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Int. J. Mol. Sci., Volume 20, Issue 22 (November-2 2019)

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Cover Story (view full-size image) A number of modifications have been developed to enhance surface cleanliness, wettability, and [...] Read more.
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Open AccessReview
MiRNAs as Players in Rhabdomyosarcoma Development
Int. J. Mol. Sci. 2019, 20(22), 5818; https://doi.org/10.3390/ijms20225818 - 19 Nov 2019
Abstract
Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood and adolescence, is a rare but aggressive malignancy that originates from immature mesenchymal cells committed to skeletal muscle differentiation. Although RMS is, generally, responsive to the modern multimodal therapeutic approaches, the prognosis of [...] Read more.
Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood and adolescence, is a rare but aggressive malignancy that originates from immature mesenchymal cells committed to skeletal muscle differentiation. Although RMS is, generally, responsive to the modern multimodal therapeutic approaches, the prognosis of RMS depends on multiple variables and for some patients the outcome remains dismal. Further comprehension of the molecular and cellular biology of RMS would lead to identification of novel therapeutic targets. MicroRNAs (miRNAs) are small non-coding RNAs proved to function as key regulators of skeletal muscle cell fate determination and to play important roles in RMS pathogenesis. The purpose of this review is to better delineate the role of miRNAs as a biomarkers or functional leaders in RMS development, so to possibly elucidate some of RMS molecular mechanisms and potentially therapeutically target them to improve clinical management of pediatric RMS. Full article
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Open AccessArticle
Molecular Signatures for Combined Targeted Treatments in Diffuse Malignant Peritoneal Mesothelioma
Int. J. Mol. Sci. 2019, 20(22), 5817; https://doi.org/10.3390/ijms20225817 - 19 Nov 2019
Abstract
Background—There are currently no effective therapies for diffuse malignant peritoneal mesothelioma (DMPM) patients with disease recurrence. In this study, we investigated the biology of DMPM by analyzing the EGFR family, Axl, and MET, in order to assess the presence of cross-talk between these [...] Read more.
Background—There are currently no effective therapies for diffuse malignant peritoneal mesothelioma (DMPM) patients with disease recurrence. In this study, we investigated the biology of DMPM by analyzing the EGFR family, Axl, and MET, in order to assess the presence of cross-talk between these receptors, suggesting the effectiveness of combined targeted treatments in DMPM. Method—We analyzed a series of 22 naïve epithelioid DMPM samples from a single institute, two of which showed higher-grade malignancy (“progressed”). EGFR, HER2, HER3, Axl, and MET activation and expression were investigated by biochemical analysis, real-time PCR immunofluorescence, immunohistochemistry, next-generation sequencing, miRNA, and mRNA in situ hybridization. Results—In most DMPMs, a strong EGFR activation was associated with HER2, HER3, Axl, and MET co-activation, mediated mainly by receptor heterodimerization and autocrine-paracrine loops induced by the expression of their cognate ligands. Axl expression was downregulated by miRNA34a. Mutations in MET Sema domain were exclusively found in two “progressed” DMPMs, and the combined Axl and MET inhibition reduced cellular motility in a DMPM cell line obtained from a “progressed” DMPM. Conclusion—The results indicate that the coordinated activity of multiple cross-talks between RTKs is directly involved in the biology of DMPM, suggesting the combined inhibition of PIK3 and mTOR as an effective strategy that may be easily implemented in clinical practice, and indicating that the combined inhibition of EGFR/HER2 and HER3 and of Axl and MET deserves further investigation. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Open AccessArticle
In Vitro Effects of Vaspin on Porcine Granulosa Cell Proliferation, Cell Cycle Progression, and Apoptosis by Activation of GRP78 Receptor and Several Kinase Signaling Pathways Including MAP3/1, AKT, and STAT3
Int. J. Mol. Sci. 2019, 20(22), 5816; https://doi.org/10.3390/ijms20225816 - 19 Nov 2019
Abstract
Vaspin, a visceral adipose tissue-derived serine protease inhibitor, is expressed in the porcine ovary; it induces the activation of various kinases and steroidogenesis. The aim of this study was to examine the effect of vaspin on granulosa (Gc) proliferation, cell cycle regulation, and [...] Read more.
Vaspin, a visceral adipose tissue-derived serine protease inhibitor, is expressed in the porcine ovary; it induces the activation of various kinases and steroidogenesis. The aim of this study was to examine the effect of vaspin on granulosa (Gc) proliferation, cell cycle regulation, and apoptosis. Porcine Gc was incubated with vaspin (0.01–10 ng/mL) for 24 to 72 h, proliferation was measured using alamarBlue assay, cell cycle progression was assessed using flow cytometry, and cyclin (D, E, and A) protein expression was measured using immunoblotting. Apoptosis was assessed by measuring caspase activity using Caspase-glo 3/7 assay. Furthermore, histone-associated DNA fragments levels were measured using a cell-death detection ELISA; BAX (bcl-2-like protein 4), BCL2 (B-cell lymphoma 2), caspases (-3, -8, and -9), p53 mRNA, and protein expression were assessed using real time PCR and immunoblotting. We found that vaspin significantly enhanced Gc proliferation and cell cycle progression into the S and G2/M phases and decreased apoptosis. We observed that siRNA silencing of the glucose-regulated protein (GRP78) receptor and pharmacological inhibitors of mitogen-activated kinase (MAP3/1/ERK1/2), Janus kinase (STAT3) and protein kinase B (AKT) blocked the ability of vaspin cell proliferation and enhanced caspase-3/7 activities. These results suggest that vaspin via mitogenic effect on porcine Gc acts as a new regulator of ovarian growth, development, or folliculogenesis. Full article
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Open AccessArticle
HSF1Base: A Comprehensive Database of HSF1 (Heat Shock Factor 1) Target Genes
Int. J. Mol. Sci. 2019, 20(22), 5815; https://doi.org/10.3390/ijms20225815 - 19 Nov 2019
Abstract
HSF1 (heat shock factor 1) is an evolutionarily conserved master transcriptional regulator of the heat shock response (HSR) in eukaryotic cells. In response to high temperatures, HSF1 upregulates genes encoding molecular chaperones, also called heat shock proteins, which assist the refolding or degradation [...] Read more.
HSF1 (heat shock factor 1) is an evolutionarily conserved master transcriptional regulator of the heat shock response (HSR) in eukaryotic cells. In response to high temperatures, HSF1 upregulates genes encoding molecular chaperones, also called heat shock proteins, which assist the refolding or degradation of damaged intracellular proteins. Accumulating evidence reveals however that HSF1 participates in several other physiological and pathological processes such as differentiation, immune response, and multidrug resistance, as well as in ageing, neurodegenerative demise, and cancer. To address how HSF1 controls these processes one should systematically analyze its target genes. Here we present a novel database called HSF1Base (hsf1base.org) that contains a nearly comprehensive list of HSF1 target genes identified so far. The list was obtained by manually curating publications on individual HSF1 targets and analyzing relevant high throughput transcriptomic and chromatin immunoprecipitation data derived from the literature and the Yeastract database. To support the biological relevance of HSF1 targets identified by high throughput methods, we performed an enrichment analysis of (potential) HSF1 targets across different tissues/cell types and organisms. We found that general HSF1 functions (targets are expressed in all tissues/cell types) are mostly related to cellular proteostasis. Furthermore, HSF1 targets that are conserved across various animal taxa operate mostly in cellular stress pathways (e.g., autophagy), chromatin remodeling, ribosome biogenesis, and ageing. Together, these data highlight diverse roles for HSF1, expanding far beyond the HSR. Full article
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Open AccessComment
Application of Nipple Aspirate Fluid miRNA Profiles for Early Breast Cancer Detection and Management
Int. J. Mol. Sci. 2019, 20(22), 5814; https://doi.org/10.3390/ijms20225814 - 19 Nov 2019
Abstract
The authors of the recently published review, “Why the Gold Standard Approach by Mammography Demands Extension by Multiomics [...] Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Open AccessArticle
HUNK Phosphorylates Rubicon to Support Autophagy
Int. J. Mol. Sci. 2019, 20(22), 5813; https://doi.org/10.3390/ijms20225813 - 19 Nov 2019
Abstract
Background: Autophagy is a catabolic cellular recycling pathway that is essential for maintaining intracellular homeostasis. Autophagosome formation is achieved via the coordination of the Beclin-1 protein complex. Rubicon is a Beclin-1 associated protein that suppresses autophagy by impairing the activity of the class [...] Read more.
Background: Autophagy is a catabolic cellular recycling pathway that is essential for maintaining intracellular homeostasis. Autophagosome formation is achieved via the coordination of the Beclin-1 protein complex. Rubicon is a Beclin-1 associated protein that suppresses autophagy by impairing the activity of the class III PI3K, Vps34. However, very little is known about the molecular mechanisms that regulate Rubicon function. Methods: In this study, co-immunoprecipitation and kinase assays were used to investigate the ability of Hormonally Upregulated Neu-associated Kinase (HUNK) to bind to and phosphorylate Rubicon. LC3B was monitored by immunofluorescence and immunoblotting to determine whether phosphorylation of Rubicon by HUNK controls the autophagy suppressive function of Rubicon. Results: Findings from this study identify Rubicon as a novel substrate of HUNK and show that phosphorylation of Rubicon inhibits its function, promoting autophagy. Full article
(This article belongs to the Section Molecular Biology)
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Open AccessArticle
Gene Losses and Variations in Chloroplast Genome of Parasitic Plant Macrosolen and Phylogenetic Relationships within Santalales
Int. J. Mol. Sci. 2019, 20(22), 5812; https://doi.org/10.3390/ijms20225812 - 19 Nov 2019
Abstract
Macrosolen plants are parasitic shrubs, several of which are important medicinal plants, that are used as folk medicine in some provinces of China. However, reports on Macrosolen are limited. In this study, the complete chloroplast genome sequences of Macrosolen cochinchinensis, Macrosolen tricolor [...] Read more.
Macrosolen plants are parasitic shrubs, several of which are important medicinal plants, that are used as folk medicine in some provinces of China. However, reports on Macrosolen are limited. In this study, the complete chloroplast genome sequences of Macrosolen cochinchinensis, Macrosolen tricolor and Macrosolen bibracteolatus are reported. The chloroplast genomes were sequenced by Illumina HiSeq X. The length of the chloroplast genomes ranged from 129,570 bp (M. cochinchinensis) to 126,621 bp (M. tricolor), with a total of 113 genes, including 35 tRNA, eight rRNA, 68 protein-coding genes, and two pseudogenes (ycf1 and rpl2). The simple sequence repeats are mainly comprised of A/T mononucleotide repeats. Comparative genome analyses of the three species detected the most divergent regions in the non-coding spacers. Phylogenetic analyses using maximum parsimony and maximum likelihood strongly supported the idea that Loranthaceae and Viscaceae are monophyletic clades. The data obtained in this study are beneficial for further investigations of Macrosolen in respect to evolution and molecular identification. Full article
(This article belongs to the Special Issue Organelle Genetics in Plants)
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Open AccessArticle
Correlation of Vitamin D with Inflammatory Cytokines, Atherosclerotic Parameters, and Lifestyle Factors in the Setting of Heart Failure: A 12-Month Follow-Up Study
Int. J. Mol. Sci. 2019, 20(22), 5811; https://doi.org/10.3390/ijms20225811 - 19 Nov 2019
Abstract
Vitamin D deficiency is highly prevalent worldwide. It has been associated with heart failure (HF) given its immunoregulatory functions. In-vitro and animal models have shown protective roles through mechanisms involving procollagen-1, JNK2, calcineurin/NFAT, NF-κB, MAPK, Th1, Th2, Th17, cytokines, cholesterol-efflux, oxLDL, and GLUT4, [...] Read more.
Vitamin D deficiency is highly prevalent worldwide. It has been associated with heart failure (HF) given its immunoregulatory functions. In-vitro and animal models have shown protective roles through mechanisms involving procollagen-1, JNK2, calcineurin/NFAT, NF-κB, MAPK, Th1, Th2, Th17, cytokines, cholesterol-efflux, oxLDL, and GLUT4, among others. A 12-month follow-up in HF patients showed a high prevalence of vitamin D deficiency, with no seasonal variation (64.7–82.4%). A positive correlation between serum 25(OH)D concentration and dietary intake of vitamin D-rich foods was found. A significant inverse correlation with IL-1β (R = −0.78), TNF-α (R = −0.53), IL-6 (R = −0.42), IL-8 (R = −0.41), IL-17A (R = −0.31), LDL-cholesterol (R = −0.51), Apo-B (R = −0.57), total-cholesterol (R = –0.48), and triglycerides (R = −0.32) was shown. Cluster analysis demonstrated that patients from cluster three, with the lowest 25(OH)D levels, presented the lowermost vitamin D intake, IL-10 (1.0 ± 0.9 pg/mL), and IL-12p70 (0.5 ± 0.4 pg/mL), but the highest TNF-α (9.1 ± 3.5 pg/mL), IL-8 (55.6 ± 117.1 pg/mL), IL-17A (3.5 ± 2.0 pg/mL), total-cholesterol (193.9 ± 61.4 mg/dL), LDL-cholesterol (127.7 ± 58.2 mg/dL), and Apo-B (101.4 ± 33.4 mg/dL) levels, compared with patients from cluster one. Although the role of vitamin D in the pathogenesis of HF in humans is still uncertain, we applied the molecular mechanisms of in-vitro and animal models to explain our findings. Vitamin D deficiency might contribute to inflammation, remodeling, fibrosis, and atherosclerosis in patients with HF. Full article
(This article belongs to the Special Issue Nutrition and Cardiovascular Health)
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Open AccessArticle
Predictive Value of Serum Antibodies and Point Mutations of AQP4, AQP1 and MOG in A Cohort of Spanish Patients with Neuromyelitis Optica Spectrum Disorders
Int. J. Mol. Sci. 2019, 20(22), 5810; https://doi.org/10.3390/ijms20225810 - 19 Nov 2019
Abstract
The detection of IgG aquaporin-4 antibodies in the serum of patients with Neuromyelitis optica (NMO) has dramatically improved the diagnosis of this disease and its distinction from multiple sclerosis. Recently, a group of patients have been described who have an NMO spectrum disorder [...] Read more.
The detection of IgG aquaporin-4 antibodies in the serum of patients with Neuromyelitis optica (NMO) has dramatically improved the diagnosis of this disease and its distinction from multiple sclerosis. Recently, a group of patients have been described who have an NMO spectrum disorder (NMOsd) and who are seronegative for AQP4 antibodies but positive for IgG aquaporin-1 (AQP1) or myelin oligodendrocyte glycoprotein (MOG) antibodies. The purpose of this study was to determine whether AQP1 and MOG could be considered new biomarkers of this disease; and if point mutations in the gDNA of AQP4, AQP1 and MOG genes could be associated with the etiology of NMOsd. We evaluated the diagnostic capability of ELISA and cell-based assays (CBA), and analyzed their reliability, specificity, and sensitivity in detecting antibodies against these three proteins. The results showed that both assays can recognize these antigen proteins under appropriate conditions, but only anti-AQP4 antibodies, and not AQP1 or MOG, appears to be a clear biomarker for NMOsd. CBA is the best method for detecting these antibodies; and serum levels of AQP4 antibodies do not correlate with the progression of this disease. So far, the sequencing analysis has not revealed a genetic basis for the etiology of NMOsd, but a more extensive analysis is required before definitive conclusions can be drawn. Full article
(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues)
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Open AccessArticle
Two Homologous Enzymes of the GalU Family in Rhodococcus opacus 1CP—RoGalU1 and RoGalU2
Int. J. Mol. Sci. 2019, 20(22), 5809; https://doi.org/10.3390/ijms20225809 - 19 Nov 2019
Abstract
Uridine-5’-diphosphate (UDP)-glucose is reported as one of the most versatile building blocks within the metabolism of pro- and eukaryotes. The activated sugar moiety is formed by the enzyme UDP-glucose pyrophosphorylase (GalU). Two homologous enzymes (designated as RoGalU1 and RoGalU2) are encoded [...] Read more.
Uridine-5’-diphosphate (UDP)-glucose is reported as one of the most versatile building blocks within the metabolism of pro- and eukaryotes. The activated sugar moiety is formed by the enzyme UDP-glucose pyrophosphorylase (GalU). Two homologous enzymes (designated as RoGalU1 and RoGalU2) are encoded by most Rhodococcus strains, known for their capability to degrade numerous compounds, but also to synthesize natural products such as trehalose comprising biosurfactants. To evaluate their functionality respective genes of a trehalose biosurfactant producing model organism—Rhodococcus opacus 1CP—were cloned and expressed, proteins produced (yield up to 47 mg per L broth) and initially biochemically characterized. In the case of RoGalU2, the Vmax was determined to be 177 U mg−1 (uridine-5’-triphosphate (UTP)) and Km to be 0.51 mM (UTP), respectively. Like other GalUs this enzyme seems to be rather specific for the substrates UTP and glucose 1-phosphate, as it accepts only dTTP and galactose 1-phoshate in addition, but both with solely 2% residual activity. In comparison to other bacterial GalU enzymes the RoGalU2 was found to be somewhat higher in activity (factor 1.8) even at elevated temperatures. However, RoGalU1 was not obtained in an active form thus it remains enigmatic if this enzyme participates in metabolism. Full article
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Open AccessReview
Radiochemical Approaches to Imaging Bacterial Infections: Intracellular versus Extracellular Targets
Int. J. Mol. Sci. 2019, 20(22), 5808; https://doi.org/10.3390/ijms20225808 - 19 Nov 2019
Abstract
The discovery of penicillin began the age of antibiotics, which was a turning point in human healthcare. However, to this day, microbial infections are still a concern throughout the world, and the rise of multidrug-resistant organisms is an increasing challenge. To combat this [...] Read more.
The discovery of penicillin began the age of antibiotics, which was a turning point in human healthcare. However, to this day, microbial infections are still a concern throughout the world, and the rise of multidrug-resistant organisms is an increasing challenge. To combat this threat, diagnostic imaging tools could be used to verify the causative organism and curb inappropriate use of antimicrobial drugs. Nuclear imaging offers the sensitivity needed to detect small numbers of bacteria in situ. Among nuclear imaging tools, radiolabeled antibiotics traditionally have lacked the sensitivity or specificity necessary to diagnose bacterial infections accurately. One reason for the lack of success is that the antibiotics were often chelated to a radiometal. This was done without addressing the ramifications of how the radiolabeling would impact probe entry to the bacterial cell, or the mechanism of binding to an intracellular target. In this review, we approach bacterial infection imaging through the lens of bacterial specific molecular targets, their intracellular or extracellular location, and discuss radiochemistry strategies to guide future probe development. Full article
(This article belongs to the Special Issue Molecular Imaging in Diabetes, Obesity and Infections)
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Open AccessArticle
Ethyl Butyrate Synthesis Catalyzed by Lipases A and B from Candida antarctica Immobilized onto Magnetic Nanoparticles. Improvement of Biocatalysts’ Performance under Ultrasonic Irradiation
Int. J. Mol. Sci. 2019, 20(22), 5807; https://doi.org/10.3390/ijms20225807 - 19 Nov 2019
Abstract
The synthesis of ethyl butyrate catalyzed by lipases A (CALA) or B (CALB) from Candida antarctica immobilized onto magnetic nanoparticles (MNP), CALA-MNP and CALB-MNP, respectively, is hereby reported. MNPs were prepared by co-precipitation, functionalized with 3-aminopropyltriethoxysilane, activated with glutaraldehyde, and then used as [...] Read more.
The synthesis of ethyl butyrate catalyzed by lipases A (CALA) or B (CALB) from Candida antarctica immobilized onto magnetic nanoparticles (MNP), CALA-MNP and CALB-MNP, respectively, is hereby reported. MNPs were prepared by co-precipitation, functionalized with 3-aminopropyltriethoxysilane, activated with glutaraldehyde, and then used as support to immobilize either CALA or CALB (immobilization yield: 100 ± 1.2% and 57.6 ± 3.8%; biocatalysts activities: 198.3 ± 2.7 Up-NPB/g and 52.9 ± 1.7 Up-NPB/g for CALA-MNP and CALB-MNP, respectively). X-ray diffraction and Raman spectroscopy analysis indicated the production of a magnetic nanomaterial with a diameter of 13.0 nm, whereas Fourier-transform infrared spectroscopy indicated functionalization, activation and enzyme immobilization. To determine the optimum conditions for the synthesis, a four-variable Central Composite Design (CCD) (biocatalyst content, molar ratio, temperature and time) was performed. Under optimized conditions (1:1, 45 °C and 6 h), it was possible to achieve 99.2 ± 0.3% of conversion for CALA-MNP (10 mg) and 97.5 ± 0.8% for CALB-MNP (12.5 mg), which retained approximately 80% of their activity after 10 consecutive cycles of esterification. Under ultrasonic irradiation, similar conversions were achieved but at 4 h of incubation, demonstrating the efficiency of ultrasound technology in the enzymatic synthesis of esters. Full article
(This article belongs to the Section Materials Science)
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Open AccessArticle
Overexpression of Maize ZmC1 and ZmR Transcription Factors in Wheat Regulates Anthocyanin Biosynthesis in a Tissue-Specific Manner
Int. J. Mol. Sci. 2019, 20(22), 5806; https://doi.org/10.3390/ijms20225806 - 19 Nov 2019
Abstract
Maize ZmC1 and ZmR transcription factors belong to the MYB-type and bHLH families, respectively, and control anthocyanin biosynthesis. In this study, Agrobacterium-mediated transformation was used to generate transgenic wheat plants that overexpress ZmC1 and ZmR or both, with the objective of developing [...] Read more.
Maize ZmC1 and ZmR transcription factors belong to the MYB-type and bHLH families, respectively, and control anthocyanin biosynthesis. In this study, Agrobacterium-mediated transformation was used to generate transgenic wheat plants that overexpress ZmC1 and ZmR or both, with the objective of developing anthocyanin-enriched wheat germplasm. Three kinds of stable transgenic wheat lines were obtained. The integration of target genes in the transgenic wheat plants was confirmed by fluorescence in situ hybridization (FISH) analysis. We found that single overexpression of ZmC1 regulates pigmentation in the vegetative tissues such as coleoptiles, auricles, and stems. The single overexpression of ZmR controls the coloration in reproductive tissue like spikelets and seeds. The simultaneous overexpression of ZmC1 and ZmR showed the strongest pigmentation in almost all tissues. Furthermore, quantitative real-time PCR (qRT-PCR) analysis revealed that expression of the two transgenes, and of two conserved homologous and six associated structural genes involved in anthocyanin biosynthesis in wheat were greatly up-regulated in the transgenic plants. Similarly, quantitative analysis for anthocyanin amounts based on HPLC-MS also confirmed that the transgenic wheat plants with combined overexpression of ZmC1 and ZmR accumulated the highest quantity of pigment products. Moreover, developing seeds overexpressing ZmR exposed to light conditions showed up-regulated transcript levels of anthocyanin biosynthesis-related genes compared to dark exposure, which suggests an important role of light in regulating anthocyanin biosynthesis. This study provides a foundation for breeding wheat materials with high anthocyanin accumulation and understanding the mechanism of anthocyanin biosynthesis in wheat. Full article
(This article belongs to the collection Genetics and Molecular Breeding in Plants)
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Open AccessReview
Current and Future Concepts for the Treatment of Impaired Fracture Healing
Int. J. Mol. Sci. 2019, 20(22), 5805; https://doi.org/10.3390/ijms20225805 - 19 Nov 2019
Abstract
Bone regeneration represents a complex process, of which basic biologic principles have been evolutionarily conserved over a broad range of different species. Bone represents one of few tissues that can heal without forming a fibrous scar and, as such, resembles a unique form [...] Read more.
Bone regeneration represents a complex process, of which basic biologic principles have been evolutionarily conserved over a broad range of different species. Bone represents one of few tissues that can heal without forming a fibrous scar and, as such, resembles a unique form of tissue regeneration. Despite a tremendous improvement in surgical techniques in the past decades, impaired bone regeneration including non-unions still affect a significant number of patients with fractures. As impaired bone regeneration is associated with high socio-economic implications, it is an essential clinical need to gain a full understanding of the pathophysiology and identify novel treatment approaches. This review focuses on the clinical implications of impaired bone regeneration, including currently available treatment options. Moreover, recent advances in the understanding of fracture healing are discussed, which have resulted in the identification and development of novel therapeutic approaches for affected patients. Full article
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Open AccessReview
Role of HYBID (Hyaluronan Binding Protein Involved in Hyaluronan Depolymerization), Alias KIAA1199/CEMIP, in Hyaluronan Degradation in Normal and Photoaged Skin
Int. J. Mol. Sci. 2019, 20(22), 5804; https://doi.org/10.3390/ijms20225804 - 19 Nov 2019
Abstract
Photoaged skin is characterized clinically by apparent manifestations such as wrinkles and sagging, and histologically by an accumulation of abnormal elastin and a severe loss of collagen fibers in the dermis. Quantitative and qualitative alterations in elastin and collagens are considered to be [...] Read more.
Photoaged skin is characterized clinically by apparent manifestations such as wrinkles and sagging, and histologically by an accumulation of abnormal elastin and a severe loss of collagen fibers in the dermis. Quantitative and qualitative alterations in elastin and collagens are considered to be responsible for the formation of wrinkles and sagging. However, since the integrity of elastin and collagen fibers in the dermis is maintained by their interactions with hyaluronan (HA) and a proteoglycan network structure, HA degradation may be the initial process, prior to the breakdown of the fibrillary components, leading to wrinkles and sagging in photoaged skin. We have recently discovered a new HA-degrading mechanism mediated by HYBID (hyaluronan binding protein involved in hyaluronan depolymerization), alias KIAA1199/CEMIP, in human skin fibroblasts, and examined the implication of HYBID for skin photoaging. In this review, we give an overview of the characteristics of HYBID and its prospective roles in HA turnover in normal skin and excessive HA degradation in photoaged skin. In addition, we describe our data on the inhibition of HYBID activity and expression by plant extracts in skin fibroblasts; and propose novel strategies to prevent or improve photoaging symptoms, such as skin wrinkling, by inhibition of HYBID-mediated HA degradation. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Skin Aging)
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Open AccessReview
Impact of Nitrogen Nutrition on Cannabis sativa: An Update on the Current Knowledge and Future Prospects
Int. J. Mol. Sci. 2019, 20(22), 5803; https://doi.org/10.3390/ijms20225803 - 18 Nov 2019
Abstract
Nitrogen (N) availability represents one of the most critical factors affecting cultivated crops. N is indeed a crucial macronutrient influencing major aspects, from plant development to productivity and final yield of lignocellulosic biomass, as well as content of bioactive molecules. N metabolism is [...] Read more.
Nitrogen (N) availability represents one of the most critical factors affecting cultivated crops. N is indeed a crucial macronutrient influencing major aspects, from plant development to productivity and final yield of lignocellulosic biomass, as well as content of bioactive molecules. N metabolism is fundamental as it is at the crossroad between primary and secondary metabolic pathways: Besides affecting the synthesis of fundamental macromolecules, such as nucleic acids and proteins, N is needed for other types of molecules intervening in the response to exogenous stresses, e.g. alkaloids and glucosinolates. By partaking in the synthesis of phenylalanine, N also directly impacts a central plant metabolic ‘hub’—the phenylpropanoid pathway—from which important classes of molecules are formed, notably monolignols, flavonoids and other types of polyphenols. In this review, an updated analysis is provided on the impact that N has on the multipurpose crop hemp (Cannabis sativa L.) due to its renewed interest as a multipurpose crop able to satisfy the needs of a bioeconomy. The hemp stalk provides both woody and cellulosic fibers used in construction and for biocomposites; different organs (leaves/flowers/roots) are sources of added-value secondary metabolites, namely cannabinoids, terpenes, flavonoids, and lignanamides. We survey the available literature data on the impact of N in hemp and highlight the importance of studying those genes responding to both N nutrition and abiotic stresses. Available hemp transcriptomic datasets obtained on plants subjected to salt and drought are here analyzed using Gene Ontology (GO) categories related to N metabolism. The ultimate goal is to shed light on interesting candidate genes that can be further studied in hemp varieties growing under different N feeding conditions and showing high biomass yield and secondary metabolite production, even under salinity and drought. Full article
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Open AccessArticle
A Novel ‘Candidatus Liberibacter asiaticus’-Encoded Sec-Dependent Secretory Protein Suppresses Programmed Cell Death in Nicotiana benthamiana
Int. J. Mol. Sci. 2019, 20(22), 5802; https://doi.org/10.3390/ijms20225802 - 18 Nov 2019
Abstract
Candidatus Liberibacter asiaticus’ (CLas) is one of the causal agents of citrus Huanglongbing (HLB), a bacterial disease of citrus trees that greatly reduces fruit yield and quality. CLas strains produce an array of currently uncharacterized Sec-dependent secretory proteins. In this study, the [...] Read more.
Candidatus Liberibacter asiaticus’ (CLas) is one of the causal agents of citrus Huanglongbing (HLB), a bacterial disease of citrus trees that greatly reduces fruit yield and quality. CLas strains produce an array of currently uncharacterized Sec-dependent secretory proteins. In this study, the conserved chromosomally encoded protein CLIBASIA_03875 was identified as a novel Sec-dependent secreted protein. We show that CLIBASIA_03875 contains a putative Sec- secretion signal peptide (SP), a 29 amino acid residue located at the N-terminus, with a mature protein (m3875) of 22 amino acids found to localize in multiple subcellular components of the leaf epidermal cells of Nicotiana benthamiana. When overexpressed via a Potato virus X (PVX)-based expression vector in N. benthamiana, m3875 suppressed programmed cell death (PCD) and the H2O2 accumulation triggered by the pro-apoptotic mouse protein BAX and the Phytophthora infestans elicitin INF1. Overexpression also resulted in a phenotype of dwarfing, leaf deformation and mosaics, suggesting that m3875 has roles in plant immune response, growth, and development. Substitution mutagenesis of the charged amino acid (D7, R9, R11, and K22) with alanine within m3875 did not recover the phenotypes for PCD and normal growth. In addition, the transiently overexpressed m3875 regulated the transcriptional levels of N. benthamiana orthologs of CNGCs (cyclic nucleotide-gated channels), BI-1 (Bax-inhibitor 1), and WRKY33 that are involved in plant defense mechanisms. To our knowledge, m3875 is the first PCD suppressor identified from CLas. Studying the function of this protein provides insight as to how CLas attenuates the host immune responses to proliferate and cause Huanglongbing disease in citrus plants. Full article
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Open AccessArticle
Calcium Polyphosphate Nanoparticles Act as an Effective Inorganic Phosphate Source during Osteogenic Differentiation of Human Mesenchymal Stem Cells
Int. J. Mol. Sci. 2019, 20(22), 5801; https://doi.org/10.3390/ijms20225801 - 18 Nov 2019
Abstract
The ability of bone-marrow-derived mesenchymal stem/stromal cells (BM-MSCs) to differentiate into osteoblasts makes them the ideal candidate for cell-based therapies targeting bone-diseases. Polyphosphate (polyP) is increasingly being studied as a potential inorganic source of phosphate for extracellular matrix mineralisation. The aim of this [...] Read more.
The ability of bone-marrow-derived mesenchymal stem/stromal cells (BM-MSCs) to differentiate into osteoblasts makes them the ideal candidate for cell-based therapies targeting bone-diseases. Polyphosphate (polyP) is increasingly being studied as a potential inorganic source of phosphate for extracellular matrix mineralisation. The aim of this study is to investigate whether polyP can effectively be used as a phosphate source during the in vitro osteogenic differentiation of human BM-MSCs. Human BM-MSCs are cultivated under osteogenic conditions for 28 days with phosphate provided in the form of organic β-glycerolphosphate (BGP) or calcium-polyP nanoparticles (polyP-NP). Mineralisation is demonstrated using Alizarin red staining, cellular ATP content, and free phosphate levels are measured in both the cells and the medium. The effects of BGP or polyP-NP on alkaline phosphatase (ALP) activity and gene expression of a range of osteogenic-related markers are also assessed. PolyP-NP supplementation displays comparable effects to the classical BGP-containing osteogenic media in terms of mineralisation, ALP activity and expression of osteogenesis-associated genes. This study shows that polyP-NP act as an effective source of phosphate during mineralisation of BM-MSC. These results open new possibilities with BM-MSC-based approaches for bone repair to be achieved through doping of conventional biomaterials with polyP-NP. Full article
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Open AccessReview
The Regulation of NFE2L2 (NRF2) Signalling and Epithelial-to-Mesenchymal Transition in Age-Related Macular Degeneration Pathology
Int. J. Mol. Sci. 2019, 20(22), 5800; https://doi.org/10.3390/ijms20225800 - 18 Nov 2019
Abstract
Age-related macular degeneration (AMD) is a mounting cause of loss of sight in the elderly in the developed countries, a trend enhanced by the continual ageing of the population. AMD is a multifactorial and only partly understood, malady. Unfortunately, there is no effective [...] Read more.
Age-related macular degeneration (AMD) is a mounting cause of loss of sight in the elderly in the developed countries, a trend enhanced by the continual ageing of the population. AMD is a multifactorial and only partly understood, malady. Unfortunately, there is no effective treatment for most AMD patients. It is known that oxidative stress (OS) damages the retinal pigment epithelium (RPE) and contributes to the progression of AMD. We review here the potential importance of two OS-related cellular systems in relation to AMD. First, the nuclear factor erythroid 2-related factor 2 (NFE2L2; NRF2)-mediated OS response signalling pathway is important in the prevention of oxidative damage and a failure of this system could be critical in the development of AMD. Second, epithelial-to-mesenchymal transition (EMT) represents a change in the cellular phenotype, which ultimately leads to the fibrosis encountered in RPE, a characteristic of AMD. Many of the pathways triggering EMT are promoted by OS. The possible interconnections between these two signalling routes are discussed here. From a broader perspective, the control of NFE2L2 and EMT as ways of preventing OS-derived cellular damage could be potentially valuable in the therapy of AMD. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Open AccessReview
An Update on Antibodies to Necleosome Components as Biomarkers of Sistemic Lupus Erythematosus and of Lupus Flares
Int. J. Mol. Sci. 2019, 20(22), 5799; https://doi.org/10.3390/ijms20225799 - 18 Nov 2019
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with variable clinical expression. It is a potentially devastating condition affecting mostly women and leading to clinically unpredictable outcomes. Remission and flares may, in fact, alternate over time and a mild involvement limited to few [...] Read more.
Systemic lupus erythematosus (SLE) is an autoimmune disease with variable clinical expression. It is a potentially devastating condition affecting mostly women and leading to clinically unpredictable outcomes. Remission and flares may, in fact, alternate over time and a mild involvement limited to few articular sites may be followed by severe and widespread organ damage. SLE is the prototype of any autoimmune condition and has, for this reason, attracted the interest of basic immunologists. Therapies have evolved over time and clinical prognosis has, in parallel, been improved. What clinicians still lack is the possibility to use biomarkers of the disease as predictors of outcome and, in this area, several studies are trying to find solutions. Circulating autoantibodies are clearly a milestone of clinical research and the concrete possibility is to integrate, in the future, classical markers of activation (like C3) with target organ autoantibodies. Anti-dsDNA antibodies represent a basic point in any predictive attempt in SLE and should be considered the benchmark for any innovative proposal in the wide field of target organ pathologies related to SLE. DNA is part of the nucleosome that is the basic unit of chromatin. It consists of DNA wrapped around a histone octamer made of 2 copies each of Histone 2A, 2B, 3, and 4. The nucleosome has a plastic organization that varies over time and has the potential to stimulate the formation of antibodies directed to the whole structure (anti-nucleosome) or its parts (anti-dsDNA and anti-Histones). Here, we present an updated review of the literature on antibodies directed to the nucleosome and the nucleosome constituents, i.e., DNA and Histones. Wetriedto merge the data first published more than twenty years ago with more recent results to create a balanced bridge between old dogma and more recent research that could serve as a stimulus to reconsider mechanisms for SLE. The formation of large networks would provide the chance of studying large cohorts of patients and confirm what already presented in small sample size during the last years. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Open AccessArticle
Interactive Effects of Salicylic Acid and Nitric Oxide in Enhancing Rice Tolerance to Cadmium Stress
Int. J. Mol. Sci. 2019, 20(22), 5798; https://doi.org/10.3390/ijms20225798 - 18 Nov 2019
Abstract
Cadmium (Cd) is one of the prominent environmental hazards, affecting plant productivity and posing human health risks worldwide. Although salicylic acid (SA) and nitric oxide (NO) are known to have stress mitigating roles, little was explored on how they work together against Cd-toxicity [...] Read more.
Cadmium (Cd) is one of the prominent environmental hazards, affecting plant productivity and posing human health risks worldwide. Although salicylic acid (SA) and nitric oxide (NO) are known to have stress mitigating roles, little was explored on how they work together against Cd-toxicity in rice. This study evaluated the individual and combined effects of SA and sodium nitroprusside (SNP), a precursor of NO, on Cd-stress tolerance in rice. Results revealed that Cd at toxic concentrations caused rice biomass reduction, which was linked to enhanced accumulation of Cd in roots and leaves, reduced photosynthetic pigment contents, and decreased leaf water status. Cd also potentiated its phytotoxicity by triggering reactive oxygen species (ROS) generation and depleting several non-enzymatic and enzymatic components in rice leaves. In contrast, SA and/or SNP supplementation with Cd resulted in growth recovery, as evidenced by greater biomass content, improved leaf water content, and protection of photosynthetic pigments. These signaling molecules were particularly effective in restricting Cd uptake and accumulation, with the highest effect being observed in “SA + SNP + Cd” plants. SA and/or SNP alleviated Cd-induced oxidative damage by reducing ROS accumulation and malondialdehyde production through the maintenance of ascorbate and glutathione levels, and redox status, as well as the better activities of antioxidant enzymes superoxide dismutase, catalase, glutathione S-transferase, and monodehydroascorbate reductase. Combined effects of SA and SNP were observed to be more prominent in Cd-stress mitigation than the individual effects of SA followed by that of SNP, suggesting that SA and NO in combination more efficiently boosted physiological and biochemical responses to alleviate Cd-toxicity than either SA or NO alone. This finding signifies a cooperative action of SA and NO in mitigating Cd-induced adverse effects in rice, and perhaps in other crop plants. Full article
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Open AccessReview
B Vitamins and Fatty Acids: What Do They Share with Small Vessel Disease-Related Dementia?
Int. J. Mol. Sci. 2019, 20(22), 5797; https://doi.org/10.3390/ijms20225797 - 18 Nov 2019
Abstract
Many studies have been written on vitamin supplementation, fatty acid, and dementia, but results are still under debate, and no definite conclusion has yet been drawn. Nevertheless, a significant amount of lab evidence confirms that vitamins of the B group are tightly related [...] Read more.
Many studies have been written on vitamin supplementation, fatty acid, and dementia, but results are still under debate, and no definite conclusion has yet been drawn. Nevertheless, a significant amount of lab evidence confirms that vitamins of the B group are tightly related to gene control for endothelium protection, act as antioxidants, play a co-enzymatic role in the most critical biochemical reactions inside the brain, and cooperate with many other elements, such as choline, for the synthesis of polyunsaturated phosphatidylcholine, through S-adenosyl-methionine (SAM) methyl donation. B-vitamins have anti-inflammatory properties and act in protective roles against neurodegenerative mechanisms, for example, through modulation of the glutamate currents and a reduction of the calcium currents. In addition, they also have extraordinary antioxidant properties. However, laboratory data are far from clinical practice. Many studies have tried to apply these results in everyday clinical activity, but results have been discouraging and far from a possible resolution of the associated mysteries, like those represented by Alzheimer’s disease (AD) or small vessel disease dementia. Above all, two significant problems emerge from the research: No consensus exists on general diagnostic criteria—MCI or AD? Which diagnostic criteria should be applied for small vessel disease-related dementia? In addition, no general schema exists for determining a possible correct time of implementation to have effective results. Here we present an up-to-date review of the literature on such topics, shedding some light on the possible interaction of vitamins and phosphatidylcholine, and their role in brain metabolism and catabolism. Further studies should take into account all of these questions, with well-designed and world-homogeneous trials. Full article
(This article belongs to the Special Issue Functional Mechanism of B-Vitamins and Their Metabolites)
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Open AccessArticle
Carotenoid Cleavage Dioxygenases: Identification, Expression, and Evolutionary Analysis of This Gene Family in Tobacco
Int. J. Mol. Sci. 2019, 20(22), 5796; https://doi.org/10.3390/ijms20225796 - 18 Nov 2019
Abstract
Carotenoid cleavage dioxygenases (CCDs) selectively catalyze carotenoids, forming smaller apocarotenoids that are essential for the synthesis of apocarotenoid flavor, aroma volatiles, and phytohormone ABA/SLs, as well as responses to abiotic stresses. Here, 19, 11, and 10 CCD genes were identified in Nicotiana tabacum [...] Read more.
Carotenoid cleavage dioxygenases (CCDs) selectively catalyze carotenoids, forming smaller apocarotenoids that are essential for the synthesis of apocarotenoid flavor, aroma volatiles, and phytohormone ABA/SLs, as well as responses to abiotic stresses. Here, 19, 11, and 10 CCD genes were identified in Nicotiana tabacum, Nicotiana tomentosiformis, and Nicotiana sylvestris, respectively. For this family, we systematically analyzed phylogeny, gene structure, conserved motifs, gene duplications, cis-elements, subcellular and chromosomal localization, miRNA-target sites, expression patterns with different treatments, and molecular evolution. CCD genes were classified into two subfamilies and nine groups. Gene structures, motifs, and tertiary structures showed similarities within the same groups. Subcellular localization analysis predicted that CCD family genes are cytoplasmic and plastid-localized, which was confirmed experimentally. Evolutionary analysis showed that purifying selection dominated the evolution of these genes. Meanwhile, seven positive sites were identified on the ancestor branch of the tobacco CCD subfamily. Cis-regulatory elements of the CCD promoters were mainly involved in light-responsiveness, hormone treatment, and physiological stress. Different CCD family genes were predominantly expressed separately in roots, flowers, seeds, and leaves and exhibited divergent expression patterns with different hormones (ABA, MeJA, IAA, SA) and abiotic (drought, cold, heat) stresses. This study provides a comprehensive overview of the NtCCD gene family and a foundation for future functional characterization of individual genes. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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Open AccessArticle
Behavioral Impairments and Oxidative Stress in the Brain, Muscle, and Gill Caused by Chronic Exposure of C70 Nanoparticles on Adult Zebrafish
Int. J. Mol. Sci. 2019, 20(22), 5795; https://doi.org/10.3390/ijms20225795 - 18 Nov 2019
Abstract
There is an imperative need to develop efficient whole-animal-based testing assays to determine the potential toxicity of engineered nanomaterials. While previous studies have demonstrated toxicity in lung and skin cells after C70 nanoparticles (NPs) exposure, the potential detrimental role of C70 [...] Read more.
There is an imperative need to develop efficient whole-animal-based testing assays to determine the potential toxicity of engineered nanomaterials. While previous studies have demonstrated toxicity in lung and skin cells after C70 nanoparticles (NPs) exposure, the potential detrimental role of C70 NPs in neurobehavior is largely unaddressed. Here, we evaluated the chronic effects of C70 NPs exposure on behavior and alterations in biochemical responses in adult zebrafish. Two different exposure doses were used for this experiment: low dose (0.5 ppm) and high dose (1.5 ppm). Behavioral tests were performed after two weeks of exposure of C70 NPs. We found decreased locomotion, exploration, mirror biting, social interaction, and shoaling activities, as well as anxiety elevation and circadian rhythm locomotor activity impairment after ~2 weeks in the C70 NP-exposed fish. The results of biochemical assays reveal that following exposure of zebrafish to 1.5 ppm of C70 NPs, the activity of superoxide dismutase (SOD) in the brain and muscle tissues increased significantly. In addition, the concentration of reactive oxygen species (ROS) also increased from 2.95 ± 0.12 U/ug to 8.46 ± 0.25 U/ug and from 0.90 ± 0.03 U/ug to 3.53 ± 0.64 U/ug in the muscle and brain tissues, respectively. Furthermore, an increased level of cortisol was also observed in muscle and brain tissues, ranging from 17.95 ± 0.90 pg/ug to 23.95 ± 0.66 pg/ug and from 3.47 ± 0.13 pg/ug to 4.91 ± 0.51 pg/ug, respectively. Increment of Hif1-α level was also observed in both tissues. The elevation was ranging from 11.65 ± 0.54 pg/ug to 18.45 ± 1.00 pg/ug in the muscle tissue and from 4.26 ± 0.11 pg/ug to 6.86 ± 0.37 pg/ug in the brain tissue. Moreover, the content of DNA damage and inflammatory markers such as ssDNA, TNF-α, and IL-1β were also increased substantially in the brain tissues. Significant changes in several biomarker levels, including catalase and malondialdehyde (MDA), were also observed in the gill tissues. Finally, we used a neurophenomic approach with a particular focus on environmental influences, which can also be easily adapted for other aquatic fish species, to assess the toxicity of metal and carbon-based nanoparticles. In summary, this is the first study to illustrate the adult zebrafish toxicity and the alterations in several neurobehavior parameters after zebrafish exposure to environmentally relevant amounts of C70 NPs. Full article
(This article belongs to the Special Issue Nanotoxicology and Nanosafety 2.0)
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Open AccessReview
Heat Shock Proteins in Glioblastoma Biology: Where Do We Stand?
Int. J. Mol. Sci. 2019, 20(22), 5794; https://doi.org/10.3390/ijms20225794 - 18 Nov 2019
Abstract
Heat shock proteins (HSPs) are evolutionary conserved proteins that work as molecular chaperones and perform broad and crucial roles in proteostasis, an important process to preserve the integrity of proteins in different cell types, in health and disease. Their function in cancer is [...] Read more.
Heat shock proteins (HSPs) are evolutionary conserved proteins that work as molecular chaperones and perform broad and crucial roles in proteostasis, an important process to preserve the integrity of proteins in different cell types, in health and disease. Their function in cancer is an important aspect to be considered for a better understanding of disease development and progression. Glioblastoma (GBM) is the most frequent and lethal brain cancer, with no effective therapies. In recent years, HSPs have been considered as possible targets for GBM therapy due their importance in different mechanisms that govern GBM malignance. In this review, we address current evidence on the role of several HSPs in the biology of GBMs, and how these molecules have been considered in different treatments in the context of this disease, including their activities in glioblastoma stem-like cells (GSCs), a small subpopulation able to drive GBM growth. Additionally, we highlight recent works that approach other classes of chaperones, such as histone and mitochondrial chaperones, as important molecules for GBM aggressiveness. Herein, we provide new insights into how HSPs and their partners play pivotal roles in GBM biology and may open new therapeutic avenues for GBM based on proteostasis machinery. Full article
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Open AccessArticle
The Chemokine CXCL16 Is a New Biomarker for Lymph Node Analysis of Colon Cancer Outcome
Int. J. Mol. Sci. 2019, 20(22), 5793; https://doi.org/10.3390/ijms20225793 - 18 Nov 2019
Abstract
Chemokines are important in the development and progression of tumors. We investigated the expression of CXCL14 and CXCL16 in colon cancer. Expression of mRNA was assessed in primary tumors and lymph nodes and CXCL16 mRNA levels were correlated to patient’s survival. Protein expression [...] Read more.
Chemokines are important in the development and progression of tumors. We investigated the expression of CXCL14 and CXCL16 in colon cancer. Expression of mRNA was assessed in primary tumors and lymph nodes and CXCL16 mRNA levels were correlated to patient’s survival. Protein expression was investigated by two-color immunofluorescence and immunomorphometry. CXCL14 and CXCL16 mRNA levels and protein expression were significantly higher in colon cancer primary tumors compared to apparently normal colon tissue. Positive cells were tumor cells, as revealed by anti-CEA and anti-EpCAM staining. CXCL16, but not CXCL14, mRNA levels were significantly higher in hematoxylin and eosin positive (H&E(+)) compared to H&E(−) colon cancer lymph nodes or control nodes (P < 0.0001). CXCL16 mRNA was expressed in 5/5 colon cancer cell lines while CXCL14 was expressed significantly in only one. Kaplan-Meier analysis revealed that colon cancer patients with lymph nodes expressing high or very high levels (7.2 and 11.4 copies/18S rRNA unit, respectively) of CXCL16 mRNA had a decreased mean survival time of 30 and 46 months at the 12-year follow-up (P = 0.04, P = 0.005, respectively). In conclusion, high expression of CXCL16 mRNA in regional lymph nodes of colon cancer patients is a sign of a poor prognosis. Full article
(This article belongs to the Special Issue Chemokines in Cancer and Inflammatory Diseases)
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Open AccessReview
PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases
Int. J. Mol. Sci. 2019, 20(22), 5792; https://doi.org/10.3390/ijms20225792 - 18 Nov 2019
Abstract
The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been implicated as a cancer target. Big pharma players and small companies have been developing small molecule inhibitors of PI3K and/or mTOR since the 1990s. Although four inhibitors have been approved, many [...] Read more.
The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been implicated as a cancer target. Big pharma players and small companies have been developing small molecule inhibitors of PI3K and/or mTOR since the 1990s. Although four inhibitors have been approved, many open questions regarding tolerability, patient selection, sensitivity markers, development of resistances, and toxicological challenges still need to be addressed. Besides clear oncological indications, PI3K and mTOR inhibitors have been suggested for treating a plethora of different diseases. In particular, genetically induced PI3K/mTOR pathway activation causes rare disorders, known as overgrowth syndromes, like PTEN (phosphatase and tensin homolog) hamartomas, tuberous sclerosis complex (TSC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum (PROS), and activated PI3-Kinase delta syndrome (PI3KCD, APDS). Some of those disorders likeTSC or hemimegalencephaly, which are one of the PROS disorders, also belong to a group of diseases called mTORopathies. This group of syndromes presents with additional neurological manifestations associated with epilepsy and other neuropsychiatric symptoms induced by neuronal mTOR pathway hyperactivation. While PI3K and mTOR inhibitors have been and still are intensively tested in oncology indications, their use in genetically defined syndromes and mTORopathies appear to be promising avenues for a pharmacological intervention. Full article
(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target)
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Open AccessArticle
VEGF-A and ICAM-1 Gene Polymorphisms as Predictors of Clinical Outcome to First-Line Bevacizumab-Based Treatment in Metastatic Colorectal Cancer
Int. J. Mol. Sci. 2019, 20(22), 5791; https://doi.org/10.3390/ijms20225791 - 18 Nov 2019
Abstract
Bevacizumab is used to treat metastatic colorectal cancer (mCRC). However, there are still no available predictors of clinical outcomes. We investigated selected single nucleotide polymorphisms (SNPs) in the genes involved in VEGF-dependent and -independent angiogenesis pathways and other major intracellular signaling pathways involved [...] Read more.
Bevacizumab is used to treat metastatic colorectal cancer (mCRC). However, there are still no available predictors of clinical outcomes. We investigated selected single nucleotide polymorphisms (SNPs) in the genes involved in VEGF-dependent and -independent angiogenesis pathways and other major intracellular signaling pathways involved in the pathogenesis of mCRC as an attempt to find predictors of clinical outcome. Forty-six patients treated with first-line bevacizumab-based chemotherapy were included in this study with a 5 year follow up. Genomic DNA was isolated from whole blood for the analysis of VEGF-A (rs2010963, 1570360, rs699947), ICAM-1 (rs5498, rs1799969) SNPs and from tumor tissue for the detection of genomic variants in KRAS, NRAS, BRAF genes. PCR and next generation sequencing were used for the analysis. The endpoints of the study were progression-free survival (PFS) and overall survival (OS). The VEGF-A rs699947 A/A allele was associated with increased PFS (p = 0.006) and OS (p = 0.043). The ICAM-1 rs1799969 G/A allele was associated with prolonged OS (p = 0.036). Finally, BRAF wild type was associated with increased OS (p = 0.027). We identified VEGF-A and ICAM-1 variants in angiogenesis and other major intracellular signaling pathways, such as BRAF, that can predict clinical outcome upon bevacizumab administration. These identified biomarkers could be used to select patients with mCRC who may achieve long-term responses and benefit from bevacizumab-based therapies. Full article
(This article belongs to the Special Issue Role of Angiogenesis Inhibitors in Cancer)
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Open AccessArticle
Tellimagrandin II, A Type of Plant Polyphenol Extracted from Trapa bispinosa Inhibits Antibiotic Resistance of Drug-Resistant Staphylococcus aureus
Int. J. Mol. Sci. 2019, 20(22), 5790; https://doi.org/10.3390/ijms20225790 - 18 Nov 2019
Abstract
The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has become a critical global concern. Identifying new candidates of anti-S. aureus agents is urgently required because the therapeutic strategies for infected patients are limited currently. Therefore, the present study investigated whether Tellimagrandin II (TGII), [...] Read more.
The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has become a critical global concern. Identifying new candidates of anti-S. aureus agents is urgently required because the therapeutic strategies for infected patients are limited currently. Therefore, the present study investigated whether Tellimagrandin II (TGII), a pure compound extracted from the shells of Trapa bispinosa, exhibits antibacterial effects against MRSA. We first showed that TGII exerted potent inhibitory activity against MRSA with a minimum inhibitory concentration of 128 μg/mL. The obtained fractional inhibitory concentration suggested that TGII could alone exert antistaphylococcal activity, and TGII combined with low doses of antibiotics displayed synergistic effects against MRSA. Moreover, we found that TGII exerted bactericidal activity by reducing the expression of mecA followed by the negative regulation of the penicillin-binding protein 2a (PBP2a) of MRSA. Transmission electron microscopy (TEM) images further confirmed that TGII destroyed the integrity of the cell wall of MRSA and caused the loss of cytoplasm content. In conclusion, we evidenced the antibacterial effects of TGII against MRSA, which enables the effective dose of current antibiotics to be reduced and the predicament of drug-resistant S. aureus isolates to be overcome. Full article
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Open AccessArticle
Connexin43 Is Required for the Effective Activation of Spleen Cells and Immunoglobulin Production
Int. J. Mol. Sci. 2019, 20(22), 5789; https://doi.org/10.3390/ijms20225789 - 18 Nov 2019
Abstract
Gap junctions (Gjs), formed by specific protein termed connexins (Cxs), regulate many important cellular processes in cellular immunity. However, little is known about their effects on humoral immunity. Here we tested whether and how Gj protein connexin43 (Cx43) affected antibody production in spleen [...] Read more.
Gap junctions (Gjs), formed by specific protein termed connexins (Cxs), regulate many important cellular processes in cellular immunity. However, little is known about their effects on humoral immunity. Here we tested whether and how Gj protein connexin43 (Cx43) affected antibody production in spleen cells. Detection of IgG in mouse tissues and serum revealed that wild-type (Cx43+/+) mouse had a significantly higher level of IgG than Cx43 heterozygous (Cx43+/−) mouse. Consistently, spleen cells from Cx43+/+ mouse produced more IgG under both basal and lipopolysaccharide (LPS)-stimulated conditions. Further analysis showed that LPS induced a more dramatic activation of ERK and cell proliferation in Cx43+/+ spleen cells, which was associated with a higher pro-oxidative state, as indicated by the increased NADPH oxidase 2 (NOX2), TXNIP, p38 activation and protein carbonylation. In support of a role of the oxidative state in the control of lymphocyte activation, exposure of spleen cells to exogenous superoxide induced Cx43 expression, p38 activation and IgG production. On the contrary, inhibition of NOX attenuated the effects of LPS. Collectively, our study characterized Cx43 as a novel molecule involved in the control of spleen cell activation and IgG production. Targeting Cx43 could be developed to treat certain antibody-related immune diseases. Full article
(This article belongs to the Special Issue Connexin-Based Channels in Inflammatory Processes)
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