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Int. J. Mol. Sci., Volume 20, Issue 4 (February-2 2019)

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Cover Story (view full-size image) Cover story (edited): The unfolded protein response is a multifactorial process that protects [...] Read more.
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Open AccessReview The Contribution of the Immune System in Bone Metastasis Pathogenesis
Int. J. Mol. Sci. 2019, 20(4), 999; https://doi.org/10.3390/ijms20040999
Received: 1 February 2019 / Revised: 18 February 2019 / Accepted: 20 February 2019 / Published: 25 February 2019
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Abstract
Bone metastasis is associated with significant morbidity for cancer patients and results in a reduced quality of life. The bone marrow is a fertile soil containing a complex composition of immune cells that may actually provide an immune-privileged niche for disseminated tumor cells [...] Read more.
Bone metastasis is associated with significant morbidity for cancer patients and results in a reduced quality of life. The bone marrow is a fertile soil containing a complex composition of immune cells that may actually provide an immune-privileged niche for disseminated tumor cells to colonize and proliferate. In this unique immune milieu, multiple immune cells including T cells, natural killer cells, macrophages, dendritic cells, myeloid-derived suppressor cells, and neutrophils are involved in the process of bone metastasis. In this review, we will discuss the crosstalk between immune cells in bone microenvironment and their involvement with cancer cell metastasis to the bone. Furthermore, we will highlight the anti-tumoral and pro-tumoral function of each immune cell type that contributes to bone metastasis. We will end with a discussion of current therapeutic strategies aimed at sensitizing immune cells. Full article
(This article belongs to the Special Issue Molecular Mechanisms in Cancer Metastasis)
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Open AccessArticle Resveratrol Promotes Mitochondrial Biogenesis and Protects against Seizure-Induced Neuronal Cell Damage in the Hippocampus Following Status Epilepticus by Activation of the PGC-1α Signaling Pathway
Int. J. Mol. Sci. 2019, 20(4), 998; https://doi.org/10.3390/ijms20040998
Received: 22 January 2019 / Revised: 13 February 2019 / Accepted: 21 February 2019 / Published: 25 February 2019
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Abstract
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is known to regulate mitochondrial biogenesis. Resveratrol is present in a variety of plants, including the skin of grapes, blueberries, raspberries, mulberries, and peanuts. It has been shown to offer protective effects against a number of [...] Read more.
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is known to regulate mitochondrial biogenesis. Resveratrol is present in a variety of plants, including the skin of grapes, blueberries, raspberries, mulberries, and peanuts. It has been shown to offer protective effects against a number of cardiovascular and neurodegenerative diseases, stroke, and epilepsy. This study examined the neuroprotective effect of resveratrol on mitochondrial biogenesis in the hippocampus following experimental status epilepticus. Kainic acid was microinjected into left hippocampal CA3 in Sprague Dawley rats to induce bilateral prolonged seizure activity. PGC-1α expression and related mitochondrial biogenesis were investigated. Amounts of nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (Tfam), cytochrome c oxidase 1 (COX1), and mitochondrial DNA (mtDNA) were measured to evaluate the extent of mitochondrial biogenesis. Increased PGC-1α and mitochondrial biogenesis machinery after prolonged seizure were found in CA3. Resveratrol increased expression of PGC-1α, NRF1, and Tfam, NRF1 binding activity, COX1 level, and mtDNA amount. In addition, resveratrol reduced activated caspase-3 activity and attenuated neuronal cell damage in the hippocampus following status epilepticus. These results suggest that resveratrol plays a pivotal role in the mitochondrial biogenesis machinery that may provide a protective mechanism counteracting seizure-induced neuronal damage by activation of the PGC-1α signaling pathway. Full article
(This article belongs to the Special Issue Health Benefits of Resveratrol)
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Open AccessArticle Transcriptomic Analysis for Indica and Japonica Rice Varieties under Aluminum Toxicity
Int. J. Mol. Sci. 2019, 20(4), 997; https://doi.org/10.3390/ijms20040997
Received: 23 January 2019 / Revised: 21 February 2019 / Accepted: 21 February 2019 / Published: 25 February 2019
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Abstract
Aluminum (Al) at high concentrations inhibits root growth, damage root systems, and causes significant reductions in rice yields. Indica and Japonica rice have been cultivated in distinctly different ecological environments with different soil acidity levels; thus, they might have different mechanisms of Al-tolerance. [...] Read more.
Aluminum (Al) at high concentrations inhibits root growth, damage root systems, and causes significant reductions in rice yields. Indica and Japonica rice have been cultivated in distinctly different ecological environments with different soil acidity levels; thus, they might have different mechanisms of Al-tolerance. In the present study, transcriptomic analysis in the root apex for Al-tolerance in the seedling stage was carried out within Al-tolerant and -sensitive varieties belonging to different subpopulations (i.e., Indica, Japonica, and mixed). We found that there were significant differences between the gene expression patterns of Indica Al-tolerant and Japonica Al-tolerant varieties, while the gene expression patterns of the Al-tolerant varieties in the mixed subgroup, which was inclined to Japonica, were similar to the Al-tolerant varieties in Japonica. Moreover, after further GO (gene ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses of the transcriptomic data, we found that eight pathways, i.e., “Terpenoid backbone biosynthesis”, “Ribosome”, “Amino sugar and nucleotide sugar metabolism”, “Plant hormone signal transduction”, “TCA cycle”, “Synthesis and degradation of ketone bodies”, and “Butanoate metabolism” were found uniquely for Indica Al-tolerant varieties, while only one pathway (i.e., “Sulfur metabolism”) was found uniquely for Japonica Al-tolerant varieties. For Al-sensitive varieties, one identical pathway was found, both in Indica and Japonica. Three pathways were found uniquely in “Starch and sucrose metabolism”, “Metabolic pathway”, and “Amino sugar and nucleotide sugar metabolism”. Full article
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Open AccessReview Aberrant Calcium Signals in Reactive Astrocytes: A Key Process in Neurological Disorders
Int. J. Mol. Sci. 2019, 20(4), 996; https://doi.org/10.3390/ijms20040996
Received: 1 February 2019 / Revised: 20 February 2019 / Accepted: 21 February 2019 / Published: 25 February 2019
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Abstract
Astrocytes are abundant cells in the brain that regulate multiple aspects of neural tissue homeostasis by providing structural and metabolic support to neurons, maintaining synaptic environments and regulating blood flow. Recent evidence indicates that astrocytes also actively participate in brain functions and play [...] Read more.
Astrocytes are abundant cells in the brain that regulate multiple aspects of neural tissue homeostasis by providing structural and metabolic support to neurons, maintaining synaptic environments and regulating blood flow. Recent evidence indicates that astrocytes also actively participate in brain functions and play a key role in brain disease by responding to neuronal activities and brain insults. Astrocytes become reactive in response to injury and inflammation, which is typically described as hypertrophy with increased expression of glial fibrillary acidic protein (GFAP). Reactive astrocytes are frequently found in many neurological disorders and are a hallmark of brain disease. Furthermore, reactive astrocytes may drive the initiation and progression of disease processes. Recent improvements in the methods to visualize the activity of reactive astrocytes in situ and in vivo have helped elucidate their functions. Ca2+ signals in reactive astrocytes are closely related to multiple aspects of disease and can be a good indicator of disease severity/state. In this review, we summarize recent findings concerning reactive astrocyte Ca2+ signals. We discuss the molecular mechanisms underlying aberrant Ca2+ signals in reactive astrocytes and the functional significance of aberrant Ca2+ signals in neurological disorders. Full article
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Open AccessArticle Quantitative Structure-Activity Relationship Study of Antioxidant Tripeptides Based on Model Population Analysis
Int. J. Mol. Sci. 2019, 20(4), 995; https://doi.org/10.3390/ijms20040995
Received: 1 January 2019 / Revised: 13 February 2019 / Accepted: 18 February 2019 / Published: 25 February 2019
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Abstract
Due to their beneficial effects on human health, antioxidant peptides have attracted much attention from researchers. However, the structure-activity relationships of antioxidant peptides have not been fully understood. In this paper, quantitative structure-activity relationships (QSAR) models were built on two datasets, i.e., the [...] Read more.
Due to their beneficial effects on human health, antioxidant peptides have attracted much attention from researchers. However, the structure-activity relationships of antioxidant peptides have not been fully understood. In this paper, quantitative structure-activity relationships (QSAR) models were built on two datasets, i.e., the ferric thiocyanate (FTC) dataset and ferric-reducing antioxidant power (FRAP) dataset, containing 214 and 172 unique antioxidant tripeptides, respectively. Sixteen amino acid descriptors were used and model population analysis (MPA) was then applied to improve the QSAR models for better prediction performance. The results showed that, by applying MPA, the cross-validated coefficient of determination (Q2) was increased from 0.6170 to 0.7471 for the FTC dataset and from 0.4878 to 0.6088 for the FRAP dataset, respectively. These findings indicate that the integration of different amino acid descriptors provide additional information for model building and MPA can efficiently extract the information for better prediction performance. Full article
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
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Open AccessReview Targeting the Iron-Response Elements of the mRNAs for the Alzheimer’s Amyloid Precursor Protein and Ferritin to Treat Acute Lead and Manganese Neurotoxicity
Int. J. Mol. Sci. 2019, 20(4), 994; https://doi.org/10.3390/ijms20040994
Received: 13 January 2019 / Revised: 8 February 2019 / Accepted: 10 February 2019 / Published: 25 February 2019
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Abstract
The therapeutic value of inhibiting translation of the amyloid precursor protein (APP) offers the possibility to reduce neurotoxic amyloid formation, particularly in cases of familial Alzheimer’s disease (AD) caused by APP gene duplications (Dup–APP) and in aging Down syndrome individuals. APP mRNA translation [...] Read more.
The therapeutic value of inhibiting translation of the amyloid precursor protein (APP) offers the possibility to reduce neurotoxic amyloid formation, particularly in cases of familial Alzheimer’s disease (AD) caused by APP gene duplications (Dup–APP) and in aging Down syndrome individuals. APP mRNA translation inhibitors such as the anticholinesterase phenserine, and high throughput screened molecules, selectively inhibited the uniquely folded iron-response element (IRE) sequences in the 5’untranslated region (5’UTR) of APP mRNA and this class of drug continues to be tested in a clinical trial as an anti-amyloid treatment for AD. By contrast, in younger age groups, APP expression is not associated with amyloidosis, instead it acts solely as a neuroprotectant while facilitating cellular ferroportin-dependent iron efflux. We have reported that the environmental metallotoxins Lead (Pb) and manganese (Mn) cause neuronal death by interfering with IRE dependent translation of APP and ferritin. The loss of these iron homeostatic neuroprotectants thereby caused an embargo of iron (Fe) export from neurons as associated with excess unstored intracellular iron and the formation of toxic reactive oxidative species (ROS). We propose that APP 5’UTR directed translation activators can be employed therapeutically to protect neurons exposed to high acute Pb and/or Mn exposure. Certainly, high potency APP translation activators, exemplified by the Food and Drug Administration (FDA) pre-approved M1 muscarinic agonist AF102B and high throughput-screened APP 5’UTR translation activators, are available for drug development to treat acute toxicity caused by Pb/Mn exposure to neurons. We conclude that APP translation activators can be predicted to prevent acute metal toxicity to neurons by a mechanism related to the 5’UTR specific yohimbine which binds and targets the canonical IRE RNA stem loop as an H-ferritin translation activator. Full article
(This article belongs to the Special Issue Translational Control)
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Open AccessArticle Myristica fragrans Kernels Prevent Paracetamol-Induced Hepatotoxicity by Inducing Anti-Apoptotic Genes and Nrf2/HO-1 Pathway
Int. J. Mol. Sci. 2019, 20(4), 993; https://doi.org/10.3390/ijms20040993
Received: 21 December 2018 / Revised: 14 February 2019 / Accepted: 20 February 2019 / Published: 25 February 2019
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Abstract
Paracetamol is responsible for acute liver failure in humans and experimental animals when taken at high doses and transformed into a reactive metabolite by the liver cytochrome P450. On the other hand, nutmeg is rich with many phytochemical ingredients that are known for [...] Read more.
Paracetamol is responsible for acute liver failure in humans and experimental animals when taken at high doses and transformed into a reactive metabolite by the liver cytochrome P450. On the other hand, nutmeg is rich with many phytochemical ingredients that are known for their ability to inhibit cytochrome P450. Hence, the present experiment was aimed at studying the hepatoprotective effect of Myristica fragrans (nutmeg), kernel extract (MFKE) in respect to paracetamol (acetaminophen; N-acetyl-p-amino-phenol (APAP))-induced hepatotoxicity in rats, focusing on its antioxidant, anti-inflammatory, and anti-apoptotic activities. Liver toxicity was induced in rats by a single oral administration of APAP (2 g/kg). To evaluate the hepatoprotective effect of MFKE against this APAP-induced hepatotoxicity, rats were pre-treated with either oral administration of MFKE at 300 mg/kg daily for seven days or silymarin at 50 mg/kg as a standard hepatoprotective agent. APAP intoxication caused a drastic elevation in liver function markers (transaminases, alkaline phosphatase, and total bilirubin), oxidative stress indicators (lipid peroxidation and nitric oxide), inflammatory biomarkers (tumour necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and nuclear factor ĸB) and the pro-apoptotic BCL2 Associated X (Bax) and caspases-3 genes. Furthermore, analyses of rat liver tissue revealed that APAP significantly depleted glutathione and inhibited the activities of antioxidant enzymes in addition to downregulating two key anti-apoptotic genes: Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) and B-cell lymphoma 2 (Bcl-2). Pre-treatment with MFKE, however, attenuated APAP-induced liver toxicity by reversing all of these toxicity biomarkers. This hepatoprotective effect of MFKE was further confirmed by improvement in histopathological findings. Interestingly, the hepatoprotective effect of MFKE was comparable to that offered by the reference hepatoprotector, silymarin. In conclusion, our results revealed that MFKE had antioxidant, anti-inflammatory, and anti-apoptotic properties, and it is suggested that this hepatoprotective effect could be linked to its ability to promote the nuclear factor erythroid 2–related factor 2 (Nrf2)/antioxidant responsive element (ARE) pathway. Full article
(This article belongs to the Special Issue Protective and Detrimental Role of Heme Oxygenase-1)
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Open AccessArticle Botulinum Neurotoxin-A Injected Intrastriatally into Hemiparkinsonian Rats Improves the Initiation Time for Left and Right Forelimbs in Both Forehand and Backhand Directions
Int. J. Mol. Sci. 2019, 20(4), 992; https://doi.org/10.3390/ijms20040992
Received: 11 February 2019 / Revised: 19 February 2019 / Accepted: 21 February 2019 / Published: 25 February 2019
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Abstract
Forelimb stepping is a widely used test for the assessment of forelimb akinesia in hemiparkinsonian (hemi-PD) rats. The initiation time (IT) is considered the most sensitive parameter in the stepping test procedure. Here we propose a novel, reliable, and simple method for the [...] Read more.
Forelimb stepping is a widely used test for the assessment of forelimb akinesia in hemiparkinsonian (hemi-PD) rats. The initiation time (IT) is considered the most sensitive parameter in the stepping test procedure. Here we propose a novel, reliable, and simple method for the measurement of IT of both forelimbs in both forehand and backhand directions in rats. Evaluating the same videos taken for quantifying adjusting steps, IT measurements were done without additional experiments. This is in contrast to the classical approach introduced by Olsson et al. (1995), in which separate experiments are necessary. We successfully applied our approach to hemi-PD rats intrastriatally treated with botulinum neurotoxin-A (BoNT-A). In naïve rats, an IT of about 0.62 s was found, and in right-sided hemi-PD rats the IT of the left forepaw increased to about 3.62 s. These hemi-PD rats showed, however, reduced ITs of the impaired left forepaws 1 month and the second time 7 months after induction of hemi-PD via the injection of 1 ng BoNT-A into the ipsilateral striatum, depending on post BoNT-A survival time. The method described offers the possibility of a precise and animal-friendly evaluation of IT in rats, including the beneficial effect of BoNT-A treatment in hemi-PD rats. Full article
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Open AccessArticle Sensory Neuropathy Affects Cardiac miRNA Expression Network Targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2 mRNAs
Int. J. Mol. Sci. 2019, 20(4), 991; https://doi.org/10.3390/ijms20040991
Received: 10 January 2019 / Revised: 14 February 2019 / Accepted: 19 February 2019 / Published: 25 February 2019
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Abstract
Background: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. Methods: Male Wistar rats were treated [...] Read more.
Background: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. Methods: Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles. Results: Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR. Conclusion: This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms. Full article
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Open AccessArticle The Modulatory Effect of Gender and Cytomegalovirus-Seropositivity on Circulating Inflammatory Factors and Cognitive Performance in Elderly Individuals
Int. J. Mol. Sci. 2019, 20(4), 990; https://doi.org/10.3390/ijms20040990
Received: 29 December 2018 / Revised: 5 February 2019 / Accepted: 21 February 2019 / Published: 25 February 2019
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Abstract
Aging is characterized by a chronic increase in the systemic levels of inflammatory cytokines even in ostensibly healthy individuals. The drivers of age-related increase in systemic inflammation are unclear but one potential contributor may be a persistent infection with Cytomegalovirus (CMV). In this [...] Read more.
Aging is characterized by a chronic increase in the systemic levels of inflammatory cytokines even in ostensibly healthy individuals. The drivers of age-related increase in systemic inflammation are unclear but one potential contributor may be a persistent infection with Cytomegalovirus (CMV). In this study, we characterized the inflammatory status of 161 older participants recruited to undergo a six-month training intervention. We investigated the influence of gender and CMV-seropositivity on the main inflammatory and anti-inflammatory circulating biomarkers, such as cytokines, receptor antagonist, soluble receptor, immune cells, and relevant metabolic markers. We found that both gender and CMV-seropositivity modulate circulating peripheral biomarkers, and that CMV-infection modifies associations among the latter. Moreover, we observed an interaction between CMV-serostatus and gender associations with cognitive abilities: gender differences in fluid intelligence (Gf) and working memory (WM) were noted only in CMV-negative individuals. Finally, we found that in the CMV-seronegative participants Gf, episodic memory (EM), and WM correlated negatively with pro-inflammatory tumor necrosis factor (TNF); and EM correlated positively with anti-inflammatory interleukin (IL)-10. In CMV-seropositive individuals EM and Gf correlated negatively with pro-inflammatory IL-6, while EM, Gf, and WM correlated negatively with anti-inflammatory IL-1RA. We conclude that both CMV-serostatus and gender may modulate neuroimmune factors, cognitive performance and the relationship between the two domains and should therefore be considered in comparative and interventional studies with elderly people. Full article
(This article belongs to the Special Issue Immunosenescence and Related Processes)
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Open AccessArticle Comparison of Reported Spinal Cord Lesions in Progressive Multiple Sclerosis with Theiler’s Murine Encephalomyelitis Virus Induced Demyelinating Disease
Int. J. Mol. Sci. 2019, 20(4), 989; https://doi.org/10.3390/ijms20040989
Received: 26 December 2018 / Revised: 10 February 2019 / Accepted: 21 February 2019 / Published: 25 February 2019
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Abstract
Background: Spinal cord (SC) lesions in Theiler’s murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) resemble important features of brain lesions in progressive multiple sclerosis (MS) including inflammation, demyelination, and axonal damage. The aim of the present study was a comparison of SC lesions [...] Read more.
Background: Spinal cord (SC) lesions in Theiler’s murine encephalomyelitis virus induced demyelinating disease (TMEV-IDD) resemble important features of brain lesions in progressive multiple sclerosis (MS) including inflammation, demyelination, and axonal damage. The aim of the present study was a comparison of SC lesions in MS and TMEV-IDD focusing on spatial and temporal distribution of demyelination, inflammation, SC atrophy (SCA), and axonal degeneration/loss in major descending motor pathways. Methods: TMEV and mock-infected mice were investigated clinically once a week. SC tissue was collected at 42, 98, 147, and 196 days post infection, and investigated using hematoxylin and eosin (HE) staining, immunohistochemistry targeting myelin basic protein (demyelination), Mac3 (microglia/macrophages), phosphorylated neurofilaments (axonal damage) and transmission electron microscopy. Results: Demyelination prevailed in SC white matter in TMEV-IDD, contrasting a predominant gray matter involvement in MS. TMEV-infected mice revealed a significant loss of axons similar to MS. Ultrastructural analysis in TMEV-IDD revealed denuded axons, degenerative myelin changes, axonal degeneration, as well as remyelination. SCA is a consistent finding in the SC of MS patients and was also detected at a late time point in TMEV-IDD. Conclusion: This comparative study further indicates the suitability of TMEV-IDD as animal model also for the investigation of progressive SC lesions in MS. Full article
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Open AccessArticle FTIR and Raman Spectroscopy-Based Biochemical Profiling Reflects Genomic Diversity of Clinical Candida Isolates That May Be Useful for Diagnosis and Targeted Therapy of Candidiasis
Int. J. Mol. Sci. 2019, 20(4), 988; https://doi.org/10.3390/ijms20040988
Received: 19 January 2019 / Revised: 16 February 2019 / Accepted: 18 February 2019 / Published: 25 February 2019
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Abstract
Despite the fact that Candida albicans is documented to be the main cause of human candidiasis, non-C. albicans Candida (NCAC) species, such as Candida glabrata and Candida tropicalis, are also suggested to be implicated in the etiopathogenesis of opportunistic fungal infections. [...] Read more.
Despite the fact that Candida albicans is documented to be the main cause of human candidiasis, non-C. albicans Candida (NCAC) species, such as Candida glabrata and Candida tropicalis, are also suggested to be implicated in the etiopathogenesis of opportunistic fungal infections. As biology, epidemiology, pathogenicity, and antifungal resistance of NCAC species may be affected as a result of genomic diversity and plasticity, rapid and unambiguous identification of Candida species in clinical samples is essential for proper diagnosis and therapy. In the present study, 25 clinical isolates of C. albicans, C. glabrata, and C. tropicalis species were characterized in terms of their karyotype patterns, DNA content, and biochemical features. Fourier transform infrared (FTIR) spectra- and Raman spectra-based molecular fingerprints corresponded to the diversity of chromosomal traits and DNA levels that provided correct species identification. Moreover, Raman spectroscopy was documented to be useful for the evaluation of ergosterol content that may be associated with azole resistance. Taken together, we found that vibrational spectroscopy-based biochemical profiling reflects the variability of chromosome patterns and DNA content of clinical Candida species isolates and may facilitate the diagnosis and targeted therapy of candidiasis. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Open AccessArticle Four Major Channels Detected in the Cytochrome P450 3A4: A Step toward Understanding Its Multispecificity
Int. J. Mol. Sci. 2019, 20(4), 987; https://doi.org/10.3390/ijms20040987
Received: 18 January 2019 / Revised: 12 February 2019 / Accepted: 20 February 2019 / Published: 25 February 2019
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Abstract
We computed the network of channels of the 3A4 isoform of the cytochrome P450 (CYP) on the basis of 16 crystal structures extracted from the Protein Data Bank (PDB). The calculations were performed with version 2 of the CCCPP software that we developed [...] Read more.
We computed the network of channels of the 3A4 isoform of the cytochrome P450 (CYP) on the basis of 16 crystal structures extracted from the Protein Data Bank (PDB). The calculations were performed with version 2 of the CCCPP software that we developed for this research project. We identified the minimal cost paths (MCPs) output by CCCPP as probable ways to access to the buried active site. The algorithm of calculation of the MCPs is presented in this paper, with its original method of visualization of the channels. We found that these MCPs constitute four major channels in CYP3A4. Among the many channels proposed by Cojocaru et al. in 2007, we found that only four of them open in 3A4. We provide a refined description of these channels together with associated quantitative data. Full article
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 2.0)
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Open AccessArticle Synthesis, Characterization, and Bacterial Fouling-Resistance Properties of Polyethylene Glycol-Grafted Polyurethane Elastomers
Int. J. Mol. Sci. 2019, 20(4), 1001; https://doi.org/10.3390/ijms20041001
Received: 25 January 2019 / Revised: 15 February 2019 / Accepted: 20 February 2019 / Published: 25 February 2019
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Abstract
Despite advances in material sciences and clinical procedures for surgical hygiene, medical device implantation still exposes patients to the risk of developing local or systemic infections. The development of efficacious antimicrobial/antifouling materials may help with addressing such an issue. In this framework, polyethylene [...] Read more.
Despite advances in material sciences and clinical procedures for surgical hygiene, medical device implantation still exposes patients to the risk of developing local or systemic infections. The development of efficacious antimicrobial/antifouling materials may help with addressing such an issue. In this framework, polyethylene glycol (PEG)-grafted segmented polyurethanes were synthesized, physico-chemically characterized, and evaluated with respect to their bacterial fouling-resistance properties. PEG grafting significantly altered the polymer bulk and surface properties. Specifically, the PEG-grafted polyurethanes possessed a more pronounced hard/soft phase segregated microstructure, which contributed to improving the mechanical resistance of the polymers. The better flexibility of the soft phase in the PEG-functionalized polyurethanes compared to the pristine polyurethane (PU) was presumably also responsible for the higher ability of the polymer to uptake water. Additionally, dynamic contact angle measurements evidenced phenomena of surface reorganization of the PEG-functionalized polyurethanes, presumably involving the exposition of the polar PEG chains towards water. As a consequence, Staphylococcus epidermidis initial adhesion onto the surface of the PEG-functionalized PU was essentially inhibited. That was not true for the pristine PU. Biofilm formation was also strongly reduced. Full article
(This article belongs to the Special Issue Polymeric Systems as Antimicrobial or Antifouling Agents)
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Open AccessArticle Discovery of Novel Acetylcholinesterase Inhibitors as Potential Candidates for the Treatment of Alzheimer’s Disease
Int. J. Mol. Sci. 2019, 20(4), 1000; https://doi.org/10.3390/ijms20041000
Received: 14 January 2019 / Revised: 12 February 2019 / Accepted: 21 February 2019 / Published: 25 February 2019
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Abstract
Acetylcholinesterase (AChE) catalyzes the hydrolysis of neurotransmitter acetylcholine to acetate and choline in a synaptic cleft. Deficits in cholinergic neurotransmitters are linked closely with the progression of Alzheimer’s disease (AD), which is a neurodegenerative disorder characterized by memory impairment, and a disordered cognitive [...] Read more.
Acetylcholinesterase (AChE) catalyzes the hydrolysis of neurotransmitter acetylcholine to acetate and choline in a synaptic cleft. Deficits in cholinergic neurotransmitters are linked closely with the progression of Alzheimer’s disease (AD), which is a neurodegenerative disorder characterized by memory impairment, and a disordered cognitive function. Since the previously approved AChE inhibitors, donepezil (Aricept), galantamine (Reminyl), and rivastigmine (Exelon), have side effects and several studies are being carried out out to develop novel AD drugs, we have applied a three-dimensional quantitative structure−activity relationship (3D QSAR) and structure-based pharmacophore modeling methodologies to identify potential candidate inhibitors against AChE. Herein, 3D QSAR and structure-based pharmacophore models were built from known inhibitors and crystal structures of human AChE in complex with donepezil, galantamine, huperzine A, and huprine W, respectively. The generated models were used as 3D queries to screen new scaffolds from various chemical databases. The hit compounds obtained from the virtual screening were subjected to an assessment of drug-like properties, followed by molecular docking. The final hit compounds were selected based on binding modes and molecular interactions in the active site of the enzyme. Furthermore, molecular dynamics simulations for AChE in complex with the final hits were performed to evaluate that they maintained stable interactions with the active site residues. The binding free energies of the final hits were also calculated using molecular mechanics/Poisson-Boltzmann surface area method. Taken together, we proposed that these hits can be promising candidates for anti-AD drugs. Full article
(This article belongs to the Section Molecular Pharmacology)
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Open AccessArticle The Proteomic Analysis of Maize Endosperm Protein Enriched by Phos-tagtm Reveals the Phosphorylation of Brittle-2 Subunit of ADP-Glc Pyrophosphorylase in Starch Biosynthesis Process
Int. J. Mol. Sci. 2019, 20(4), 986; https://doi.org/10.3390/ijms20040986
Received: 22 January 2019 / Revised: 14 February 2019 / Accepted: 18 February 2019 / Published: 24 February 2019
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Abstract
AGPase catalyzes a key rate-limiting step that converts ATP and Glc-1-p into ADP-glucose and diphosphate in maize starch biosynthesis. Previous studies suggest that AGPase is modulated by redox, thermal and allosteric regulation. However, the phosphorylation of AGPase is unclear in the kernel starch [...] Read more.
AGPase catalyzes a key rate-limiting step that converts ATP and Glc-1-p into ADP-glucose and diphosphate in maize starch biosynthesis. Previous studies suggest that AGPase is modulated by redox, thermal and allosteric regulation. However, the phosphorylation of AGPase is unclear in the kernel starch biosynthesis process. Phos-tagTM technology is a novel method using phos-tagTM agarose beads for separation, purification, and detection of phosphorylated proteins. Here we identified phos-tagTM agarose binding proteins from maize endosperm. Results showed a total of 1733 proteins identified from 10,678 distinct peptides. Interestingly, a total of 21 unique peptides for AGPase sub-unit Brittle-2 (Bt2) were identified. Bt2 was demonstrated by immunoblot when enriched maize endosperm protein with phos-tagTM agarose was in different pollination stages. In contrast, Bt2 would lose binding to phos-tagTM when samples were treated with alkaline phosphatase (ALP). Furthermore, Bt2 could be detected by Pro-Q diamond staining specifically for phosphorylated protein. We further identified the phosphorylation sites of Bt2 at Ser10, Thr451, and Thr462 by iTRAQ. In addition, dephosphorylation of Bt2 decreased the activity of AGPase in the native gel assay through ALP treatment. Taking together, these results strongly suggest that the phosphorylation of AGPase may be a new model to regulate AGPase activity in the starch biosynthesis process. Full article
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Open AccessReview Modulation of Obesity and Insulin Resistance by the Redox Enzyme and Adaptor Protein p66Shc
Int. J. Mol. Sci. 2019, 20(4), 985; https://doi.org/10.3390/ijms20040985
Received: 1 February 2019 / Revised: 15 February 2019 / Accepted: 21 February 2019 / Published: 24 February 2019
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Abstract
Initially reported as a longevity-related protein, the 66 kDa isoform of the mammalian Shc1 locus has been implicated in several metabolic pathways, being able to act both as an adaptor protein and as a redox enzyme capable of generating reactive oxygen species (ROS) [...] Read more.
Initially reported as a longevity-related protein, the 66 kDa isoform of the mammalian Shc1 locus has been implicated in several metabolic pathways, being able to act both as an adaptor protein and as a redox enzyme capable of generating reactive oxygen species (ROS) when it localizes to the mitochondrion. Ablation of p66Shc has been shown to be protective against obesity and the insurgence of insulin resistance, but not all the studies available in the literature agree on these points. This review will focus in particular on the role of p66Shc in the modulation of glucose homeostasis, obesity, body temperature, and respiration/energy expenditure. In view of the obesity and diabetes epidemic, p66Shc may represent a promising therapeutic target with enormous implications for human health. Full article
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Open AccessArticle Differential Involvement of Autophagy and Apoptosis in Response to Chemoendocrine and Endocrine Therapy in Breast Cancer: JBCRG-07TR
Int. J. Mol. Sci. 2019, 20(4), 984; https://doi.org/10.3390/ijms20040984
Received: 7 February 2019 / Accepted: 21 February 2019 / Published: 24 February 2019
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Abstract
Endocrine therapy is an essential component in the curative treatment of hormone receptor (HR)-positive breast cancer. To improve treatment efficacy, the addition of metronomic chemotherapy has been tested and shown to improve therapeutic effects. To better understand cellular reactions to metronomic chemoendocrine therapy, [...] Read more.
Endocrine therapy is an essential component in the curative treatment of hormone receptor (HR)-positive breast cancer. To improve treatment efficacy, the addition of metronomic chemotherapy has been tested and shown to improve therapeutic effects. To better understand cellular reactions to metronomic chemoendocrine therapy, we studied autophagy-related markers, beclin 1 and LC3, and apoptosis-related markers, TUNEL and M30, in pre- and post-treatment cancer tissues from a multicenter neoadjuvant trial, JBCRG-07, in which oral cyclophosphamide plus letrozole were administered to postmenopausal patients with HR-positive breast cancer. Changes in the levels of markers were compared with those following neoadjuvant endocrine therapy according to clinical response. Apoptosis, in addition to autophagy-related markers, increased following metronomic chemoendocrine therapy and such increases were associated with clinical response. By contrast, following endocrine therapy, the levels of apoptosis-related markers did not increase regardless of clinical response, whereas the levels of autophagy-related markers increased. Furthermore, levels of the apoptosis-related marker, M30, decreased in responders of endocrine therapy, suggesting that the induction of apoptosis by metronomic chemoendocrine therapy was involved in the improved clinical outcome compared with endocrine therapy. In conclusion, metronomic chemoendocrine therapy induced a different cellular reaction from that of endocrine therapy, including the induction of apoptosis, which is likely to contribute to improved efficacy compared with endocrine therapy alone. Full article
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Open AccessArticle Ginseng Berry Extract Rich in Phenolic Compounds Attenuates Oxidative Stress but not Cardiac Remodeling post Myocardial Infarction
Int. J. Mol. Sci. 2019, 20(4), 983; https://doi.org/10.3390/ijms20040983
Received: 22 December 2018 / Revised: 14 February 2019 / Accepted: 20 February 2019 / Published: 24 February 2019
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Abstract
The cardioprotective effects of ginseng root extracts have been reported. However, nothing is known about the myocardial actions of the phenolic compounds enriched in ginseng berry. Therefore, this study was undertaken to investigate the effects of American ginseng berry extract (GBE) in an [...] Read more.
The cardioprotective effects of ginseng root extracts have been reported. However, nothing is known about the myocardial actions of the phenolic compounds enriched in ginseng berry. Therefore, this study was undertaken to investigate the effects of American ginseng berry extract (GBE) in an experimental model of myocardial infarction (MI). Coronary artery ligation was performed on Sprague–Dawley male rats to induce MI after which animals were randomized into groups receiving either distilled water or GBE intragastrically for 8 weeks. Echocardiography and assays for malondialdehyde (MDA) and TNF-α were conducted. Flow cytometry was used to test the effects of GBE on T cell phenotypes and cytokine production. Although GBE did not improve the cardiac functional parameters, it significantly attenuated oxidative stress in post-MI rat hearts. GBE treatment also resulted in lower than control levels of TNF-α in post-MI rat hearts indicating a strong neutralizing effect of GBE on this cytokine. However, there was no effect of GBE on the proportion of different T cell subsets or ex-vivo cytokine production. Taken together, the present study demonstrates GBE reduces oxidative stress, however no effect on cardiac structure and function in post-MI rats. Moreover, reduction of TNF-α levels below baseline raises concern regarding its use as prophylactic or preventive adjunct therapy in cardiovascular disease. Full article
(This article belongs to the Special Issue Nutrition and Cardiovascular Health)
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Open AccessReview Enhancement of Functionality and Therapeutic Efficacy of Cell-Based Therapy Using Mesenchymal Stem Cells for Cardiovascular Disease
Int. J. Mol. Sci. 2019, 20(4), 982; https://doi.org/10.3390/ijms20040982
Received: 9 January 2019 / Revised: 20 February 2019 / Accepted: 21 February 2019 / Published: 24 February 2019
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Abstract
Cardiovascular disease usually triggers coronary heart disease, stroke, and ischemic diseases, thus promoting the development of functional failure. Mesenchymal stem cells (MSCs) are cells that can be isolated from various human tissues, with multipotent and immunomodulatory characteristics to help damaged tissue repair and [...] Read more.
Cardiovascular disease usually triggers coronary heart disease, stroke, and ischemic diseases, thus promoting the development of functional failure. Mesenchymal stem cells (MSCs) are cells that can be isolated from various human tissues, with multipotent and immunomodulatory characteristics to help damaged tissue repair and avoidance of immune responses. Much research has proved the feasibility, safety, and efficiency of MSC-based therapy for cardiovascular disease. Despite the fact that the precise mechanism of MSCs remains unclear, their therapeutic capability to treat ischemic diseases has been tested in phase I/II clinical trials. MSCs have the potential to become an effective therapeutic strategy for the treatment of ischemic and non-ischemic cardiovascular disorders. The molecular mechanism underlying the efficacy of MSCs in promoting engraftment and accelerating the functional recovery of injury sites is still unclear. It is hypothesized that the mechanisms of paracrine effects for the cardiac repair, optimization of the niche for cell survival, and cardiac remodeling by inflammatory control are involved in the interaction between MSCs and the damaged myocardial environment. This review focuses on recent experimental and clinical findings related to cardiovascular disease. We focus on MSCs, highlighting their roles in cardiovascular disease repair, differentiation, and MSC niche, and discuss their therapeutic efficacy and the current status of MSC-based cardiovascular disease therapies. Full article
(This article belongs to the Special Issue Role and Application of Stem Cells in Regenerative Medicine)
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Open AccessArticle Role of Histamine H3 Receptor Antagonists on Intraocular Pressure Reduction in Rabbit Models of Transient Ocular Hypertension and Glaucoma
Int. J. Mol. Sci. 2019, 20(4), 981; https://doi.org/10.3390/ijms20040981
Received: 22 January 2019 / Revised: 19 February 2019 / Accepted: 21 February 2019 / Published: 24 February 2019
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Abstract
Intraocular pressure (IOP) has a tendency to fluctuate throughout the day, reaching its peak in the early morning in healthy subjects or glaucoma patients. Likewise, histamine tone also fluctuates over time, being lower at nighttime. Numerous studies have demonstrated a correlation between short-term [...] Read more.
Intraocular pressure (IOP) has a tendency to fluctuate throughout the day, reaching its peak in the early morning in healthy subjects or glaucoma patients. Likewise, histamine tone also fluctuates over time, being lower at nighttime. Numerous studies have demonstrated a correlation between short-term IOP fluctuation and glaucoma progression; however, it has not yet been determined whether histamine plays a role in IOP fluctuations. The aim of this research was to establish the distribution of the histamine receptor proteins and respective mRNAs in the eye by western blot, immunohistochemistry and RT-PCR in New Zealand rabbits. Furthermore, we used a transient ocular hypertension (OHT) model induced by injection of 50 µL of 5% hypertonic saline into the vitreous and a stable OHT model (100 µL 0.1% carbomer in the anterior chamber) to address the potential IOP-lowering ability of H3 receptor (H3R) antagonists (ciproxifan, DL76 and GSK189254). IOPs were performed with a Tono-Pen at baseline and 60, 120 and 240 min post treatment after transient OHT induction and, every day for 12 days in the stable OHT model. All histamine receptor subtypes were localized in the rabbit retina and ciliary body/trabecular meshwork. All the treatments lowered IOP in a dose-dependent fashion between 0.3% and 1%. More specifically, the effects were maximal with ciproxifan at 60 min post-dose (IOP60 change = −18.84 ± 4.85 mmHg, at 1%), remained stable until 120 min (IOP120 change = −16.38 ± 3.8 mmHg, at 1%) and decayed thereafter to reach baseline values at 240 min. These effects were highly specific and dependent on histamine release as pre-treatment with imetit (H3R agonist, 1%) or pyrilamine (H1R antagonist, 1%) largely blocked ciproxifan-mediated effects. Color Doppler ultrasound examination was performed to evaluate changes in ophtalmic artery resistivity index (RI) before and after repeated dosing with DL 76, GSK189254, ciproxifan and timolol. Chronic treatments with H3R antagonists and timolol improved the vascular performance of ophthalmic arteries and reduced retinal ganglion cell death. Oxidative stress was also reduced and measured 8-Hydroxy-2′-deoxyguanosine (8OHdG) expression, and by dihidroethydium (DHE) staining. These results demonstrated that the histamine system participates in IOP regulation and that H3R antagonists could represent a future promising therapy for glaucoma. Further studies should be focused on the long-term IOP circadian fluctuations. Full article
(This article belongs to the Special Issue Histamine-Related Molecules as Therapeutic Targets)
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Open AccessArticle Metallothionein 3 Is a Hypoxia-Upregulated Oncogene Enhancing Cell Invasion and Tumorigenesis in Human Bladder Carcinoma Cells
Int. J. Mol. Sci. 2019, 20(4), 980; https://doi.org/10.3390/ijms20040980
Received: 27 January 2019 / Revised: 19 February 2019 / Accepted: 20 February 2019 / Published: 23 February 2019
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Abstract
Metallothioneins have been viewed as modulators in a number of biological regulations regarding cancerous development; however, the function of metallothionein 3 (MT3) in bladder cancer is unexplored. We determined the regulatory mechanisms and potential function of MT3 in bladder carcinoma cells. [...] Read more.
Metallothioneins have been viewed as modulators in a number of biological regulations regarding cancerous development; however, the function of metallothionein 3 (MT3) in bladder cancer is unexplored. We determined the regulatory mechanisms and potential function of MT3 in bladder carcinoma cells. Real-Time Reverse Transcriptase-Polymerase Chain Reaction (RT-qPCR) assays revealed that TSGH-8301 cells expressed more MT3 levels than RT-4, HT1376, and T24 cells. Immunoblot and RT-qPCR assays showed that arsenic (AS2O3) treatments enhanced the gene expression of MT3. Hypoxia induced HIF-1α, HIF-2α, and MT3 expression; furthermore, HIF-2α-knockdown attenuated hypoxic activation on MT3 expression. Ectopic overexpression of MT3 increased cell proliferation, invasion, and tumorigenesis significantly in T24 and HT1376 cells in vitro and in vivo; however, MT3-knockdown in TSGH-8301 cells had the reverse effect. Moreover, knockdown of MT3 enhanced arsenic-induced apoptosis determined by the Annexin V-FITC apoptosis assay. MT3-overexpression downregulated the gene expressions of N-myc downstream regulated gene 1 (NDRG1), N-myc downstream regulated gene 2 (NDRG2), and the mammary serine protease inhibitor (MASPIN) in HT1376 and T24 cells, whereas MT3-knockdown in TSGH-8301 cells had the opposite effect. The experiments indicated that MT3 is an arsenic- and hypoxia-upregulated oncogene that promotes cell growth and invasion of bladder carcinoma cells via downregulation of NDRG1, NDRG2, and MASPIN expressions. Full article
(This article belongs to the Section Molecular Biology)
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Open AccessArticle Genome-Wide Detection of Major and Epistatic Effect QTLs for Seed Protein and Oil Content in Soybean Under Multiple Environments Using High-Density Bin Map
Int. J. Mol. Sci. 2019, 20(4), 979; https://doi.org/10.3390/ijms20040979
Received: 26 December 2018 / Revised: 1 February 2019 / Accepted: 19 February 2019 / Published: 23 February 2019
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Abstract
Seed protein and oil content are the two important traits determining the quality and value of soybean. Development of improved cultivars requires detailed understanding of the genetic basis underlying the trait of interest. However, it is prerequisite to have a high-density linkage map [...] Read more.
Seed protein and oil content are the two important traits determining the quality and value of soybean. Development of improved cultivars requires detailed understanding of the genetic basis underlying the trait of interest. However, it is prerequisite to have a high-density linkage map for precisely mapping genomic regions, and therefore the present study used high-density genetic map containing 2267 recombination bin markers distributed on 20 chromosomes and spanned 2453.79 cM with an average distance of 1.08 cM between markers using restriction-site-associated DNA sequencing (RAD-seq) approach. A recombinant inbred line (RIL) population of 104 lines derived from a cross between Linhefenqingdou and Meng 8206 cultivars was evaluated in six different environments to identify main- and epistatic-effect quantitative trait loci (QTLs)as well as their interaction with environments. A total of 44 main-effect QTLs for protein and oil content were found to be distributed on 17 chromosomes, and 15 novel QTL were identified for the first time. Out of these QTLs, four were major and stable QTLs, viz., qPro-7-1, qOil-8-3, qOil-10-2 and qOil-10-4, detected in at least two environments plus combined environment with R2 values >10%. Within the physical intervals of these four QTLs, 111 candidate genes were screened for their direct or indirect involvement in seed protein and oil biosynthesis/metabolism processes based on gene ontology and annotation information. Based on RNA sequencing (RNA-seq) data analysis, 15 of the 111 genes were highly expressed during seed development stage and root nodules that might be considered as the potential candidate genes. Seven QTLs associated with protein and oil content exhibited significant additive and additive × environment interaction effects, and environment-independent QTLs revealed higher additive effects. Moreover, three digenic epistatic QTLs pairs were identified, and no main-effect QTLs showed epistasis. In conclusion, the use of a high-density map identified closely linked flanking markers, provided better understanding of genetic architecture and candidate gene information, and revealed the scope available for improvement of soybean quality through marker assisted selection (MAS). Full article
(This article belongs to the Special Issue Seed Development, Dormancy and Germination)
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Open AccessArticle BGFE: A Deep Learning Model for ncRNA-Protein Interaction Predictions Based on Improved Sequence Information
Int. J. Mol. Sci. 2019, 20(4), 978; https://doi.org/10.3390/ijms20040978
Received: 1 January 2019 / Revised: 19 February 2019 / Accepted: 20 February 2019 / Published: 23 February 2019
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Abstract
The interactions between ncRNAs and proteins are critical for regulating various cellular processes in organisms, such as gene expression regulations. However, due to limitations, including financial and material consumptions in recent experimental methods for predicting ncRNA and protein interactions, it is essential to [...] Read more.
The interactions between ncRNAs and proteins are critical for regulating various cellular processes in organisms, such as gene expression regulations. However, due to limitations, including financial and material consumptions in recent experimental methods for predicting ncRNA and protein interactions, it is essential to propose an innovative and practical approach with convincing performance of prediction accuracy. In this study, based on the protein sequences from a biological perspective, we put forward an effective deep learning method, named BGFE, to predict ncRNA and protein interactions. Protein sequences are represented by bi-gram probability feature extraction method from Position Specific Scoring Matrix (PSSM), and for ncRNA sequences, k-mers sparse matrices are employed to represent them. Furthermore, to extract hidden high-level feature information, a stacked auto-encoder network is employed with the stacked ensemble integration strategy. We evaluate the performance of the proposed method by using three datasets and a five-fold cross-validation after classifying the features through the random forest classifier. The experimental results clearly demonstrate the effectiveness and the prediction accuracy of our approach. In general, the proposed method is helpful for ncRNA and protein interacting predictions and it provides some serviceable guidance in future biological research. Full article
(This article belongs to the Special Issue Special Protein or RNA Molecules Computational Identification 2018)
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Open AccessArticle Compositional Features of HDL Particles Interact with Albuminuria to Modulate Cardiovascular Disease Risk
Int. J. Mol. Sci. 2019, 20(4), 977; https://doi.org/10.3390/ijms20040977
Received: 25 January 2019 / Revised: 17 February 2019 / Accepted: 19 February 2019 / Published: 23 February 2019
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Abstract
Lipoproteins containing apolipoprotein B modify associations of elevated urinary albumin excretion (UAE) with cardiovascular disease (CVD). Additionally, it is known that elevated UAE alters high-density lipoprotein functionality. Accordingly, we examined whether HDL features might also modify UAE-associated CVD. Multivariable Cox proportional-hazards modeling was [...] Read more.
Lipoproteins containing apolipoprotein B modify associations of elevated urinary albumin excretion (UAE) with cardiovascular disease (CVD). Additionally, it is known that elevated UAE alters high-density lipoprotein functionality. Accordingly, we examined whether HDL features might also modify UAE-associated CVD. Multivariable Cox proportional-hazards modeling was performed on participants of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study at the baseline screening with standard lipid/lipoprotein analyses and, three-to-four years later (second screen), with nuclear magnetic resonance lipoprotein analyses focusing on HDL parameters including HDL particle (HDL-P) and apolipoprotein A-I concentrations. These were used with UAE and derived measures of HDL apoA-I content (apoA-I/HDL-C and apoA-I/HDL-P) in risk models adjusted for gender, age, apoB, diabetes, past CVD history, CRP and GFR. Interaction analysis was also performed. Baseline screening revealed significant associations inverse for HDL-C and apoA-I and direct for apoA-I/HDL-C. The second screening demonstrated associations inverse for HDL-P, large HDL-P, medium HDL-P, HDL size, and apoA-I/HDL-P. Significant interactions with UAE included apoA-I/HDL-C at the baseline screening, and apoA-I/HDL-P and medium HDL-P but not apoA-I/HDL-C at the second screening. We conclude that features of HDL particles including apoA-I/HDL-P, indicative of HDL apoA-I content, and medium HDL-P modify associations of elevated UAE with CVD risk. Full article
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Open AccessReview Materials for Photovoltaics: State of Art and Recent Developments
Int. J. Mol. Sci. 2019, 20(4), 976; https://doi.org/10.3390/ijms20040976
Received: 22 January 2019 / Revised: 14 February 2019 / Accepted: 19 February 2019 / Published: 23 February 2019
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Abstract
In recent years, photovoltaic cell technology has grown extraordinarily as a sustainable source of energy, as a consequence of the increasing concern over the impact of fossil fuel-based energy on global warming and climate change. The different photovoltaic cells developed up to date [...] Read more.
In recent years, photovoltaic cell technology has grown extraordinarily as a sustainable source of energy, as a consequence of the increasing concern over the impact of fossil fuel-based energy on global warming and climate change. The different photovoltaic cells developed up to date can be classified into four main categories called generations (GEN), and the current market is mainly covered by the first two GEN. The 1GEN (mono or polycrystalline silicon cells and gallium arsenide) comprises well-known medium/low cost technologies that lead to moderate yields. The 2GEN (thin-film technologies) includes devices that have lower efficiency albeit are cheaper to manufacture. The 3GEN presents the use of novel materials, as well as a great variability of designs, and comprises expensive but very efficient cells. The 4GEN, also known as “inorganics-in-organics”, combines the low cost/flexibility of polymer thin films with the stability of novel inorganic nanostructures (i.e., metal nanoparticles and metal oxides) with organic-based nanomaterials (i.e., carbon nanotubes, graphene and its derivatives), and are currently under investigation. The main goal of this review is to show the current state of art on photovoltaic cell technology in terms of the materials used for the manufacture, efficiency and production costs. A comprehensive comparative analysis of the four generations is performed, including the device architectures, their advantages and limitations. Special emphasis is placed on the 4GEN, where the diverse roles of the organic and nano-components are discussed. Finally, conclusions and future perspectives are summarized. Full article
(This article belongs to the Special Issue Materials for Energy Applications)
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Open AccessArticle Synthesis, Spectroscopic Study and Radical Scavenging Activity of Kaempferol Derivatives: Enhanced Water Solubility and Antioxidant Activity
Int. J. Mol. Sci. 2019, 20(4), 975; https://doi.org/10.3390/ijms20040975
Received: 29 December 2018 / Revised: 13 February 2019 / Accepted: 19 February 2019 / Published: 23 February 2019
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Abstract
Kaempferol (Kae) is a natural flavonoid with potent antioxidant activity, but its therapeutic use is limited by its low aqueous solubility. Here, a series of Kae derivatives were synthesized to improve Kae dissolution property in water and antioxidant activity. These compounds included sulfonated [...] Read more.
Kaempferol (Kae) is a natural flavonoid with potent antioxidant activity, but its therapeutic use is limited by its low aqueous solubility. Here, a series of Kae derivatives were synthesized to improve Kae dissolution property in water and antioxidant activity. These compounds included sulfonated Kae (Kae-SO3), gallium (Ga) complexes with Kae (Kae-Ga) and Kae-SO3 (Kae-SO3-Ga). The compound structures were characterized by high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR) spectroscopy, ultraviolet-visible (UV-Vis) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy and thermal methods (TG/DSC). The results showed that a sulfonic group (-SO3) was successfully tethered on the C3’ of Kae to form Kae-SO3. And in the metal complexation, 4-CO and 3-OH of the ligand participated in the coordination with Ga(III). The metal-to-ligand ratio 1:2 was suggested for both complexes. Interestingly, Kae-SO3-Ga was obviously superior to other compounds in terms of overcoming the poor water-solubility of free Kae, and the solubility of Kae-SO3-Ga was about 300-fold higher than that of Kae-Ga. Furthermore, the evaluation of antioxidant activities in vitro was carried out for Kae derivatives by using α,α-diphenyl-β-picrylhydrazyl (DPPH) and 2,2’-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) diammonium salt (ABTS) free radical scavenging. The results showed that Kae-SO3-Ga was also optimal for scavenging free radicals in a dose-dependent manner. These data demonstrate that sulfonate kaempferol-gallium complex has a promising future as a potential antioxidant and as a potential therapeutic agent for further biomedical studies. Full article
(This article belongs to the Section Physical Chemistry and Chemical Physics)
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Open AccessReview Niacin in the Central Nervous System: An Update of Biological Aspects and Clinical Applications
Int. J. Mol. Sci. 2019, 20(4), 974; https://doi.org/10.3390/ijms20040974
Received: 30 January 2019 / Revised: 19 February 2019 / Accepted: 20 February 2019 / Published: 23 February 2019
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Abstract
Niacin (also known as “vitamin B3” or “vitamin PP”) includes two vitamers (nicotinic acid and nicotinamide) giving rise to the coenzymatic forms nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The two coenzymes are required for oxidative reactions crucial [...] Read more.
Niacin (also known as “vitamin B3” or “vitamin PP”) includes two vitamers (nicotinic acid and nicotinamide) giving rise to the coenzymatic forms nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The two coenzymes are required for oxidative reactions crucial for energy production, but they are also substrates for enzymes involved in non-redox signaling pathways, thus regulating biological functions, including gene expression, cell cycle progression, DNA repair and cell death. In the central nervous system, vitamin B3 has long been recognized as a key mediator of neuronal development and survival. Here, we will overview available literature data on the neuroprotective role of niacin and its derivatives, especially focusing especially on its involvement in neurodegenerative diseases (Alzheimer’s, Parkinson’s, and Huntington’s diseases), as well as in other neuropathological conditions (ischemic and traumatic injuries, headache and psychiatric disorders). Full article
(This article belongs to the Special Issue Functional Mechanism of B-Vitamins and Their Metabolites)
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Open AccessArticle Developmental Impairments in a Rat Model of Methyl Donor Deficiency: Effects of a Late Maternal Supplementation with Folic Acid
Int. J. Mol. Sci. 2019, 20(4), 973; https://doi.org/10.3390/ijms20040973
Received: 31 January 2019 / Revised: 18 February 2019 / Accepted: 19 February 2019 / Published: 23 February 2019
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Abstract
Vitamins B9 (folate) and B12 act as methyl donors in the one-carbon metabolism which influences epigenetic mechanisms. We previously showed that an embryofetal deficiency of vitamins B9 and B12 in the rat increased brain expression of let-7a and miR-34a microRNAs involved in the [...] Read more.
Vitamins B9 (folate) and B12 act as methyl donors in the one-carbon metabolism which influences epigenetic mechanisms. We previously showed that an embryofetal deficiency of vitamins B9 and B12 in the rat increased brain expression of let-7a and miR-34a microRNAs involved in the developmental control of gene expression. This was reversed by the maternal supply with folic acid (3 mg/kg/day) during the last third of gestation, resulting in a significant reduction of associated birth defects. Since the postnatal brain is subject to intensive developmental processes, we tested whether further folate supplementation during lactation could bring additional benefits. Vitamin deficiency resulted in weaned pups (21 days) in growth retardation, delayed ossification, brain atrophy and cognitive deficits, along with unchanged brain level of let-7a and decreased expression of miR-34a and miR-23a. Whereas maternal folic acid supplementation helped restore the levels of affected microRNAs, it led to a reduction of structural and functional defects taking place during the perinatal/postnatal periods, such as learning/memory capacities. Our data suggest that a gestational B-vitamin deficiency could affect the temporal control of the microRNA regulation required for normal development. Moreover, they also point out that the continuation of folate supplementation after birth may help to ameliorate neurological symptoms commonly associated with developmental deficiencies in folate and B12. Full article
(This article belongs to the Special Issue Functional Mechanism of B-Vitamins and Their Metabolites)
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Open AccessReview Role of p90RSK in Kidney and Other Diseases
Int. J. Mol. Sci. 2019, 20(4), 972; https://doi.org/10.3390/ijms20040972
Received: 29 January 2019 / Revised: 18 February 2019 / Accepted: 20 February 2019 / Published: 23 February 2019
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Abstract
The 90 kDa ribosomal s6 kinases (RSKs) are a group of serine/threonine kinases consisting of 4 RSK isoforms (RSK1-4), of which RSK1 is also designated as p90RSK. p90RSK plays an important role in the Ras-mitogen-activated protein kinase (MAPK) signalling cascade and is the [...] Read more.
The 90 kDa ribosomal s6 kinases (RSKs) are a group of serine/threonine kinases consisting of 4 RSK isoforms (RSK1-4), of which RSK1 is also designated as p90RSK. p90RSK plays an important role in the Ras-mitogen-activated protein kinase (MAPK) signalling cascade and is the direct downstream effector of Ras-extracellular signal-regulated kinase (ERK1/2) signalling. ERK1/2 activation directly phosphorylates and activates p90RSK, which, in turn, activates various signalling events through selection of different phosphorylation substrates. Upregulation of p90RSK has been reported in numerous human diseases. p90RSK plays an important role in the regulation of diverse cellular processes. Thus, aberrant activation of p90RSK plays a critical role in the pathogenesis of organ dysfunction and damage. In this review, we focus on the current understanding of p90RSK functions and roles in the development and progression of kidney diseases. Roles of p90RSK, as well as other RSKs, in cardiovascular disorders and cancers are also discussed. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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