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Int. J. Mol. Sci., Volume 21, Issue 8 (April-2 2020) – 371 articles

Cover Story (view full-size image): In this review article, we discuss the effects of traumatic brain injury (TBI) on the cerebrovascular system and the blood–brain barrier (BBB), where damage to the BBB further contributes to the loss of neural tissue and impairs neuroprotection. Additionally, we discuss the post-traumatic impacts of chronic smoking, which has been shown to damage BBB viability by promoting inflammation and oxidative stress, thus acting as a premorbid condition that worsens the TBI outcome. View this paper.
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Article
Elimination of Viroids from Tobacco Pollen Involves a Decrease in Propagation Rate and an Increase of the Degradation Processes
Int. J. Mol. Sci. 2020, 21(8), 3029; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083029 - 24 Apr 2020
Cited by 4 | Viewed by 1324
Abstract
Some viroids—single-stranded, non-coding, circular RNA parasites of plants—are not transmissible through pollen to seeds and to next generation. We analyzed the cause for the elimination of apple fruit crinkle viroid (AFCVd) and citrus bark cracking viroid (CBCVd) from male gametophyte cells of Nicotiana [...] Read more.
Some viroids—single-stranded, non-coding, circular RNA parasites of plants—are not transmissible through pollen to seeds and to next generation. We analyzed the cause for the elimination of apple fruit crinkle viroid (AFCVd) and citrus bark cracking viroid (CBCVd) from male gametophyte cells of Nicotiana tabacum by RNA deep sequencing and molecular methods using infected and transformed tobacco pollen tissues at different developmental stages. AFCVd was not transferable from pollen to seeds in reciprocal pollinations, due to a complete viroid eradication during the last steps of pollen development and fertilization. In pollen, the viroid replication pathway proceeds with detectable replication intermediates, but is dramatically depressed in comparison to leaves. Specific and unspecific viroid degradation with some preference for (−) chains occurred in pollen, as detected by analysis of viroid-derived small RNAs, by quantification of viroid levels and by detection of viroid degradation products forming “comets” on Northern blots. The decrease of viroid levels during pollen development correlated with mRNA accumulation of several RNA-degrading factors, such as AGO5 nuclease, DICER-like and TUDOR S-like nuclease. In addition, the functional status of pollen, as a tissue with high ribosome content, could play a role during suppression of AFCVd replication involving transcription factors IIIA and ribosomal protein L5. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Viroids and Viroid Diseases)
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Review
Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies
Int. J. Mol. Sci. 2020, 21(8), 3028; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083028 - 24 Apr 2020
Cited by 24 | Viewed by 1879
Abstract
Alterations in autophagy and the ubiquitin proteasome system (UPS) are commonly implicated in protein aggregation and toxicity which manifest in a number of neurological disorders. In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called [...] Read more.
Alterations in autophagy and the ubiquitin proteasome system (UPS) are commonly implicated in protein aggregation and toxicity which manifest in a number of neurological disorders. In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called prionoid proteins, including alpha synuclein (α-syn), amyloid-beta (Aβ), tau, huntingtin, superoxide dismutase-1 (SOD-1), TAR-DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS). Recent biochemical and morphological studies add to this scenario, focusing on the coordinated, either synergistic or compensatory, interplay that occurs between autophagy and the UPS. In fact, a number of biochemical pathways such as mammalian target of rapamycin (mTOR), transcription factor EB (TFEB), Bcl2-associated athanogene 1/3 (BAG3/1) and glycogen synthase kinase beta (GSk3β), which are widely explored as potential targets in neurodegenerative proteinopathies, operate at the crossroad between autophagy and UPS. These biochemical steps are key in orchestrating the specificity and magnitude of the two degradation systems for effective protein homeostasis, while intermingling with intracellular secretory/trafficking and inflammatory pathways. The findings discussed in the present manuscript are supposed to add novel viewpoints which may further enrich our insight on the complex interactions occurring between cell-clearing systems, protein misfolding and propagation. Discovering novel mechanisms enabling a cross-talk between the UPS and autophagy is expected to provide novel potential molecular targets in proteinopathies. Full article
(This article belongs to the Special Issue Proteotoxicity and Neurodegenerative Diseases)
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Article
Increased Protein S-Glutathionylation in Leber’s Hereditary Optic Neuropathy (LHON)
Int. J. Mol. Sci. 2020, 21(8), 3027; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083027 - 24 Apr 2020
Cited by 3 | Viewed by 1760
Abstract
Leber’s hereditary optic neuropathy (LHON, MIM#535000) is the most common form of inherited optic neuropathies and mitochondrial DNA-related diseases. The pathogenicity of mutations in genes encoding components of mitochondrial Complex I is well established, but the underlying pathomechanisms of the disease are still [...] Read more.
Leber’s hereditary optic neuropathy (LHON, MIM#535000) is the most common form of inherited optic neuropathies and mitochondrial DNA-related diseases. The pathogenicity of mutations in genes encoding components of mitochondrial Complex I is well established, but the underlying pathomechanisms of the disease are still unclear. Hypothesizing that oxidative stress related to Complex I deficiency may increase protein S-glutathionylation, we investigated the proteome-wide S-glutathionylation profiles in LHON (n = 11) and control (n = 7) fibroblasts, using the GluICAT platform that we recently developed. Glutathionylation was also studied in healthy fibroblasts (n = 6) after experimental Complex I inhibition. The significantly increased reactive oxygen species (ROS) production in the LHON group by Complex I was shown experimentally. Among the 540 proteins which were globally identified as glutathionylated, 79 showed a significantly increased glutathionylation (p < 0.05) in LHON and 94 in Complex I-inhibited fibroblasts. Approximately 42% (33/79) of the altered proteins were shared by the two groups, suggesting that Complex I deficiency was the main cause of increased glutathionylation. Among the 79 affected proteins in LHON fibroblasts, 23% (18/79) were involved in energetic metabolism, 31% (24/79) exhibited catalytic activity, 73% (58/79) showed various non-mitochondrial localizations, and 38% (30/79) affected the cell protein quality control. Integrated proteo-metabolomic analysis using our previous metabolomic study of LHON fibroblasts also revealed similar alterations of protein metabolism and, in particular, of aminoacyl-tRNA synthetases. S-glutathionylation is mainly known to be responsible for protein loss of function, and molecular dynamics simulations and 3D structure predictions confirmed such deleterious impacts on adenine nucleotide translocator 2 (ANT2), by weakening its affinity to ATP/ADP. Our study reveals a broad impact throughout the cell of Complex I-related LHON pathogenesis, involving a generalized protein stress response, and provides a therapeutic rationale for targeting S-glutathionylation by antioxidative strategies. Full article
(This article belongs to the Special Issue S-Glutathionylation in Redox Protein Signaling and Health Outcomes)
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Article
The Anti-Inflammatory and Antioxidant Effects of Sodium Propionate
Int. J. Mol. Sci. 2020, 21(8), 3026; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083026 - 24 Apr 2020
Cited by 9 | Viewed by 1621
Abstract
The major end-products of dietary fiber fermentation by gut microbiota are the short-chain fatty acids (SCFAs) acetate, propionate, and butyrate, which have been shown to modulate host metabolism via effects on metabolic pathways at different tissue sites. Several studies showed the inhibitory effects [...] Read more.
The major end-products of dietary fiber fermentation by gut microbiota are the short-chain fatty acids (SCFAs) acetate, propionate, and butyrate, which have been shown to modulate host metabolism via effects on metabolic pathways at different tissue sites. Several studies showed the inhibitory effects of sodium propionate (SP) on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. We carried out an in vitro model of inflammation on the J774-A1 cell line, by stimulation with lipopolysaccharide (LPS) and H2O2, followed by the pre-treatment with SP at 0.1, 1 mM and 10 mM. To evaluate the effect on acute inflammation and superoxide anion-induced pain, we performed a model of carrageenan (CAR)-induced rat paw inflammation and intraplantar injection of KO2 where rats received SP orally (10, 30, and 100 mg/kg). SP decreased in concentration-dependent-manner the expression of cicloxigenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) following LPS stimulation. SP was able to enhance anti-oxidant enzyme production such as manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO-1) following H2O2 stimulation. In in vivo models, SP (30 and 100 mg/kg) reduced paw inflammation and tissue damage after CAR and KO2 injection. Our results demonstrated the anti-inflammatory and anti-oxidant properties of SP; therefore, we propose that SP may be an effective strategy for the treatment of inflammatory diseases. Full article
(This article belongs to the Special Issue Modulation of Oxidative Stress: Molecular and Pharmacological Aspects)
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Article
Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia—A Retrospective Analysis in 337 Patients
Int. J. Mol. Sci. 2020, 21(8), 3025; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083025 - 24 Apr 2020
Cited by 6 | Viewed by 1094
Abstract
Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations [...] Read more.
Although the RAS-pathway has been implicated as an important driver in the pathogenesis of chronic myelomonocytic leukemia (CMML) a comprehensive study including molecular and functional analyses in patients with progression and transformation has not been performed. A close correlation between RASopathy gene mutations and spontaneous in vitro myeloid colony (CFU-GM) growth in CMML has been described. Molecular and/or functional analyses were performed in three cohorts of 337 CMML patients: in patients without (A, n = 236) and with (B, n = 61) progression/transformation during follow-up, and in patients already transformed at the time of sampling (C, n = 40 + 26 who were before in B). The frequencies of RAS-pathway mutations (variant allele frequency ≥ 20%) in cohorts A, B, and C were 30%, 47%, and 71% (p < 0.0001), and of high colony growth (≥20/105 peripheral blood mononuclear cells) 31%, 44%, and 80% (p < 0.0001), respectively. Increases in allele burden of RAS-pathway mutations and in numbers of spontaneously formed CFU-GM before and after transformation could be shown in individual patients. Finally, the presence of mutations in RASopathy genes as well as the presence of high colony growth prior to transformation was significantly associated with an increased risk of acute myeloid leukemia (AML) development. Together, RAS-pathway mutations in CMML correlate with an augmented autonomous expansion of neoplastic precursor cells and indicate an increased risk of AML development which may be relevant for targeted treatment strategies. Full article
(This article belongs to the Special Issue Genetics, Biology, and Treatment of Acute Myeloid Leukemia 2.0)
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Article
Potential Use of Extracellular Vesicles Generated by Microbubble-Assisted Ultrasound as Drug Nanocarriers for Cancer Treatment
Int. J. Mol. Sci. 2020, 21(8), 3024; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083024 - 24 Apr 2020
Cited by 7 | Viewed by 1579
Abstract
Extracellular vesicles (EVs)-carrying biomolecules derived from parental cells have achieved substantial scientific interest for their potential use as drug nanocarriers. Ultrasound (US) in combination with microbubbles (MB) have been shown to trigger the release of EVs from cancer cells. In the current study, [...] Read more.
Extracellular vesicles (EVs)-carrying biomolecules derived from parental cells have achieved substantial scientific interest for their potential use as drug nanocarriers. Ultrasound (US) in combination with microbubbles (MB) have been shown to trigger the release of EVs from cancer cells. In the current study, the use of microbubbles-assisted ultrasound (USMB) to generate EVs containing drug cargo was investigated. The model drug, CellTracker™ green fluorescent dye (CTG) or bovine serum albumin conjugated with fluorescein isothiocyanate (BSA FITC) was loaded into primary human endothelial cells in vitro using USMB. We found that USMB loaded CTG and BSA FITC into human endothelial cells (HUVECs) and triggered the release of EVs containing these compounds in the cell supernatant within 2 h after treatment. The amount of EV released seemed to be correlated with the increase of US acoustic pressure. Co-culturing these EVs resulted in uptake by the recipient tumour cells within 4 h. In conclusion, USMB was able to load the model drugs into endothelial cells and simultaneously trigger the release of EVs-carrying model drugs, highlighting the potential of EVs as drug nanocarriers for future drug delivery in cancer. Full article
(This article belongs to the Special Issue Extracellular Vesicles: Biology and Potentials in Cancer Therapeutics)
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Review
The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration
Int. J. Mol. Sci. 2020, 21(8), 3023; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083023 - 24 Apr 2020
Cited by 4 | Viewed by 1281
Abstract
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine expressed by different cell types and exerting multiple biological functions. It has been shown that MIF may be involved in several disorders, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), [...] Read more.
Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine expressed by different cell types and exerting multiple biological functions. It has been shown that MIF may be involved in several disorders, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), and Huntington disease (HD), that represent an unmet medical need. Therefore, further studies are needed to identify novel pathogenetic mechanisms that may translate into tailored therapeutic approaches so to improve patients’ survival and quality of life. Here, we reviewed the preclinical and clinical studies investigating the role of MIF in ALS, PD, and HD. The emerging results suggest that MIF might play a dichotomic role in these disorders, exerting a protective action in ALS, a pathogenetic action in HD, and a yet undefined and debated role in PD. The better understanding of the role of MIF in these diseases could allow its use as a novel diagnostic and therapeutic tool for the monitoring and treatment of the patients and for eventual biomarker-driven therapeutic approaches. Full article
(This article belongs to the Special Issue CNS Drug Action in Neurodegenerative Diseases)
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Review
Role of Bone Targeting Agents in the Prevention of Bone Metastases from Breast Cancer
Int. J. Mol. Sci. 2020, 21(8), 3022; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083022 - 24 Apr 2020
Cited by 3 | Viewed by 1408
Abstract
Breast cancer (BC) is the most common malignancy in women worldwide and leads, in more than 70% of patients with advanced disease, to skeleton colonization and formation of bone metastases (BM). This condition implies a severe disability and deterioration of the quality of [...] Read more.
Breast cancer (BC) is the most common malignancy in women worldwide and leads, in more than 70% of patients with advanced disease, to skeleton colonization and formation of bone metastases (BM). This condition implies a severe disability and deterioration of the quality of life, with consequent additional social costs. In recent decades, several studies explored the role of agents acting within the bone microenvironment to counteract BM development, and several bone-targeting agents (BTAs) have been introduced in the clinical practice to manage bone lesions and reduce the risk of skeletal complications. However, long-term exposure to these agents is not free from potential toxicities and needs careful monitoring. In this context, the potential capability to prevent BM onset in selected BC patients, through the early administration of BTAs, has been explored by several researchers, with the belief that “prevention is better than cure” and that, ultimately, metastatic BC is an incurable condition. Here, we revised the mechanisms of BM development in BC as well as the strategies for selecting high-risk patients suitable for early BTA treatment. Full article
(This article belongs to the Special Issue Metastasis Inhibition)
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Project Report
The EDCMET Project: Metabolic Effects of Endocrine Disruptors
Int. J. Mol. Sci. 2020, 21(8), 3021; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083021 - 24 Apr 2020
Cited by 3 | Viewed by 2008
Abstract
Endocrine disruptors (EDs) are defined as chemicals that mimic, block, or interfere with hormones in the body’s endocrine systems and have been associated with a diverse array of health issues. The concept of endocrine disruption has recently been extended to metabolic alterations that [...] Read more.
Endocrine disruptors (EDs) are defined as chemicals that mimic, block, or interfere with hormones in the body’s endocrine systems and have been associated with a diverse array of health issues. The concept of endocrine disruption has recently been extended to metabolic alterations that may result in diseases, such as obesity, diabetes, and fatty liver disease, and constitute an increasing health concern worldwide. However, while epidemiological and experimental data on the close association of EDs and adverse metabolic effects are mounting, predictive methods and models to evaluate the detailed mechanisms and pathways behind these observed effects are lacking, thus restricting the regulatory risk assessment of EDs. The EDCMET (Metabolic effects of Endocrine Disrupting Chemicals: novel testing METhods and adverse outcome pathways) project brings together systems toxicologists; experimental biologists with a thorough understanding of the molecular mechanisms of metabolic disease and comprehensive in vitro and in vivo methodological skills; and, ultimately, epidemiologists linking environmental exposure to adverse metabolic outcomes. During its 5-year journey, EDCMET aims to identify novel ED mechanisms of action, to generate (pre)validated test methods to assess the metabolic effects of Eds, and to predict emergent adverse biological phenotypes by following the adverse outcome pathway (AOP) paradigm. Full article
(This article belongs to the Special Issue Advances in the Research of Endocrine Disrupting Chemicals 2.0)
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Review
Thermogenesis in Adipose Tissue Activated by Thyroid Hormone
Int. J. Mol. Sci. 2020, 21(8), 3020; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083020 - 24 Apr 2020
Cited by 16 | Viewed by 2257
Abstract
Thermogenesis is the production of heat that occurs in all warm-blooded animals. During cold exposure, there is obligatory thermogenesis derived from body metabolism as well as adaptive thermogenesis through shivering and non-shivering mechanisms. The latter mainly occurs in brown adipose tissue (BAT) and [...] Read more.
Thermogenesis is the production of heat that occurs in all warm-blooded animals. During cold exposure, there is obligatory thermogenesis derived from body metabolism as well as adaptive thermogenesis through shivering and non-shivering mechanisms. The latter mainly occurs in brown adipose tissue (BAT) and muscle; however, white adipose tissue (WAT) also can undergo browning via adrenergic stimulation to acquire thermogenic potential. Thyroid hormone (TH) also exerts profound effects on thermoregulation, as decreased body temperature and increased body temperature occur during hypothyroidism and hyperthyroidism, respectively. We have termed the TH-mediated thermogenesis under thermoneutral conditions “activated” thermogenesis. TH acts on the brown and/or white adipose tissues to induce uncoupled respiration through the induction of the uncoupling protein (Ucp1) to generate heat. TH acts centrally to activate the BAT and browning through the sympathetic nervous system. However, recent studies also show that TH acts peripherally on the BAT to directly stimulate Ucp1 expression and thermogenesis through an autophagy-dependent mechanism. Additionally, THs can exert Ucp1-independent effects on thermogenesis, most likely through activation of exothermic metabolic pathways. This review summarizes thermogenic effects of THs on adipose tissues. Full article
(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors 2.0)
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Article
Wood Architecture and Composition Are Deeply Remodeled in Frost Sensitive Eucalyptus Overexpressing CBF/DREB1 Transcription Factors
Int. J. Mol. Sci. 2020, 21(8), 3019; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083019 - 24 Apr 2020
Cited by 3 | Viewed by 1395
Abstract
Eucalypts are the most planted trees worldwide, but most of them are frost sensitive. Overexpressing transcription factors for CRT-repeat binding factors (CBFs) in transgenic Eucalyptus confer cold resistance both in leaves and stems. While wood plays crucial roles in trees and [...] Read more.
Eucalypts are the most planted trees worldwide, but most of them are frost sensitive. Overexpressing transcription factors for CRT-repeat binding factors (CBFs) in transgenic Eucalyptus confer cold resistance both in leaves and stems. While wood plays crucial roles in trees and is affected by environmental cues, its potential role in adaptation to cold stress has been neglected. Here, we addressed this question by investigating the changes occurring in wood in response to the overexpression of two CBFs, taking advantage of available transgenic Eucalyptus lines. We performed histological, biochemical, and transcriptomic analyses on xylem samples. CBF ectopic expression led to a reduction of both primary and secondary growth, and triggered changes in xylem architecture with smaller and more frequent vessels and fibers exhibiting reduced lumens. In addition, lignin content and syringyl/guaiacyl (S/G) ratio increased. Consistently, many genes of the phenylpropanoid and lignin branch pathway were upregulated. Most of the features of xylem remodeling induced by CBF overexpression are reminiscent of those observed after long exposure of Eucalyptus trees to chilling temperatures. Altogether, these results suggest that CBF plays a central role in the cross-talk between response to cold and wood formation and that the remodeling of wood is part of the adaptive strategies to face cold stress. Full article
(This article belongs to the Special Issue Woody Formation and Lignin Biosynthesis in Plants)
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Review
CDKs in Sarcoma: Mediators of Disease and Emerging Therapeutic Targets
Int. J. Mol. Sci. 2020, 21(8), 3018; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083018 - 24 Apr 2020
Cited by 7 | Viewed by 1426
Abstract
Sarcomas represent one of the most challenging tumor types to treat due to their diverse nature and our incomplete understanding of their underlying biology. Recent work suggests cyclin-dependent kinase (CDK) pathway activation is a powerful driver of sarcomagenesis. CDK proteins participate in numerous [...] Read more.
Sarcomas represent one of the most challenging tumor types to treat due to their diverse nature and our incomplete understanding of their underlying biology. Recent work suggests cyclin-dependent kinase (CDK) pathway activation is a powerful driver of sarcomagenesis. CDK proteins participate in numerous cellular processes required for normal cell function, but their dysregulation is a hallmark of many pathologies including cancer. The contributions and significance of aberrant CDK activity to sarcoma development, however, is only partly understood. Here, we describe what is known about CDK-related alterations in the most common subtypes of sarcoma and highlight areas that warrant further investigation. As disruptions in CDK pathways appear in most, if not all, subtypes of sarcoma, we discuss the history and value of pharmacologically targeting CDKs to combat these tumors. The goals of this review are to (1) assess the prevalence and importance of CDK pathway alterations in sarcomas, (2) highlight the gap in knowledge for certain CDKs in these tumors, and (3) provide insight into studies focused on CDK inhibition for sarcoma treatment. Overall, growing evidence demonstrates a crucial role for activated CDKs in sarcoma development and as important targets for sarcoma therapy. Full article
(This article belongs to the Special Issue Cyclin-Dependent Kinases in Health and Diseases)
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Article
Sweet Cherry (Prunus avium L.) PaPIP1;4 Is a Functional Aquaporin Upregulated by Pre-Harvest Calcium Treatments that Prevent Cracking
Int. J. Mol. Sci. 2020, 21(8), 3017; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083017 - 24 Apr 2020
Cited by 2 | Viewed by 1183
Abstract
The involvement of aquaporins in rain-induced sweet cherry (Prunus avium L.) fruit cracking is an important research topic with potential agricultural applications. In the present study, we performed the functional characterization of PaPIP1;4, the most expressed aquaporin in sweet cherry fruit. Field [...] Read more.
The involvement of aquaporins in rain-induced sweet cherry (Prunus avium L.) fruit cracking is an important research topic with potential agricultural applications. In the present study, we performed the functional characterization of PaPIP1;4, the most expressed aquaporin in sweet cherry fruit. Field experiments focused on the pre-harvest exogenous application to sweet cherry trees, cultivar Skeena, with a solution of 0.5% CaCl2, which is the most common treatment to prevent cracking. Results show that PaPIP1;4 was mostly expressed in the fruit peduncle, but its steady-state transcript levels were higher in fruits from CaCl2-treated plants than in controls. The transient expression of PaPIP1;4-GFP in tobacco epidermal cells and the overexpression of PaPIP1;4 in YSH1172 yeast mutation showed that PaPIP1;4 is a plasma membrane protein able to transport water and hydrogen peroxide. In this study, we characterized for the first time a plasma membrane sweet cherry aquaporin able to transport water and H2O2 that is upregulated by the pre-harvest exogenous application of CaCl2 supplements. Full article
(This article belongs to the Special Issue Channels and Transporters in Cells and Tissues 2.0)
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Review
The Role of miRNA and Related Pathways in Pathophysiology of Uterine Fibroids—From Bench to Bedside
Int. J. Mol. Sci. 2020, 21(8), 3016; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083016 - 24 Apr 2020
Cited by 7 | Viewed by 2812
Abstract
Uterine fibroids (UFs) are the most common benign tumors of the female genital tract. Their prevalence usually is estimated at 30–40%, but may reach up to 70–80% in predisposed groups of women. UFs may cause various clinical issues which might constitute the major [...] Read more.
Uterine fibroids (UFs) are the most common benign tumors of the female genital tract. Their prevalence usually is estimated at 30–40%, but may reach up to 70–80% in predisposed groups of women. UFs may cause various clinical issues which might constitute the major reason of the overall deterioration of the quality of life. The mechanisms leading to UFs formation and growth still remain poorly understood. The transformation of smooth muscle cells of the uterus into abnormal, immortal cells, capable of clonal division, is thought to be a starting point of all pathways leading to UF formation. Micro-ribonucleic acids (miRNAs) are non-coding single-stranded RNAs about 22 nucleotides in length, that regulate gene expression. One of recent advances in this field is the comprehension of the role of miRNAs in tumorigenesis. Alterations in the levels of miRNAs are related to the formation and growth of several tumors which show a distinct miRNA signature. The aim of this review is to summarize the current data about the role of miRNAs in the pathophysiology of UFs. We also discuss future directions in the miRNA research area with an emphasis on novel diagnostic opportunities or patient-tailored therapies. In our opinion data concerning the regulation of miRNA and its gene targets in the UFs are still insufficient in comparison with gynecological malignancies. The potential translational use of miRNA and derived technologies in the clinical care is at the early phase and needs far more evidence. However, it is one of the main areas of interest for the future as the use of miRNAs in the diagnostics and treatment of UFs is a new and exciting opportunity. Full article
(This article belongs to the Special Issue Therapeutic Molecular Targets in Tumor Microenvironment)
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Article
Genome-Scale Analysis of Homologous Genes among Subgenomes of Bread Wheat (Triticum aestivum L.)
Int. J. Mol. Sci. 2020, 21(8), 3015; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083015 - 24 Apr 2020
Cited by 3 | Viewed by 1005
Abstract
Determining the distribution and correspondence of genome-scale homologous genes in wheat are effective ways to uncover chromosome rearrangement that has occurred during crop evolution and domestication, which can contribute to improvements in crop breeding. High-resolution and comprehensive analysis of the wheat genome by [...] Read more.
Determining the distribution and correspondence of genome-scale homologous genes in wheat are effective ways to uncover chromosome rearrangement that has occurred during crop evolution and domestication, which can contribute to improvements in crop breeding. High-resolution and comprehensive analysis of the wheat genome by the International Wheat Genome Sequencing Consortium (IWGSC) revealed a total of 88,733 high-confidence homologous genes of four major types (1:1:1, 1:1:0, 0:1:1 and 1:0:1) among the A, B and D subgenomes of wheat. This data was used to compare homologous gene densities among chromosomes, clarify their distribution and correspondence relationship, and compare their functional enrichment. The average density of 1:1:1 homologous genes was about 10 times more than the density of the other three types of homologous genes, although the homologous gene densities of the various chromosomes were similar within each homologous type. Three regions of exceptional density were detected in 1:1:1 homologous genes, the isolate peak on the tail of chromosome 4A, and the desert regions at the start of chromosome 7A and 7D. The correspondence between homologous genes of the wheat subgenomes demonstrated translocation between the tail segments of chromosome 4A and 5A, and the inversion of the segment of original 5A and 7B into the tail of 4A. The homologous genes on the inserting segments of 5A and 7B to 4A were highly enriched in nitrogen, primary metabolite and small molecular metabolism processes, compared with genes on other regions of the original 4A chromosome. This study provides a refined genome-scale reference of homologous genes for wheat molecular research and breeding, which will help to broaden the application of the wheat genome and can be used as a template for research on other polyploid plants. Full article
(This article belongs to the Special Issue Wheat Breeding through Genetic and Physical Mapping)
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Article
HMGA1-Regulating microRNAs Let-7a and miR-26a are Downregulated in Human Seminomas
Int. J. Mol. Sci. 2020, 21(8), 3014; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083014 - 24 Apr 2020
Cited by 7 | Viewed by 1083
Abstract
Background: Recent studies have underlined HMGA protein’s key role in the onset of testicular germ cell tumors, where HMGA1 is differently expressed with respect to the state of differentiation, suggesting its fine regulation as master regulator in testicular tumorigenesis. Several studies have highlighted [...] Read more.
Background: Recent studies have underlined HMGA protein’s key role in the onset of testicular germ cell tumors, where HMGA1 is differently expressed with respect to the state of differentiation, suggesting its fine regulation as master regulator in testicular tumorigenesis. Several studies have highlighted that the HMGA1 transcript is strictly regulated by a set of inhibitory microRNAs. Thus, the aim of this study is to test whether HMGA1 overexpression in human seminomas may be induced by the deregulation of miR-26a and Let-7a—two HMGA1-targeting microRNAs. Methods: HMGA1 mRNA and Let-7a and miR-26a levels were measured in a seminoma dataset available in the Cancer Genome Atlas database and confirmed in a subset of seminomas by qRT-PCR and western blot. A TCam-2 seminoma cell line was then transfected with Let-7a and miR-26a and tested for proliferation and motility abilities. Results: an inverse correlation was found between the expression of miR-26a and Let-7a and HMGA1 expression levels in seminomas samples, suggesting a critical role of these microRNAs in HMGA1 levels regulation. Accordingly, functional studies showed that miR-26a and Let-7a inhibited the proliferation, migration and invasion capabilities of the human seminoma derived cell line TCam-2. Conclusions: these data strongly support that the upregulation of HMGA1 levels occurring in seminoma is—at least in part—due to the downregulation of HMGA1-targeting microRNAs. Full article
(This article belongs to the Special Issue Germ Cells and Genitourinary Cancers)
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Review
Role of Non-Coding RNAs in Lung Circadian Clock Related Diseases
Int. J. Mol. Sci. 2020, 21(8), 3013; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083013 - 24 Apr 2020
Cited by 2 | Viewed by 1097
Abstract
Circadian oscillations are regulated at both central and peripheral levels to maintain physiological homeostasis. The central circadian clock consists of a central pacemaker in the suprachiasmatic nucleus that is entrained by light dark cycles and this, in turn, synchronizes the peripheral clock inherent [...] Read more.
Circadian oscillations are regulated at both central and peripheral levels to maintain physiological homeostasis. The central circadian clock consists of a central pacemaker in the suprachiasmatic nucleus that is entrained by light dark cycles and this, in turn, synchronizes the peripheral clock inherent in other organs. Circadian dysregulation has been attributed to dysregulation of peripheral clock and also associated with several diseases. Components of the molecular clock are disrupted in lung diseases like chronic obstructive pulmonary disease (COPD), asthma and IPF. Airway epithelial cells play an important role in temporally organizing magnitude of immune response, DNA damage response and acute airway inflammation. Non-coding RNAs play an important role in regulation of molecular clock and in turn are also regulated by clock components. Dysregulation of these non-coding RNAs have been shown to impact the expression of core clock genes as well as clock output genes in many organs. However, no studies have currently looked at the potential impact of these non-coding RNAs on lung molecular clock. This review focuses on the ways how these non-coding RNAs regulate and in turn are regulated by the lung molecular clock and its potential impact on lung diseases. Full article
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Article
FGCaMP7, an Improved Version of Fungi-Based Ratiometric Calcium Indicator for In Vivo Visualization of Neuronal Activity
Int. J. Mol. Sci. 2020, 21(8), 3012; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083012 - 24 Apr 2020
Cited by 8 | Viewed by 2192
Abstract
Genetically encoded calcium indicators (GECIs) have become a widespread tool for the visualization of neuronal activity. As compared to popular GCaMP GECIs, the FGCaMP indicator benefits from calmodulin and M13-peptide from the fungi Aspergillus niger and Aspergillus fumigatus, which prevent its interaction [...] Read more.
Genetically encoded calcium indicators (GECIs) have become a widespread tool for the visualization of neuronal activity. As compared to popular GCaMP GECIs, the FGCaMP indicator benefits from calmodulin and M13-peptide from the fungi Aspergillus niger and Aspergillus fumigatus, which prevent its interaction with the intracellular environment. However, FGCaMP exhibits a two-phase fluorescence behavior with the variation of calcium ion concentration, has moderate sensitivity in neurons (as compared to the GCaMP6s indicator), and has not been fully characterized in vitro and in vivo. To address these limitations, we developed an enhanced version of FGCaMP, called FGCaMP7. FGCaMP7 preserves the ratiometric phenotype of FGCaMP, with a 3.1-fold larger ratiometric dynamic range in vitro. FGCaMP7 demonstrates 2.7- and 8.7-fold greater photostability compared to mEGFP and mTagBFP2 fluorescent proteins in vitro, respectively. The ratiometric response of FGCaMP7 is 1.6- and 1.4-fold higher, compared to the intensiometric response of GCaMP6s, in non-stimulated and stimulated neuronal cultures, respectively. We reveal the inertness of FGCaMP7 to the intracellular environment of HeLa cells using its truncated version with a deleted M13-like peptide; in contrast to the similarly truncated variant of GCaMP6s. We characterize the crystal structure of the parental FGCaMP indicator. Finally, we test the in vivo performance of FGCaMP7 in mouse brain using a two-photon microscope and an NVista miniscope; and in zebrafish using two-color ratiometric confocal imaging. Full article
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Article
MfPIF1 of Resurrection Plant Myrothamnus flabellifolia Plays a Positive Regulatory Role in Responding to Drought and Salinity Stresses in Arabidopsis
Int. J. Mol. Sci. 2020, 21(8), 3011; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083011 - 24 Apr 2020
Cited by 2 | Viewed by 1054
Abstract
Phytochrome-interacting factors (PIFs), a subfamily of basic helix-loop-helix (bHLH) transcription factors (TFs), play critical roles in regulating plant growth and development. The resurrection plant Myrothamnus flabellifolia possesses a noteworthy tolerance to desiccation, but no PIFs related to the response to abiotic stress have [...] Read more.
Phytochrome-interacting factors (PIFs), a subfamily of basic helix-loop-helix (bHLH) transcription factors (TFs), play critical roles in regulating plant growth and development. The resurrection plant Myrothamnus flabellifolia possesses a noteworthy tolerance to desiccation, but no PIFs related to the response to abiotic stress have been functionally studied. In this study, a dehydration-inducible PIF gene, MfPIF1, was cloned and characterized. Subcellular localization assay revealed that MfPIF1 is localized predominantly in the nucleus. Overexpression of MfPIF1 in Arabidopsis thaliana led to enhanced drought and salinity tolerance, which was attributed to higher contents of chlorophyll, proline (Pro), soluble protein, and soluble sugar, activities of antioxidant enzymes as well as lower water loss rate, malondialdehyde (MDA) content, and reactive oxygen species (ROS) accumulation in transgenic lines compared with control plants. Moreover, MfPIF1 decreased stomatal aperture after drought and abscisic acid (ABA) treatment, and increased expression of both ABA biosynthesis and ABA-responsive genes including NCED3, P5CS, and RD29A. Overall, these results indicated that MfPIF1 may act as a positive regulator to drought and salinity responses, and therefore could be considered as a potential gene for plant genetic improvement of drought and salinity tolerance. Full article
(This article belongs to the Section Molecular Plant Sciences)
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Review
Novel Insights into the Pathogenesis of Spinal Sarcopenia and Related Therapeutic Approaches: A Narrative Review
Int. J. Mol. Sci. 2020, 21(8), 3010; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083010 - 24 Apr 2020
Cited by 2 | Viewed by 1705
Abstract
Spinal sarcopenia is a complex and multifactorial disorder associated with a loss of strength, increased frailty, and increased risks of fractures and falls. In addition, spinal sarcopenia has been associated with lumbar spine disorders and osteoporosis, which renders making decisions on treatment modalities [...] Read more.
Spinal sarcopenia is a complex and multifactorial disorder associated with a loss of strength, increased frailty, and increased risks of fractures and falls. In addition, spinal sarcopenia has been associated with lumbar spine disorders and osteoporosis, which renders making decisions on treatment modalities difficult. Patients with spinal sarcopenia typically exhibit lower cumulative survival, a higher risk of in-hospital complications, prolonged hospital stays, higher postoperative costs, and higher rates of blood transfusion after thoracolumbar spine surgery. Several studies have focused on the relationships between spinal sarcopenia, appendicular muscle mass, and bone-related problems—such as osteoporotic fractures and low bone mineral density—and malnutrition and vitamin D deficiency. Although several techniques are available for measuring sarcopenia, each of them has its advantages and shortcomings. For treating spinal sarcopenia, nutrition, physical therapy, and medication have been proven to be effective; regenerative therapeutic options seem to be promising owing to their repair and regeneration potential. Therefore, in this narrative review, we summarize the characteristics, detection methodologies, and treatment options for spinal sarcopenia, as well as its role in spinal disorders. Full article
(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Sarcopenia)
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Communication
Human NANOS1 Represses Apoptosis by Downregulating Pro-Apoptotic Genes in the Male Germ Cell Line
Int. J. Mol. Sci. 2020, 21(8), 3009; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083009 - 24 Apr 2020
Cited by 2 | Viewed by 1154
Abstract
While two mouse NANOS paralogues, NANOS2 and NANOS3, are crucial for maintenance of germ cells by suppression of apoptosis, the mouse NANOS1 paralogue does not seem to regulate these processes. Previously, we described a human NANOS1 p.[(Pro34Thr);(Ser83del)] mutation associated with the absence of [...] Read more.
While two mouse NANOS paralogues, NANOS2 and NANOS3, are crucial for maintenance of germ cells by suppression of apoptosis, the mouse NANOS1 paralogue does not seem to regulate these processes. Previously, we described a human NANOS1 p.[(Pro34Thr);(Ser83del)] mutation associated with the absence of germ cells in seminiferous tubules of infertile patients, which might suggest an anti-apoptotic role of human NANOS1. In this study, we aimed to determine a potential influence of human NANOS1 on the maintenance of TCam-2 model germ cells by investigating proliferation, cell cycle, and apoptosis. Constructs encoding wild-type or mutated human NANOS1 were used for transfection of TCam-2 cells, in order to investigate the effect of NANOS1 on cell proliferation, which was studied using a colorimetric assay, as well as apoptosis and the cell cycle, which were measured by flow cytometry. RNA-Seq (RNA sequencing) analysis followed by RT-qPCR (reverse transcription and quantitative polymerase chain reaction) was conducted for identifying pro-apoptotic genes repressed by NANOS1. Here, we show that overexpression of NANOS1 downregulates apoptosis in TCam-2 cells. Moreover, we found that NANOS1 represses a set of pro-apoptotic genes at the mRNA level. We also found that the infertility-associated p.[(Pro34Thr);(Ser83del)] mutation causes NANOS1 to functionally switch from being anti-apoptotic to pro-apoptotic in the human male germ cell line. Thus, this report is the first to show an anti-apoptotic role of NANOS1 exerted by negative regulation of mRNAs of pro-apoptotic genes. Full article
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Article
Fear Learning Enhances Prefrontal Cortical Suppression of Auditory Thalamic Inputs to the Amygdala in Adults, but Not Adolescents
Int. J. Mol. Sci. 2020, 21(8), 3008; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083008 - 24 Apr 2020
Cited by 4 | Viewed by 1061
Abstract
Adolescence is characterized by increased susceptibility to the development of fear- and anxiety-related disorders. Adolescents also show elevated fear responding and aversive learning that is resistant to behavioral interventions, which may be related to alterations in the circuitry supporting fear learning. These features [...] Read more.
Adolescence is characterized by increased susceptibility to the development of fear- and anxiety-related disorders. Adolescents also show elevated fear responding and aversive learning that is resistant to behavioral interventions, which may be related to alterations in the circuitry supporting fear learning. These features are linked to ongoing adolescent development of medial prefrontal cortical (PFC) inputs to the basolateral amygdala (BLA) that regulate neural activity and contribute to the refinement of fear responses. Here, we tested the hypothesis that the extent of PFC inhibition of the BLA following fear learning is greater in adults than in adolescents, using anesthetized in vivo recordings to measure local field potentials (LFPs) evoked by stimulation of PFC or auditory thalamic (MgN) inputs to BLA. We found that BLA LFPs evoked by stimulation of MgN inputs were enhanced in adults following fear conditioning. Fear conditioning also led to reduced summation of BLA LFPs evoked in response to PFC train stimulation, and increased the capacity of PFC inhibition of MgN inputs in adults. These data suggest that fear conditioning recruits additional inhibitory capacity by PFC inputs to BLA in adults, but that this capacity is weaker in adolescents. These results provide insight into how the development of PFC inputs may relate to age differences in memory retention and persistence following aversive learning. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Memory Formation and Modification)
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Review
Deubiquitinase MYSM1 in the Hematopoietic System and beyond: A Current Review
Int. J. Mol. Sci. 2020, 21(8), 3007; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083007 - 24 Apr 2020
Cited by 7 | Viewed by 1406
Abstract
MYSM1 has emerged as an important regulator of hematopoietic stem cell function, blood cell production, immune response, and other aspects of mammalian physiology. It is a metalloprotease family protein with deubiquitinase catalytic activity, as well as SANT and SWIRM domains. MYSM1 normally localizes [...] Read more.
MYSM1 has emerged as an important regulator of hematopoietic stem cell function, blood cell production, immune response, and other aspects of mammalian physiology. It is a metalloprotease family protein with deubiquitinase catalytic activity, as well as SANT and SWIRM domains. MYSM1 normally localizes to the nucleus, where it can interact with chromatin and regulate gene expression, through deubiquitination of histone H2A and non-catalytic contacts with other transcriptional regulators. A cytosolic form of MYSM1 protein was also recently described and demonstrated to regulate signal transduction pathways of innate immunity, by promoting the deubiquitination of TRAF3, TRAF6, and RIP2. In this work we review the current knowledge on the molecular mechanisms of action of MYSM1 protein in transcriptional regulation, signal transduction, and potentially other cellular processes. The functions of MYSM1 in different cell types and aspects of mammalian physiology are also reviewed, highlighting the key checkpoints in hematopoiesis, immunity, and beyond regulated by MYSM1. Importantly, mutations in MYSM1 in human were recently linked to a rare hereditary disorder characterized by leukopenia, anemia, and other hematopoietic and developmental abnormalities. Our growing knowledge of MYSM1 functions and mechanisms of actions sheds important insights into its role in mammalian physiology and the etiology of the MYSM1-deficiency disorder in human. Full article
(This article belongs to the Special Issue Ubiquitination in Health and Diseases)
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Article
Transcriptomic Profiling of Circular RNA in Different Brain Regions of Parkinson’s Disease in a Mouse Model
Int. J. Mol. Sci. 2020, 21(8), 3006; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083006 - 24 Apr 2020
Cited by 13 | Viewed by 1423
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease and although many studies have been done on this disease, the underlying mechanisms are still poorly understood and further studies are warranted. Therefore, this study identified circRNA expression profiles in the cerebral cortex [...] Read more.
Parkinson’s disease (PD) is the second most common neurodegenerative disease and although many studies have been done on this disease, the underlying mechanisms are still poorly understood and further studies are warranted. Therefore, this study identified circRNA expression profiles in the cerebral cortex (CC), hippocampus (HP), striatum (ST), and cerebellum (CB) regions of the 1-methyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model using RNA sequencing (RNA-seq), and differentially expressed circRNA were validated using reverse transcription quantitative real-time PCR (qRT-PCR). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and competing endogenous RNA (ceRNA) network analyses were also performed to explore the potential function of circRNAs. The results show that, compared with the control group, 24, 66, 71, and 121 differentially expressed circRNAs (DE-circRNAs) were found in the CC, HP, ST, and CB, respectively. PDST vs. PDCB, PDST vs. PDHP, and PDCB vs. PDHP groups have 578, 110, and 749 DE-circRNAs, respectively. Then, seven DE-cirRNAs were selected for qRT-PCR verification, where the expressions were consistent with the sequencing analysis. The GO and KEGG pathway analyses revealed that these DE-circRNAs participate in several biological functions and signaling pathways, including glutamic synapse, neuron to neuron synapse, cell morphogenesis involved in neuron differentiation, Parkinson’s disease, axon guidance, cGMP-PKG signaling pathway, and PI3K-Akt signaling pathway. Furthermore, the KEGG analysis of the target genes predicted by DE-circRNAs indicated that the target genes predicted by mmu_circRNA_0003292, mmu_circRNA_0001320, mmu_circRNA_0005976, and mmu_circRNA_0005388 were involved in the PD-related pathway. Overall, this is the first study on the expression profile of circRNAs in the different brain regions of PD mouse model. These results might facilitate our understanding of the potential roles of circRNAs in the pathogenesis of PD. Moreover, the results also indicate that the mmu_circRNA_0003292-miRNA-132-Nr4a2 pathway might be involved in the regulation of the molecular mechanism of Parkinson’s disease. Full article
(This article belongs to the Section Molecular Neurobiology)
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Review
Epigenetic Regulation of Circadian Rhythm and Its Possible Role in Diabetes Mellitus
Int. J. Mol. Sci. 2020, 21(8), 3005; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083005 - 24 Apr 2020
Cited by 5 | Viewed by 1689
Abstract
This review aims to summarize the knowledge about the relationship between circadian rhythms and their influence on the development of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Circadian rhythms are controlled by internal molecular feedback loops that synchronize the organism with the [...] Read more.
This review aims to summarize the knowledge about the relationship between circadian rhythms and their influence on the development of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Circadian rhythms are controlled by internal molecular feedback loops that synchronize the organism with the external environment. These loops are affected by genetic and epigenetic factors. Genetic factors include polymorphisms and mutations of circadian genes. The expression of circadian genes is regulated by epigenetic mechanisms that change from prenatal development to old age. Epigenetic modifications are influenced by the external environment. Most of these modifications are affected by our own life style. Irregular circadian rhythm and low quality of sleep have been shown to increase the risk of developing T2DM and other metabolic disorders. Here, we attempt to provide a wide description of mutual relationships between epigenetic regulation, circadian rhythm, aging process and highlight new evidences that show possible therapeutic advance in the field of chrono-medicine which will be more important in the upcoming years. Full article
(This article belongs to the Special Issue Epigenetics of Diabetes and Related Complications)
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Commentary
RT-qPCR Testing of SARS-CoV-2: A Primer
Int. J. Mol. Sci. 2020, 21(8), 3004; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083004 - 24 Apr 2020
Cited by 57 | Viewed by 7079
Abstract
Testing for the presence of coronavirus is an essential diagnostic tool for monitoring and managing the current COVID-19 pandemic. The only reliable test in current use for testing acute infection targets the genome of SARS-CoV-2, and the most widely used method is quantitative [...] Read more.
Testing for the presence of coronavirus is an essential diagnostic tool for monitoring and managing the current COVID-19 pandemic. The only reliable test in current use for testing acute infection targets the genome of SARS-CoV-2, and the most widely used method is quantitative fluorescence-based reverse transcription polymerase chain reaction (RT-qPCR). Despite its ubiquity, there is a significant amount of uncertainty about how this test works, potential throughput and reliability. This has resulted in widespread misrepresentation of the problems faced using this test during the current COVID-19 epidemic. This primer provides simple, straightforward and impartial information about RT-qPCR. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Commentary
COVID-19 and RAS: Unravelling an Unclear Relationship
Int. J. Mol. Sci. 2020, 21(8), 3003; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083003 - 24 Apr 2020
Cited by 35 | Viewed by 3845
Abstract
The renin-angiotensin system (RAS) plays a main role in regulating blood pressure and electrolyte and liquid balance. Previous evidence suggests that RAS may represent an important target for the treatment of lung pathologies, especially for acute respiratory distress syndrome and chronic fibrotic disease. [...] Read more.
The renin-angiotensin system (RAS) plays a main role in regulating blood pressure and electrolyte and liquid balance. Previous evidence suggests that RAS may represent an important target for the treatment of lung pathologies, especially for acute respiratory distress syndrome and chronic fibrotic disease. The scientific community has recently focused its attention on angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor 1 (AT1R) inhibitors and their possible benefit/harms for patients infected by Coronavirus disease (COVID-19) who experience pneumonia, but there are still some doubts about the effects of these drugs in this setting. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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Review
Naltrexone Use in Treating Hypersexuality Induced by Dopamine Replacement Therapy: Impact of OPRM1 A/G Polymorphism on Its Effectiveness
Int. J. Mol. Sci. 2020, 21(8), 3002; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083002 - 24 Apr 2020
Cited by 4 | Viewed by 1226
Abstract
Hypersexuality is a well-known adverse side effect of dopamine replacement therapy (DRT), and anti-craving drugs could be an effective therapeutic option. Our aim was to update the knowledge on this issue, particularly on the influence of an Opioid Receptor Mu 1 (OPRM1 [...] Read more.
Hypersexuality is a well-known adverse side effect of dopamine replacement therapy (DRT), and anti-craving drugs could be an effective therapeutic option. Our aim was to update the knowledge on this issue, particularly on the influence of an Opioid Receptor Mu 1 (OPRM1) genetic polymorphism. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We also analyzed a case of iatrogenic hypersexuality that occurred in a patient treated with DRT. An analysis of the OPRM1 gene was performed on said patient. Our search identified 597 publications, of which only 7 were included in the final data synthesis. All seven publications involved naltrexone use. Five of them were case reports. None of the publications mentioned DRT side effects, nor did they report genetic data. Regarding our case report, the introduction of naltrexone corresponded with the resolution of the patient’s hypersexuality. Moreover, the patient carried the A/G genotype, which has been reported to be associated with a stronger response to naltrexone for patients with an alcohol use disorder. Although studies are inconclusive so far, naltrexone could be an interesting therapeutic option for resistant hypersexuality due to DRT. Carrying the A/G genotype could help explain a good response to treatment. Full article
(This article belongs to the Special Issue Pharmacogenomics)
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Article
Epidemiological and Genomic Characterization of Campylobacter jejuni Isolates from a Foodborne Outbreak at Hangzhou, China
Int. J. Mol. Sci. 2020, 21(8), 3001; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083001 - 24 Apr 2020
Cited by 15 | Viewed by 1330
Abstract
Background: Foodborne outbreaks caused by Campylobacter jejuni have become a significant public health problem worldwide. Applying genomic sequencing as a routine part of foodborne outbreak investigation remains in its infancy in China. We applied both traditional PFGE profiling and genomic investigation to understand [...] Read more.
Background: Foodborne outbreaks caused by Campylobacter jejuni have become a significant public health problem worldwide. Applying genomic sequencing as a routine part of foodborne outbreak investigation remains in its infancy in China. We applied both traditional PFGE profiling and genomic investigation to understand the cause of a foodborne outbreak in Hangzhou in December 2018. Method: A total of 43 fecal samples, including 27 sick patients and 16 canteen employees from a high school in Hangzhou city in Zhejiang province, were recruited. Routine real-time fluorescent PCR assays were used for scanning the potential infectious agents, including viral pathogens (norovirus, rotavirus, adenovirus, and astrovirus), and bacterial pathogens (Salmonella, Shigella, Campylobacter jejuni, Vibrio parahaemolyticus and Vibrio cholerae). Bacterial selection medium was used to isolate and identify the positive bacteria identified by molecular test. Pulsed field gel electrophoresis (PFGE), and next generation sequencing (NGS) were applied to fifteen recovered C. jejuni isolates to further understand the case linkage of this particular outbreak. Additionally, we retrieved reference genomes from the NCBI database and performed a comparative genomics analysis with the examined genomes produced in this study. Results: The analyzed samples were found to be negative for the queried viruses. Additionally, Salmonella, Shigella, Vibrio parahaemolyticus and Vibrio cholera were not detected. Fifteen C. jejuni strains were identified by the real-time PCR assay and bacterial selection medium. These C. jejuni strains were classified into two genetic profiles defined by the PFGE. Out of fifteen C. jejuni strains, fourteen have a unified consistent genotype belonging to ST2988, and the other strain belongs to ST8149, with a 66.7% similarity in comparison with the rest of the strains. Moreover, all fifteen strains harbored blaOXA-61 and tet(O), in addition to a chromosomal mutation in gyrA (T86I). The examined fourteen strains of ST2988 from CC354 clone group have very minimal genetic difference (3~66 SNPs), demonstrated by the phylogenomic investigation. Conclusion: Both genomic investigation and PFGE profiling confirmed that C. jejuni ST2988, a new derivative from CC354, was responsible for the foodborne outbreak Illustrated in this study. Full article
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Article
HIF-1β Positively Regulates NF-κB Activity via Direct Control of TRAF6
Int. J. Mol. Sci. 2020, 21(8), 3000; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083000 - 24 Apr 2020
Cited by 2 | Viewed by 1800
Abstract
NF-κB signalling is crucial for cellular responses to inflammation but is also associated with the hypoxia response. NF-κB and hypoxia inducible factor (HIF) transcription factors possess an intense molecular crosstalk. Although it is known that HIF-1α modulates NF-κB transcriptional response, very little is [...] Read more.
NF-κB signalling is crucial for cellular responses to inflammation but is also associated with the hypoxia response. NF-κB and hypoxia inducible factor (HIF) transcription factors possess an intense molecular crosstalk. Although it is known that HIF-1α modulates NF-κB transcriptional response, very little is understood regarding how HIF-1β contributes to NF-κB signalling. Here, we demonstrate that HIF-1β is required for full NF-κB activation in cells following canonical and non-canonical stimuli. We found that HIF-1β specifically controls TRAF6 expression in human cells but also in Drosophila melanogaster. HIF-1β binds to the TRAF6 gene and controls its expression independently of HIF-1α. Furthermore, exogenous TRAF6 expression is able to rescue all of the cellular phenotypes observed in the absence of HIF-1β. These results indicate that HIF-1β is an important regulator of NF-κB with consequences for homeostasis and human disease. Full article
(This article belongs to the Special Issue NF-κB and Disease)
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