertscher, Volker Hans Schartinger and Herbert Riechelmann
Int. J. Mol. Sci. 2018, 19(6), 1771; https://doi.org/10.3390/ijms19061771 - 14 Jun 2018
Cited by 26 | Viewed by 5535
Abstract
Neurotrophins and their receptors might regulate cell survival in head and neck squamous cell carcinoma (HNSCC). mRNA expression of nerve growth factor (NGF) and protein synthesis of high (NTRK1) and low affinity neurotrophin (p75 neurotrophin receptor; NTR) receptors were investigated in normal oral [...] Read more.
Neurotrophins and their receptors might regulate cell survival in head and neck squamous cell carcinoma (HNSCC). mRNA expression of nerve growth factor (NGF) and protein synthesis of high (NTRK1) and low affinity neurotrophin (p75 neurotrophin receptor; NTR) receptors were investigated in normal oral mucosa and in HNSCC. HNSCC cell lines were treated with mitomycin C (MMC) and cell survival was investigated. Normal and malignant epithelial cells expressed NGF mRNA. NTRK1 was upregulated in 80% of HNSCC tissue, and 50% of HNSCC samples were p75NTR positive. Interestingly, in HNSCC tissue: NTRK1 and p75NTR immunohistochemical reactions were mutually exclusive. Detroit 562 cell line contained only p75NTR, UPCI-SCC090 cells synthesized NTRK1 but not p75NTR and SCC-25 culture had p75NTR and NTRK1 in different cells. NGF (100 ng/mL) significantly improved (1.4-fold) the survival of cultured UPCI-SCC090 cells after MMC-induced cell cycle arrest, while Detroit 562 cells with high levels of p75NTR did not even get arrested by single short MMC treatment. p75NTR in HNSCC might be related with NGF-independent therapy resistance, while NTRK1 might transduce a survival signal of NGF and contribute in this way to improved tumor cell survival after cell cycle arrest. Full article
(This article belongs to the Special Issue Oral Cancer—Diagnosis and Therapeutics)
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17 pages, 3345 KiB  
Article
Phloretin Promotes Adipogenesis via Mitogen-Activated Protein Kinase Pathways in Mouse Marrow Stromal ST2 Cells
by Ayumu Takeno, Ippei Kanazawa, Masakazu Notsu, Ken-ichiro Tanaka and Toshitsugu Sugimoto
Int. J. Mol. Sci. 2018, 19(6), 1772; https://doi.org/10.3390/ijms19061772 - 14 Jun 2018
Cited by 26 | Viewed by 4301
Abstract
Phloretin, a glucose transporter (GLUT) inhibitor, has pleiotropic effects. The present study examined the effects of phloretin on the commitment of marrow stromal cells to adipocytes, using the mouse marrow stromal cell line ST2. Oil red O staining showed that treatment with phloretin [...] Read more.
Phloretin, a glucose transporter (GLUT) inhibitor, has pleiotropic effects. The present study examined the effects of phloretin on the commitment of marrow stromal cells to adipocytes, using the mouse marrow stromal cell line ST2. Oil red O staining showed that treatment with phloretin 10–100 µM promoted lipid accumulation. Real-time PCR showed that phloretin significantly increased the expression of adipogenic markers, including PPARγ, C/EBPα, fatty acid synthase, fatty acid-binding protein 4, and adiponectin. Western blotting showed that phloretin inhibited ERK1/2 and JNK but activated p38 MAPK. Treatment with a MAPK/ERK kinase inhibitor and a JNK inhibitor enhanced adipogenesis, similar to phloretin. In contrast, a p38 MAPK inhibitor suppressed phloretin-induced adipogenesis. Although phloretin phosphorylated AMP-activated protein kinase (AMPK), co-incubation with an AMPK inhibitor did not block phloretin-induced adipogenesis. The 2-deoxyglucose colorimetric assay showed that phloretin and siRNA silencing of GLUT1 decreased glucose uptake. However, unlike phloretin treatment, GLUT1 silencing inhibited adipogenesis. In addition, phloretin enhanced adipogenesis in GLUT1 knocked-down cells. Taken together, phloretin induced adipogenesis of marrow stromal cells by inhibiting ERK1/2 and JNK and by activating p38 MAPK. The adipogenic effects of phloretin were independent of glucose uptake inhibition. Phloretin may affect energy metabolism by influencing adipogenesis and adiponectin expression. Full article
(This article belongs to the Section Biochemistry)
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11 pages, 840 KiB  
Article
SeqSVM: A Sequence-Based Support Vector Machine Method for Identifying Antioxidant Proteins
by Lei Xu, Guangmin Liang, Shuhua Shi and Changrui Liao
Int. J. Mol. Sci. 2018, 19(6), 1773; https://doi.org/10.3390/ijms19061773 - 15 Jun 2018
Cited by 85 | Viewed by 5045
Abstract
Antioxidant proteins can be beneficial in disease prevention. More attention has been paid to the functionality of antioxidant proteins. Therefore, identifying antioxidant proteins is important for the study. In our work, we propose a computational method, called SeqSVM, for predicting antioxidant proteins based [...] Read more.
Antioxidant proteins can be beneficial in disease prevention. More attention has been paid to the functionality of antioxidant proteins. Therefore, identifying antioxidant proteins is important for the study. In our work, we propose a computational method, called SeqSVM, for predicting antioxidant proteins based on their primary sequence features. The features are removed to reduce the redundancy by max relevance max distance method. Finally, the antioxidant proteins are identified by support vector machine (SVM). The experimental results demonstrated that our method performs better than existing methods, with the overall accuracy of 89.46%. Although a proposed computational method can attain an encouraging classification result, the experimental results are verified based on the biochemical approaches, such as wet biochemistry and molecular biology techniques. Full article
(This article belongs to the Special Issue Special Protein or RNA Molecules Computational Identification 2018)
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7 pages, 31605 KiB  
Communication
Plasma Membrane-Localized Calcium Pumps and Copines Coordinately Regulate Pollen Germination and Fertility in Arabidopsis
by Yun Li, Jinping Guo, Ziyuan Yang and Dong-Lei Yang
Int. J. Mol. Sci. 2018, 19(6), 1774; https://doi.org/10.3390/ijms19061774 - 15 Jun 2018
Cited by 28 | Viewed by 5790
Abstract
Calcium plays an important role in plant growth, development, and response to environmental stimuli. Copines are conserved plasma membrane-localized calcium-binding proteins which regulate plant immune responses and development. In this study, we found that copine proteins BON2 and BON3, the paralogs of BON1, [...] Read more.
Calcium plays an important role in plant growth, development, and response to environmental stimuli. Copines are conserved plasma membrane-localized calcium-binding proteins which regulate plant immune responses and development. In this study, we found that copine proteins BON2 and BON3, the paralogs of BON1, physically interact with calcium pumps ACA8 and ACA10 in Arabidopsis. Notably, ACA9, the closest homologue of ACA8 and ACA10 functioning in pollen tube growth, interacts with all three copines. This is consistent with the protein–protein interactions between the two protein families, the aca8, aca10, aca8/aca10, bon1/2/3 mutants as well as aca9 mutant exhibited defects on pollen germination and seed production. Taken together, plasma membrane-localized interacting calcium pumps and copines coordinately control pollen tube growth, likely through manipulating calcium efflux. Full article
(This article belongs to the Special Issue Calcium Signals in Plant Cells)
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12 pages, 544 KiB  
Review
Human Papilloma Virus and Autophagy
by Domenico Mattoscio, Alessandro Medda and Susanna Chiocca
Int. J. Mol. Sci. 2018, 19(6), 1775; https://doi.org/10.3390/ijms19061775 - 15 Jun 2018
Cited by 74 | Viewed by 11339
Abstract
Human papilloma viruses (HPVs) are a group of double-stranded DNA viruses known to be the primary cause of cervical cancer. In addition, evidence has now established their role in non-melanoma skin cancers, head and neck cancer (HNC), and the development of other anogenital [...] Read more.
Human papilloma viruses (HPVs) are a group of double-stranded DNA viruses known to be the primary cause of cervical cancer. In addition, evidence has now established their role in non-melanoma skin cancers, head and neck cancer (HNC), and the development of other anogenital malignancies. The prevalence of HPV-related HNC, in particular oropharyngeal cancers, is rapidly increasing, foreseeing that HPV-positive oropharyngeal cancers will outnumber uterine cervical cancers in the next 15–20 years. Therefore, despite the successful advent of vaccines originally licensed for cervical cancer prevention, HPV burden is still very high, and a better understanding of HPV biology is urgently needed. Autophagy is the physiological cellular route that accounts for removal, degradation, and recycling of damaged organelles, proteins, and lipids in lysosomal vacuoles. In addition to this scavenger function, autophagy plays a fundamental role during viral infections and cancers and is, therefore, frequently exploited by viruses to their own benefit. Recently, a link between HPV and autophagy has clearly emerged, leading to the conceivable development of novel anti-viral strategies aimed at restraining HPV infectivity. Here, recent findings on how oncogenic HPV16 usurp autophagy are described, highlighting similarities and differences with mechanisms adopted by other oncoviruses. Full article
(This article belongs to the Special Issue Human Polyomaviruses and Papillomaviruses)
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17 pages, 764 KiB  
Review
Translational Regenerative Therapies for Chronic Spinal Cord Injury
by Kyriakos Dalamagkas, Magdalini Tsintou, Amelia Seifalian and Alexander M. Seifalian
Int. J. Mol. Sci. 2018, 19(6), 1776; https://doi.org/10.3390/ijms19061776 - 15 Jun 2018
Cited by 54 | Viewed by 9324
Abstract
Spinal cord injury is a chronic and debilitating neurological condition that is currently being managed symptomatically with no real therapeutic strategies available. Even though there is no consensus on the best time to start interventions, the chronic phase is definitely the most stable [...] Read more.
Spinal cord injury is a chronic and debilitating neurological condition that is currently being managed symptomatically with no real therapeutic strategies available. Even though there is no consensus on the best time to start interventions, the chronic phase is definitely the most stable target in order to determine whether a therapy can effectively restore neurological function. The advancements of nanoscience and stem cell technology, combined with the powerful, novel neuroimaging modalities that have arisen can now accelerate the path of promising novel therapeutic strategies from bench to bedside. Several types of stem cells have reached up to clinical trials phase II, including adult neural stem cells, human spinal cord stem cells, olfactory ensheathing cells, autologous Schwann cells, umbilical cord blood-derived mononuclear cells, adult mesenchymal cells, and autologous bone-marrow-derived stem cells. There also have been combinations of different molecular therapies; these have been either alone or combined with supportive scaffolds with nanostructures to facilitate favorable cell–material interactions. The results already show promise but it will take some coordinated actions in order to develop a proper step-by-step approach to solve impactful problems with neural repair. Full article
(This article belongs to the Special Issue Therapeutic Strategies to Spinal Cord Injury)
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13 pages, 575 KiB  
Review
Nuclear Receptor Regulation of Aquaglyceroporins in Metabolic Organs
by Matteo Tardelli, Thierry Claudel, Francesca Virginia Bruschi and Michael Trauner
Int. J. Mol. Sci. 2018, 19(6), 1777; https://doi.org/10.3390/ijms19061777 - 15 Jun 2018
Cited by 14 | Viewed by 5333
Abstract
Nuclear receptors, such as the farnesoid X receptor (FXR) and the peroxisome proliferator-activated receptors gamma and alpha (PPAR-γ, -α), are major metabolic regulators in adipose tissue and the liver, where they govern lipid, glucose, and bile acid homeostasis, as well as inflammatory cascades. [...] Read more.
Nuclear receptors, such as the farnesoid X receptor (FXR) and the peroxisome proliferator-activated receptors gamma and alpha (PPAR-γ, -α), are major metabolic regulators in adipose tissue and the liver, where they govern lipid, glucose, and bile acid homeostasis, as well as inflammatory cascades. Glycerol and free fatty acids are the end products of lipid droplet catabolism driven by PPARs. Aquaporins (AQPs), a family of 13 small transmembrane proteins, facilitate the shuttling of water, urea, and/or glycerol. The peculiar role of AQPs in glycerol transport makes them pivotal targets in lipid metabolism, especially considering their tissue-specific regulation by the nuclear receptors PPARγ and PPARα. Here, we review the role of nuclear receptors in the regulation of glycerol shuttling in liver and adipose tissue through the function and expression of AQPs. Full article
(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)
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11 pages, 1811 KiB  
Review
Connexin 43-Based Therapeutics for Dermal Wound Healing
by Jade Montgomery, Gautam S. Ghatnekar, Christina L. Grek, Kurtis E. Moyer and Robert G. Gourdie
Int. J. Mol. Sci. 2018, 19(6), 1778; https://doi.org/10.3390/ijms19061778 - 15 Jun 2018
Cited by 60 | Viewed by 11006
Abstract
The most ubiquitous gap junction protein within the body, connexin 43 (Cx43), is a target of interest for modulating the dermal wound healing response. Observational studies found associations between Cx43 at the wound edge and poor healing response, and subsequent studies utilizing local [...] Read more.
The most ubiquitous gap junction protein within the body, connexin 43 (Cx43), is a target of interest for modulating the dermal wound healing response. Observational studies found associations between Cx43 at the wound edge and poor healing response, and subsequent studies utilizing local knockdown of Cx43 found improvements in wound closure rate and final scar appearance. Further preclinical work conducted using Cx43-based peptide therapeutics, including alpha connexin carboxyl terminus 1 (αCT1), a peptide mimetic of the Cx43 carboxyl terminus, reported similar improvements in wound healing and scar formation. Clinical trials and further study into the mode of action have since been conducted on αCT1, and Phase III testing for treatment of diabetic foot ulcers is currently underway. Therapeutics targeting connexin activity show promise in beneficially modulating the human body’s natural healing response for improved patient outcomes across a variety of injuries. Full article
(This article belongs to the Special Issue Interplay of Connexins and Pannexins in Tissue Function and Disease)
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12 pages, 1326 KiB  
Article
Identification of Bacteriophage Virion Proteins Using Multinomial Naïve Bayes with g-Gap Feature Tree
by Yanyuan Pan, Hui Gao, Hao Lin, Zhen Liu, Lixia Tang and Songtao Li
Int. J. Mol. Sci. 2018, 19(6), 1779; https://doi.org/10.3390/ijms19061779 - 15 Jun 2018
Cited by 33 | Viewed by 4138
Abstract
Bacteriophages, which are tremendously important to the ecology and evolution of bacteria, play a key role in the development of genetic engineering. Bacteriophage virion proteins are essential materials of the infectious viral particles and in charge of several of biological functions. The correct [...] Read more.
Bacteriophages, which are tremendously important to the ecology and evolution of bacteria, play a key role in the development of genetic engineering. Bacteriophage virion proteins are essential materials of the infectious viral particles and in charge of several of biological functions. The correct identification of bacteriophage virion proteins is of great importance for understanding both life at the molecular level and genetic evolution. However, few computational methods are available for identifying bacteriophage virion proteins. In this paper, we proposed a new method to predict bacteriophage virion proteins using a Multinomial Naïve Bayes classification model based on discrete feature generated from the g-gap feature tree. The accuracy of the proposed model reaches 98.37% with MCC of 96.27% in 10-fold cross-validation. This result suggests that the proposed method can be a useful approach in identifying bacteriophage virion proteins from sequence information. For the convenience of experimental scientists, a web server (PhagePred) that implements the proposed predictor is available, which can be freely accessed on the Internet. Full article
(This article belongs to the Special Issue Special Protein or RNA Molecules Computational Identification 2018)
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13 pages, 953 KiB  
Review
The Role of Low-Density Lipoprotein Receptor-Related Protein 1 in Lipid Metabolism, Glucose Homeostasis and Inflammation
by Virginia Actis Dato and Gustavo Alberto Chiabrando
Int. J. Mol. Sci. 2018, 19(6), 1780; https://doi.org/10.3390/ijms19061780 - 15 Jun 2018
Cited by 94 | Viewed by 10568
Abstract
Metabolic syndrome (MetS) is a highly prevalent disorder which can be used to identify individuals with a higher risk for cardiovascular disease and type 2 diabetes. This metabolic syndrome is characterized by a combination of physiological, metabolic, and molecular alterations such as insulin [...] Read more.
Metabolic syndrome (MetS) is a highly prevalent disorder which can be used to identify individuals with a higher risk for cardiovascular disease and type 2 diabetes. This metabolic syndrome is characterized by a combination of physiological, metabolic, and molecular alterations such as insulin resistance, dyslipidemia, and central obesity. The low-density lipoprotein receptor-related protein 1 (LRP1—A member of the LDL receptor family) is an endocytic and signaling receptor that is expressed in several tissues. It is involved in the clearance of chylomicron remnants from circulation, and has been demonstrated to play a key role in the lipid metabolism at the hepatic level. Recent studies have shown that LRP1 is involved in insulin receptor (IR) trafficking and intracellular signaling activity, which have an impact on the regulation of glucose homeostasis in adipocytes, muscle cells, and brain. In addition, LRP1 has the potential to inhibit or sustain inflammation in macrophages, depending on its cellular expression, as well as the presence of particular types of ligands in the extracellular microenvironment. In this review, we summarize existing perspectives and the latest innovations concerning the role of tissue-specific LRP1 in lipoprotein and glucose metabolism, and examine its ability to mediate inflammatory processes related to MetS and atherosclerosis. Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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17 pages, 697 KiB  
Review
Annexins in Translational Research: Hidden Treasures to Be Found
by Sebastian Schloer, Denise Pajonczyk and Ursula Rescher
Int. J. Mol. Sci. 2018, 19(6), 1781; https://doi.org/10.3390/ijms19061781 - 15 Jun 2018
Cited by 66 | Viewed by 6032
Abstract
The vertebrate annexin superfamily (AnxA) consists of 12 members of a calcium (Ca2+) and phospholipid binding protein family which share a high structural homology. In keeping with this hallmark feature, annexins have been implicated in the Ca2+-controlled regulation of [...] Read more.
The vertebrate annexin superfamily (AnxA) consists of 12 members of a calcium (Ca2+) and phospholipid binding protein family which share a high structural homology. In keeping with this hallmark feature, annexins have been implicated in the Ca2+-controlled regulation of a broad range of membrane events. In this review, we identify and discuss several themes of annexin actions that hold a potential therapeutic value, namely, the regulation of the immune response and the control of tissue homeostasis, and that repeatedly surface in the annexin activity profile. Our aim is to identify and discuss those annexin properties which might be exploited from a translational science and specifically, a clinical point of view. Full article
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20 pages, 4227 KiB  
Article
Novel Insights from Comparative In Silico Analysis of Green Microalgal Cellulases
by Gea Guerriero, Kjell Sergeant, Sylvain Legay, Jean-Francois Hausman, Henry-Michel Cauchie, Irshad Ahmad and Khawar Sohail Siddiqui
Int. J. Mol. Sci. 2018, 19(6), 1782; https://doi.org/10.3390/ijms19061782 - 15 Jun 2018
Cited by 18 | Viewed by 6185
Abstract
The assumption that cellulose degradation and assimilation can only be carried out by heterotrophic organisms was shattered in 2012 when it was discovered that the unicellular green alga, Chlamydomonas reinhardtii (Cr), can utilize cellulose for growth under CO2-limiting conditions. Publications of [...] Read more.
The assumption that cellulose degradation and assimilation can only be carried out by heterotrophic organisms was shattered in 2012 when it was discovered that the unicellular green alga, Chlamydomonas reinhardtii (Cr), can utilize cellulose for growth under CO2-limiting conditions. Publications of genomes/transcriptomes of the colonial microalgae, Gonium pectorale (Gp) and Volvox carteri (Vc), between 2010–2016 prompted us to look for cellulase genes in these algae and to compare them to cellulases from bacteria, fungi, lower/higher plants, and invertebrate metazoans. Interestingly, algal catalytic domains (CDs), belonging to the family GH9, clustered separately and showed the highest (33–42%) and lowest (17–36%) sequence identity with respect to cellulases from invertebrate metazoans and bacteria, respectively, whereas the identity with cellulases from plants was only 27–33%. Based on comparative multiple alignments and homology models, the domain arrangement and active-site architecture of algal cellulases are described in detail. It was found that all algal cellulases are modular, consisting of putative novel cysteine-rich carbohydrate-binding modules (CBMs) and proline/serine-(PS) rich linkers. Two genes were found to encode a protein with a putative Ig-like domain and a cellulase with an unknown domain, respectively. A feature observed in one cellulase homolog from Gp and shared by a spinach cellulase is the existence of two CDs separated by linkers and with a C-terminal CBM. Dockerin and Fn-3-like domains, typically found in bacterial cellulases, are absent in algal enzymes. The targeted gene expression analysis shows that two Gp cellulases consisting, respectively, of a single and two CDs were upregulated upon filter paper addition to the medium. Full article
(This article belongs to the Special Issue Plant Cell Wall Proteins and Development)
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13 pages, 1884 KiB  
Article
Suppression of Plant Defenses by Herbivorous Mites Is Not Associated with Adaptation to Host Plants
by Jéssica T. Paulo, Diogo P. Godinho, Anabela Silva, Cristina Branquinho and Sara Magalhães
Int. J. Mol. Sci. 2018, 19(6), 1783; https://doi.org/10.3390/ijms19061783 - 15 Jun 2018
Cited by 10 | Viewed by 4711
Abstract
Some herbivores suppress plant defenses, which may be viewed as a result of the coevolutionary arms race between plants and herbivores. However, this ability is usually studied in a one-herbivore-one-plant system, which hampers comparative studies that could corroborate this hypothesis. Here, we extend [...] Read more.
Some herbivores suppress plant defenses, which may be viewed as a result of the coevolutionary arms race between plants and herbivores. However, this ability is usually studied in a one-herbivore-one-plant system, which hampers comparative studies that could corroborate this hypothesis. Here, we extend this paradigm and ask whether the herbivorous spider-mite Tetranychus evansi, which suppresses the jasmonic-acid pathway in tomato plants, is also able to suppress defenses in other host plants at different phylogenetic distances from tomatoes. We test this using different plants from the Solanales order, namely tomato, jimsonweed, tobacco, and morning glory (three Solanaceae and one Convolvulaceae), and bean plants (Fabales). First, we compare the performance of T. evansi to that of the other two most-commonly found species of the same genus, T. urticae and T. ludeni, on several plants. We found that the performance of T. evansi is higher than that of the other species only on tomato plants. We then showed, by measuring trypsin inhibitor activity and life history traits of conspecific mites on either clean or pre-infested plants, that T. evansi can suppress plant defenses on all plants except tobacco. This study suggests that the suppression of plant defenses may occur on host plants other than those to which herbivores are adapted. Full article
(This article belongs to the Special Issue Plant Defense Genes Against Biotic Stresses)
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16 pages, 26280 KiB  
Article
Endocrine Disruption at the Androgen Receptor: Employing Molecular Dynamics and Docking for Improved Virtual Screening and Toxicity Prediction
by Joel Wahl and Martin Smieško
Int. J. Mol. Sci. 2018, 19(6), 1784; https://doi.org/10.3390/ijms19061784 - 15 Jun 2018
Cited by 34 | Viewed by 6529
Abstract
The androgen receptor (AR) is a key target for the development of drugs targeting hormone-dependent prostate cancer, but has also an important role in endocrine disruption. Reliable prediction of the binding of ligands towards the AR is therefore of great relevance. Molecular docking [...] Read more.
The androgen receptor (AR) is a key target for the development of drugs targeting hormone-dependent prostate cancer, but has also an important role in endocrine disruption. Reliable prediction of the binding of ligands towards the AR is therefore of great relevance. Molecular docking is a powerful computational method for exploring small-ligand binding to proteins. It can be applied for virtual screening experiments but also for predicting molecular initiating events in toxicology. However, in case of AR, there is no antagonist-bound crystal structure yet available. Our study demonstrates that molecular docking approaches are not able to satisfactorily screen for AR antagonists because of this reason. Therefore, we applied Molecular Dynamics simulations to generate antagonist AR structures and showed that this leads to a vast improvement for the docking of AR antagonists. We benchmarked the ability of these antagonist AR structures discriminate between AR antagonists and decoys using an ensemble docking approach and obtained promising results with good enrichment. However, distinguishing AR antagonists from agonists with high confidence is not possible with the current approach alone. Full article
(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)
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25 pages, 1867 KiB  
Review
Mathematical Models in the Description of Pregnane X Receptor (PXR)-Regulated Cytochrome P450 Enzyme Induction
by Jurjen Duintjer Tebbens, Malek Azar, Elfriede Friedmann, Martin Lanzendörfer and Petr Pávek
Int. J. Mol. Sci. 2018, 19(6), 1785; https://doi.org/10.3390/ijms19061785 - 15 Jun 2018
Cited by 29 | Viewed by 7165
Abstract
The pregnane X receptor (PXR) is a drug/xenobiotic-activated transcription factor of crucial importance for major cytochrome P450 xenobiotic-metabolizing enzymes (CYP) expression and regulation in the liver and the intestine. One of the major target genes regulated by PXR is the cytochrome P450 enzyme [...] Read more.
The pregnane X receptor (PXR) is a drug/xenobiotic-activated transcription factor of crucial importance for major cytochrome P450 xenobiotic-metabolizing enzymes (CYP) expression and regulation in the liver and the intestine. One of the major target genes regulated by PXR is the cytochrome P450 enzyme (CYP3A4), which is the most important human drug-metabolizing enzyme. In addition, PXR is supposed to be involved both in basal and/or inducible expression of many other CYPs, such as CYP2B6, CYP2C8, 2C9 and 2C19, CYP3A5, CYP3A7, and CYP2A6. Interestingly, the dynamics of PXR-mediated target genes regulation has not been systematically studied and we have only a few mechanistic mathematical and biologically based models describing gene expression dynamics after PXR activation in cellular models. Furthermore, few indirect mathematical PKPD models for prediction of CYP3A metabolic activity in vivo have been built based on compartmental models with respect to drug–drug interactions or hormonal crosstalk. Importantly, several negative feedback loops have been described in PXR regulation. Although current mathematical models propose these adaptive mechanisms, a comprehensive mathematical model based on sufficient experimental data is still missing. In the current review, we summarize and compare these models and address some issues that should be considered for the improvement of PXR-mediated gene regulation modelling as well as for our better understanding of the quantitative and spatial dynamics of CYPs expression. Full article
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism and Bioactivation)
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14 pages, 2785 KiB  
Article
Quercetin Lowers Plasma Triglycerides Accompanied by White Adipose Tissue Browning in Diet-Induced Obese Mice
by Eline N. Kuipers, Andrea D. van Dam, Ntsiki M. Held, Isabel M. Mol, Riekelt H. Houtkooper, Patrick C.N. Rensen and Mariëtte R. Boon
Int. J. Mol. Sci. 2018, 19(6), 1786; https://doi.org/10.3390/ijms19061786 - 16 Jun 2018
Cited by 70 | Viewed by 6606
Abstract
Obesity and dyslipidemia are major risk factors for the development of cardiovascular diseases (CVD). Quercetin, a natural flavonoid, lowers plasma triglycerides (TG) in human intervention studies, and its intake is associated with lower CVD risk. The aim of this study was to elucidate [...] Read more.
Obesity and dyslipidemia are major risk factors for the development of cardiovascular diseases (CVD). Quercetin, a natural flavonoid, lowers plasma triglycerides (TG) in human intervention studies, and its intake is associated with lower CVD risk. The aim of this study was to elucidate the mechanism by which quercetin lowers plasma TG levels in diet-induced obesity. C57Bl/6J mice received a high-fat diet (45% of calories derived from fat) with or without quercetin (0.1% w/w) for 12 weeks. Quercetin decreased plasma TG levels from nine weeks onwards (−19%, p < 0.05), without affecting food intake, body composition, or energy expenditure. Mechanistically, quercetin did not reduce intestinal fatty acid (FA) absorption. Rather, quercetin induced a slight reduction in liver Apob expression (−13%, p < 0.05), which suggests decreased very-low density lipoprotein-TG production. Interestingly, quercetin also markedly increased the uptake of [3H]oleate, which was derived from glycerol tri[3H]oleate-labeled lipoprotein-like particles by subcutaneous white adipose tissue (sWAT, +60%, p < 0.05). Furthermore, quercetin also markedly increased mRNA expression of Ucp1 (+229%, p < 0.05) and Elovl3 (+138%, p < 0.05), specifically in sWAT. Accordingly, only quercetin-treated animals showed uncoupling protein-1 protein-positive cells in sWAT, which is fully compatible with increased browning. Taken together, the TG-lowering effect of quercetin may, at least in part, be due to increased TG-derived FA uptake by sWAT as a consequence of browning. Full article
(This article belongs to the Special Issue Nutrition, Brown and White Adipose Tissue)
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21 pages, 775 KiB  
Review
STAT3 Interactors as Potential Therapeutic Targets for Cancer Treatment
by Federica Laudisi, Fabio Cherubini, Giovanni Monteleone and Carmine Stolfi
Int. J. Mol. Sci. 2018, 19(6), 1787; https://doi.org/10.3390/ijms19061787 - 16 Jun 2018
Cited by 122 | Viewed by 10179
Abstract
Signal transducers and activators of transcription (STATs) mediate essential signaling pathways in different biological processes, including immune responses, hematopoiesis, and neurogenesis. Among the STAT members, STAT3 plays crucial roles in cell proliferation, survival, and differentiation. While STAT3 activation is transient in physiological conditions, [...] Read more.
Signal transducers and activators of transcription (STATs) mediate essential signaling pathways in different biological processes, including immune responses, hematopoiesis, and neurogenesis. Among the STAT members, STAT3 plays crucial roles in cell proliferation, survival, and differentiation. While STAT3 activation is transient in physiological conditions, STAT3 becomes persistently activated in a high percentage of solid and hematopoietic malignancies (e.g., melanoma, multiple myeloma, breast, prostate, ovarian, and colon cancers), thus contributing to malignant transformation and progression. This makes STAT3 an attractive therapeutic target for cancers. Initial strategies aimed at inhibiting STAT3 functions have focused on blocking the action of its activating kinases or sequestering its DNA binding ability. More recently, the diffusion of proteomic-based techniques, which have allowed for the identification and characterization of novel STAT3-interacting proteins able to modulate STAT3 activity via its subcellular localization, interact with upstream kinases, and recruit transcriptional machinery, has raised the possibility to target such cofactors to specifically restrain STAT3 oncogenic functions. In this article, we summarize the available data about the function of STAT3 interactors in malignant cells and discuss their role as potential therapeutic targets for cancer treatment. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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17 pages, 1093 KiB  
Review
Big Lessons from Tiny Flies: Drosophila melanogaster as a Model to Explore Dysfunction of Dopaminergic and Serotonergic Neurotransmitter Systems
by Ameya Sanjay Kasture, Thomas Hummel, Sonja Sucic and Michael Freissmuth
Int. J. Mol. Sci. 2018, 19(6), 1788; https://doi.org/10.3390/ijms19061788 - 16 Jun 2018
Cited by 65 | Viewed by 14863
Abstract
The brain of Drosophila melanogaster is comprised of some 100,000 neurons, 127 and 80 of which are dopaminergic and serotonergic, respectively. Their activity regulates behavioral functions equivalent to those in mammals, e.g., motor activity, reward and aversion, memory formation, feeding, sexual appetite, etc. [...] Read more.
The brain of Drosophila melanogaster is comprised of some 100,000 neurons, 127 and 80 of which are dopaminergic and serotonergic, respectively. Their activity regulates behavioral functions equivalent to those in mammals, e.g., motor activity, reward and aversion, memory formation, feeding, sexual appetite, etc. Mammalian dopaminergic and serotonergic neurons are known to be heterogeneous. They differ in their projections and in their gene expression profile. A sophisticated genetic tool box is available, which allows for targeting virtually any gene with amazing precision in Drosophila melanogaster. Similarly, Drosophila genes can be replaced by their human orthologs including disease-associated alleles. Finally, genetic manipulation can be restricted to single fly neurons. This has allowed for addressing the role of individual neurons in circuits, which determine attraction and aversion, sleep and arousal, odor preference, etc. Flies harboring mutated human orthologs provide models which can be interrogated to understand the effect of the mutant protein on cell fate and neuronal connectivity. These models are also useful for proof-of-concept studies to examine the corrective action of therapeutic strategies. Finally, experiments in Drosophila can be readily scaled up to an extent, which allows for drug screening with reasonably high throughput. Full article
(This article belongs to the Special Issue Drosophila Model and Human Disease)
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13 pages, 1297 KiB  
Article
A Noninvasive Test for MicroRNA Expression in Oral Squamous Cell Carcinoma
by Davide B. Gissi, Luca Morandi, Andrea Gabusi, Achille Tarsitano, Claudio Marchetti, Francesca Cura, Annalisa Palmieri, Lucio Montebugnoli, Sofia Asioli, Maria P. Foschini and Luca Scapoli
Int. J. Mol. Sci. 2018, 19(6), 1789; https://doi.org/10.3390/ijms19061789 - 16 Jun 2018
Cited by 36 | Viewed by 4964
Abstract
MicroRNAs have recently been proposed as non-invasive biomarkers in Oral Squamous Cell Carcinoma (OSCC). The aim of this study was to analyze the expression of a panel of miRNAs in epithelial cells collected by oral brushing from OSCCs from regenerative areas after OSCC [...] Read more.
MicroRNAs have recently been proposed as non-invasive biomarkers in Oral Squamous Cell Carcinoma (OSCC). The aim of this study was to analyze the expression of a panel of miRNAs in epithelial cells collected by oral brushing from OSCCs from regenerative areas after OSCC surgical resection and from their respective normal distant mucosa. Oral brushing specimens were collected from 24 healthy donors, 14 OSCC patients with specimens from tumour and normal distant mucosa, and from 13 patients who had OSCC resection, with samples from regenerative areas after OSCC resection and normal distant mucosa. Expression levels of eight targets (miR-21, miR-375, miR-345, miR-181b, miR-146a, miR-649, miR-518b, and miR-191) were evaluated by real-time Polymerase Chain Reaction (PCR). A highly significant between-group difference was found for miR-21 (F = 6.58, p < 0.001), miR-146a (F = 6.974, p < 0.001), and miR-191 (F = 17.07, p < 0.001). The major difference was observed between samples from healthy donors and from OSCC brushing, whereas no significant differences were observed between areas infiltrated by OSCC and their respective normal distant mucosa. Furthermore, altered expression of miR-146a and miR-191 was also observed in regenerative areas after OSCC resection. Conclusions: Oral brushing could be proposed as a noninvasive method to study microRNA expression in oral mucosa in OSCC patients. Full article
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12 pages, 1142 KiB  
Article
Effect of Nicotine on CYP2B1 Expression in a Glioma Animal Model and Analysis of CYP2B6 Expression in Pediatric Gliomas
by Sonia Nava-Salazar, Saúl Gómez-Manzo, Jaime Marcial-Quino, Alfonso Marhx-Bracho, Bryan V. Phillips-Farfán, Carlos Diaz-Avalos and America Vanoye-Carlo
Int. J. Mol. Sci. 2018, 19(6), 1790; https://doi.org/10.3390/ijms19061790 - 16 Jun 2018
Cited by 6 | Viewed by 6371
Abstract
Cyclophosphamide (CPA) is a pro-drug commonly used in the chemotherapeutic schemes for glioma treatment but has high toxicity and the side effects include brain damage and even death. Since CPA is activated mainly by CY2B6, over-expression of the enzyme in the tumor cells [...] Read more.
Cyclophosphamide (CPA) is a pro-drug commonly used in the chemotherapeutic schemes for glioma treatment but has high toxicity and the side effects include brain damage and even death. Since CPA is activated mainly by CY2B6, over-expression of the enzyme in the tumor cells has been proposed to enhance CPA activation. In this study, we explored the induction of the Cyp2b1 (homologous to CYP2B6) by nicotine in an animal rat model with glioma. Gene expression and protein levels were analyzed by RT-PCR and Western blot. Nicotine treatment increased CYP2B1 protein levels in the healthy animals’ brain tissue. In the brain tissue of animals with glioma, the CYP2B1 showed a high expression, even before nicotine treatment. Nicotine did not increase significantly the CYP2B1 protein expression in the tumor, but increased its expression in the tumor vicinity, especially around blood vessels in the cortex. We also explored CY2B6 expression in glioma samples derived from pediatric patients. Tumor tissue showed a variable expression of the enzyme, which could depend on the tumor malignancy grade. Induction of the CYP2B6 in pediatric gliomas with lower expression of the enzyme, could be an alternative to improve the antitumoral effect of CPA treatment. Full article
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism and Bioactivation)
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24 pages, 3756 KiB  
Article
Graviola (Annona muricata) Exerts Anti-Proliferative, Anti-Clonogenic and Pro-Apoptotic Effects in Human Non-Melanoma Skin Cancer UW-BCC1 and A431 Cells In Vitro: Involvement of Hedgehog Signaling
by Jean Christopher Chamcheu, Islam Rady, Roxane-Cherille N. Chamcheu, Abu Bakar Siddique, Melissa B. Bloch, Sergette Banang Mbeumi, Abiola S. Babatunde, Mohammad B. Uddin, Felicite K. Noubissi, Peter W. Jurutka, Yong-Yu Liu, Vladimir S. Spiegelman, G. Kerr Whitfield and Khalid A. El Sayed
Int. J. Mol. Sci. 2018, 19(6), 1791; https://doi.org/10.3390/ijms19061791 - 16 Jun 2018
Cited by 33 | Viewed by 11606
Abstract
Non-melanoma skin cancers (NMSCs) are the leading cause of skin cancer-related morbidity and mortality. Effective strategies are needed to control NMSC occurrence and progression. Non-toxic, plant-derived extracts have been shown to exert multiple anti-cancer effects. Graviola (Annona muricata), a tropical fruit-bearing [...] Read more.
Non-melanoma skin cancers (NMSCs) are the leading cause of skin cancer-related morbidity and mortality. Effective strategies are needed to control NMSC occurrence and progression. Non-toxic, plant-derived extracts have been shown to exert multiple anti-cancer effects. Graviola (Annona muricata), a tropical fruit-bearing plant, has been used in traditional medicine against multiple human diseases including cancer. The current study investigated the effects of graviola leaf and stem extract (GLSE) and its solvent-extracted fractions on two human NMSC cell lines, UW-BCC1 and A431. GLSE was found to: (i) dose-dependently suppress UW-BCC1 and A431 cell growth, motility, wound closure, and clonogenicity; (ii) induce G0/G1 cell cycle arrest by downregulating cyclin/cdk factors while upregulating cdk inhibitors, and (iii) induce apoptosis as evidenced by cleavage of caspases-3, -8 and PARP. Further, GLSE suppressed levels of activated hedgehog (Hh) pathway components Smo, Gli 1/2, and Shh while inducing SuFu. GLSE also decreased the expression of pro-apoptotic protein Bax while decreasing the expression of the anti-apoptotic protein Bcl-2. We determined that these activities were concentrated in an acetogenin/alkaloid-rich dichloromethane subfraction of GLSE. Our data identify graviola extracts and their constituents as promising sources for new chemopreventive and therapeutic agent(s) to be further developed for the control of NMSCs. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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16 pages, 1644 KiB  
Review
The Expensive-Tissue Hypothesis in Vertebrates: Gut Microbiota Effect, a Review
by Chun Hua Huang, Xin Yu and Wen Bo Liao
Int. J. Mol. Sci. 2018, 19(6), 1792; https://doi.org/10.3390/ijms19061792 - 17 Jun 2018
Cited by 25 | Viewed by 9813
Abstract
The gut microbiota is integral to an organism’s digestive structure and has been shown to play an important role in producing substrates for gluconeogenesis and energy production, vasodilator, and gut motility. Numerous studies have demonstrated that variation in diet types is associated with [...] Read more.
The gut microbiota is integral to an organism’s digestive structure and has been shown to play an important role in producing substrates for gluconeogenesis and energy production, vasodilator, and gut motility. Numerous studies have demonstrated that variation in diet types is associated with the abundance and diversity of the gut microbiota, a relationship that plays a significant role in nutrient absorption and affects gut size. The Expensive-Tissue Hypothesis states (ETH) that the metabolic requirement of relatively large brains is offset by a corresponding reduction of the other tissues, such as gut size. However, how the trade-off between gut size and brain size in vertebrates is associated with the gut microbiota through metabolic requirements still remains unexplored. Here, we review research relating to and discuss the potential influence of gut microbiota on the ETH. Full article
(This article belongs to the Special Issue The (Microbiota)–Gut–Brain Axis: Hype or Revolution?)
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14 pages, 1022 KiB  
Review
Epigenomic Control of Thermogenic Adipocyte Differentiation and Function
by Xu Peng, Qiongyi Zhang, Cheng Liao, Weiping Han and Feng Xu
Int. J. Mol. Sci. 2018, 19(6), 1793; https://doi.org/10.3390/ijms19061793 - 17 Jun 2018
Cited by 14 | Viewed by 6320
Abstract
Obesity and its associated metabolic disorders are spreading at a fast pace throughout the world; thus, effective therapeutic approaches are necessary to combat this epidemic. Obesity develops when there is a greater caloric intake than energy expenditure. Promoting energy expenditure has recently attracted [...] Read more.
Obesity and its associated metabolic disorders are spreading at a fast pace throughout the world; thus, effective therapeutic approaches are necessary to combat this epidemic. Obesity develops when there is a greater caloric intake than energy expenditure. Promoting energy expenditure has recently attracted much attention as a promising approach for the management of body weight. Thermogenic adipocytes are capable of burning fat to dissipate chemical energy into heat, thereby enhancing energy expenditure. After the recent re-discovery of thermogenic adipocytes in adult humans, much effort has focused on understanding the molecular mechanisms, especially the epigenetic mechanisms, which regulate thermogenic adipocyte development and function. A number of chromatin signatures, such as histone modifications, DNA methylation, chromatin accessibilities, and interactions, have been profiled at the genome level and analyzed in various murine and human thermogenic fat cell systems. Moreover, writers and erasers, as well as readers of the epigenome are also investigated using genomic tools in thermogenic adipocytes. In this review, we summarize and discuss the recent advance in these studies and highlight the insights gained into the epigenomic regulation of thermogenic program as well as the pathogenesis of human metabolic diseases. Full article
(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)
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13 pages, 1639 KiB  
Review
Scorpins in the DNA Damage Response
by Dario Palmieri, Anna Tessari and Vincenzo Coppola
Int. J. Mol. Sci. 2018, 19(6), 1794; https://doi.org/10.3390/ijms19061794 - 17 Jun 2018
Cited by 10 | Viewed by 5520
Abstract
The DNA Damage Response (DDR) is a complex signaling network that comes into play when cells experience genotoxic stress. Upon DNA damage, cellular signaling pathways are rewired to slow down cell cycle progression and allow recovery. However, when the damage is beyond repair, [...] Read more.
The DNA Damage Response (DDR) is a complex signaling network that comes into play when cells experience genotoxic stress. Upon DNA damage, cellular signaling pathways are rewired to slow down cell cycle progression and allow recovery. However, when the damage is beyond repair, cells activate complex and still not fully understood mechanisms, leading to a complete proliferative arrest or cell death. Several conventional and novel anti-neoplastic treatments rely on causing DNA damage or on the inhibition of the DDR in cancer cells. However, the identification of molecular determinants directing cancer cells toward recovery or death upon DNA damage is still far from complete, and it is object of intense investigation. SPRY-containing RAN binding Proteins (Scorpins) RANBP9 and RANBP10 are evolutionarily conserved and ubiquitously expressed proteins whose biological functions are still debated. RANBP9 has been previously implicated in cell proliferation, survival, apoptosis and migration. Recent studies also showed that RANBP9 is involved in the Ataxia Telangiectasia Mutated (ATM) signaling upon DNA damage. Accordingly, cells lacking RANBP9 show increased sensitivity to genotoxic treatment. Although there is no published evidence, extensive protein similarities suggest that RANBP10 might have partially overlapping functions with RANBP9. Like RANBP9, RANBP10 bears sites putative target of PIK-kinases and high throughput studies found RANBP10 to be phosphorylated following genotoxic stress. Therefore, this second Scorpin might be another overlooked player of the DDR alone or in combination with RANBP9. This review focuses on the relatively unknown role played by RANBP9 and RANBP10 in responding to genotoxic stress. Full article
(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)
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38 pages, 4933 KiB  
Review
Shining Light on Chitosan: A Review on the Usage of Chitosan for Photonics and Nanomaterials Research
by Sreekar B. Marpu and Erin N. Benton
Int. J. Mol. Sci. 2018, 19(6), 1795; https://doi.org/10.3390/ijms19061795 - 17 Jun 2018
Cited by 63 | Viewed by 9435
Abstract
Chitosan (CS) is a natural polymer derived from chitin that has found its usage both in research and commercial applications due to its unique solubility and chemical and biological attributes. The biocompatibility and biodegradability of CS have helped researchers identify its utility in [...] Read more.
Chitosan (CS) is a natural polymer derived from chitin that has found its usage both in research and commercial applications due to its unique solubility and chemical and biological attributes. The biocompatibility and biodegradability of CS have helped researchers identify its utility in the delivery of therapeutic agents, tissue engineering, wound healing, and more. Industrial applications include cosmetic and personal care products, wastewater treatment, and corrosion protection, to name a few. Many researchers have published numerous reviews outlining the physical and chemical properties of CS, as well as its use for many of the above-mentioned applications. Recently, the cationic polyelectrolyte nature of CS was found to be advantageous for stabilizing fascinating photonic materials including plasmonic nanoparticles (e.g., gold and silver), semiconductor nanoparticles (e.g., zinc oxide, cadmium sulfide), fluorescent organic dyes (e.g., fluorescein isothiocyanate (FITC)), luminescent transitional and lanthanide complexes (e.g., Au(I) and Ru(II), and Eu(III)). These photonic systems have been extensively investigated for their usage in antimicrobial, wound healing, diagnostics, sensing, and imaging applications. Highlighted in this review are the different works involving some of the above-mentioned molecular-nano systems that are prepared or stabilized using the CS polymer. The advantages and the role of the CS for synthesizing and stabilizing the above-mentioned optically active materials have been illustrated. Full article
(This article belongs to the Special Issue Chitins 2018)
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26 pages, 37748 KiB  
Review
Bioengineering Approaches for Bladder Regeneration
by Ángel Serrano-Aroca, César David Vera-Donoso and Victoria Moreno-Manzano
Int. J. Mol. Sci. 2018, 19(6), 1796; https://doi.org/10.3390/ijms19061796 - 17 Jun 2018
Cited by 73 | Viewed by 12088
Abstract
Current clinical strategies for bladder reconstruction or substitution are associated to serious problems. Therefore, new alternative approaches are becoming more and more necessary. The purpose of this work is to review the state of the art of the current bioengineering advances and obstacles [...] Read more.
Current clinical strategies for bladder reconstruction or substitution are associated to serious problems. Therefore, new alternative approaches are becoming more and more necessary. The purpose of this work is to review the state of the art of the current bioengineering advances and obstacles reported in bladder regeneration. Tissue bladder engineering requires an ideal engineered bladder scaffold composed of a biocompatible material suitable to sustain the mechanical forces necessary for bladder filling and emptying. In addition, an engineered bladder needs to reconstruct a compliant muscular wall and a highly specialized urothelium, well-orchestrated under control of autonomic and sensory innervations. Bioreactors play a very important role allowing cell growth and specialization into a tissue-engineered vascular construct within a physiological environment. Bioprinting technology is rapidly progressing, achieving the generation of custom-made structural supports using an increasing number of different polymers as ink with a high capacity of reproducibility. Although many promising results have been achieved, few of them have been tested with clinical success. This lack of satisfactory applications is a good reason to discourage researchers in this field and explains, somehow, the limited high-impact scientific production in this area during the last decade, emphasizing that still much more progress is required before bioengineered bladders become a commonplace in the clinical setting. Full article
(This article belongs to the Special Issue Cell Colonization in Scaffolds)
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29 pages, 5040 KiB  
Review
Role of MicroRNAs in Renal Parenchymal Diseases—A New Dimension
by Saeed Kamran Shaffi, David Galas, Alton Etheridge and Christos Argyropoulos
Int. J. Mol. Sci. 2018, 19(6), 1797; https://doi.org/10.3390/ijms19061797 - 17 Jun 2018
Cited by 24 | Viewed by 5628
Abstract
Since their discovery in 1993, numerous microRNAs (miRNAs) have been identified in humans and other eukaryotic organisms, and their role as key regulators of gene expression is still being elucidated. It is now known that miRNAs not only play a central role in [...] Read more.
Since their discovery in 1993, numerous microRNAs (miRNAs) have been identified in humans and other eukaryotic organisms, and their role as key regulators of gene expression is still being elucidated. It is now known that miRNAs not only play a central role in the processes that ensure normal development and physiology, but they are often dysregulated in various diseases. In this review, we present an overview of the role of miRNAs in normal renal development and physiology, in maladaptive renal repair after injury, and in the pathogenesis of renal parenchymal diseases. In addition, we describe methods used for their detection and their potential as therapeutic targets. Continued research on renal miRNAs will undoubtedly improve our understanding of diseases affecting the kidneys and may also lead to new therapeutic agents. Full article
(This article belongs to the Special Issue The Role of MicroRNAs in Human Diseases)
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18 pages, 3795 KiB  
Article
Regulation and Function of TMEM16F in Renal Podocytes
by Laura K. Schenk, Jiraporn Ousingsawat, Boris V. Skryabin, Rainer Schreiber, Hermann Pavenstädt and Karl Kunzelmann
Int. J. Mol. Sci. 2018, 19(6), 1798; https://doi.org/10.3390/ijms19061798 - 18 Jun 2018
Cited by 6 | Viewed by 5483
Abstract
The Ca2+-activated phospholipid scramblase and ion channel TMEM16F is expressed in podocytes of renal glomeruli. Podocytes are specialized cells that form interdigitating foot processes as an essential component of the glomerular filter. These cells, which participate in generation of the primary [...] Read more.
The Ca2+-activated phospholipid scramblase and ion channel TMEM16F is expressed in podocytes of renal glomeruli. Podocytes are specialized cells that form interdigitating foot processes as an essential component of the glomerular filter. These cells, which participate in generation of the primary urine, are often affected during primary glomerular diseases, such as glomerulonephritis and secondary hypertensive or diabetic nephropathy, which always leads to proteinuria. Because the function of podocytes is known to be controlled by intracellular Ca2+ signaling, it is important to know about the role of Ca2+-activated TMEM16F in these cells. To that end, we generated an inducible TMEM16F knockdown in the podocyte cell line AB8, and produced a conditional mouse model with knockout of TMEM16F in podocytes and renal epithelial cells of the nephron. We found that knockdown of TMEM16F did not produce proteinuria or any obvious phenotypic changes. Knockdown of TMEM16F affected cell death of tubular epithelial cells but not of glomerular podocytes when analyzed in TUNEL assays. Surprisingly, and in contrast to other cell types, TMEM16F did not control intracellular Ca2+ signaling and was not responsible for Ca2+-activated whole cell currents in podocytes. TMEM16F levels in podocytes were enhanced after inhibition of the endolysosomal pathway and after treatment with angiotensin II. Renal knockout of TMEM16F did not compromise renal morphology and serum electrolytes. Taken together, in contrast to other cell types, such as platelets, bone cells, and immune cells, TMEM16F shows little effect on basal properties of podocytes and does not appear to be essential for renal function. Full article
(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)
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16 pages, 4737 KiB  
Article
STIM1 Knockout Enhances PDGF-Mediated Ca2+ Signaling through Upregulation of the PDGFR–PLCγ–STIM2 Cascade
by Tzu-Yu Huang, Yi-Hsin Lin, Heng-Ai Chang, Tzu-Ying Yeh, Ya-Han Chang, Yi-Fan Chen, Ying-Chi Chen, Chun-Chun Li and Wen-Tai Chiu
Int. J. Mol. Sci. 2018, 19(6), 1799; https://doi.org/10.3390/ijms19061799 - 18 Jun 2018
Cited by 11 | Viewed by 5486
Abstract
Platelet-derived growth factor (PDGF) has mitogenic and chemotactic effects on fibroblasts. An increase in intracellular Ca2+ is one of the first events that occurs following the stimulation of PDGF receptors (PDGFRs). PDGF activates Ca2+ elevation by activating the phospholipase C gamma [...] Read more.
Platelet-derived growth factor (PDGF) has mitogenic and chemotactic effects on fibroblasts. An increase in intracellular Ca2+ is one of the first events that occurs following the stimulation of PDGF receptors (PDGFRs). PDGF activates Ca2+ elevation by activating the phospholipase C gamma (PLCγ)-signaling pathway, resulting in ER Ca2+ release. Store-operated Ca2+ entry (SOCE) is the major form of extracellular Ca2+ influx following depletion of ER Ca2+ stores and stromal interaction molecule 1 (STIM1) is a key molecule in the regulation of SOCE. In this study, wild-type and STIM1 knockout mouse embryonic fibroblasts (MEF) cells were used to investigate the role of STIM1 in PDGF-induced Ca2+ oscillation and its functions in MEF cells. The unexpected findings suggest that STIM1 knockout enhances PDGFR–PLCγ–STIM2 signaling, which in turn increases PDGF-BB-induced Ca2+ elevation. Enhanced expressions of PDGFRs and PLCγ in STIM1 knockout cells induce Ca2+ release from the ER store through PLCγ–IP3 signaling. Moreover, STIM2 replaces STIM1 to act as the major ER Ca2+ sensor in activating SOCE. However, activation of PDGFRs also activate Akt, ERK, and JNK to regulate cellular functions, such as cell migration. These results suggest that alternative switchable pathways can be observed in cells, which act downstream of the growth factors that regulate Ca2+ signaling. Full article
(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases)
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15 pages, 2793 KiB  
Article
MK-0677, a Ghrelin Agonist, Alleviates Amyloid Beta-Related Pathology in 5XFAD Mice, an Animal Model of Alzheimer’s Disease
by Yu-on Jeong, Soo Jung Shin, Jun Yong Park, Bo Kyeong Ku, Ji Soo Song, Jwa-Jin Kim, Seong Gak Jeon, Sang Min Lee and Minho Moon
Int. J. Mol. Sci. 2018, 19(6), 1800; https://doi.org/10.3390/ijms19061800 - 18 Jun 2018
Cited by 39 | Viewed by 12419
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, neuroinflammation, and neuronal death. The primary pathogenic cause is believed to be the accumulation of pathogenic amyloid beta (Aβ) assemblies in the brain. Ghrelin, which is a peptide hormone predominantly secreted [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, neuroinflammation, and neuronal death. The primary pathogenic cause is believed to be the accumulation of pathogenic amyloid beta (Aβ) assemblies in the brain. Ghrelin, which is a peptide hormone predominantly secreted from the stomach, is an endogenous ligand for the growth hormone secretagogue-receptor type 1a (GHS-R1a). MK-0677 is a ghrelin agonist that potently stimulates the GHS-R1a ghrelin receptor. Interestingly, previous studies have shown that ghrelin improves cognitive impairments and attenuates neuronal death and neuroinflammation in several neurological disorders. However, it is unknown whether MK-0677 can affect Aβ accumulation or Aβ-mediated pathology in the brains of patients with AD. Therefore, we examined the effects of MK-0677 administration on AD-related pathology in 5XFAD mice, an Aβ-overexpressing transgenic mouse model of AD. MK-0677 was intraperitoneally administered to three-month-old 5XFAD mice. To visualize Aβ accumulation, neuroinflammation, and neurodegeneration, thioflavin-S staining and immunostaining with antibodies against Aβ (4G8), ionized calcium-binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), neuronal nuclear antigen (NeuN), and synaptophysin were conducted in the neocortex of 5XFAD and wild-type mice, and to evaluate changes of phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein (pCREB) levels, immunostaining with antibody against pCREB was performed in dentate gyrus of the hippocampus of 5XFAD and wild-type mice. The histological analyses indicated that MK-0677-treated 5XFAD mice showed reduced Aβ deposition, gliosis, and neuronal and synaptic loss in the deep cortical layers, and inhibited the decrement of pCREB levels in dentate gyrus of the hippocampus compared to vehicle-treated 5XFAD mice. Our results showed that activation of the ghrelin receptor with MK-0677 inhibited the Aβ burden, neuroinflammation, and neurodegeneration, which suggested that MK-0677 might have potential as a treatment of the early phase of AD. Full article
(This article belongs to the Special Issue Amyloid Fibrils and Methods for Their Study)
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15 pages, 666 KiB  
Review
Role of Human Macrophage Polarization in Inflammation during Infectious Diseases
by Chiraz Atri, Fatma Z. Guerfali and Dhafer Laouini
Int. J. Mol. Sci. 2018, 19(6), 1801; https://doi.org/10.3390/ijms19061801 - 19 Jun 2018
Cited by 1041 | Viewed by 39984
Abstract
Experimental models have often been at the origin of immunological paradigms such as the M1/M2 dichotomy following macrophage polarization. However, this clear dichotomy in animal models is not as obvious in humans, and the separating line between M1-like and M2-like macrophages is rather [...] Read more.
Experimental models have often been at the origin of immunological paradigms such as the M1/M2 dichotomy following macrophage polarization. However, this clear dichotomy in animal models is not as obvious in humans, and the separating line between M1-like and M2-like macrophages is rather represented by a continuum, where boundaries are still unclear. Indeed, human infectious diseases, are characterized by either a back and forth or often a mixed profile between the pro-inflammatory microenvironment (dominated by interleukin (IL)-1β, IL-6, IL-12, IL-23 and Tumor Necrosis Factor (TNF)-α cytokines) and tissue injury driven by classically activated macrophages (M1-like) and wound healing driven by alternatively activated macrophages (M2-like) in an anti-inflammatory environment (dominated by IL-10, Transforming growth factor (TGF)-β, chemokine ligand (CCL)1, CCL2, CCL17, CCL18, and CCL22). This review brews the complexity of the situation during infectious diseases by stressing on this continuum between M1-like and M2-like extremes. We first discuss the basic biology of macrophage polarization, function, and role in the inflammatory process and its resolution. Secondly, we discuss the relevance of the macrophage polarization continuum during infectious and neglected diseases, and the possibility to interfere with such activation states as a promising therapeutic strategy in the treatment of such diseases. Full article
(This article belongs to the Special Issue Macrophages in Inflammation)
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17 pages, 2358 KiB  
Article
Structure–Activity Relationship of Piplartine and Synthetic Analogues against Schistosoma mansoni and Cytotoxicity to Mammalian Cells
by Yuri Campelo, Alicia Ombredane, Andreanne G. Vasconcelos, Lucas Albuquerque, Daniel C. Moreira, Alexandra Plácido, Jefferson Rocha, Harold Hilarion Fokoue, Lydia Yamaguchi, Ana Mafud, Yvonne P. Mascarenhas, Cristina Delerue-Matos, Tatiana Borges, Graziella A. Joanitti, Daniel D.R. Arcanjo, Massuo J. Kato, Selma A. S. Kuckelhaus, Marcos P. N. Silva, Josué De Moraes and José Roberto S. A. Leite
Int. J. Mol. Sci. 2018, 19(6), 1802; https://doi.org/10.3390/ijms19061802 - 19 Jun 2018
Cited by 16 | Viewed by 5479
Abstract
Schistosomiasis, caused by helminth flatworms of the genus Schistosoma, is an infectious disease mainly associated with poverty that affects millions of people worldwide. Since treatment for this disease relies only on the use of praziquantel, there is an urgent need to identify [...] Read more.
Schistosomiasis, caused by helminth flatworms of the genus Schistosoma, is an infectious disease mainly associated with poverty that affects millions of people worldwide. Since treatment for this disease relies only on the use of praziquantel, there is an urgent need to identify new antischistosomal drugs. Piplartine is an amide alkaloid found in several Piper species (Piperaceae) that exhibits antischistosomal properties. The aim of this study was to evaluate the structure–function relationship between piplartine and its five synthetic analogues (19A, 1G, 1M, 14B and 6B) against Schistosoma mansoni adult worms, as well as its cytotoxicity to mammalian cells using murine fibroblast (NIH-3T3) and BALB/cN macrophage (J774A.1) cell lines. In addition, density functional theory calculations and in silico analysis were used to predict physicochemical and toxicity parameters. Bioassays revealed that piplartine is active against S. mansoni at low concentrations (5–10 µM), but its analogues did not. In contrast, based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, piplartine exhibited toxicity in mammalian cells at 785 µM, while its analogues 19A and 6B did not reduce cell viability at the same concentrations. This study demonstrated that piplartine analogues showed less activity against S. mansoni but presented lower toxicity than piplartine. Full article
(This article belongs to the Section Biochemistry)
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14 pages, 1127 KiB  
Review
STAT3 in Tumor-Associated Myeloid Cells: Multitasking to Disrupt Immunity
by Yu-Lin Su, Shuvomoy Banerjee, Seok Voon White and Marcin Kortylewski
Int. J. Mol. Sci. 2018, 19(6), 1803; https://doi.org/10.3390/ijms19061803 - 19 Jun 2018
Cited by 92 | Viewed by 9326
Abstract
Myeloid immune cells, such as dendritic cells, monocytes, and macrophages, play a central role in the generation of immune responses and thus are often either disabled or even hijacked by tumors. These new tolerogenic activities of tumor-associated myeloid cells are controlled by an [...] Read more.
Myeloid immune cells, such as dendritic cells, monocytes, and macrophages, play a central role in the generation of immune responses and thus are often either disabled or even hijacked by tumors. These new tolerogenic activities of tumor-associated myeloid cells are controlled by an oncogenic transcription factor, signal transducer and activator of transcription 3 (STAT3). STAT3 multitasks to ensure tumors escape immune detection by impairing antigen presentation and reducing production of immunostimulatory molecules while augmenting the release of tolerogenic mediators, thereby reducing innate and adaptive antitumor immunity. Tumor-associated myeloid cells and STAT3 signaling in this compartment are now commonly recognized as an attractive cellular target for improving efficacy of standard therapies and immunotherapies. Hereby, we review the importance and functional complexity of STAT3 signaling in this immune cell compartment as well as potential strategies for cancer therapy. Full article
(This article belongs to the Special Issue Advances in Biological Functions of STAT3)
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20 pages, 1415 KiB  
Review
The Type 3 Deiodinase: Epigenetic Control of Brain Thyroid Hormone Action and Neurological Function
by Arturo Hernandez and J. Patrizia Stohn
Int. J. Mol. Sci. 2018, 19(6), 1804; https://doi.org/10.3390/ijms19061804 - 19 Jun 2018
Cited by 35 | Viewed by 11570
Abstract
Thyroid hormones (THs) influence multiple processes in the developing and adult central nervous system, and their local availability needs to be maintained at levels that are tailored to the requirements of their biological targets. The local complement of TH transporters, deiodinase enzymes, and [...] Read more.
Thyroid hormones (THs) influence multiple processes in the developing and adult central nervous system, and their local availability needs to be maintained at levels that are tailored to the requirements of their biological targets. The local complement of TH transporters, deiodinase enzymes, and receptors is critical to ensure specific levels of TH action in neural cells. The type 3 iodothyronine deiodinase (DIO3) inactivates THs and is highly present in the developing and adult brain, where it limits their availability and action. DIO3 deficiency in mice results in a host of neurodevelopmental and behavioral abnormalities, demonstrating the deleterious effects of TH excess, and revealing the critical role of DIO3 in the regulation of TH action in the brain. The fact the Dio3 is an imprinted gene and that its allelic expression pattern varies across brain regions and during development introduces an additional level of control to deliver specific levels of hormone action in the central nervous system (CNS). The sensitive epigenetic nature of the mechanisms controlling the genomic imprinting of Dio3 renders brain TH action particularly susceptible to disruption due to exogenous treatments and environmental exposures, with potential implications for the etiology of human neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Epigenetics of Neurodevelopmental Disorders)
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17 pages, 2320 KiB  
Article
Inter-Individual Variability in Acute Toxicity of R-Pulegone and R-Menthofuran in Human Liver Slices and Their Influence on miRNA Expression Changes in Comparison to Acetaminophen
by Tomáš Zárybnický, Petra Matoušková, Bibiána Lancošová, Zdeněk Šubrt, Lenka Skálová and Iva Boušová
Int. J. Mol. Sci. 2018, 19(6), 1805; https://doi.org/10.3390/ijms19061805 - 19 Jun 2018
Cited by 20 | Viewed by 5343
Abstract
Monoterpenes R-pulegone (PUL) and R-menthofuran (MF), abundant in the Lamiaceae family, are frequently used in herb and food products. Although their hepatotoxicity was shown in rodent species, information about their effects in human liver has been limited. The aim of our study was [...] Read more.
Monoterpenes R-pulegone (PUL) and R-menthofuran (MF), abundant in the Lamiaceae family, are frequently used in herb and food products. Although their hepatotoxicity was shown in rodent species, information about their effects in human liver has been limited. The aim of our study was to test the effects of PUL, MF and acetaminophen (APAP, as a reference compound) on cell viability and microRNA (miRNA) expression in human precision-cut liver slices. Slices from five patients were used to follow up on the inter-individual variability. PUL was toxic in all liver samples (the half-maximal effective concentration was 4.0 µg/mg of tissue), while MF and surprisingly APAP only in two and three liver samples, respectively. PUL also changed miRNA expression more significantly than MF and APAP. The most pronounced effect was a marked decrease of miR-155-5p expression caused by PUL even in non-toxic concentrations in all five liver samples. Our results showed that PUL is much more toxic than MF and APAP in human liver and that miR-155-5p could be a good marker of PUL early hepatotoxicity. Marked inter-individual variabilities in all our results demonstrate the high probability of significant differences in the hepatotoxicity of tested compounds among people. Full article
(This article belongs to the Special Issue Hepatotoxicity: Molecular Mechanisms and Pathophysiology)
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21 pages, 6664 KiB  
Article
5-Azacitidine Induces Cell Death in a Tissue Culture of Brachypodium distachyon
by Alexander Betekhtin, Anna Milewska-Hendel, Lukasz Chajec, Magdalena Rojek, Katarzyna Nowak, Jolanta Kwasniewska, Elzbieta Wolny, Ewa Kurczynska and Robert Hasterok
Int. J. Mol. Sci. 2018, 19(6), 1806; https://doi.org/10.3390/ijms19061806 - 19 Jun 2018
Cited by 22 | Viewed by 6477
Abstract
Morphological and histological observations revealed that, at a concentration of 50 µM, 5-azacitidine (5-azaC) totally inhibited the induction of embryogenic masses (EM), while the cultivation of explants (zygotic embryos; ZEs) in the presence of 5 µM of 5-azaC led to the formation of [...] Read more.
Morphological and histological observations revealed that, at a concentration of 50 µM, 5-azacitidine (5-azaC) totally inhibited the induction of embryogenic masses (EM), while the cultivation of explants (zygotic embryos; ZEs) in the presence of 5 µM of 5-azaC led to the formation of a callus with EM in 10% of the cases. Transmission electron microscopy (TEM) analyzes revealed the presence of the morphological and ultrastructural features that are typical for the vacuolar type of cell death in the callus cells that were treated. A TUNEL assay confirmed the presence of DNA double-strand breaks for the callus cells that had been treated with both 5 and 50 µM 5-azaC concentrations. Analysis of the gene expression of selected cell death markers demonstrated a reduced expression of metacaspase, protein executer 1 (EX1), and thioredoxin (TRX) in the callus cells that had been treated compared to the control culture. The strongest increase in the gene activity was characteristic for glutathione S-transferase (GST). Our studies also included an analysis of the distribution of some arabinogalactan proteins (AGPs) and extensin epitopes, which can be used as markers of cells that are undergoing death in a Brachypodium distachyon tissue culture. Full article
(This article belongs to the Section Molecular Plant Sciences)
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21 pages, 4835 KiB  
Article
Collagen as Coating Material for 45S5 Bioactive Glass-Based Scaffolds for Bone Tissue Engineering
by Jasmin Hum and Aldo R. Boccaccini
Int. J. Mol. Sci. 2018, 19(6), 1807; https://doi.org/10.3390/ijms19061807 - 19 Jun 2018
Cited by 63 | Viewed by 9157
Abstract
Highly porous 45S5 bioactive glass-based scaffolds were fabricated by the foam replica technique and coated with collagen by a novel method. After an initial cleaning step of the bioactive glass surface to expose reactive –OH groups, samples were surface functionalized by (3-aminopropyl)triethoxysilane (APTS). [...] Read more.
Highly porous 45S5 bioactive glass-based scaffolds were fabricated by the foam replica technique and coated with collagen by a novel method. After an initial cleaning step of the bioactive glass surface to expose reactive –OH groups, samples were surface functionalized by (3-aminopropyl)triethoxysilane (APTS). Functionalized scaffolds were immersed in a collagen solution, left for gelling at 37 °C, and dried at room temperature. The collagen coating was further stabilized by crosslinking with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS). Applying this coating method, a layer thickness of a few micrometers was obtained without affecting the overall scaffold macroporosity. In addition, values of compressive strength were enhanced by a factor of five, increasing from 0.04 ± 0.02 MPa for uncoated scaffolds to 0.18 ± 0.03 MPa for crosslinked collagen-coated scaffolds. The composite material developed in this study exhibited positive cell (MG-63) viability as well as suitable cell attachment and proliferation on the surface. The combination of bioactivity, mechanical competence, and cellular response makes this novel scaffold system attractive for bone tissue engineering. Full article
(This article belongs to the Special Issue Novel Biomaterials for Tissue Engineering 2018)
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25 pages, 3259 KiB  
Article
Co-Expression Network Analysis of AMPK and Autophagy Gene Products during Adipocyte Differentiation
by Mahmoud Ahmed, Jin Seok Hwang, Trang Huyen Lai, Sahib Zada, Huynh Quoc Nguyen, Trang Min Pham, Miyong Yun and Deok Ryong Kim
Int. J. Mol. Sci. 2018, 19(6), 1808; https://doi.org/10.3390/ijms19061808 - 19 Jun 2018
Cited by 8 | Viewed by 6514
Abstract
Autophagy is involved in the development and differentiation of many cell types. It is essential for the pre-adipocytes to respond to the differentiation stimuli and may contribute to reorganizing the intracellulum to adapt the morphological and metabolic demands. Although AMPK, an energy sensor, [...] Read more.
Autophagy is involved in the development and differentiation of many cell types. It is essential for the pre-adipocytes to respond to the differentiation stimuli and may contribute to reorganizing the intracellulum to adapt the morphological and metabolic demands. Although AMPK, an energy sensor, has been associated with autophagy in several cellular processes, how it connects to autophagy during the adipocyte differentiation remains to be investigated. Here, we studied the interaction between AMPK and autophagy gene products at the mRNA level during adipocyte differentiation using public-access datasets. We used the weighted-gene co-expression analysis to detect and validate multiple interconnected modules of co-expressed genes in a dataset of MDI-induced 3T3-L1 pre-adipocytes. These modules were found to be highly correlated with the differentiation course of the adipocytes. Several novel interactions between AMPK and autophagy gene products were identified. Together, it is possible that AMPK-autophagy interaction is temporally and locally modulated in response to the differentiation stimuli. Full article
(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)
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13 pages, 2899 KiB  
Article
Diethyl Blechnic, a Novel Natural Product Isolated from Salvia miltiorrhiza Bunge, Inhibits Doxorubicin-Induced Apoptosis by Inhibiting ROS and Activating JNK1/2
by Jie Yu, Hongwei Gao, Chuanhong Wu, Qiong-Ming Xu, Jin-Jian Lu and Xiuping Chen
Int. J. Mol. Sci. 2018, 19(6), 1809; https://doi.org/10.3390/ijms19061809 - 19 Jun 2018
Cited by 19 | Viewed by 4887
Abstract
Doxorubicin (DOX) is a widely used antineoplastic agent in clinics. However, its clinical application is largely limited by its cardiotoxicity. Diethyl blechnic (DB) is a novel compound isolated from Salvia miltiorrhiza Bunge. Here, we study the effect of DB on DOX-induced cardiotoxicity and [...] Read more.
Doxorubicin (DOX) is a widely used antineoplastic agent in clinics. However, its clinical application is largely limited by its cardiotoxicity. Diethyl blechnic (DB) is a novel compound isolated from Salvia miltiorrhiza Bunge. Here, we study the effect of DB on DOX-induced cardiotoxicity and its underlying mechanisms. Cellular viability was tested by 3-[-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and protein level was evaluated by Western blotting. 5,5’,6,6’-tetrachloro-1,1’,3,3’-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining was performed to determine the mitochondrial membrane potential (MMP). Hoechst 33342 staining and TUNEL staining was performed to test the apoptosis. Reactive oxygen species (ROS) generation was investigated by using flow cytometry. DB significantly inhibited DOX-induced apoptosis in H9c2 cells and primary cultured cardiomyocytes. Moreover, DB decreased cell apoptotic morphological changes and reversed the mitochondrial membrane potential induced by DOX. Meanwhile, pre-treatment with DB increased the expression levels of B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xl), and survivin and reduced the expression levels of Bcl-2-associated X protein (Bax), p-p53, cytochrome c (cyt c), and cleaved-caspase 3, 7, 8, 9 in the protein levels in DOX-treated H9c2 cells. Furthermore, DB suppressed ROS generation. The DB-mediated protective effects were accompanied by increased c-Jun N-terminal kinase1/2 (JNK1/2) expression. In addition, SP600125, the inhibitor of JNK1/2, abolished the protective effect of DB. We concluded that DB protected cardiomyocytes against DOX-induced cytotoxicity by inhibiting ROS and activating the JNK1/2 pathway. Therefore, DB is a promising candidate as a cardioprotective agent against DOX-induced cardiotoxicity. Full article
(This article belongs to the Special Issue Free Radicals and Oxidants in Pathogenesis)
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13 pages, 1643 KiB  
Article
Differential Expression and Pathway Analysis in Drug-Resistant Triple-Negative Breast Cancer Cell Lines Using RNASeq Analysis
by Safa Shaheen, Febin Fawaz, Shaheen Shah and Dietrich Büsselberg
Int. J. Mol. Sci. 2018, 19(6), 1810; https://doi.org/10.3390/ijms19061810 - 19 Jun 2018
Cited by 26 | Viewed by 10597
Abstract
Triple-negative breast cancer (TNBC) is among the most notorious types of breast cancer, the treatment of which does not give consistent results due to the absence of the three receptors (estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 [...] Read more.
Triple-negative breast cancer (TNBC) is among the most notorious types of breast cancer, the treatment of which does not give consistent results due to the absence of the three receptors (estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as well as high amount of molecular variability. Drug resistance also contributes to treatment unresponsiveness. We studied differentially expressed genes, their biological roles, as well as pathways from RNA-Seq datasets of two different TNBC drug-resistant cell lines of Basal B subtype SUM159 and MDA-MB-231 treated with drugs JQ1 and Dexamethasone, respectively, to elucidate the mechanism of drug resistance. RNA sequencing(RNA-Seq) data analysis was done using edgeR which is an efficient program for determining the most significant Differentially Expressed Genes (DEGs), Gene Ontology (GO) terms, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. iPathway analysis was further used to obtain validated results using analysis that takes into consideration type, function, and interactions of genes in the pathway. The significant similarities and differences throw light into the molecular heterogeneity of TNBC, giving clues into the aspects that can be focused to overcome drug resistance. From this study, cytokine-cytokine receptor interaction pathway appeared to be a key factor in TNBC drug resistance. Full article
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13 pages, 1557 KiB  
Review
Role of Membrane Cholesterol Levels in Activation of Lyn upon Cell Detachment
by Takao Morinaga, Noritaka Yamaguchi, Yuji Nakayama, Masatoshi Tagawa and Naoto Yamaguchi
Int. J. Mol. Sci. 2018, 19(6), 1811; https://doi.org/10.3390/ijms19061811 - 19 Jun 2018
Cited by 6 | Viewed by 6323
Abstract
Cholesterol, a major component of the plasma membrane, determines the physical
properties of biological membranes and plays a critical role in the assembly of membrane
microdomains. Enrichment or deprivation of membrane cholesterol affects the activities of many
signaling molecules at the plasma membrane.
[...] Read more.
Cholesterol, a major component of the plasma membrane, determines the physical
properties of biological membranes and plays a critical role in the assembly of membrane
microdomains. Enrichment or deprivation of membrane cholesterol affects the activities of many
signaling molecules at the plasma membrane. Cell detachment changes the structure of the plasma
membrane and influences the localizations of lipids, including cholesterol. Recent studies showed
that cell detachment changes the activities of a variety of signaling molecules. We previously reported
that the localization and the function of the Src-family kinase Lyn are critically regulated by its
membrane anchorage through lipid modifications. More recently, we found that the localization and
the activity of Lyn were changed upon cell detachment, although the manners of which vary between
cell types. In this review, we highlight the changes in the localization of Lyn and a role of cholesterol
in the regulation of Lyn’s activation following cell detachment.

Full article
(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)
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25 pages, 720 KiB  
Review
Anti-Inflammatory Effects of Resveratrol: Mechanistic Insights
by Diego De Sá Coutinho, Maria Talita Pacheco, Rudimar Luiz Frozza and Andressa Bernardi
Int. J. Mol. Sci. 2018, 19(6), 1812; https://doi.org/10.3390/ijms19061812 - 20 Jun 2018
Cited by 236 | Viewed by 14629
Abstract
Inflammation is the principal response invoked by the body to address injuries. Despite inflammation constituting a crucial component of tissue repair, it is well known that unchecked or chronic inflammation becomes deleterious, leading to progressive tissue damage. Studies over the past years focused [...] Read more.
Inflammation is the principal response invoked by the body to address injuries. Despite inflammation constituting a crucial component of tissue repair, it is well known that unchecked or chronic inflammation becomes deleterious, leading to progressive tissue damage. Studies over the past years focused on foods rich in polyphenols with anti-inflammatory and immunomodulatory properties, since inflammation was recognized to play a central role in several diseases. In this review, we discuss the beneficial effects of resveratrol, the most widely investigated polyphenol, on cancer and neurodegenerative, respiratory, metabolic, and cardiovascular diseases. We highlight how resveratrol, despite its unfavorable pharmacokinetics, can modulate the inflammatory pathways underlying those diseases, and we identify future opportunities for the evaluation of its clinical feasibility. Full article
(This article belongs to the Special Issue Natural Anti-Inflammatory Agents 2018)
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24 pages, 988 KiB  
Review
Lead (Pb) Exposure Enhances Expression of Factors Associated with Inflammation
by Emilia Metryka, Karina Chibowska, Izabela Gutowska, Anna Falkowska, Patrycja Kupnicka, Katarzyna Barczak, Dariusz Chlubek and Irena Baranowska-Bosiacka
Int. J. Mol. Sci. 2018, 19(6), 1813; https://doi.org/10.3390/ijms19061813 - 20 Jun 2018
Cited by 178 | Viewed by 10385
Abstract
The human immune system is constantly exposed to xenobiotics and pathogens from the environment. Although the mechanisms underlying their influence have already been at least partially recognized, the effects of some factors, such as lead (Pb), still need to be clarified. The results [...] Read more.
The human immune system is constantly exposed to xenobiotics and pathogens from the environment. Although the mechanisms underlying their influence have already been at least partially recognized, the effects of some factors, such as lead (Pb), still need to be clarified. The results of many studies indicate that Pb has a negative effect on the immune system, and in our review, we summarize the most recent evidence that Pb can promote inflammatory response. We also discuss possible molecular and biochemical mechanisms of its proinflammatory action, including the influence of Pb on cytokine metabolism (interleukins IL-2, IL-4, IL-8, IL-1b, IL-6), interferon gamma (IFNγ), and tumor necrosis factor alpha (TNF-α); the activity and expression of enzymes involved in the inflammatory process (cyclooxygenases); and the effect on selected acute phase proteins: C-reactive protein (CRP), haptoglobin, and ceruloplasmin. We also discuss the influence of Pb on the immune system cells (T and B lymphocytes, macrophages, Langerhans cells) and the secretion of IgA, IgE, IgG, histamine, and endothelin. Full article
(This article belongs to the Section Molecular Toxicology)
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15 pages, 2699 KiB  
Article
Yeast-Based Screen to Identify Natural Compounds with a Potential Therapeutic Effect in Hailey-Hailey Disease
by Graziella Ficociello, Azzurra Zonfrilli, Samantha Cialfi, Claudio Talora and Daniela Uccelletti
Int. J. Mol. Sci. 2018, 19(6), 1814; https://doi.org/10.3390/ijms19061814 - 20 Jun 2018
Cited by 6 | Viewed by 5660
Abstract
The term orthodisease defines human disorders in which the pathogenic gene has orthologs in model organism genomes. Yeasts have been instrumental for gaining insights into the molecular basis of many human disorders, particularly those resulting from impaired cellular metabolism. We and others have [...] Read more.
The term orthodisease defines human disorders in which the pathogenic gene has orthologs in model organism genomes. Yeasts have been instrumental for gaining insights into the molecular basis of many human disorders, particularly those resulting from impaired cellular metabolism. We and others have used yeasts as a model system to study the molecular basis of Hailey-Hailey disease (HHD), a human blistering skin disorder caused by haploinsufficiency of the gene ATP2C1 the orthologous of the yeast gene PMR1. We observed that K. lactis cells defective for PMR1 gene share several biological similarities with HHD derived keratinocytes. Based on the conservation of ATP2C1/PMR1 function from yeast to human, here we used a yeast-based assay to screen for molecules able to influence the pleiotropy associated with PMR1 deletion. We identified six compounds, Kaempferol, Indirubin, Lappaconite, Cyclocytidine, Azomycin and Nalidixic Acid that induced different major shape phenotypes in K. lactis. These include mitochondrial and the cell-wall morphology-related phenotypes. Interestingly, a secondary assay in mammalian cells confirmed activity for Kaempferol. Indeed, this compound was also active on human keratinocytes depleted of ATP2C1 function by siRNA-treatment used as an in-vitro model of HHD. We found that Kaempferol was a potent NRF2 regulator, strongly inducing its expression and its downstream target NQO1. In addition, Kaempferol could decrease oxidative stress of ATP2C1 defective keratinocytes, characterized by reduced NRF2-expression. Our results indicated that the activation of these pathways might provide protection to the HHD-skin cells. As oxidative stress plays pivotal roles in promoting the skin lesions of Hailey-Hailey, the NRF2 pathway could be a viable therapeutic target for HHD. Full article
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies)
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11 pages, 1792 KiB  
Article
Exploring the Mechanism of Inhibition of Au Nanoparticles on the Aggregation of Amyloid-β(16-22) Peptides at the Atom Level by All-Atom Molecular Dynamics
by Menghua Song, Yunxiang Sun, Yin Luo, Yanyan Zhu, Yongsheng Liu and Huiyu Li
Int. J. Mol. Sci. 2018, 19(6), 1815; https://doi.org/10.3390/ijms19061815 - 20 Jun 2018
Cited by 48 | Viewed by 6060
Abstract
The abnormal self-assembly of the amyloid-β peptide into toxic β-rich aggregates can cause Alzheimer’s disease. Recently, it has been shown that small gold nanoparticles (AuNPs) inhibit Aβ aggregation and fibrillation by slowing down the nucleation process in experimental studies. However, the effects of [...] Read more.
The abnormal self-assembly of the amyloid-β peptide into toxic β-rich aggregates can cause Alzheimer’s disease. Recently, it has been shown that small gold nanoparticles (AuNPs) inhibit Aβ aggregation and fibrillation by slowing down the nucleation process in experimental studies. However, the effects of AuNPs on Aβ oligomeric structures are still unclear. In this study, we investigate the conformation of Aβ(16-22) tetramers/octamers in the absence and presence of AuNPs using extensive all-atom molecular-dynamics simulations in explicit solvent. Our studies demonstrate that the addition of AuNPs into Aβ(16-22) solution prevents β-sheet formation, and the inhibition depends on the concentration of Aβ(16-22) peptides. A detailed analysis of the Aβ(16-22)/Aβ(16-22)/water/AuNPs interactions reveals that AuNPs inhibit the β-sheet formation resulting from the same physical forces: hydrophobic interactions. Overall, our computational study provides evidence that AuNPs are likely to inhibit Aβ(16-22) and full-length Aβ fibrillation. Thus, this work provides theoretical insights into the development of inorganic nanoparticles as drug candidates for treatment of AD. Full article
(This article belongs to the Special Issue Translating Gold Nanoparticles to Diagnostics and Therapeutics)
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14 pages, 557 KiB  
Review
Diabetic Retinopathy: Pathophysiology and Treatments
by Wei Wang and Amy C. Y. Lo
Int. J. Mol. Sci. 2018, 19(6), 1816; https://doi.org/10.3390/ijms19061816 - 20 Jun 2018
Cited by 1042 | Viewed by 50176
Abstract
Diabetic retinopathy (DR) is the most common complication of diabetes mellitus (DM). It has long been recognized as a microvascular disease. The diagnosis of DR relies on the detection of microvascular lesions. The treatment of DR remains challenging. The advent of anti-vascular endothelial [...] Read more.
Diabetic retinopathy (DR) is the most common complication of diabetes mellitus (DM). It has long been recognized as a microvascular disease. The diagnosis of DR relies on the detection of microvascular lesions. The treatment of DR remains challenging. The advent of anti-vascular endothelial growth factor (VEGF) therapy demonstrated remarkable clinical benefits in DR patients; however, the majority of patients failed to achieve clinically-significant visual improvement. Therefore, there is an urgent need for the development of new treatments. Laboratory and clinical evidence showed that in addition to microvascular changes, inflammation and retinal neurodegeneration may contribute to diabetic retinal damage in the early stages of DR. Further investigation of the underlying molecular mechanisms may provide targets for the development of new early interventions. Here, we present a review of the current understanding and new insights into pathophysiology in DR, as well as clinical treatments for DR patients. Recent laboratory findings and related clinical trials are also reviewed. Full article
(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)
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21 pages, 2754 KiB  
Article
Studies of Microbiota Dynamics Reveals Association of “Candidatus Liberibacter Asiaticus” Infection with Citrus (Citrus sinensis) Decline in South of Iran
by Alessandro Passera, Hamidreza Alizadeh, Mehdi Azadvar, Fabio Quaglino, Asma Alizadeh, Paola Casati and Piero A. Bianco
Int. J. Mol. Sci. 2018, 19(6), 1817; https://doi.org/10.3390/ijms19061817 - 20 Jun 2018
Cited by 13 | Viewed by 4376
Abstract
Citrus Decline Disease was recently reported to affect several citrus species in Iran when grafted on a local rootstock variety, Bakraee. Preliminary studies found “Candidatus Phytoplasma aurantifoliae” and “Candidatus Liberibacter asiaticus” as putative etiological agents, but were not ultimately able to [...] Read more.
Citrus Decline Disease was recently reported to affect several citrus species in Iran when grafted on a local rootstock variety, Bakraee. Preliminary studies found “Candidatus Phytoplasma aurantifoliae” and “Candidatus Liberibacter asiaticus” as putative etiological agents, but were not ultimately able to determine which one, or if an association of both, were causing the disease. The current study has the aim of characterizing the microbiota of citrus plants that are either asymptomatic, showing early symptoms, or showing late symptoms through amplification of the V1–V3 region of 16S rRNA gene using an Illumina sequencer in order to (i) clarify the etiology of the disease, and (ii) describe the microbiota associated to different symptom stages. Our results suggest that liberibacter may be the main pathogen causing Citrus Decline Disease, but cannot rule out the possibility of phytoplasma being involved as well. The characterization of microbiota shows that the leaves show only two kinds of communities, either symptomatic or asymptomatic, while roots show clear distinction between early and late symptoms. These results could lead to the identification of bacteria that are related to successful plant defense response and, therefore, to immunity to the Citrus Decline Disease. Full article
(This article belongs to the Special Issue Plant Innate Immunity 2.0)
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12 pages, 3185 KiB  
Review
Possible Molecular Targets of Novel Ruthenium Complexes in Antiplatelet Therapy
by Thanasekaran Jayakumar, Chia-Yuan Hsu, Themmila Khamrang, Chih-Hsuan Hsia, Chih-Wei Hsia, Manjunath Manubolu and Joen-Rong Sheu
Int. J. Mol. Sci. 2018, 19(6), 1818; https://doi.org/10.3390/ijms19061818 - 20 Jun 2018
Cited by 13 | Viewed by 5106
Abstract
In oncotherapy, ruthenium (Ru) complexes are reflected as potential alternatives for platinum compounds and have been proved as encouraging anticancer drugs with high efficacy and low side effects. Cardiovascular diseases (CVDs) are mutually considered as the number one killer globally, and thrombosis is [...] Read more.
In oncotherapy, ruthenium (Ru) complexes are reflected as potential alternatives for platinum compounds and have been proved as encouraging anticancer drugs with high efficacy and low side effects. Cardiovascular diseases (CVDs) are mutually considered as the number one killer globally, and thrombosis is liable for the majority of CVD-related deaths. Platelets, an anuclear and small circulating blood cell, play key roles in hemostasis by inhibiting unnecessary blood loss of vascular damage by making blood clot. Platelet activation also plays a role in cancer metastasis and progression. Nevertheless, abnormal activation of platelets results in thrombosis under pathological settings such as the rupture of atherosclerotic plaques. Thrombosis diminishes the blood supply to the heart and brain resulting in heart attacks and strokes, respectively. While currently used anti-platelet drugs such as aspirin and clopidogrel demonstrate efficacy in many patients, they exert undesirable side effects. Therefore, the development of effective therapeutic strategies for the prevention and treatment of thrombotic diseases is a demanding priority. Recently, precious metal drugs have conquered the subject of metal-based drugs, and several investigators have motivated their attention on the synthesis of various ruthenium (Ru) complexes due to their prospective therapeutic values. Similarly, our recent studies established that novel ruthenium-based compounds suppressed platelet aggregation via inhibiting several signaling cascades. Our study also described the structure antiplatelet-activity relationship (SAR) of three newly synthesized ruthenium-based compounds. This review summarizes the antiplatelet activity of newly synthesized ruthenium-based compounds with their potential molecular mechanisms. Full article
(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)
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14 pages, 2727 KiB  
Article
Effect of Surfactant Type and Sonication Energy on the Electrical Conductivity Properties of Nanocellulose-CNT Nanocomposite Films
by Sanna Siljander, Pasi Keinänen, Anna Räty, Karthik Ram Ramakrishnan, Sampo Tuukkanen, Vesa Kunnari, Ali Harlin, Jyrki Vuorinen and Mikko Kanerva
Int. J. Mol. Sci. 2018, 19(6), 1819; https://doi.org/10.3390/ijms19061819 - 20 Jun 2018
Cited by 40 | Viewed by 6650
Abstract
We present a detailed study on the influence of sonication energy and surfactant type on the electrical conductivity of nanocellulose-carbon nanotube (NFC-CNT) nanocomposite films. The study was made using a minimum amount of processing steps, chemicals and materials, to optimize the conductivity properties [...] Read more.
We present a detailed study on the influence of sonication energy and surfactant type on the electrical conductivity of nanocellulose-carbon nanotube (NFC-CNT) nanocomposite films. The study was made using a minimum amount of processing steps, chemicals and materials, to optimize the conductivity properties of free-standing flexible nanocomposite films. In general, the NFC-CNT film preparation process is sensitive concerning the dispersing phase of CNTs into a solution with NFC. In our study, we used sonication to carry out the dispersing phase of processing in the presence of surfactant. In the final phase, the films were prepared from the dispersion using centrifugal cast molding. The solid films were analyzed regarding their electrical conductivity using a four-probe measuring technique. We also characterized how conductivity properties were enhanced when surfactant was removed from nanocomposite films; to our knowledge this has not been reported previously. The results of our study indicated that the optimization of the surfactant type clearly affected the formation of freestanding films. The effect of sonication energy was significant in terms of conductivity. Using a relatively low 16 wt. % concentration of multiwall carbon nanotubes we achieved the highest conductivity value of 8.4 S/cm for nanocellulose-CNT films ever published in the current literature. This was achieved by optimizing the surfactant type and sonication energy per dry mass. Additionally, to further increase the conductivity, we defined a preparation step to remove the used surfactant from the final nanocomposite structure. Full article
(This article belongs to the Special Issue Synthesis and Applications of Biopolymer Composites)
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13 pages, 3009 KiB  
Article
Does the Automatic Measurement of Interleukin 6 Allow for Prediction of Complications during the First 48 h of Acute Pancreatitis?
by Witold Kolber, Paulina Dumnicka, Małgorzata Maraj, Beata Kuśnierz-Cabala, Piotr Ceranowicz, Michał Pędziwiatr, Barbara Maziarz, Małgorzata Mazur-Laskowska, Marek Kuźniewski, Mateusz Sporek and Jerzy Walocha
Int. J. Mol. Sci. 2018, 19(6), 1820; https://doi.org/10.3390/ijms19061820 - 20 Jun 2018
Cited by 24 | Viewed by 5789
Abstract
Acute pancreatitis (AP) in most patients takes a course of self-limiting local inflammation. However, up to 20% of patients develop severe AP (SAP), associated with systemic inflammation and/or pancreatic necrosis. Early prediction of SAP allows for the appropriate intensive treatment of severe cases, [...] Read more.
Acute pancreatitis (AP) in most patients takes a course of self-limiting local inflammation. However, up to 20% of patients develop severe AP (SAP), associated with systemic inflammation and/or pancreatic necrosis. Early prediction of SAP allows for the appropriate intensive treatment of severe cases, which reduces mortality. Serum interleukin-6 (IL-6) has been proposed as a biomarker to assist early diagnosis of SAP, however, most data come from studies utilizing IL-6 measurements with ELISA. Our aim was to verify the diagnostic usefulness of IL-6 for the prediction of SAP, organ failure, and need for intensive care in the course of AP using a fully automated assay. The study included 95 adult patients with AP of various severity (29 mild, 58 moderately-severe, 8 severe) admitted to a hospital within 24 h from the onset of symptoms. Serum IL-6 was measured using electochemiluminescence immunoassay in samples collected on admission and on the next day of hospital stay. On both days, patients with SAP presented the highest IL-6 levels. IL-6 correlated positively with other inflammatory markers (white blood cell and neutrophil counts, C-reactive protein, procalcitonin), the markers of renal injury (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), and the markers of endothelial dysfunction (angiopoietin-2, soluble fms-like tyrosine kinase-1). IL-6 on admission significantly predicted SAP, vital organ failure, and the need for intensive care or death, with areas under the receiver operating curve between 0.75 and 0.78, not significantly different from multi-variable prognostic scores. The fully automated assay allows for fast and repeatable measurements of serum IL-6, enabling wider clinical use of this valuable biomarker. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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35 pages, 2440 KiB  
Review
Rho GTPases in Intellectual Disability: From Genetics to Therapeutic Opportunities
by Valentina Zamboni, Rebecca Jones, Alessandro Umbach, Alessandra Ammoni, Maria Passafaro, Emilio Hirsch and Giorgio R. Merlo
Int. J. Mol. Sci. 2018, 19(6), 1821; https://doi.org/10.3390/ijms19061821 - 20 Jun 2018
Cited by 65 | Viewed by 10036
Abstract
Rho-class small GTPases are implicated in basic cellular processes at nearly all brain developmental steps, from neurogenesis and migration to axon guidance and synaptic plasticity. GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction [...] Read more.
Rho-class small GTPases are implicated in basic cellular processes at nearly all brain developmental steps, from neurogenesis and migration to axon guidance and synaptic plasticity. GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function and plasticity. Rho GTPases are highly regulated by a complex set of activating (GEFs) and inactivating (GAPs) partners, via protein:protein interactions (PPI). Misregulated RhoA, Rac1/Rac3 and cdc42 activity has been linked with intellectual disability (ID) and other neurodevelopmental conditions that comprise ID. All genetic evidences indicate that in these disorders the RhoA pathway is hyperactive while the Rac1 and cdc42 pathways are consistently hypoactive. Adopting cultured neurons for in vitro testing and specific animal models of ID for in vivo examination, the endophenotypes associated with these conditions are emerging and include altered neuronal networking, unbalanced excitation/inhibition and altered synaptic activity and plasticity. As we approach a clearer definition of these phenotype(s) and the role of hyper- and hypo-active GTPases in the construction of neuronal networks, there is an increasing possibility that selective inhibitors and activators might be designed via PPI, or identified by screening, that counteract the misregulation of small GTPases and result in alleviation of the cognitive condition. Here we review all knowledge in support of this possibility. Full article
(This article belongs to the Special Issue Small GTPases)
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