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Int. J. Mol. Sci., Volume 19, Issue 10 (October 2018)

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Cover Story (view full-size image) Tissue-specific responses to oxidative stressors reflect the organ-related variable vulnerability [...] Read more.
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Open AccessArticle Type I Interferon Signaling Is Required for Dacryoadenitis in the Nonobese Diabetic Mouse Model of Sjögren Syndrome
Int. J. Mol. Sci. 2018, 19(10), 3259; https://doi.org/10.3390/ijms19103259 (registering DOI)
Received: 31 August 2018 / Revised: 1 October 2018 / Accepted: 13 October 2018 / Published: 20 October 2018
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Abstract
Nonobese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity similar to human Sjögren syndrome. In both humans and NOD mice, the early immune response that drives T-cell infiltration into lacrimal and salivary glands is poorly understood. In NOD mice, lacrimal gland
[...] Read more.
Nonobese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity similar to human Sjögren syndrome. In both humans and NOD mice, the early immune response that drives T-cell infiltration into lacrimal and salivary glands is poorly understood. In NOD mice, lacrimal gland autoimmunity spontaneously occurs only in males with testosterone playing a role in promoting lacrimal gland inflammation, while female lacrimal glands are protected by regulatory T cells (Tregs). The mechanisms of this male-specific lacrimal gland autoimmunity are not known. Here, we studied the effects of Treg depletion in hormone-manipulated NOD mice and lacrimal gland gene expression to determine early signals required for lacrimal gland inflammation. While Treg-depletion was not sufficient to drive dacryoadenitis in castrated male NOD mice, chemokines (Cxcl9, Ccl19) and other potentially disease-relevant genes (Epsti1, Ubd) were upregulated in male lacrimal glands. Expression of Cxcl9 and Ccl19, in particular, remained significantly upregulated in the lacrimal glands of lymphocyte-deficient NOD-severe combined immunodeficiency (SCID) mice and their expression was modulated by type I interferon signaling. Notably, Ifnar1-deficient NOD mice did not develop dacryoadenitis. Together these data identify disease-relevant genes upregulated in the context of male-specific dacryoadenitis and demonstrate a requisite role for type I interferon signaling in lacrimal gland autoimmunity in NOD mice. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Open AccessReview Pazopanib, Cabozantinib, and Vandetanib in the Treatment of Progressive Medullary Thyroid Cancer with a Special Focus on the Adverse Effects on Hypertension
Int. J. Mol. Sci. 2018, 19(10), 3258; https://doi.org/10.3390/ijms19103258 (registering DOI)
Received: 31 August 2018 / Revised: 19 September 2018 / Accepted: 17 October 2018 / Published: 20 October 2018
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Abstract
Medullary thyroid cancer (MTC) is a rare malignancy with a poor prognosis. First line therapy is surgery, which is the only curative method of the disease. However, in non-operable cases or with tumor progression and metastases, a systemic treatment is necessary. This form
[...] Read more.
Medullary thyroid cancer (MTC) is a rare malignancy with a poor prognosis. First line therapy is surgery, which is the only curative method of the disease. However, in non-operable cases or with tumor progression and metastases, a systemic treatment is necessary. This form of cancer is often insensitive to conventional chemotherapy, but the use of tyrosine kinase inhibitors (TKIs), such as pazopanib, cabozantinib, and vandetanib, has shown promising results with an increase in progression-free survival and prolonged lifetime. Therefore, we focused on the pharmacological characteristics of TKIs, their mechanism of action, their application as a secondary treatment option for MTC, their efficacy as a cancer drug treatment, and reviewed the ongoing clinical trials. TKIs also act systemically causing various adverse events (AEs). One common AE of this treatment is hypertension, known to be associated with cardiovascular disease and can therefore potentially worsen the well-being of the treated patients. The available treatment strategies of drug-induced hypertension were discussed. The mechanism behind the development of hypertension is still unclear. Therefore, the treatment of this AE remains symptomatic. Thus, future studies are necessary to investigate the link between tumor growth inhibition and hypertension. In addition, optimized, individual treatment strategies should be implemented. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders)
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Open AccessArticle C-C Motif Ligand 20 (CCL20) and C-C Motif Chemokine Receptor 6 (CCR6) in Human Peripheral Blood Mononuclear Cells: Dysregulated in Ulcerative Colitis and a Potential Role for CCL20 in IL-1β Release
Int. J. Mol. Sci. 2018, 19(10), 3257; https://doi.org/10.3390/ijms19103257 (registering DOI)
Received: 15 August 2018 / Revised: 21 September 2018 / Accepted: 12 October 2018 / Published: 20 October 2018
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Abstract
The chemokine C-C motif ligand 20 (CCL20) is increased in the colonic mucosa during active inflammatory bowel disease (IBD) and can be found both in the epithelium and immune cells in the lamina propria. The present study investigated CCL20 and C-C motif Chemokine
[...] Read more.
The chemokine C-C motif ligand 20 (CCL20) is increased in the colonic mucosa during active inflammatory bowel disease (IBD) and can be found both in the epithelium and immune cells in the lamina propria. The present study investigated CCL20 and C-C motif Chemokine Receptor 6 (CCR6) in peripheral blood mononuclear cells (PBMCs) (n = 40) from IBD patients and healthy controls, to identify inductors of CCL20 release encountered in a local proinflammatory environment. CCL20 release from PBMCs was increased when activating TLR2/1 or NOD2, suggesting that CCL20 is part of a first line response to danger-associated molecular patterns also in immune cells. Overall, ulcerative colitis (UC) had a significantly stronger CCL20 release than Crohn’s disease (CD) (+242%, p < 0.01), indicating that the CCL20-CCR6 axis may be more involved in UC. The CCL20 receptor CCR6 is essential for the chemotactic function of CCL20. UC with active inflammation had significantly decreased CCR6 expression and a reduction in CCR6+ cells in circulation, indicating chemoattraction of CCR6+ cells from circulation towards peripheral tissues. We further examined CCL20 induced release of cytokines from PBMCs. Stimulation with CCL20 combined with TNF increased IL-1β release from PBMCs. By attracting additional immune cells, as well as inducing proinflammatory IL-1β release from immune cells, CCL20 may protract the inflammatory response in ulcerative colitis. Full article
(This article belongs to the Special Issue Update on Basic and Molecular Research in Inflammatory Bowel Disease)
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Open AccessArticle How to Process Sputum Samples and Extract Bacterial DNA for Microbiota Analysis
Int. J. Mol. Sci. 2018, 19(10), 3256; https://doi.org/10.3390/ijms19103256 (registering DOI)
Received: 31 August 2018 / Revised: 9 October 2018 / Accepted: 13 October 2018 / Published: 20 October 2018
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Abstract
Different steps and conditions for DNA extraction for microbiota analysis in sputum have been reported in the literature. We aimed at testing both dithiothreitol (DTT) and enzymatic treatments of sputum samples and identifying the most suitable DNA extraction technique for the microbiota analysis
[...] Read more.
Different steps and conditions for DNA extraction for microbiota analysis in sputum have been reported in the literature. We aimed at testing both dithiothreitol (DTT) and enzymatic treatments of sputum samples and identifying the most suitable DNA extraction technique for the microbiota analysis of sputum. Sputum treatments with and without DTT were compared in terms of their median levels and the coefficient of variation between replicates of both DNA extraction yield and real-time PCR for the 16S rRNA gene. Treatments with and without lysozyme and lysostaphin were compared in terms of their median levels of real-time PCR for S. aureus. Two enzyme-based and three beads-based techniques for DNA extraction were compared in terms of their DNA extraction yield, real-time PCR for the 16S rRNA gene and microbiota analysis. DTT treatment decreased the coefficient of variation between replicates of both DNA extraction yield and real-time PCR. Lysostaphin (either 0.18 or 0.36 mg/mL) and lysozyme treatments increased S. aureus detection. One enzyme-based kit offered the highest DNA yield and 16S rRNA gene real-time PCR with no significant differences in terms of alpha-diversity indexes. A condition using both DTT and lysostaphin/lysozyme treatments along with an enzymatic kit seems to be preferred for the microbiota analysis of sputum samples. Full article
(This article belongs to the Special Issue Lung Infections: From Molecular Biology to Therapy)
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Open AccessReview Detours to Replication: Functions of Specialized DNA Polymerases during Oncogene-induced Replication Stress
Int. J. Mol. Sci. 2018, 19(10), 3255; https://doi.org/10.3390/ijms19103255 (registering DOI)
Received: 8 September 2018 / Revised: 15 October 2018 / Accepted: 15 October 2018 / Published: 20 October 2018
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Abstract
Incomplete and low-fidelity genome duplication contribute to genomic instability and cancer development. Difficult-to-Replicate Sequences, or DiToRS, are natural impediments in the genome that require specialized DNA polymerases and repair pathways to complete and maintain faithful DNA synthesis. DiToRS include non B-DNA secondary structures
[...] Read more.
Incomplete and low-fidelity genome duplication contribute to genomic instability and cancer development. Difficult-to-Replicate Sequences, or DiToRS, are natural impediments in the genome that require specialized DNA polymerases and repair pathways to complete and maintain faithful DNA synthesis. DiToRS include non B-DNA secondary structures formed by repetitive sequences, for example within chromosomal fragile sites and telomeres, which inhibit DNA replication under endogenous stress conditions. Oncogene activation alters DNA replication dynamics and creates oncogenic replication stress, resulting in persistent activation of the DNA damage and replication stress responses, cell cycle arrest, and cell death. The response to oncogenic replication stress is highly complex and must be tightly regulated to prevent mutations and tumorigenesis. In this review, we summarize types of known DiToRS and the experimental evidence supporting replication inhibition, with a focus on the specialized DNA polymerases utilized to cope with these obstacles. In addition, we discuss different causes of oncogenic replication stress and its impact on DiToRS stability. We highlight recent findings regarding the regulation of DNA polymerases during oncogenic replication stress and the implications for cancer development. Full article
(This article belongs to the Special Issue DNA Replication Stress)
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Open AccessArticle Bivalent Ligand UDCA-LPE Inhibits Pro-Fibrogenic Integrin Signalling by Inducing Lipid Raft-Mediated Internalization
Int. J. Mol. Sci. 2018, 19(10), 3254; https://doi.org/10.3390/ijms19103254 (registering DOI)
Received: 5 September 2018 / Revised: 8 October 2018 / Accepted: 10 October 2018 / Published: 20 October 2018
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Abstract
Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a synthetic bile acid-phospholipid conjugate with profound hepatoprotective and anti-fibrogenic functions in vitro and in vivo. Herein, we aimed to demonstrate the inhibitory effects of UDCA-LPE on pro-fibrogenic integrin signalling. UDCA-LPE treatment of human embryonic liver cell line CL48
[...] Read more.
Ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE) is a synthetic bile acid-phospholipid conjugate with profound hepatoprotective and anti-fibrogenic functions in vitro and in vivo. Herein, we aimed to demonstrate the inhibitory effects of UDCA-LPE on pro-fibrogenic integrin signalling. UDCA-LPE treatment of human embryonic liver cell line CL48 and primary human hepatic stellate cells induced a non-classical internalization of integrin β1 resulting in dephosphorylation and inhibition of SRC and focal adhesion kinase (FAK). Signalling analyses suggested that UDCA-LPE may act as a heterobivalent ligand for integrins and lysophospholipid receptor1 (LPAR1) and co-immunoprecipitation demonstrated the bridging effect of UDCA-LPE on integrin β1 and LPAR1. The disruption of either the UDCA-moiety binding to integrins by RGD-containing peptide GRGDSP or the LPE-moiety binding to LPAR1 by LPAR1 antagonist Ki16425 reversed inhibitory functions of UDCA-LPE. The lack of inhibitory functions of UDCA-PE and UDCA-LPE derivatives (14:0 and 12:0, LPE-moiety containing shorter fatty acid chain) as well as the consistency of the translocation of UDCA-LPE and integrins, which co-fractionated with LPE but not UDCA, suggested that the observed UDCA-LPE-induced translocation of integrins was mediated by LPE endocytic transport pathway. Full article
(This article belongs to the Special Issue Bioactive Lipids and Lipidomics 2018)
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Open AccessArticle Metallothionein and Superoxide Dismutase—Antioxidative Protein Status in Fullerene-Doxorubicin Delivery to MCF-7 Human Breast Cancer Cells
Int. J. Mol. Sci. 2018, 19(10), 3253; https://doi.org/10.3390/ijms19103253 (registering DOI)
Received: 7 October 2018 / Revised: 16 October 2018 / Accepted: 16 October 2018 / Published: 20 October 2018
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Abstract
Doxorubicin (DOX) is one of the most frequently used anticancer drugs in breast cancer treatment. However, clinical applications of DOX are restricted, largely due to the fact that its action disturbs the pro/antioxidant balance in both cancerous and non-cancerous cells. The aim of
[...] Read more.
Doxorubicin (DOX) is one of the most frequently used anticancer drugs in breast cancer treatment. However, clinical applications of DOX are restricted, largely due to the fact that its action disturbs the pro/antioxidant balance in both cancerous and non-cancerous cells. The aim of this study was to investigate the influence of fullerene (C60) in cell treatment by DOX on the proliferation of human breast cancer cells (MCF-7), concentration of metallothionein (MT) and superoxide dismutase (SOD), and SOD activity in these cells. The use of C60 in complexes with DOX causes a change in the level of cell proliferation of about 5% more than when caused by DOX alone (from 60–65% to 70%). The use of C60 as a DOX nanotransporter reduced the MT level increase induced by DOX. C60 alone caused an increase of SOD1 concentration. On the other hand, it led to a decrease of SOD activity. C60 in complex with DOX caused a decrease of the DOX-induced SOD activity level. Exposure of MCF-7 cells to DOX-C60 complexes results in a decrease in viable cells and may become a new therapeutic approach to breast cancer. The effects of C60 in complexes with DOX on MCF-7 cells included a decreased enzymatic (SOD activity) and nonenzymatic (MT) antioxidant status, thus indicating their prooxidant role in MCF-7 cells. Full article
(This article belongs to the Special Issue Frontiers in Drug Toxicity Prediction)
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Open AccessArticle Pomalidomide Ameliorates H2O2-Induced Oxidative Stress Injury and Cell Death in Rat Primary Cortical Neuronal Cultures by Inducing Anti-Oxidative and Anti-Apoptosis Effects
Int. J. Mol. Sci. 2018, 19(10), 3252; https://doi.org/10.3390/ijms19103252 (registering DOI)
Received: 20 September 2018 / Revised: 16 October 2018 / Accepted: 17 October 2018 / Published: 19 October 2018
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Abstract
Due to its high oxygen demand and abundance of peroxidation-susceptible lipid cells, the brain is particularly vulnerable to oxidative stress. Induced by a redox state imbalance involving either excessive generation of reactive oxygen species (ROS) or dysfunction of the antioxidant system, oxidative stress
[...] Read more.
Due to its high oxygen demand and abundance of peroxidation-susceptible lipid cells, the brain is particularly vulnerable to oxidative stress. Induced by a redox state imbalance involving either excessive generation of reactive oxygen species (ROS) or dysfunction of the antioxidant system, oxidative stress plays a central role in a common pathophysiology that underpins neuronal cell death in acute neurological disorders epitomized by stroke and chronic ones such as Alzheimer’s disease. After cerebral ischemia, for example, inflammation bears a key responsibility in the development of permanent neurological damage. ROS are involved in the mechanism of post-ischemic inflammation. The activation of several inflammatory enzymes produces ROS, which subsequently suppress mitochondrial activity, leading to further tissue damage. Pomalidomide (POM) is a clinically available immunomodulatory and anti-inflammatory agent. Using H2O2-treated rat primary cortical neuronal cultures, we found POM displayed neuroprotective effects against oxidative stress and cell death that associated with changes in the nuclear factor erythroid derived 2/superoxide dismutase 2/catalase signaling pathway. POM also suppressed nuclear factor kappa-light-chain-enhancer (NF-κB) levels and significantly mitigated cortical neuronal apoptosis by regulating Bax, Cytochrome c and Poly (ADP-ribose) polymerase. In summary, POM exerted neuroprotective effects via its anti-oxidative and anti-inflammatory actions against H2O2-induced injury. POM consequently represents a potential therapeutic agent against brain damage and related disorders and warrants further evaluation. Full article
(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases)
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Open AccessArticle PSMA-Oriented Target Delivery of Novel Anticancer Prodrugs: Design, Synthesis, and Biological Evaluations of Oligopeptide-Camptothecin Conjugates
Int. J. Mol. Sci. 2018, 19(10), 3251; https://doi.org/10.3390/ijms19103251 (registering DOI)
Received: 20 August 2018 / Revised: 9 October 2018 / Accepted: 14 October 2018 / Published: 19 October 2018
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Abstract
Clinical applications of camptothecin (CPT) have been heavily hindered due to its non-targeted toxicity, active lactone ring instability, and poor water solubility. Targeted drug delivery systems may offer the possibility to overcome the above issues as reported. In this research, a
[...] Read more.
Clinical applications of camptothecin (CPT) have been heavily hindered due to its non-targeted toxicity, active lactone ring instability, and poor water solubility. Targeted drug delivery systems may offer the possibility to overcome the above issues as reported. In this research, a series of prostate-specific membrane antigen (PSMA)-activated CPT prodrugs were designed and synthesized by coupling water-soluble pentapeptide, a PSMA hydrolyzing substrate, to CPT through an appropriate linker. The cytotoxicity of CPT prodrugs was masked temporarily until they were hydrolyzed by the PSMA present within the tumor sites, which restored cytotoxicity. The in vitro selective cytotoxic activities of the prodrugs were evaluated against PSMA-expressing human prostate cancer cells LNCaP-FGC and non-PSMA-expressing cancer cells HepG2, Hela, MCF-7, DU145, PC-3 and normal cells MDCK, LO2 by standard methylthiazol tetrazolium (MTT) assay. Most of the newly synthesized CPT prodrugs showed excellent selective toxicity to PSMA-producing prostate cancer cells LNCaP-FGC with improved water solubility. From among the library, CPT-HT-J-ZL12 showed the best cytotoxic selectivity between the PSMA-expressing and the non-PSMA-expressing cancer cells. For example, the cytotoxicity of CPT-HT-J-ZL12 (IC50 = 1.00 ± 0.20 µM) against LNCaP-FGC (PSMA+) was 40-fold, 40-fold, 21-fold, 5-fold and 40-fold, respectively, higher than that against the non-PSMA-expressing cells HepG2 (IC50 > 40.00 µM), Hela (IC50 > 40.00 µM), MCF-7 (IC50 = 21.68 ± 4.96 µM), DU145 (IC50 = 5.40 ± 1.22 µM), PC-3 (IC50 = 42.96 ± 3.69 µM) cells. Moreover, CPT-HT-J-ZL12 exhibited low cytotoxicity (IC50 > 40 μM) towards MDCK and LO2 cells. The cellular uptake experiment demonstrated the superior PSMA-targeting ability of the CPT-HT-J-ZL12, which was significantly accumulated in LNCaP-FGC (PSMA+), while it was minimized in HepG2 (PSMA) cells. Further cell apoptosis analyses indicated that it showed a dramatically higher apoptosis-inducing activity in LNCaP-FGC (PSMA+) cells than in HepG2 (PSMA) cells. Cell cycle analysis indicated that CPT-HT-J-ZL12 could induce cell cycle arrest at the S phase. Full article
(This article belongs to the Section Biochemistry)
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Open AccessArticle PR/SET Domain Family and Cancer: Novel Insights from the Cancer Genome Atlas
Int. J. Mol. Sci. 2018, 19(10), 3250; https://doi.org/10.3390/ijms19103250
Received: 30 September 2018 / Revised: 12 October 2018 / Accepted: 17 October 2018 / Published: 19 October 2018
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Abstract
The PR/SET domain gene family (PRDM) encodes 19 different transcription factors that share a subtype of the SET domain [Su(var)3-9, enhancer-of-zeste and trithorax] known as the PRDF1-RIZ (PR) homology domain. This domain, with its potential methyltransferase activity, is followed by a variable number
[...] Read more.
The PR/SET domain gene family (PRDM) encodes 19 different transcription factors that share a subtype of the SET domain [Su(var)3-9, enhancer-of-zeste and trithorax] known as the PRDF1-RIZ (PR) homology domain. This domain, with its potential methyltransferase activity, is followed by a variable number of zinc-finger motifs, which likely mediate protein–protein, protein–RNA, or protein–DNA interactions. Intriguingly, almost all PRDM family members express different isoforms, which likely play opposite roles in oncogenesis. Remarkably, several studies have described alterations in most of the family members in malignancies. Here, to obtain a pan-cancer overview of the genomic and transcriptomic alterations of PRDM genes, we reanalyzed the Exome- and RNA-Seq public datasets available at The Cancer Genome Atlas portal. Overall, PRDM2, PRDM3/MECOM, PRDM9, PRDM16 and ZFPM2/FOG2 were the most mutated genes with pan-cancer frequencies of protein-affecting mutations higher than 1%. Moreover, we observed heterogeneity in the mutation frequencies of these genes across tumors, with cancer types also reaching a value of about 20% of mutated samples for a specific PRDM gene. Of note, ZFPM1/FOG1 mutations occurred in 50% of adrenocortical carcinoma patients and were localized in a hotspot region. These findings, together with OncodriveCLUST results, suggest it could be putatively considered a cancer driver gene in this malignancy. Finally, transcriptome analysis from RNA-Seq data of paired samples revealed that transcription of PRDMs was significantly altered in several tumors. Specifically, PRDM12 and PRDM13 were largely overexpressed in many cancers whereas PRDM16 and ZFPM2/FOG2 were often downregulated. Some of these findings were also confirmed by real-time-PCR on primary tumors. Full article
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Open AccessReview Translational Research Opportunities Regarding Homologous Recombination in Ovarian Cancer
Int. J. Mol. Sci. 2018, 19(10), 3249; https://doi.org/10.3390/ijms19103249
Received: 29 September 2018 / Revised: 29 September 2018 / Accepted: 16 October 2018 / Published: 19 October 2018
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Abstract
Homologous recombination (HR) is a DNA repair pathway that is deficient in 50% of high-grade serous ovarian carcinomas (HGSOC). Deficient HR (DHR) constitutes a therapeutic opportunity for these patients, thanks to poly (ADP-ribose) polymerases (PARP) inhibitors (PARPi; olaparib, niraparib, and rucaparib are already
[...] Read more.
Homologous recombination (HR) is a DNA repair pathway that is deficient in 50% of high-grade serous ovarian carcinomas (HGSOC). Deficient HR (DHR) constitutes a therapeutic opportunity for these patients, thanks to poly (ADP-ribose) polymerases (PARP) inhibitors (PARPi; olaparib, niraparib, and rucaparib are already commercialized). Although initially, PARPi were developed for patients with BRCA1/2 mutations, robust clinical data have shown their benefit in a broader population without DHR. This breakthrough in daily practice has raised several questions that necessitate further research: How can populations that will most benefit from PARPi be selected? At which stage of ovarian cancer should PARPi be used? Which strategies are reasonable to overcome PARPi resistance? In this paper, we present a summary of the literature and discuss the present clinical research involving PARPi (after reviewing ClinicalTrials.gov) from a translational perspective. Research into the functional biomarkers of DHR and clinical trials testing PARPi benefits as first-line setting or rechallenge are currently ongoing. Additionally, in the clinical setting, only secondary restoring mutations of BRCA1/2 have been identified as events inducing resistance to PARPi. The clinical frequency of this and other mechanisms that have been described in preclinics is unknown. It is of great importance to study mechanisms of resistance to PARPi to guide the clinical development of drug combinations. Full article
(This article belongs to the Special Issue Ovarian Cancer: Pathogenesis, Diagnosis, and Treatment)
Open AccessArticle Non-Invasive Detection of Extracellular Matrix Metalloproteinase Inducer EMMPRIN, a New Therapeutic Target against Atherosclerosis, Inhibited by Endothelial Nitric Oxide
Int. J. Mol. Sci. 2018, 19(10), 3248; https://doi.org/10.3390/ijms19103248
Received: 14 September 2018 / Revised: 30 September 2018 / Accepted: 10 October 2018 / Published: 19 October 2018
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Abstract
Lack of endothelial nitric oxide causes endothelial dysfunction and circulating monocyte infiltration, contributing to systemic atheroma plaque formation in arterial territories. Among the different inflammatory products, macrophage-derived foam cells and smooth muscle cells synthesize matrix metalloproteinases (MMPs), playing a pivotal role in early
[...] Read more.
Lack of endothelial nitric oxide causes endothelial dysfunction and circulating monocyte infiltration, contributing to systemic atheroma plaque formation in arterial territories. Among the different inflammatory products, macrophage-derived foam cells and smooth muscle cells synthesize matrix metalloproteinases (MMPs), playing a pivotal role in early plaque formation and enlargement. We found increased levels of MMP-9 and MMP-13 in human endarterectomies with advanced atherosclerosis, together with significant amounts of extracellular matrix (ECM) metalloproteinase inducer EMMPRIN. To test whether the absence of NO may aggravate atherosclerosis through EMMPRIN activation, double NOS3/apoE knockout (KO) mice expressed high levels of EMMPRIN in carotid plaques, suggesting that targeting extracellular matrix degradation may represent a new mechanism by which endothelial NO prevents atherosclerosis. Based on our previous experience, by using gadolinium-enriched paramagnetic fluorescence micellar nanoparticles conjugated with AP9 (NAP9), an EMMPRIN-specific binding peptide, magnetic resonance sequences allowed non-invasive visualization of carotid EMMPRIN in NOS3/apoE over apoE control mice, in which atheroma plaques were significantly reduced. Taken together, these results point to EMMPRIN as a new therapeutic target of NO-mediated protection against atherosclerosis, and NAP9 as a non-invasive molecular tool to target atherosclerosis. Full article
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Open AccessArticle Effects of OsCDPK1 on the Structure and Physicochemical Properties of Starch in Developing Rice Seeds
Int. J. Mol. Sci. 2018, 19(10), 3247; https://doi.org/10.3390/ijms19103247
Received: 2 September 2018 / Revised: 7 October 2018 / Accepted: 16 October 2018 / Published: 19 October 2018
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Abstract
Overexpression of a constitutively active truncated form of OsCDPK1 (OEtr) in rice produced smaller seeds, but a double-stranded RNA gene-silenced form of OsCDPK1 (Ri) yielded larger seeds, suggesting that OsCDPK1 plays a functional role in rice seed development. In
[...] Read more.
Overexpression of a constitutively active truncated form of OsCDPK1 (OEtr) in rice produced smaller seeds, but a double-stranded RNA gene-silenced form of OsCDPK1 (Ri) yielded larger seeds, suggesting that OsCDPK1 plays a functional role in rice seed development. In the study presented here, we propose a model in which OsCDPK1 plays key roles in negatively controlling the grain size, amylose content, and endosperm appearance, and also affects the physicochemical properties of the starch. The dehulled transgenic OEtr grains were smaller than the dehulled wild-type grains, and the OEtr endosperm was opaque and had a low amylose content and numerous small loosely packed polyhedral starch granules. However, the OEtr grain sizes and endosperm appearances were not affected by temperature, which ranged from low (22 °C) to high (31 °C) during the grain-filling phase. In contrast, the transgenic Ri grains were larger, had higher amylose content, and had more transparent endosperms filled with tightly packed polyhedral starch granules. This demonstrates that OsCDPK1 plays a novel functional role in starch biosynthesis during seed development and affects the transparent appearance of the endosperm. These results improve our understanding of the molecular mechanisms through which the grain-filling process occurs in rice. Full article
(This article belongs to the Special Issue Plant Genetics and Molecular Breeding)
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Open AccessArticle Genome-Wide Characterization of the sHsp Gene Family in Salix suchowensis Reveals Its Functions under Different Abiotic Stresses
Int. J. Mol. Sci. 2018, 19(10), 3246; https://doi.org/10.3390/ijms19103246
Received: 22 September 2018 / Revised: 15 October 2018 / Accepted: 16 October 2018 / Published: 19 October 2018
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Abstract
Small heat shock proteins (sHsps) function mainly as molecular chaperones that play vital roles in response to diverse stresses, especially high temperature. However, little is known about the molecular characteristics and evolutionary history of the sHsp family in Salix suchowensis, an important bioenergy
[...] Read more.
Small heat shock proteins (sHsps) function mainly as molecular chaperones that play vital roles in response to diverse stresses, especially high temperature. However, little is known about the molecular characteristics and evolutionary history of the sHsp family in Salix suchowensis, an important bioenergy woody plant. In this study, 35 non-redundant sHsp genes were identified in S. suchowensis, and they were divided into four subfamilies (C, CP, PX, and MT) based on their phylogenetic relationships and predicted subcellular localization. Though the gene structure and conserved motif were relatively conserved, the sequences of the Hsp20 domain were diversified. Eight paralogous pairs were identified in the Ssu-sHsp family, in which five pairs were generated by tandem duplication events. Ka/Ks analysis indicated that Ssu-sHsps had undergone purifying selection. The expression profiles analysis showed Ssu-Hsps tissue-specific expression patterns, and they were induced by at least one abiotic stress. The expression correlation between two paralogous pairs (Ssu-sHsp22.2-CV/23.0-CV and 23.8-MT/25.6-MT) were less than 0.6, indicating that they were divergent during the evolution. Various cis-acting elements related to stress responses, hormone or development, were detected in the promoter of Ssu-sHsps. Furthermore, the co-expression network revealed the potential mechanism of Ssu-sHsps under stress tolerance and development. These results provide a foundation for further functional research on the Ssu-sHsp gene family in S. suchowensis. Full article
(This article belongs to the Section Molecular Plant Sciences)
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Open AccessReview γ-Tubulin–γ-Tubulin Interactions as the Basis for the Formation of a Meshwork
Int. J. Mol. Sci. 2018, 19(10), 3245; https://doi.org/10.3390/ijms19103245
Received: 6 September 2018 / Revised: 2 October 2018 / Accepted: 16 October 2018 / Published: 19 October 2018
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Abstract
In cytoplasm, protein γ-tubulin joins with various γ-tubulin complex proteins (GCPs) to form a heterotetramer γ-tubulin small complex (γ-TuSC) that can grow into a ring-shaped structure called the γ-tubulin ring complex (γ-TuRC). Both γ-TuSC and γ-TuRC are required for microtubule nucleation. Recent knowledge
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In cytoplasm, protein γ-tubulin joins with various γ-tubulin complex proteins (GCPs) to form a heterotetramer γ-tubulin small complex (γ-TuSC) that can grow into a ring-shaped structure called the γ-tubulin ring complex (γ-TuRC). Both γ-TuSC and γ-TuRC are required for microtubule nucleation. Recent knowledge on γ-tubulin with regard to its cellular functions beyond participation in its creation of microtubules suggests that this protein forms a cellular meshwork. The present review summarizes the recognized functions of γ-tubulin and aims to unite the current views on this protein. Full article
(This article belongs to the Special Issue Regulatory Mechanisms of Tubulin-Like Proteins)
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Open AccessReview The Proposal of Molecular Mechanisms of Weak Organic Acids Intake-Induced Improvement of Insulin Resistance in Diabetes Mellitus via Elevation of Interstitial Fluid pH
Int. J. Mol. Sci. 2018, 19(10), 3244; https://doi.org/10.3390/ijms19103244
Received: 4 September 2018 / Revised: 30 September 2018 / Accepted: 17 October 2018 / Published: 19 October 2018
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Abstract
Blood contains powerful pH-buffering molecules such as hemoglobin (Hb) and albumin, while interstitial fluids have little pH-buffering molecules. Thus, even under metabolic disorder conditions except severe cases, arterial blood pH is kept constant within the normal range (7.35~7.45), but the interstitial fluid pH
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Blood contains powerful pH-buffering molecules such as hemoglobin (Hb) and albumin, while interstitial fluids have little pH-buffering molecules. Thus, even under metabolic disorder conditions except severe cases, arterial blood pH is kept constant within the normal range (7.35~7.45), but the interstitial fluid pH under metabolic disorder conditions becomes lower than the normal level. Insulin resistance is one of the most important key factors in pathogenesis of diabetes mellitus, nevertheless the molecular mechanism of insulin resistance occurrence is still unclear. Our studies indicate that lowered interstitial fluid pH occurs in diabetes mellitus, causing insulin resistance via reduction of the binding affinity of insulin to its receptor. Therefore, the key point for improvement of insulin resistance occurring in diabetes mellitus is development of methods or techniques elevating the lowered interstitial fluid pH. Intake of weak organic acids is found to improve the insulin resistance by elevating the lowered interstitial fluid pH in diabetes mellitus. One of the molecular mechanisms of the pH elevation is that: (1) the carboxyl group (R-COO) but not H+ composing weak organic acids in foods is absorbed into the body, and (2) the absorbed the carboxyl group (R-COO) behaves as a pH buffer material, elevating the interstitial fluid pH. On the other hand, high salt intake has been suggested to cause diabetes mellitus; however, the molecular mechanism is unclear. A possible mechanism of high salt intake-caused diabetes mellitus is proposed from a viewpoint of regulation of the interstitial fluid pH: high salt intake lowers the interstitial fluid pH via high production of H+ associated with ATP synthesis required for the Na+,K+-ATPase to extrude the high leveled intracellular Na+ caused by high salt intake. This review article introduces the molecular mechanism causing the lowered interstitial fluid pH and insulin resistance in diabetes mellitus, the improvement of insulin resistance via intake of weak organic acid-containing foods, and a proposal mechanism of high salt intake-caused diabetes mellitus. Full article
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Open AccessArticle Inhibition of LINE-1 Retrotransposition by Capsaicin
Int. J. Mol. Sci. 2018, 19(10), 3243; https://doi.org/10.3390/ijms19103243
Received: 19 September 2018 / Revised: 13 October 2018 / Accepted: 16 October 2018 / Published: 19 October 2018
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Abstract
Long interspersed nuclear element 1 (LINE-1 or L1) is a non-long terminal repeat (LTR) retrotransposon that constitutes approximately 17% of the human genome. Since approximately 100 copies are still competent for retrotransposition to other genomic loci, dysregulated retrotransposition of L1 is considered to
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Long interspersed nuclear element 1 (LINE-1 or L1) is a non-long terminal repeat (LTR) retrotransposon that constitutes approximately 17% of the human genome. Since approximately 100 copies are still competent for retrotransposition to other genomic loci, dysregulated retrotransposition of L1 is considered to be a major risk factor of endogenous mutagenesis in humans. Thus, it is important to find drugs to regulate this process. Although various chemicals are reportedly capable of affecting L1 retrotransposition, it is poorly understood whether phytochemicals modulate L1 retrotransposition. Here, we screened a library of compounds that were derived from phytochemicals for reverse transcriptase (RT) inhibition with an in vitro RT assay. We identified capsaicin as a novel RT inhibitor that also suppressed L1 retrotransposition. The inhibitory effect of capsaicin on L1 retrotransposition was mediated neither through its receptor, nor through its modulation of the L1 promoter and/or antisense promoter activity, excluding the possibility that capsaicin indirectly affected L1 retrotransposition. Collectively, capsaicin suppressed L1 retrotransposition most likely by inhibiting the RT activity of L1 ORF2p, which is the L1-encoded RT responsible for L1 retrotransposition. Given that L1-mediated mutagenesis can cause tumorigenesis, our findings suggest the potential of capsaicin for suppressing cancer development. Full article
(This article belongs to the Special Issue Transposable Elements)
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Open AccessArticle Anti-Angiogenic miR-222, miR-195, and miR-21a Plasma Levels in T1DM Are Improved by Metformin Therapy, Thus Elucidating Its Cardioprotective Effect: The MERIT Study
Int. J. Mol. Sci. 2018, 19(10), 3242; https://doi.org/10.3390/ijms19103242
Received: 27 July 2018 / Revised: 4 September 2018 / Accepted: 6 September 2018 / Published: 19 October 2018
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Abstract
Type 1 diabetes (T1DM) is associated with increased cardiovascular disease (CVD) and reduced life expectancy. We thus hypothesized that anti-angiogenic miRs are increased in T1DM, and the cardioprotective effect of metformin is mediated via reducing those miRs. In an open label, case-controlled study,
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Type 1 diabetes (T1DM) is associated with increased cardiovascular disease (CVD) and reduced life expectancy. We thus hypothesized that anti-angiogenic miRs are increased in T1DM, and the cardioprotective effect of metformin is mediated via reducing those miRs. In an open label, case-controlled study, 23 T1DM patients without CVD were treated with metformin for eight weeks (TG), matched with nine T1DM patients on standard treatment (SG) and 23 controls (CG). Plasma miR-222, miR-195, miR-21a and miR-126 were assayed by real-time RT-qPCR. The results were correlated with: endothelial function (RHI), circulating endothelial progenitor cells (cEPCs) (vascular repair marker, CD45dimCD34+VEGFR2+ cells) and circulating endothelial cells (cECs) (vascular injury marker, CD45dimCD34+CD133-CD144+ cells). miR-222, miR-195 and miR-21a were higher in T1DM than CG; p = 0.009, p < 0.0001, p = 0.0001, respectively. There was an inverse correlation between logmiR-222 and logRHI (p < 0.05) and a direct correlation between logmiR-222 and logCD34+ (p < 0.05) in TG. Metformin reduced miR-222, miR-195 and miR-21a levels in TG; p = 0.007, p = 0.002 p = 0.0012, respectively. miRs remained unchanged in SG. miR-126 was similar in all groups. There was a positive association between changes in logmiR-222 and logcECs after metformin in TG (p < 0.05). Anti-angiogenic miRs are increased in T1DM. Metformin has cardioprotective effects through downregulating miR-222, miR-195 and miR-21a, beyond improving glycemic control. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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Open AccessArticle Outer Membrane Protein of Gut Commensal Microorganism Induces Autoantibody Production and Extra-Intestinal Gland Inflammation in Mice
Int. J. Mol. Sci. 2018, 19(10), 3241; https://doi.org/10.3390/ijms19103241
Received: 30 August 2018 / Revised: 25 September 2018 / Accepted: 15 October 2018 / Published: 19 October 2018
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Abstract
Gut commensal microorganisms have been linked with chronic inflammation at the extra-intestinal niche of the body. The object of the study was to investigate on the chronic effects of a gut commensal Escherichia coli on extra-intestinal glands. The presence of autoimmune response was
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Gut commensal microorganisms have been linked with chronic inflammation at the extra-intestinal niche of the body. The object of the study was to investigate on the chronic effects of a gut commensal Escherichia coli on extra-intestinal glands. The presence of autoimmune response was diagnosed by autoantibody levels and histological methods. Repeated injection of E. coli induced mononuclear cell inflammation in the Harderian and submandibular salivary glands of female C57BL/6 mice. Inflammation was reproduced by adoptive transfer of splenocytes to immune-deficient Rag2 knockout mice and CD4+ T cells to mature T cell-deficient TCRβ-TCRδ knockout mice. MALDI TOF mass spectrometry of the protein to which sera of E. coli-treated mice reacted was determined as the outer membrane protein A (OmpA) of E. coli. Multiple genera of the Enterobacteriaceae possessed OmpA with high amino-acid sequence similarities. Repeated injection of recombinant OmpA reproduced mononuclear cell inflammation of the Harderian and salivary glands in mice and elevation of autoantibodies against Sjögren’s-syndrome-related antigens SSA/Ro and SSB/La. The results indicated the possibility of chronic stimuli from commensal bacteria-originated components as a pathogenic factor to elicit extra-intestinal autoimmunity. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Open AccessReview Endometrial Stem Cell Markers: Current Concepts and Unresolved Questions
Int. J. Mol. Sci. 2018, 19(10), 3240; https://doi.org/10.3390/ijms19103240
Received: 2 August 2018 / Revised: 7 September 2018 / Accepted: 10 October 2018 / Published: 19 October 2018
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Abstract
The human endometrium is a highly regenerative organ undergoing over 400 cycles of shedding and regeneration over a woman’s lifetime. Menstrual shedding and the subsequent repair of the functional layer of the endometrium is a process unique to humans and higher-order primates. This
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The human endometrium is a highly regenerative organ undergoing over 400 cycles of shedding and regeneration over a woman’s lifetime. Menstrual shedding and the subsequent repair of the functional layer of the endometrium is a process unique to humans and higher-order primates. This massive regenerative capacity is thought to have a stem cell basis, with human endometrial stromal stem cells having already been extensively studied. Studies on endometrial epithelial stem cells are sparse, and the current belief is that the endometrial epithelial stem cells reside in the terminal ends of the basalis glands at the endometrial/myometrial interface. Since almost all endometrial pathologies are thought to originate from aberrations in stem cells that regularly regenerate the functionalis layer, expansion of our current understanding of stem cells is necessary in order for curative treatment strategies to be developed. This review critically appraises the postulated markers in order to identify endometrial stem cells. It also examines the current evidence supporting the existence of epithelial stem cells in the human endometrium that are likely to be involved both in glandular regeneration and in the pathogenesis of endometrial proliferative diseases such as endometriosis and endometrial cancer. Full article
(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)
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Open AccessReview miRNA-Mediated Interactions in and between Plants and Insects
Int. J. Mol. Sci. 2018, 19(10), 3239; https://doi.org/10.3390/ijms19103239
Received: 17 September 2018 / Revised: 12 October 2018 / Accepted: 15 October 2018 / Published: 19 October 2018
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Abstract
Our understanding of microRNA (miRNA) regulation of gene expression and protein translation, as a critical area of cellular regulation, has blossomed in the last two decades. Recently, it has become apparent that in plant-insect interactions, both plants and insects use miRNAs to regulate
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Our understanding of microRNA (miRNA) regulation of gene expression and protein translation, as a critical area of cellular regulation, has blossomed in the last two decades. Recently, it has become apparent that in plant-insect interactions, both plants and insects use miRNAs to regulate their biological processes, as well as co-opting each others’ miRNA systems. In this review article, we discuss the current paradigms of miRNA-mediated cellular regulation and provide examples of plant-insect interactions that utilize this regulation. Lastly, we discuss the potential biotechnological applications of utilizing miRNAs in agriculture. Full article
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Open AccessReview AMPK: An Epigenetic Landscape Modulator
Int. J. Mol. Sci. 2018, 19(10), 3238; https://doi.org/10.3390/ijms19103238
Received: 26 September 2018 / Revised: 14 October 2018 / Accepted: 17 October 2018 / Published: 19 October 2018
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Abstract
Activated by AMP-dependent and -independent mechanisms, AMP-activated protein kinase (AMPK) plays a central role in the regulation of cellular bioenergetics and cellular survival. AMPK regulates a diverse set of signaling networks that converge to epigenetically mediate transcriptional events. Reversible histone and DNA modifications,
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Activated by AMP-dependent and -independent mechanisms, AMP-activated protein kinase (AMPK) plays a central role in the regulation of cellular bioenergetics and cellular survival. AMPK regulates a diverse set of signaling networks that converge to epigenetically mediate transcriptional events. Reversible histone and DNA modifications, such as acetylation and methylation, result in structural chromatin alterations that influence transcriptional machinery access to genomic regulatory elements. The orchestration of these epigenetic events differentiates physiological from pathophysiological phenotypes. AMPK phosphorylation of histones, DNA methyltransferases and histone post-translational modifiers establish AMPK as a key player in epigenetic regulation. This review focuses on the role of AMPK as a mediator of cellular survival through its regulation of chromatin remodeling and the implications this has for health and disease. Full article
(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)
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Open AccessArticle Genome-Wide Association Study Reveals Novel Genomic Regions Associated with 10 Grain Minerals in Synthetic Hexaploid Wheat
Int. J. Mol. Sci. 2018, 19(10), 3237; https://doi.org/10.3390/ijms19103237
Received: 20 September 2018 / Revised: 5 October 2018 / Accepted: 12 October 2018 / Published: 19 October 2018
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Abstract
Synthetic hexaploid wheat (SHW; Triticum durum L. × Aegilops tauschii Coss.) is a means of introducing novel genes/genomic regions into bread wheat (T. aestivum L.) and a potential genetic resource for improving grain mineral concentrations. We quantified 10 grain minerals (Ca, Cd,
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Synthetic hexaploid wheat (SHW; Triticum durum L. × Aegilops tauschii Coss.) is a means of introducing novel genes/genomic regions into bread wheat (T. aestivum L.) and a potential genetic resource for improving grain mineral concentrations. We quantified 10 grain minerals (Ca, Cd, Cu, Co, Fe, Li, Mg, Mn, Ni, and Zn) using an inductively coupled mass spectrometer in 123 SHWs for a genome-wide association study (GWAS). A GWAS with 35,648 single nucleotide polymorphism (SNP) markers identified 92 marker-trait associations (MTAs), of which 60 were novel and 40 were within genes, and the genes underlying 20 MTAs had annotations suggesting a potential role in grain mineral concentration. Twenty-four MTAs on the D-genome were novel and showed the potential of Ae. tauschii for improving grain mineral concentrations such as Ca, Co, Cu, Li, Mg, Mn, and Ni. Interestingly, the large number of novel MTAs (36) identified on the AB genome of these SHWs indicated that there is a lot of variation yet to be explored and to be used in the A and B genome along with the D-genome. Regression analysis identified a positive correlation between a cumulative number of favorable alleles at MTA loci in a genotype and grain mineral concentration. Additionally, we identified multi-traits and stable MTAs and recommended 13 top 10% SHWs with a higher concentration of beneficial grain minerals (Cu, Fe, Mg, Mn, Ni, and Zn), a large number of favorable alleles compared to low ranking genotypes and checks that could be utilized in the breeding program for the genetic biofortification. This study will further enhance our understanding of the genetic architecture of grain minerals in wheat and related cereals. Full article
(This article belongs to the Special Issue Molecular Advances in Wheat and Barley)
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Open AccessReview Allogeneic Mesenchymal Stem Cells and Biomaterials: The Perfect Match for Cardiac Repair?
Int. J. Mol. Sci. 2018, 19(10), 3236; https://doi.org/10.3390/ijms19103236
Received: 24 September 2018 / Revised: 16 October 2018 / Accepted: 17 October 2018 / Published: 19 October 2018
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Abstract
Coronary heart disease is the leading cause of death worldwide with huge socio-economic consequences. Cell therapy, and particularly mesenchymal stem cells (MSC), are considered a promising option to treat this disorder, due to their robust trophic and immunomodulatory properties. However, limitations such as
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Coronary heart disease is the leading cause of death worldwide with huge socio-economic consequences. Cell therapy, and particularly mesenchymal stem cells (MSC), are considered a promising option to treat this disorder, due to their robust trophic and immunomodulatory properties. However, limitations such as their low rate of engraftment and poor survival after administration into the heart have precluded their large-scale clinical use. Nevertheless, the combination of MSC with polymer-made scaffolds or hydrogels has proven to enhance their retention and, therefore, their efficacy. Additionally, their allogeneic use could permit the creation of ready-to-use cell patches able to improve their feasibility and promote their application in clinical settings. In this review, the experimental and clinical results derived from the use of MSC in cardiac pathology, as well as advances in the bioengineering field to improve the potential of therapeutic cells, are extensively discussed. Additionally, the current understanding of the heart response to the allogeneic MSC transplants is addressed. Full article
(This article belongs to the Special Issue Cell-Biomaterial Interaction)
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Open AccessArticle Sub-Chronic Stress Exacerbates the Pro-Thrombotic Phenotype in BDNFVal/Met Mice: Gene-Environment Interaction in the Modulation of Arterial Thrombosis
Int. J. Mol. Sci. 2018, 19(10), 3235; https://doi.org/10.3390/ijms19103235
Received: 14 September 2018 / Revised: 15 October 2018 / Accepted: 17 October 2018 / Published: 19 October 2018
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Abstract
Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been associated with increased susceptibility to develop mood disorders and recently it has been also linked with cardiovascular disease (CVD). Interestingly, stressful conditions unveil the anxious/depressive-like behavioral phenotype in heterozygous BDNFVal66Met (BDNFVal/Met) mice, suggesting
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Brain-Derived Neurotrophic Factor (BDNF) Val66Met polymorphism has been associated with increased susceptibility to develop mood disorders and recently it has been also linked with cardiovascular disease (CVD). Interestingly, stressful conditions unveil the anxious/depressive-like behavioral phenotype in heterozygous BDNFVal66Met (BDNFVal/Met) mice, suggesting an important relationship in terms of gene-environment interaction (GxE). However, the interplay between stress and BDNFVal/Met in relation to CVD is completely unknown. Here, we showed that BDNFVal/Met mice display a greater propensity to arterial thrombosis than wild type BDNFVal/Val mice after 7 days of restraint stress (RS). RS markedly increased the number of leukocytes and platelets, and induced hyper-responsive platelets as showed by increased circulating platelet/leukocyte aggregates and enhanced expression of P-selectin and GPIIbIIIa in heterozygous mutant mice. In addition, stressed BDNFVal/Met mice had a greater number of large and reticulated platelets but comparable number and maturation profile of bone marrow megakaryocytes compared to BDNFVal/Val mice. Interestingly, RS led to a significant reduction of BDNF expression accompanied by an increased activity of tissue factor in the aorta of both BDNFVal/Val and BDNFVal/Met mice. In conclusion, we provide evidence that sub-chronic stress unveils prothrombotic phenotype in heterozygous BDNF Val66Met mice affecting both the number and functionality of blood circulating cells, and the expression of key thrombotic molecules in aorta. Human studies will be crucial to understand whether this GxE interaction need to be taken into account in risk stratification of coronary artery disease (CAD) patients. Full article
(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor 2018)
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Open AccessArticle Sorafenib in Combination with Betulinic Acid Synergistically Induces Cell Cycle Arrest and Inhibits Clonogenic Activity in Pancreatic Ductal Adenocarcinoma Cells
Int. J. Mol. Sci. 2018, 19(10), 3234; https://doi.org/10.3390/ijms19103234
Received: 24 August 2018 / Revised: 15 October 2018 / Accepted: 16 October 2018 / Published: 19 October 2018
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers in the world due to late diagnosis and poor response to available treatments. It is important to identify treatment strategies that will increase the efficacy and reduce the toxicity of the currently
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Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers in the world due to late diagnosis and poor response to available treatments. It is important to identify treatment strategies that will increase the efficacy and reduce the toxicity of the currently used therapeutics. In this study, the PDAC cell lines AsPC-1, BxPC-3, and Capan-1 were treated with sorafenib and betulinic acid alone and in combination. We examined the effect of combined treatments on viability (MTS test), proliferation and apoptosis (annexin V staining), cell cycle arrest (PI staining), alterations in signaling pathways (Western blotting), and colony-forming ability. The combination of sorafenib with betulinic acid inhibited the viability and proliferation of PDAC cells without the induction of apoptosis. The antiproliferative effect, caused by G2 cell cycle arrest, was strongly associated with increased expression of p21 and decreased expression of c-Myc and cyclin D1, and was induced only by combined treatment. Additionally, decreased proliferation could also be associated with the inhibition of the P13K/Akt and MAPK signaling pathways. Importantly, combination treatment reduced the colony-forming ability of PDAC cells, as compared to both compounds alone. Collectively, we showed that combined treatment with low concentrations of sorafenib and betulinic acid had the capacity to inhibit proliferation and abolish clonogenic activity in PDAC cell lines. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)
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Open AccessReview Emerging Role of Follicular T Helper Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis
Int. J. Mol. Sci. 2018, 19(10), 3233; https://doi.org/10.3390/ijms19103233
Received: 2 October 2018 / Revised: 18 October 2018 / Accepted: 18 October 2018 / Published: 19 October 2018
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Abstract
Multiple sclerosis (MS) is an autoimmune disorder where both T cells and B cells are implicated in pathology. However, it remains unclear how these two distinct populations cooperate to drive disease. There is ample evidence from studies in both MS patients and mouse
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Multiple sclerosis (MS) is an autoimmune disorder where both T cells and B cells are implicated in pathology. However, it remains unclear how these two distinct populations cooperate to drive disease. There is ample evidence from studies in both MS patients and mouse models that Th17, B cells, and follicular T helper (TFH) cells contribute to disease. This review article describes the literature that identifies mechanisms by which Th17, TFH, and B cells cooperatively drive disease activity in MS and experimental autoimmune encephalomyelitis (EAE). The curation of this literature has identified that central nervous system (CNS) infiltrating TFH cells act with TH17 cell to contribute to an inflammatory B cell response in neuroinflammation. This demonstrates that TFH cells and their products are promising targets for therapies in MS. Full article
(This article belongs to the Special Issue New Molecular Mechanisms in Multiple Sclerosis)
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Open AccessArticle Epigallocatechin Gallate-Modified Gelatins with Different Compositions Alter the Quality of Regenerated Bones
Int. J. Mol. Sci. 2018, 19(10), 3232; https://doi.org/10.3390/ijms19103232
Received: 20 September 2018 / Revised: 15 October 2018 / Accepted: 16 October 2018 / Published: 19 October 2018
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Abstract
Bone quality is a significant indicator of the result of bone treatments. However, information regarding the quality of regenerated bones is limited. The study investigates the effect of different compositions of vacuum heated epigallocatechin gallate-modified gelatins sponge (vhEGCG-GS) on the quality of regenerated
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Bone quality is a significant indicator of the result of bone treatments. However, information regarding the quality of regenerated bones is limited. The study investigates the effect of different compositions of vacuum heated epigallocatechin gallate-modified gelatins sponge (vhEGCG-GS) on the quality of regenerated bones in critical size defects (9 mm) of rat calvariae. Five different compositions of vhEGCG-GSs containing the same amount of EGCG and different amounts of gelatin were tested. Following four weeks after implantation, the harvested regenerated bones were evaluated by using micro-computed tomography analysis, histological evaluation (hematoxylin-eosin and Villaneueva Goldner staining), picrosirius red-staining with polarized microscopic observation for collagen maturation, and Fourier transform infrared spectroscopy microscopy and imaging analysis for mineral-matrix ratio. The results indicated that increasing content of gelatin in the vhEGCG-GSs promoted bone and osteoid formation but yielded porous bones. Furthermore, tissue mineral density decreased and the maximum mineral-matrix ratio increased. In contrast, vhEGCG-GSs containing smaller amount of gelatin formed mature collagen matrix in the regenerated bones. These results suggest that the alteration of composition of vhEGCG-GSs affected the bone forming capability and quality of regenerated bone and provides valuable insight for the fabrication of new bone substitute materials. Full article
(This article belongs to the Special Issue Biomaterials for Bone Tissue Engineering)
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Open AccessArticle Fullerene Derivatives of Nucleoside HIV Reverse Transcriptase Inhibitors—In Silico Activity Prediction
Int. J. Mol. Sci. 2018, 19(10), 3231; https://doi.org/10.3390/ijms19103231
Received: 20 September 2018 / Revised: 9 October 2018 / Accepted: 17 October 2018 / Published: 19 October 2018
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Abstract
Here we present new derivatives of nucleoside reverse transcriptase inhibitors with a C20 fullerene. The computational chemistry methods used in this study evaluate affinity of designed compounds towards the HIV-1 reverse transcriptase (RT) binding site and select the most active ones. The
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Here we present new derivatives of nucleoside reverse transcriptase inhibitors with a C20 fullerene. The computational chemistry methods used in this study evaluate affinity of designed compounds towards the HIV-1 reverse transcriptase (RT) binding site and select the most active ones. The best of the designed compounds have superior or similar affinity to RT active site in comparison to most active test compounds, including drugs used in anti-HIV therapy. Full article
(This article belongs to the collection Proteins and Protein-Ligand Interactions)
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Open AccessArticle Optical Graphene-Based Biosensor for Nucleic Acid Detection; Influence of Graphene Functionalization and Ionic Strength
Int. J. Mol. Sci. 2018, 19(10), 3230; https://doi.org/10.3390/ijms19103230
Received: 19 September 2018 / Revised: 15 October 2018 / Accepted: 16 October 2018 / Published: 19 October 2018
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Abstract
A main challenge for optical graphene-based biosensors detecting nucleic acid is the selection of key parameters e.g. graphenic chemical structure, nanomaterial dispersion, ionic strength, and appropriate molecular interaction mechanisms. Herein we study interactions between a fluorescein-labelled DNA (FAM-DNA) probe and target single-stranded complementary
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A main challenge for optical graphene-based biosensors detecting nucleic acid is the selection of key parameters e.g. graphenic chemical structure, nanomaterial dispersion, ionic strength, and appropriate molecular interaction mechanisms. Herein we study interactions between a fluorescein-labelled DNA (FAM-DNA) probe and target single-stranded complementary DNA (cDNA) on three graphenic species, aiming to determine the most suitable platform for nucleic acid detection. Graphene oxide (GO), carboxyl graphene (GO-COOH) and reduced graphene oxide functionalized with PEGylated amino groups (rGO-PEG-NH2, PEG (polyethylene glycol)) were dispersed and characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The influence of ionic strength on molecular interaction with DNA was examined by fluorescence resonance energy transfer (FRET) comparing fluorescence intensity and anisotropy. Results indicated an effect of graphene functionalization, dispersion and concentration-dependent quenching, with GO and GO-COOH having the highest quenching abilities for FAM-DNA. Furthermore, GO and GO-COOH quenching was accentuated by the addition of either MgCl2 or MgSO4 cations. At 10 mM MgCl2 or MgSO4, the cDNA induced a decrease in fluorescence signal that was 2.7-fold for GO, 3.4-fold for GO-COOH and 4.1-fold for rGO-PEG-NH2. Best results, allowing accurate target detection, were observed when selecting rGO-PEG-NH2, MgCl2 and fluorescence anisotropy as an advantageous combination suitable for nucleic acid detection and further rational design biosensor development. Full article
(This article belongs to the Special Issue Graphene: Biological Applications)
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