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Int. J. Mol. Sci., Volume 19, Issue 11 (November 2018)

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Cover Story (view full-size image) Fluctuations of protein three-dimensional structures and large-scale conformational transitions are [...] Read more.
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Open AccessArticle Jatrorrhizine Hydrochloride Suppresses RANKL-Induced Osteoclastogenesis and Protects against Wear Particle-Induced Osteolysis
Int. J. Mol. Sci. 2018, 19(11), 3698; https://doi.org/10.3390/ijms19113698
Received: 23 September 2018 / Revised: 12 November 2018 / Accepted: 15 November 2018 / Published: 21 November 2018
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Abstract
Wear particle-induced aseptic prosthetic loosening is a major complication associated with total joint arthroplasty (TJA). A growing body of evidence suggests that receptor activator of nuclear factor κ-B ligand (RANKL)-stimulated osteoclastogenesis and bone resorption are responsible for peri-implant loosening. Thus, agents which attenuate
[...] Read more.
Wear particle-induced aseptic prosthetic loosening is a major complication associated with total joint arthroplasty (TJA). A growing body of evidence suggests that receptor activator of nuclear factor κ-B ligand (RANKL)-stimulated osteoclastogenesis and bone resorption are responsible for peri-implant loosening. Thus, agents which attenuate excessive osteoclast differentiation and function have been considered to offer therapeutic potential for prolonging the life of TJA implants. Jatrorrhizine hydrochloride (JH), a major protoberberine alkaloid isolated from the traditional Chinese herb Coptis chinensis, has been reported to have antimicrobial, antitumor, and antihypercholesterolemic and neuroprotective activities. However, its effects on osteoclast biology remain unknown. Here, we found that JH inhibited RANKL-induced osteoclast formation and bone resorption in vitro and exerted protection against titanium (Ti) particle-induced osteolysis in vivo. Biochemical analysis demonstrated that JH suppressed RANKL-induced activation of MAPKs (p38 and ERK) which down-regulated the production of NFATc1 and NFATc1-regulated osteoclastic marker genes, such as TRAP, CTR and CTSK. Collectively, our findings suggest that JH may be a promising anti-osteoclastogenesis agent for treating periprosthetic osteolysis or other osteoclast-related osteolytic diseases. Full article
(This article belongs to the Section Molecular Pharmacology)
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Open AccessArticle Medium-Chain Triglycerides Attenuate Liver Injury in Lipopolysaccharide-Challenged Pigs by Inhibiting Necroptotic and Inflammatory Signaling Pathways
Int. J. Mol. Sci. 2018, 19(11), 3697; https://doi.org/10.3390/ijms19113697
Received: 19 September 2018 / Revised: 8 November 2018 / Accepted: 16 November 2018 / Published: 21 November 2018
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Abstract
This study was conducted to investigate whether medium-chain triglycerides (MCTs) attenuated lipopolysaccharide (LPS)-induced liver injury by down-regulating necroptotic and inflammatory signaling pathways. A total of 24 pigs were randomly allotted to four treatments in a 2 × 2 factorial design including diet (0
[...] Read more.
This study was conducted to investigate whether medium-chain triglycerides (MCTs) attenuated lipopolysaccharide (LPS)-induced liver injury by down-regulating necroptotic and inflammatory signaling pathways. A total of 24 pigs were randomly allotted to four treatments in a 2 × 2 factorial design including diet (0 and 4% MCTs) and immunological challenge (saline and LPS). After three weeks of feeding with or without 4% MCTs, pigs were challenged with saline or LPS. MCTs led to a significant increase in eicosapentaenoic acid, docosahexaenoic acid and total (n-3) polyunsaturated fatty acid concentrations. MCTs attenuated LPS-induced liver injury as indicated by an improvement in liver histomorphology and ultrastructural morphology of hepatocytes, a reduction in serum alanine aminotransferase and alkaline phosphatase activities as well as an increase in claudin-1 protein expression. In addition, MCTs also reduced serum tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 concentrations, liver TNF-α and IL-1β mRNA expression and protein concentrations and enhanced liver heat shock protein 70 protein expression in LPS-challenged pigs. Moreover, MCTs decreased mRNA expression of receptor-interacting serine/threonine-protein kinase (RIP) 3, mixed-lineage kinase domain-like protein (MLKL) and phosphoglycerate mutase 5 and inhibited MLKL phosphorylation in the liver. Finally, MCTs decreased liver mRNA expression of toll-like receptor (TLR) 4, nucleotide-binding oligomerization domain protein (NOD) 1 and multiple downstream signaling molecules. MCTs also suppressed LPS-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation and increased extracellular signal-related kinase 1/2 phosphorylation in the liver. These results indicated that MCTs are capable of attenuating LPS-induced liver damage by suppressing hepatic necroptotic (RIP1/RIP3/MLKL) and inflammatory (TLR4/NOD1/p38 MAPK) signaling pathways. Full article
(This article belongs to the Special Issue Liver Damage and Repair)
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Open AccessArticle Uric Acid and Xanthine Levels in Pregnancy Complicated by Gestational Diabetes Mellitus—The Effect on Adverse Pregnancy Outcomes
Int. J. Mol. Sci. 2018, 19(11), 3696; https://doi.org/10.3390/ijms19113696
Received: 12 October 2018 / Revised: 17 November 2018 / Accepted: 19 November 2018 / Published: 21 November 2018
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Abstract
Uric acid (UA) levels are associated with many diseases including those related to lifestyle. The aim of this study was to evaluate the influence of clinical and anthropometric parameters on UA and xanthine (X) levels during pregnancy and postpartum in women with physiological
[...] Read more.
Uric acid (UA) levels are associated with many diseases including those related to lifestyle. The aim of this study was to evaluate the influence of clinical and anthropometric parameters on UA and xanthine (X) levels during pregnancy and postpartum in women with physiological pregnancy and pregnancy complicated by gestational diabetes mellitus (GDM), and to evaluate their impact on adverse perinatal outcomes. A total of 143 participants were included. Analyte levels were determined by HPLC with ultraviolet detection (HPLC-UV). Several single-nucleotide polymorphisms (SNPs) in UA transporters were genotyped using commercial assays. UA levels were higher within GDM women with pre-gestational obesity, those in high-risk groups, and those who required insulin during pregnancy. X levels were higher in the GDM group during pregnancy and also postpartum. Positive correlations between UA and X levels with body mass index (BMI) and glycemia levels were found. Gestational age at delivery was negatively correlated with UA and X levels postpartum. Postpartum X levels were significantly higher in women who underwent caesarean sections. Our data support a possible link between increased UA levels and a high-risk GDM subtype. UA levels were higher among women whose glucose tolerance was severely disturbed. Mid-gestational UA and X levels were not linked to adverse perinatal outcomes. Full article
(This article belongs to the Special Issue Risk Factors and Molecular Mechanisms of Gestational Diabetes)
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Open AccessReview Prenatal Programming of Neuroendocrine System Development by Lipopolysaccharide: Long-Term Effects
Int. J. Mol. Sci. 2018, 19(11), 3695; https://doi.org/10.3390/ijms19113695
Received: 17 October 2018 / Revised: 16 November 2018 / Accepted: 19 November 2018 / Published: 21 November 2018
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Abstract
Various stress factors during critical periods of fetal development modulate the epigenetic mechanisms controlling specific genes, which can affect the structure and function of physiological systems. Maternal immune stress by bacterial infection simulated by lipopolysaccharide (LPS) in an experiment is considered to be
[...] Read more.
Various stress factors during critical periods of fetal development modulate the epigenetic mechanisms controlling specific genes, which can affect the structure and function of physiological systems. Maternal immune stress by bacterial infection simulated by lipopolysaccharide (LPS) in an experiment is considered to be a powerful programming factor of fetal development. Studies of the molecular mechanisms controlling the formation and functioning of physiological systems are in the pilot stage. LPSs are the most potent natural inflammation factors. LPS-induced increases in fetal levels of pro- and anti-inflammatory cytokines can affect brain development and have long-term effects on behavior and neuroendocrine functions. The degradation of serotonergic neurons induced by LPS in the fetus is attributed to the increased levels of interleukin (IL)-6 and tumor necrosis factor (TNFα) as well as to anxiety and depression in children. Dopamine deficiency causes dysthymia, learning disability, and Parkinson’s disease. According to our data, an LPS-induced increase in the levels of IL-6, leukemia inhibitory factor (LIF), and monocyte chemotactic protein (MCP-1) in maternal and fetal rats during early pregnancy disturbs the development and functioning of gonadotropin-releasing hormone production and reproductive systems. It is important to note the high responsiveness of epigenetic developmental mechanisms to many regulatory factors, which offers opportunities to correct the defects. Full article
(This article belongs to the Section Biochemistry)
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Open AccessEditorial International Journal of Molecular Science 2018 Best Paper Award
Int. J. Mol. Sci. 2018, 19(11), 3694; https://doi.org/10.3390/ijms19113694
Received: 20 November 2018 / Accepted: 20 November 2018 / Published: 21 November 2018
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Abstract
The Editors of the International Journal of Molecular Sciences have established the Best Paper Award to recognize the most outstanding articles published in the areas of molecular biology, molecular physics, and chemistry that have been published in the International Journal of Molecular Sciences
[...] Read more.
The Editors of the International Journal of Molecular Sciences have established the Best Paper Award to recognize the most outstanding articles published in the areas of molecular biology, molecular physics, and chemistry that have been published in the International Journal of Molecular Sciences. [...] Full article
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Open AccessArticle Experimental Combined Immunotherapy of Tumours with Major Histocompatibility Complex Class I Downregulation
Int. J. Mol. Sci. 2018, 19(11), 3693; https://doi.org/10.3390/ijms19113693
Received: 12 October 2018 / Revised: 14 November 2018 / Accepted: 17 November 2018 / Published: 21 November 2018
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Abstract
Combined immunotherapy constitutes a novel, advanced strategy in cancer treatment. In this study, we investigated immunotherapy in the mouse TC-1/A9 model of human papillomavirus type 16 (HPV16)-associated tumors characterized by major histocompatibility complex class I (MHC-I) downregulation. We found that the induction of
[...] Read more.
Combined immunotherapy constitutes a novel, advanced strategy in cancer treatment. In this study, we investigated immunotherapy in the mouse TC-1/A9 model of human papillomavirus type 16 (HPV16)-associated tumors characterized by major histocompatibility complex class I (MHC-I) downregulation. We found that the induction of a significant anti-tumor response required a combination of DNA vaccination with the administration of an adjuvant, either the synthetic oligodeoxynucleotide ODN1826, carrying immunostimulatory CpG motifs, or α-galactosylceramide (α-GalCer). The most profound anti-tumor effect was achieved when these adjuvants were applied in a mix with a one-week delay relative to DNA immunization. Combined immunotherapy induced tumor infiltration with various subsets of immune cells contributing to tumor regression, of which cluster of differentiation (CD) 8+ T cells were the predominant subpopulation. In contrast, the numbers of tumor-associated macrophages (TAMs) were not markedly increased after immunotherapy but in vivo and in vitro results showed that they could be repolarized to an anti-tumor M1 phenotype. A blockade of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) immune checkpoint had a negligible effect on anti-tumor immunity and TAMs repolarization. Our results demonstrate a benefit of combined immunotherapy comprising the activation of both adaptive and innate immunity in the treatment of tumors with reduced MHC-I expression. Full article
(This article belongs to the Special Issue Cancer Immunology and Immunotherapy)
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Open AccessArticle Metformin Inhibits Migration and Invasion by Suppressing ROS Production and COX2 Expression in MDA-MB-231 Breast Cancer Cells
Int. J. Mol. Sci. 2018, 19(11), 3692; https://doi.org/10.3390/ijms19113692
Received: 21 September 2018 / Revised: 16 November 2018 / Accepted: 17 November 2018 / Published: 21 November 2018
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Abstract
Background: Several mechanisms of action have been proposed to explain the apparent antineoplastic functions of metformin, many of which are observed at high concentrations that may not be reflective of achievable tissue concentrations. We propose that metformin at low concentrations functions to inhibit
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Background: Several mechanisms of action have been proposed to explain the apparent antineoplastic functions of metformin, many of which are observed at high concentrations that may not be reflective of achievable tissue concentrations. We propose that metformin at low concentrations functions to inhibit ROS production and inflammatory signaling in breast cancer, thereby reducing metastasis. Methods: Using the highly invasive MDA-MB-231 breast carcinoma model, we ascertained the impact of metformin on cell viability by DNA content analysis and fluorescent dye exclusion. Migration and invasion assays were performed using a modified Boyden chamber assay and metastasis was ascertained using the chorioallantoic membrane (CAM) assay. PGE2 production was measured by Enzyme-Linked Immunosorbent Assay (ELISA). COX2 and ICAM1 levels were determined by flow cytometry immunoassay. Results: Metformin acutely decreased cell viability and caused G2 cell cycle arrest only at high concentrations (10 mM). At 100 µM, however, metformin reduced ICAM1 and COX2 expression, as well as reduced PGE2 production and endogenous mitochondrial ROS production while failing to significantly impact cell viability. Consequently, metformin inhibited migration, invasion in vitro and PGE2-dependent metastasis in CAM assays. Conclusion: At pharmacologically achievable concentrations, metformin does not drastically impact cell viability, but inhibits inflammatory signaling and metastatic progression in breast cancer cells. Full article
(This article belongs to the Section Biochemistry)
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Open AccessReview Insect Transcription Factors: A Landscape of Their Structures and Biological Functions in Drosophila and beyond
Int. J. Mol. Sci. 2018, 19(11), 3691; https://doi.org/10.3390/ijms19113691
Received: 23 October 2018 / Revised: 16 November 2018 / Accepted: 16 November 2018 / Published: 21 November 2018
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Abstract
Transcription factors (TFs) play essential roles in the transcriptional regulation of functional genes, and are involved in diverse physiological processes in living organisms. The fruit fly Drosophila melanogaster, a simple and easily manipulated organismal model, has been extensively applied to study the
[...] Read more.
Transcription factors (TFs) play essential roles in the transcriptional regulation of functional genes, and are involved in diverse physiological processes in living organisms. The fruit fly Drosophila melanogaster, a simple and easily manipulated organismal model, has been extensively applied to study the biological functions of TFs and their related transcriptional regulation mechanisms. It is noteworthy that with the development of genetic tools such as CRISPR/Cas9 and the next-generation genome sequencing techniques in recent years, identification and dissection the complex genetic regulatory networks of TFs have also made great progress in other insects beyond Drosophila. However, unfortunately, there is no comprehensive review that systematically summarizes the structures and biological functions of TFs in both model and non-model insects. Here, we spend extensive effort in collecting vast related studies, and attempt to provide an impartial overview of the progress of the structure and biological functions of current documented TFs in insects, as well as the classical and emerging research methods for studying their regulatory functions. Consequently, considering the importance of versatile TFs in orchestrating diverse insect physiological processes, this review will assist a growing number of entomologists to interrogate this understudied field, and to propel the progress of their contributions to pest control and even human health. Full article
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Open AccessArticle Gramicidin Lateral Distribution in Phospholipid Membranes: Fluorescence Phasor Plots and Statistical Mechanical Model
Int. J. Mol. Sci. 2018, 19(11), 3690; https://doi.org/10.3390/ijms19113690
Received: 18 October 2018 / Revised: 14 November 2018 / Accepted: 15 November 2018 / Published: 21 November 2018
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Abstract
When using small mole fraction increments to study gramicidins in phospholipid membranes, we found that the phasor dots of intrinsic fluorescence of gramicidin D and gramicidin A in dimyristoyl-sn-glycero-3-phosphocholine (DMPC) unilamellar and multilamellar vesicles exhibit a biphasic change with peptide content
[...] Read more.
When using small mole fraction increments to study gramicidins in phospholipid membranes, we found that the phasor dots of intrinsic fluorescence of gramicidin D and gramicidin A in dimyristoyl-sn-glycero-3-phosphocholine (DMPC) unilamellar and multilamellar vesicles exhibit a biphasic change with peptide content at 0.143 gramicidin mole fraction. To understand this phenomenon, we developed a statistical mechanical model of gramicidin/DMPC mixtures. Our model assumes a sludge-like mixture of fluid phase and aggregates of rigid clusters. In the fluid phase, gramicidin monomers are randomly distributed. A rigid cluster is formed by a gramicidin dimer and DMPC molecules that are condensed to the dimer, following particular stoichiometries (critical gramicidin mole fractions, Xcr including 0.143). Rigid clusters form aggregates in which gramicidin dimers are regularly distributed, in some cases, even to superlattices. At Xcr, the size of cluster aggregates and regular distributions reach a local maximum. Before a similar model was developed for cholesterol/DMPC mixtures (Sugar and Chong (2012) J. Am. Chem. Soc. 134, 1164–1171) and here the similarities and differences are discussed between these two models. Full article
(This article belongs to the Section Molecular Biophysics)
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Open AccessArticle Synergistic Effects of Weightlessness, Isoproterenol, and Radiation on DNA Damage Response and Cytokine Production in Immune Cells
Int. J. Mol. Sci. 2018, 19(11), 3689; https://doi.org/10.3390/ijms19113689
Received: 24 October 2018 / Revised: 10 November 2018 / Accepted: 11 November 2018 / Published: 21 November 2018
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Abstract
The implementation of rotating-wall vessels (RWVs) for studying the effect of lack of gravity has attracted attention, especially in the fields of stem cells, tissue regeneration, and cancer research. Immune cells incubated in RWVs exhibit several features of immunosuppression including impaired leukocyte proliferation,
[...] Read more.
The implementation of rotating-wall vessels (RWVs) for studying the effect of lack of gravity has attracted attention, especially in the fields of stem cells, tissue regeneration, and cancer research. Immune cells incubated in RWVs exhibit several features of immunosuppression including impaired leukocyte proliferation, cytokine responses, and antibody production. Interestingly, stress hormones influence cellular immune pathways affected by microgravity, such as cell proliferation, apoptosis, DNA repair, and T cell activation. These pathways are crucial defense mechanisms that protect the cell from toxins, pathogens, and radiation. Despite the importance of the adrenergic receptor in regulating the immune system, the effect of microgravity on the adrenergic system has been poorly studied. Thus, we elected to investigate the synergistic effects of isoproterenol (a sympathomimetic drug), radiation, and microgravity in nonstimulated immune cells. Peripheral blood mononuclear cells were treated with the sympathomimetic drug isoproterenol, exposed to 0.8 or 2 Gy γ-radiation, and incubated in RWVs. Mixed model regression analyses showed significant synergistic effects on the expression of the β2-adrenergic receptor gene (ADRB2). Radiation alone increased ADRB2 expression, and cells incubated in microgravity had more DNA strand breaks than cells incubated in normal gravity. We observed radiation-induced cytokine production only in microgravity. Prior treatment with isoproterenol clearly prevents most of the microgravity-mediated effects. RWVs may be a useful tool to provide insight into novel regulatory pathways, providing benefit not only to astronauts but also to patients suffering from immune disorders or undergoing radiotherapy. Full article
(This article belongs to the Special Issue Adaptation of Living Organisms in Space: From Mammals to Plants)
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Open AccessReview The Question of a Role for Statins in Age-Related Macular Degeneration
Int. J. Mol. Sci. 2018, 19(11), 3688; https://doi.org/10.3390/ijms19113688
Received: 18 October 2018 / Revised: 18 November 2018 / Accepted: 19 November 2018 / Published: 21 November 2018
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Abstract
Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss in patients over the age of 65 years in industrialized countries. Epidemiologic studies suggest that high dietary fat intake is a risk factor for the development and progression of both
[...] Read more.
Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss in patients over the age of 65 years in industrialized countries. Epidemiologic studies suggest that high dietary fat intake is a risk factor for the development and progression of both vascular and retinal disease. These, and other associations, suggest a hypothesis linking elevated cholesterol and AMD progression. It follows, therefore, that cholesterol-lowering medications, such as statins, may influence the onset and progression of AMD. However, the findings have been inconclusive as to whether statins play a role in AMD. Due to the significant public health implications of a potential inhibitory effect of statins on the onset and progression of AMD, it is important to continually evaluate emerging findings germane to this question. Full article
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD))
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Open AccessArticle Hierarchical Clustering of DNA k-mer Counts in RNAseq Fastq Files Identifies Sample Heterogeneities
Int. J. Mol. Sci. 2018, 19(11), 3687; https://doi.org/10.3390/ijms19113687
Received: 5 November 2018 / Accepted: 15 November 2018 / Published: 21 November 2018
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Abstract
We apply hierarchical clustering (HC) of DNA k-mer counts on multiple Fastq files. The tree structures produced by HC may reflect experimental groups and thereby indicate experimental effects, but clustering of preparation groups indicates the presence of batch effects. Hence, HC of DNA
[...] Read more.
We apply hierarchical clustering (HC) of DNA k-mer counts on multiple Fastq files. The tree structures produced by HC may reflect experimental groups and thereby indicate experimental effects, but clustering of preparation groups indicates the presence of batch effects. Hence, HC of DNA k-mer counts may serve as a diagnostic device. In order to provide a simple applicable tool we implemented sequential analysis of Fastq reads with low memory usage in an R package (seqTools) available on Bioconductor. The approach is validated by analysis of Fastq file batches containing RNAseq data. Analysis of three Fastq batches downloaded from ArrayExpress indicated experimental effects. Analysis of RNAseq data from two cell types (dermal fibroblasts and Jurkat cells) sequenced in our facility indicate presence of batch effects. The observed batch effects were also present in reads mapped to the human genome and also in reads filtered for high quality (Phred > 30). We propose, that hierarchical clustering of DNA k-mer counts provides an unspecific diagnostic tool for RNAseq experiments. Further exploration is required once samples are identified as outliers in HC derived trees. Full article
(This article belongs to the Section Biochemistry)
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Open AccessArticle Interactions Between Spermine-Derivatized Tentacle Porphyrins and The Human Telomeric DNA G-Quadruplex
Int. J. Mol. Sci. 2018, 19(11), 3686; https://doi.org/10.3390/ijms19113686
Received: 16 October 2018 / Revised: 14 November 2018 / Accepted: 17 November 2018 / Published: 21 November 2018
Cited by 1 | Viewed by 334 | PDF Full-text (3500 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
G-rich DNA sequences have the potential to fold into non-canonical G-Quadruplex (GQ) structures implicated in aging and human diseases, notably cancers. Because stabilization of GQs at telomeres and oncogene promoters may prevent cancer, there is an interest in developing small molecules that selectively
[...] Read more.
G-rich DNA sequences have the potential to fold into non-canonical G-Quadruplex (GQ) structures implicated in aging and human diseases, notably cancers. Because stabilization of GQs at telomeres and oncogene promoters may prevent cancer, there is an interest in developing small molecules that selectively target GQs. Herein, we investigate the interactions of meso-tetrakis-(4-carboxysperminephenyl)porphyrin (TCPPSpm4) and its Zn(II) derivative (ZnTCPPSpm4) with human telomeric DNA (Tel22) via UV-Vis, circular dichroism (CD), and fluorescence spectroscopies, resonance light scattering (RLS), and fluorescence resonance energy transfer (FRET) assays. UV-Vis titrations reveal binding constants of 4.7 × 106 and 1.4 × 107 M−1 and binding stoichiometry of 2–4:1 and 10–12:1 for TCPPSpm4 and ZnTCPPSpm4, respectively. High stoichiometry is supported by the Job plot data, CD titrations, and RLS data. FRET melting indicates that TCPPSpm4 stabilizes Tel22 by 36 ± 2 °C at 7.5 eq., and that ZnTCPPSpm4 stabilizes Tel22 by 33 ± 2 °C at ~20 eq.; at least 8 eq. of ZnTCPPSpm4 are required to achieve significant stabilization of Tel22, in agreement with its high binding stoichiometry. FRET competition studies show that both porphyrins are mildly selective for human telomeric GQ vs duplex DNA. Spectroscopic studies, combined, point to end-stacking and porphyrin self-association as major binding modes. This work advances our understanding of ligand interactions with GQ DNA. Full article
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Open AccessReview Biotherapeutics: Challenges and Opportunities for Predictive Toxicology of Monoclonal Antibodies
Int. J. Mol. Sci. 2018, 19(11), 3685; https://doi.org/10.3390/ijms19113685
Received: 29 October 2018 / Revised: 18 November 2018 / Accepted: 19 November 2018 / Published: 21 November 2018
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Abstract
Biotherapeutics are a rapidly growing portion of the total pharmaceutical market accounting for almost one-half of recent new drug approvals. A major portion of these approvals each year are monoclonal antibodies (mAbs). During development, non-clinical pharmacology and toxicology testing of mAbs differs from
[...] Read more.
Biotherapeutics are a rapidly growing portion of the total pharmaceutical market accounting for almost one-half of recent new drug approvals. A major portion of these approvals each year are monoclonal antibodies (mAbs). During development, non-clinical pharmacology and toxicology testing of mAbs differs from that done with chemical entities since these biotherapeutics are derived from a biological source and therefore the animal models must share the same epitopes (targets) as humans to elicit a pharmacological response. Mechanisms of toxicity of mAbs are both pharmacological and non-pharmacological in nature; however, standard in silico predictive toxicological methods used in research and development of chemical entities currently do not apply to these biotherapeutics. Challenges and potential opportunities exist for new methodologies to provide a more predictive program to assess and monitor potential adverse drug reactions of mAbs for specific patients before and during clinical trials and after market approval. Full article
(This article belongs to the Special Issue Frontiers in Drug Toxicity Prediction)
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Open AccessArticle Functional Biological Activity of Sorafenib as a Tumor-Treating Field Sensitizer for Glioblastoma Therapy
Int. J. Mol. Sci. 2018, 19(11), 3684; https://doi.org/10.3390/ijms19113684
Received: 1 October 2018 / Revised: 9 November 2018 / Accepted: 16 November 2018 / Published: 21 November 2018
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Abstract
Glioblastoma, the most common primary brain tumor in adults, is an incurable malignancy with poor short-term survival and is typically treated with radiotherapy along with temozolomide. While the development of tumor-treating fields (TTFields), electric fields with alternating low and intermediate intensity has facilitated
[...] Read more.
Glioblastoma, the most common primary brain tumor in adults, is an incurable malignancy with poor short-term survival and is typically treated with radiotherapy along with temozolomide. While the development of tumor-treating fields (TTFields), electric fields with alternating low and intermediate intensity has facilitated glioblastoma treatment, clinical outcomes of TTFields are reportedly inconsistent. However, combinatorial administration of chemotherapy with TTFields has proven effective for glioblastoma patients. Sorafenib, an anti-proliferative and apoptogenic agent, is used as first-line treatment for glioblastoma. This study aimed to investigate the effect of sorafenib on TTFields-induced anti-tumor and anti-angiogenesis responses in glioblastoma cells in vitro and in vivo. Sorafenib sensitized glioblastoma cells to TTFields, as evident from significantly decreased post-TTFields cell viability (p < 0.05), and combinatorial treatment with sorafenib and TTFields accelerated apoptosis via reactive oxygen species (ROS) generation, as evident from Poly (ADP-ribose) polymerase (PARP) cleavage. Furthermore, use of sorafenib plus TTFields increased autophagy, as evident from LC3 upregulation and autophagic vacuole formation. Cell cycle markers accumulated, and cells underwent a G2/M arrest, with an increased G0/G1 cell ratio. In addition, the combinatorial treatment significantly inhibited tumor cell motility and invasiveness, and angiogenesis. Our results suggest that combination therapy with sorafenib and TTFields is slightly better than each individual therapy and could potentially be used to treat glioblastoma in clinic, which requires further studies. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Open AccessArticle Metabolic Changes of Amino Acids and Flavonoids in Tea Plants in Response to Inorganic Phosphate Limitation
Int. J. Mol. Sci. 2018, 19(11), 3683; https://doi.org/10.3390/ijms19113683
Received: 12 October 2018 / Revised: 14 November 2018 / Accepted: 17 November 2018 / Published: 21 November 2018
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Abstract
The qualities of tea (Camellia sinensis) are not clearly understood in terms of integrated leading molecular regulatory network mechanisms behind inorganic phosphate (Pi) limitation. Thus, the present work aims to elucidate transcription factor-dependent responses of quality-related metabolites and the expression of
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The qualities of tea (Camellia sinensis) are not clearly understood in terms of integrated leading molecular regulatory network mechanisms behind inorganic phosphate (Pi) limitation. Thus, the present work aims to elucidate transcription factor-dependent responses of quality-related metabolites and the expression of genes to phosphate (P) starvation. The tea plant organs were subjected to metabolomics analysis by GC×GC-TOF/MS and UPLC-Q-TOF/MS along with transcription factors and 13 metabolic genes by qRT-PCR. We found P starvation upregulated SPX2 and the change response of Pi is highly dependent on young shoots. This led to increased change in abundance of carbohydrates (fructose and glucose), amino acids in leaves (threonine and methionine), and root (phenylalanine, alanine, tryptophan, and tyrosine). Flavonoids and their glycosides accumulated in leaves and root exposed to P limitation was consistent with the upregulated expression of anthocyanidin reductase (EC 1.3.1.77), leucoanthocyanidin dioxygenase (EC 1.4.11.19) and glycosyltransferases (UGT78D1, UGT78D2 and UGT57L12). Despite the similar kinetics and high correlation response of Pi and SPX2 in young shoots, predominating theanine and other amino acids (serine, threonine, glutamate, valine, methionine, phenylalanine) and catechin (EGC, EGCG and CG) content displayed opposite changes in response to Pi limitation between Fengqing and Longjing-43 tea cultivars. Full article
(This article belongs to the Special Issue Plant Metabolism in Crops: A Systems Biology Perspective)
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Open AccessCommunication A Cysteine-Reactive Small Photo-Crosslinker Possessing Caged-Fluorescence Properties: Binding-Site Determination of a Combinatorially-Selected Peptide by Fluorescence Imaging/Tandem Mass Spectrometry
Int. J. Mol. Sci. 2018, 19(11), 3682; https://doi.org/10.3390/ijms19113682
Received: 28 September 2018 / Revised: 15 November 2018 / Accepted: 16 November 2018 / Published: 21 November 2018
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Abstract
To determine the binding-site of a combinatorially-selected peptide possessing a fluoroprobe, a novel cysteine reactive small photo-crosslinker that can be excited by a conventional long-wavelength ultraviolet handlamp (365 nm) was synthesized via Suzuki coupling with three steps. The crosslinker is rationally designed, not
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To determine the binding-site of a combinatorially-selected peptide possessing a fluoroprobe, a novel cysteine reactive small photo-crosslinker that can be excited by a conventional long-wavelength ultraviolet handlamp (365 nm) was synthesized via Suzuki coupling with three steps. The crosslinker is rationally designed, not only as a bioisostere of the fluoroprobe, but as a caged-fluorophore, and the photo-crosslinked target protein became fluorescent with a large Stokes-shift. By introducing the crosslinker to a designated sulfhydryl (SH) group of a combinatorially-selected peptide, the protein-binding site of the targeted peptide was deduced by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)/fluorescence imaging followed by matrix-assisted laser desorption ionization-time of flight tandem mass spectrometry (MALDI-TOF-MS/MS) analysis. Full article
(This article belongs to the Section Physical Chemistry and Chemical Physics)
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Open AccessReview Biological Roles of Ornithine Aminotransferase (OAT) in Plant Stress Tolerance: Present Progress and Future Perspectives
Int. J. Mol. Sci. 2018, 19(11), 3681; https://doi.org/10.3390/ijms19113681
Received: 30 September 2018 / Revised: 14 November 2018 / Accepted: 16 November 2018 / Published: 21 November 2018
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Abstract
Plant tolerance to biotic and abiotic stresses is complicated by interactions between different stresses. Maintaining crop yield under abiotic stresses is the most daunting challenge for breeding resilient crop varieties. In response to environmental stresses, plants produce several metabolites, such as proline (Pro),
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Plant tolerance to biotic and abiotic stresses is complicated by interactions between different stresses. Maintaining crop yield under abiotic stresses is the most daunting challenge for breeding resilient crop varieties. In response to environmental stresses, plants produce several metabolites, such as proline (Pro), polyamines (PAs), asparagine, serine, carbohydrates including glucose and fructose, and pools of antioxidant reactive oxygen species. Among these metabolites, Pro has long been known to accumulate in cells and to be closely related to drought, salt, and pathogen resistance. Pyrroline-5-carboxylate (P5C) is a common intermediate of Pro synthesis and metabolism that is produced by ornithine aminotransferase (OAT), an enzyme that functions in an alternative Pro metabolic pathway in the mitochondria under stress conditions. OAT is highly conserved and, to date, has been found in all prokaryotic and eukaryotic organisms. In addition, ornithine (Orn) and arginine (Arg) are both precursors of PAs, which confer plant resistance to drought and salt stresses. OAT is localized in the cytosol in prokaryotes and fungi, while OAT is localized in the mitochondria in higher plants. We have comprehensively reviewed the research on Orn, Arg, and Pro metabolism in plants, as all these compounds allow plants to tolerate different kinds of stresses. Full article
(This article belongs to the Special Issue Mechanisms of Drought Stress Tolerance in Plants)
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Open AccessArticle Evolution and Expression Characteristics of Receptor-Like Cytoplasmic Protein Kinases in Maize, Rice and Arabidopsis
Int. J. Mol. Sci. 2018, 19(11), 3680; https://doi.org/10.3390/ijms19113680
Received: 29 October 2018 / Revised: 15 November 2018 / Accepted: 17 November 2018 / Published: 21 November 2018
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Abstract
Receptor-like cytoplasmic protein kinases (RLCKs) are involved in various activities in plant growth and development. We have totally identified 162, 160, and 402 RLCK genes in maize, rice, and Arabidopsis genomes, respectively. Phylogenetic analyses divided 724 RLCK genes into 15 subfamilies and similar
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Receptor-like cytoplasmic protein kinases (RLCKs) are involved in various activities in plant growth and development. We have totally identified 162, 160, and 402 RLCK genes in maize, rice, and Arabidopsis genomes, respectively. Phylogenetic analyses divided 724 RLCK genes into 15 subfamilies and similar structural patterns of kinase activity sites and functional sites were observed within the subfamilies. Furthermore, the structural patterns of intron/exon in the same subfamilies were similar, implicating their close evolutionary relationship. Chromosome distribution indicated that segmental duplication of RLCK genes might be a major mechanism contributing to the expansion of the RLCK superfamilies in maize, rice, and Arabidopsis, respectively. The analysis of the synteny relationship and gene structure indicated that the evolution of most RLCKs in maize were prior to rice and Arabidopsis. Most of the ratio of Ka/Ks is inferior to one, suggesting that RLCK genes have experienced the negative selection in maize, rice and Arabidopsis. Duplication time revealed that the maize was the earliest emergence among these three species. The expression profiles showed that there are some specifically expressed RLCK genes in maize root, leaf, ear, and tassel. These specific expression genes may participate in the developmental regulation of these maize tissues. Our results will be useful in providing new insights into evolution of RLCKs and revealing the regulatory network of maize, rice, and Arabidopsis development. Full article
(This article belongs to the Section Molecular Plant Sciences)
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Open AccessArticle Effect of Pretreatment with the NADPH Oxidase Inhibitor Apocynin on the Therapeutic Efficacy of Human Placenta-Derived Mesenchymal Stem Cells in Intracerebral Hemorrhage
Int. J. Mol. Sci. 2018, 19(11), 3679; https://doi.org/10.3390/ijms19113679
Received: 30 September 2018 / Revised: 16 November 2018 / Accepted: 19 November 2018 / Published: 21 November 2018
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Abstract
Several studies have demonstrated the beneficial effect of mesenchymal stem cells (MSCs) on intracerebral hemorrhage (ICH). Enhancement of the therapeutic efficacy of MSCs in ICH is necessary, considering the diseases high association with mortality and morbidity. Various preconditioning methods to enhance the beneficial
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Several studies have demonstrated the beneficial effect of mesenchymal stem cells (MSCs) on intracerebral hemorrhage (ICH). Enhancement of the therapeutic efficacy of MSCs in ICH is necessary, considering the diseases high association with mortality and morbidity. Various preconditioning methods to enhance the beneficial properties of MSCs have been introduced. We suggested apocynin, a well-known nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, as a novel preconditioning regimen to enhance the therapeutic efficacy of MSCs in ICH. Rat ICH models were made using bacterial collagenase. 24 h after ICH induction, the rats were randomly divided into apocynin-preconditioned MSC-treated (Apo-MSC), naïve MSC-treated and control groups. Hematoma volume, brain edema, and degenerating neuron count were compared at 48 h after the ICH induction. The expression of tight junction proteins (occludin, zona occludens [ZO]-1) were also compared. Hematoma size, hemispheric enlargement and degenerating neuron count were significantly lower in the Apo-MSC group than in the naïve MSC group (p = 0.004, 0.013 and 0.043, respectively), while the expression of occludin was higher (p = 0.024). Apocynin treatment enhances the therapeutic efficacy of MSCs in ICH in the acute stage, through the improvement of the beneficial properties of MSCs, such as neuroprotection and the reinforcement of endovascular integrity of cerebral vasculature. Full article
(This article belongs to the Special Issue Role of NADPH Oxidase on Neuron Death or on Neurogenesis)
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Open AccessArticle Anti-inflammatory and Neuroprotective Effects of Fungal Immunomodulatory Protein Involving Microglial Inhibition
Int. J. Mol. Sci. 2018, 19(11), 3678; https://doi.org/10.3390/ijms19113678
Received: 26 October 2018 / Revised: 9 November 2018 / Accepted: 19 November 2018 / Published: 21 November 2018
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Abstract
Microglia polarization of classical activation state is crucial to the induction of neuroinflammation, and has been implicated in the pathogenesis of numerous neurodegenerative diseases. Fungal immunomodulatory proteins are emerging health-promoting natural substances with multiple pharmacological activities, including immunomodulation. Herein, we investigated the anti-inflammatory
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Microglia polarization of classical activation state is crucial to the induction of neuroinflammation, and has been implicated in the pathogenesis of numerous neurodegenerative diseases. Fungal immunomodulatory proteins are emerging health-promoting natural substances with multiple pharmacological activities, including immunomodulation. Herein, we investigated the anti-inflammatory and neuroprotective potential of fungal immunomodulatory protein extracted from Ganoderma microsporum (GMI) in an in vitro rodent model of primary cultures. Using primary neuron/glia cultures consisting of neurons, astrocytes, and microglia, a GMI showed an alleviating effect on lipopolysaccharide (LPS)/interferon-γ (IFN-γ)-induced inflammatory mediator production and neuronal cell death. The events of neuroprotection caused by GMI were accompanied by the suppression of Nitric Oxide (NO), Tumor Necrosis Factor-α (TNF-α), Interleukin-1β (IL-1β), and Prostaglandin E2 (PGE2) production, along with the inhibition of microglia activation. Mechanistic studies showed that the suppression of microglia pro-inflammatory polarization by GMI was accompanied by the resolution of oxidative stress, the preservation of protein tyrosine phosphatase and serine/threonine phosphatase activity, and the reduction of NF-κB, AP-1, cyclic AMP response element-binding protein (CREB), along with signal transducers and activators of transcription (Stat1) transcriptional activities and associated upstream activators. These findings suggest that GMI may have considerable potential towards the treatment of neuroinflammation-mediated neurodegenerative diseases. Full article
(This article belongs to the Special Issue Natural Anti-Inflammatory Agents 2018)
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Open AccessReview Targeting Smoothened as a New Frontier in the Functional Recovery of Central Nervous System Demyelinating Pathologies
Int. J. Mol. Sci. 2018, 19(11), 3677; https://doi.org/10.3390/ijms19113677
Received: 17 October 2018 / Revised: 9 November 2018 / Accepted: 14 November 2018 / Published: 20 November 2018
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Abstract
Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune or genetic diseases. Remyelination is a natural process that restores the myelin sheath and, consequently, neuronal function after a
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Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune or genetic diseases. Remyelination is a natural process that restores the myelin sheath and, consequently, neuronal function after a demyelination event, preventing neurodegeneration and thereby neuron functional loss. Pharmacological approaches to remyelination represent a promising new frontier in the therapy of human demyelination pathologies and might provide novel tools to improve adaptive myelination in aged individuals. Recent phenotypical screens have identified agonists of the atypical G protein-coupled receptor Smoothened and inhibitors of the glioma-associated oncogene 1 as being amongst the most potent stimulators of oligodendrocyte precursor cell (OPC) differentiation in vitro and remyelination in the central nervous system (CNS) of mice. Here, we discuss the current state-of-the-art of studies on the role of Sonic Hedgehog reactivation during remyelination, referring readers to other reviews for the role of Hedgehog signaling in cancer and stem cell maintenance. Full article
(This article belongs to the Special Issue Hedgehog Signaling)
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Open AccessCorrection Correction: Serwotka-Suszczak, A. M. et al. A Conjugate Based on Anti-HER2 Diaffibody and Auristatin E Targets HER2-Positive Cancer Cells. Int. J. Mol. Sci. 2017, 18, 401
Int. J. Mol. Sci. 2018, 19(11), 3676; https://doi.org/10.3390/ijms19113676
Received: 8 November 2018 / Accepted: 10 November 2018 / Published: 20 November 2018
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Abstract
It has been brought to our attention that the affiliation of Dr. Jerzy Pieczykolan at the time when he was responsible for the work described in the paper [...] Full article
Open AccessCase Report Microduplication of 15q13.3 and Microdeletion of 18q21.32 in a Patient with Moyamoya Syndrome
Int. J. Mol. Sci. 2018, 19(11), 3675; https://doi.org/10.3390/ijms19113675
Received: 24 October 2018 / Revised: 13 November 2018 / Accepted: 16 November 2018 / Published: 20 November 2018
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Abstract
Moyamoya angiopathy (MA) is a cerebrovascular disease determining a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and their proximal branches and the compensatory development of abnormal “moyamoya” vessels. MA occurs as an isolated cerebral angiopathy (so-called moyamoya disease)
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Moyamoya angiopathy (MA) is a cerebrovascular disease determining a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and their proximal branches and the compensatory development of abnormal “moyamoya” vessels. MA occurs as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes) including several heritable conditions such as Down syndrome, neurofibromatosis type 1 and other genomic defects. Although the mechanism that links MA to these genetic syndromes is still unclear, it is believed that the involved genes may contribute to the disease susceptibility. Herein, we describe the case of a 43 years old woman with bilateral MA and peculiar facial characteristics, having a 484-kb microduplication of the chromosomal region 15q13.3 and a previously unreported 786 kb microdeletion in 18q21.32. This patient may have a newly-recognized genetic syndrome associated with MA. Although the relationship between these genetic variants and MA is unclear, our report would contribute to widening the genetic scenario of MA, in which not only genic mutation, but also genome unbalances are possible candidate susceptibility factors. Full article
(This article belongs to the Section Molecular Neurobiology)
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Open AccessReview YAP/TAZ Signaling as a Molecular Link between Fibrosis and Cancer
Int. J. Mol. Sci. 2018, 19(11), 3674; https://doi.org/10.3390/ijms19113674
Received: 23 October 2018 / Revised: 13 November 2018 / Accepted: 16 November 2018 / Published: 20 November 2018
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Abstract
Tissue fibrosis is a pathological condition that is associated with impaired epithelial repair and excessive deposition of extracellular matrix (ECM). Fibrotic lesions increase the risk of cancer in various tissues, but the mechanism linking fibrosis and cancer is unclear. Yes-associated protein (YAP) and
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Tissue fibrosis is a pathological condition that is associated with impaired epithelial repair and excessive deposition of extracellular matrix (ECM). Fibrotic lesions increase the risk of cancer in various tissues, but the mechanism linking fibrosis and cancer is unclear. Yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are core components of the Hippo pathway, which have multiple biological functions in the development, homeostasis, and regeneration of tissues and organs. YAP/TAZ act as sensors of the structural and mechanical features of the cell microenvironment. Recent studies have shown aberrant YAP/TAZ activation in both fibrosis and cancer in animal models and human tissues. In fibroblasts, ECM stiffness mechanoactivates YAP/TAZ, which promote the production of profibrotic mediators and ECM proteins. This results in tissue stiffness, thus establishing a feed-forward loop of fibroblast activation and tissue fibrosis. In contrast, in epithelial cells, YAP/TAZ are activated by the disruption of cell polarity and increased ECM stiffness in fibrotic tissues, which promotes the proliferation and survival of epithelial cells. YAP/TAZ are also involved in the epithelial–mesenchymal transition (EMT), which contributes to tumor progression and cancer stemness. Importantly, the crosstalk with transforming growth factor (TGF)-β signaling and Wnt signaling is essential for the profibrotic and tumorigenic roles of YAP/TAZ. In this article, we review the latest advances in the pathobiological roles of YAP/TAZ signaling and their function as a molecular link between fibrosis and cancer. Full article
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Open AccessArticle Sedoheptulose-1,7-Bisphosphatase is Involved in Methyl Jasmonate- and Dark-Induced Leaf Senescence in Tomato Plants
Int. J. Mol. Sci. 2018, 19(11), 3673; https://doi.org/10.3390/ijms19113673
Received: 29 October 2018 / Revised: 18 November 2018 / Accepted: 19 November 2018 / Published: 20 November 2018
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Abstract
Leaf senescence represents the final stage of leaf development and is regulated by diverse internal and environmental factors. Jasmonates (JAs) have been demonstrated to induce leaf senescence in several species; however, the mechanisms of JA-induced leaf senescence remain largely unknown in tomato plants
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Leaf senescence represents the final stage of leaf development and is regulated by diverse internal and environmental factors. Jasmonates (JAs) have been demonstrated to induce leaf senescence in several species; however, the mechanisms of JA-induced leaf senescence remain largely unknown in tomato plants (Solanum lycopersicum). In the present study, we tested the hypothesis that sedoheptulose-1,7-bisphosphatase (SBPase), an enzyme functioning in the photosynthetic carbon fixation in the Calvin–Benson cycle, was involved in methyl jasmonate (MeJA)- and dark-induced leaf senescence in tomato plants. We found that MeJA and dark induced senescence in detached tomato leaves and concomitantly downregulated the expression of SlSBPASE and reduced SBPase activity. Furthermore, CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9)-mediated mutagenesis of SlSBPASE led to senescence-associated characteristics in slsbpase mutant plants, including loss of chlorophyll, repressed photosynthesis, increased membrane ion leakage, and enhanced transcript abundance of senescence-associated genes. Collectively, our data suggest that repression of SBPase by MeJA and dark treatment plays a role in JA- and dark-induced leaf senescence. Full article
(This article belongs to the Section Molecular Plant Sciences)
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Open AccessReview Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor β
Int. J. Mol. Sci. 2018, 19(11), 3672; https://doi.org/10.3390/ijms19113672
Received: 5 October 2018 / Revised: 12 November 2018 / Accepted: 14 November 2018 / Published: 20 November 2018
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Abstract
Metastasis of tumor cells from primary sites of malignancy to neighboring stromal tissue or distant localities entails in several instances, but not in every case, the epithelial-mesenchymal transition (EMT). EMT weakens the strong adhesion forces between differentiated epithelial cells so that carcinoma cells
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Metastasis of tumor cells from primary sites of malignancy to neighboring stromal tissue or distant localities entails in several instances, but not in every case, the epithelial-mesenchymal transition (EMT). EMT weakens the strong adhesion forces between differentiated epithelial cells so that carcinoma cells can achieve solitary or collective motility, which makes the EMT an intuitive mechanism for the initiation of tumor metastasis. EMT initiates after primary oncogenic events lead to secondary secretion of cytokines. The interaction between tumor-secreted cytokines and oncogenic stimuli facilitates EMT progression. A classic case of this mechanism is the cooperation between oncogenic Ras and the transforming growth factor β (TGFβ). The power of TGFβ to mediate EMT during metastasis depends on versatile signaling crosstalk and on the regulation of successive waves of expression of many other cytokines and the progressive remodeling of the extracellular matrix that facilitates motility through basement membranes. Since metastasis involves many organs in the body, whereas EMT affects carcinoma cell differentiation locally, it has frequently been debated whether EMT truly contributes to metastasis. Despite controversies, studies of circulating tumor cells, studies of acquired chemoresistance by metastatic cells, and several (but not all) metastatic animal models, support a link between EMT and metastasis, with TGFβ, often being a common denominator in this link. This article aims at discussing mechanistic cases where TGFβ signaling and EMT facilitate tumor cell dissemination. Full article
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT))
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Open AccessReview It’s Hard to Avoid Avoidance: Uncoupling the Evolutionary Connection between Plant Growth, Productivity and Stress “Tolerance”
Int. J. Mol. Sci. 2018, 19(11), 3671; https://doi.org/10.3390/ijms19113671
Received: 13 October 2018 / Revised: 6 November 2018 / Accepted: 15 November 2018 / Published: 20 November 2018
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In the last 100 years, agricultural developments have favoured selection for highly productive crops, a fact that has been commonly associated with loss of key traits for environmental stress tolerance. We argue here that this is not exactly the case. We reason that
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In the last 100 years, agricultural developments have favoured selection for highly productive crops, a fact that has been commonly associated with loss of key traits for environmental stress tolerance. We argue here that this is not exactly the case. We reason that high yield under near optimal environments came along with hypersensitization of plant stress perception and consequently early activation of stress avoidance mechanisms, such as slow growth, which were originally needed for survival over long evolutionary time periods. Therefore, mechanisms employed by plants to cope with a stressful environment during evolution were overwhelmingly geared to avoid detrimental effects so as to ensure survival and that plant stress “tolerance” is fundamentally and evolutionarily based on “avoidance” of injury and death which may be referred to as evolutionary avoidance (EVOL-Avoidance). As a consequence, slow growth results from being exposed to stress because genes and genetic programs to adjust growth rates to external circumstances have evolved as a survival but not productivity strategy that has allowed extant plants to avoid extinction. To improve productivity under moderate stressful conditions, the evolution-oriented plant stress response circuits must be changed from a survival mode to a continued productivity mode or to avoid the evolutionary avoidance response, as it were. This may be referred to as Agricultural (AGRI-Avoidance). Clearly, highly productive crops have kept the slow, reduced growth response to stress that they evolved to ensure survival. Breeding programs and genetic engineering have not succeeded to genetically remove these responses because they are polygenic and redundantly programmed. From the beginning of modern plant breeding, we have not fully appreciated that our crop plants react overly-cautiously to stress conditions. They over-reduce growth to be able to survive stresses for a period of time much longer than a cropping season. If we are able to remove this polygenic redundant survival safety net we may improve yield in moderately stressful environments, yet we will face the requirement to replace it with either an emergency slow or no growth (dormancy) response to extreme stress or use resource management to rescue crops under extreme stress (or both). Full article
(This article belongs to the Section Molecular Plant Sciences)
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Open AccessArticle Functionalized Keratin as Nanotechnology-Based Drug Delivery System for the Pharmacological Treatment of Osteosarcoma
Int. J. Mol. Sci. 2018, 19(11), 3670; https://doi.org/10.3390/ijms19113670
Received: 19 October 2018 / Revised: 12 November 2018 / Accepted: 14 November 2018 / Published: 20 November 2018
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Osteosarcoma therapy might be moving toward nanotechnology-based drug delivery systems to reduce the cytotoxicity of antineoplastic drugs and improve their pharmacokinetics. In this paper, we present, for the first time, an extensive chemical and in vitro characterization of dual-loaded photo- and chemo-active keratin
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Osteosarcoma therapy might be moving toward nanotechnology-based drug delivery systems to reduce the cytotoxicity of antineoplastic drugs and improve their pharmacokinetics. In this paper, we present, for the first time, an extensive chemical and in vitro characterization of dual-loaded photo- and chemo-active keratin nanoparticles as a novel drug delivery system to treat osteosarcoma. The nanoparticles are prepared from high molecular weight and hydrosoluble keratin, suitably functionalized with the photosensitizer Chlorin-e6 (Ce6) and then loaded with the chemotherapeutic drug Paclitaxel (PTX). This multi-modal [email protected] nanoformulation is prepared by both drug-induced aggregation and desolvation methods, and a comprehensive physicochemical characterization is performed. [email protected] efficacy is tested on osteosarcoma tumor cell lines, including chemo-resistant cells, using 2D and 3D model systems. The single and combined contributions of PTX and Ce6 is evaluated, and results show that PTX retains its activity while being vehiculated through keratin. Moreover, PTX and Ce6 act in an additive manner, demonstrating that the combination of the cytostatic blockage of PTX and the oxidative damage of ROS upon light irradiation have a far superior effect compared to singularly administered PTX or Ce6. Our findings provide the proof of principle for the development of a novel, nanotechnology-based drug delivery system for the treatment of osteosarcoma. Full article
(This article belongs to the Special Issue Current Advances in Soft Tissue and Bone Sarcoma)
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Open AccessReview Central Nervous System Responses to Simulated Galactic Cosmic Rays
Int. J. Mol. Sci. 2018, 19(11), 3669; https://doi.org/10.3390/ijms19113669
Received: 10 October 2018 / Revised: 8 November 2018 / Accepted: 12 November 2018 / Published: 20 November 2018
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In preparation for lunar and Mars missions it is essential to consider the challenges to human health that are posed by long-duration deep space habitation via multiple stressors, including ionizing radiation, gravitational changes during flight and in orbit, other aspects of the space
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In preparation for lunar and Mars missions it is essential to consider the challenges to human health that are posed by long-duration deep space habitation via multiple stressors, including ionizing radiation, gravitational changes during flight and in orbit, other aspects of the space environment such as high level of carbon dioxide, and psychological stress from confined environment and social isolation. It remains unclear how these stressors individually or in combination impact the central nervous system (CNS), presenting potential obstacles for astronauts engaged in deep space travel. Although human spaceflight research only within the last decade has started to include the effects of radiation transmitted by galactic cosmic rays to the CNS, radiation is currently considered to be one of the main stressors for prolonged spaceflight and deep space exploration. Here we will review the current knowledge of CNS damage caused by simulated space radiation with an emphasis on neuronal and glial responses along with cognitive functions. Furthermore, we will present novel experimental approaches to integrate the knowledge into more comprehensive studies, including multiple stressors at once and potential translation to human functions. Finally, we will discuss the need for developing biomarkers as predictors for cognitive decline and therapeutic countermeasures to prevent CNS damage and the loss of cognitive abilities. Full article
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