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Int. J. Mol. Sci., Volume 22, Issue 7 (April-1 2021) – 512 articles

Cover Story (view full-size image): Alveolar macrophages (AMs) are the most abundant cell type in the bronchioalveolar space. With every breath, the human organism is confronted with a variety of pathogens, particles, or molecules. Here, AMs sense these various invaders and, thus, represent a crucial cell type within innate pulmonary immunity. AMs have been shown to be a highly plastic cell type, able to orchestrate not only pulmonary host response but also to maintain lung tissue homeostasis. Thus, dysfunction and/or impaired development of AMs can lead to various lung diseases, ranging from increased susceptibility to pathogens, congenital lung diseases or progressive lung disorders. Thus, insights into the role of AMs have laid the foundation for new drugs and even macrophage-based immunotherapies. View this paper.
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Review
Granulocytes and Cells of Granulocyte Origin—The Relevant Players in Colorectal Cancer
Int. J. Mol. Sci. 2021, 22(7), 3801; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073801 - 06 Apr 2021
Viewed by 1088
Abstract
Colorectal cancer (CRC) is one of the most common malignancy and cause of cancer death worldwide, and it still remains a therapeutic challenge for western medicine. There is strong evidence that, in addition to genetic predispositions, environmental factors have also a substantial impact [...] Read more.
Colorectal cancer (CRC) is one of the most common malignancy and cause of cancer death worldwide, and it still remains a therapeutic challenge for western medicine. There is strong evidence that, in addition to genetic predispositions, environmental factors have also a substantial impact in CRC development. The risk of CRC is attributed, among others to dietary habits, alcohol consumption, whereas physical activity, food containing dietary fiber, dairy products, and calcium supplements have a protective effect. Despite progress in the available therapies, surgery remains a basic treatment option for CRC. Implementation of additional methods of treatment such as chemo- and/or targeted immunotherapy, improved survival rates, however, the results are still far from satisfactory. One of the reasons may be the lack of deeper understanding of the interactions between the tumor and different types of cells, including tumor infiltrating granulocytes. While the role of neutrophils is quite well explored in many cancers, role of eosinophils and basophils is often underestimated. As part of this review, we focused on the function of different granulocyte subsets in CRC, emphasizing the beneficial role of eosinophils and basophils, as well as dichotomic mode of neutrophils action. In addition, we addressed the current knowledge on cells of granulocyte origin, specifically granulocytic myeloid derived suppressor cells (Gr-MDSCs) and their role in development and progression of CRC. Full article
(This article belongs to the Special Issue Tumor Microenvironment: Interactions and Therapeutic Response)
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Review
Antibacterial Titanium Implants Biofunctionalized by Plasma Electrolytic Oxidation with Silver, Zinc, and Copper: A Systematic Review
Int. J. Mol. Sci. 2021, 22(7), 3800; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073800 - 06 Apr 2021
Cited by 5 | Viewed by 1132
Abstract
Patients receiving orthopedic implants are at risk of implant-associated infections (IAI). A growing number of antibiotic-resistant bacteria threaten to hamper the treatment of IAI. The focus has, therefore, shifted towards the development of implants with intrinsic antibacterial activity to prevent the occurrence of [...] Read more.
Patients receiving orthopedic implants are at risk of implant-associated infections (IAI). A growing number of antibiotic-resistant bacteria threaten to hamper the treatment of IAI. The focus has, therefore, shifted towards the development of implants with intrinsic antibacterial activity to prevent the occurrence of infection. The use of Ag, Cu, and Zn has gained momentum as these elements display strong antibacterial behavior and target a wide spectrum of bacteria. In order to incorporate these elements into the surface of titanium-based bone implants, plasma electrolytic oxidation (PEO) has been widely investigated as a single-step process that can biofunctionalize these (highly porous) implant surfaces. Here, we present a systematic review of the studies published between 2009 until 2020 on the biomaterial properties, antibacterial behavior, and biocompatibility of titanium implants biofunctionalized by PEO using Ag, Cu, and Zn. We observed that 100% of surfaces bearing Ag (Ag-surfaces), 93% of surfaces bearing Cu (Cu-surfaces), 73% of surfaces bearing Zn (Zn-surfaces), and 100% of surfaces combining Ag, Cu, and Zn resulted in a significant (i.e., >50%) reduction of bacterial load, while 13% of Ag-surfaces, 10% of Cu-surfaces, and none of Zn or combined Ag, Cu, and Zn surfaces reported cytotoxicity against osteoblasts, stem cells, and immune cells. A majority of the studies investigated the antibacterial activity against S. aureus. Important areas for future research include the biofunctionalization of additively manufactured porous implants and surfaces combining Ag, Cu, and Zn. Furthermore, the antibacterial activity of such implants should be determined in assays focused on prevention, rather than the treatment of IAIs. These implants should be tested using appropriate in vivo bone infection models capable of assessing whether titanium implants biofunctionalized by PEO with Ag, Cu, and Zn can contribute to protect patients against IAI. Full article
(This article belongs to the Special Issue Antimicrobial Materials with Medical Applications)
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Review
Altered Metabolic Flexibility in Inherited Metabolic Diseases of Mitochondrial Fatty Acid Metabolism
Int. J. Mol. Sci. 2021, 22(7), 3799; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073799 - 06 Apr 2021
Cited by 2 | Viewed by 992
Abstract
In general, metabolic flexibility refers to an organism’s capacity to adapt to metabolic changes due to differing energy demands. The aim of this work is to summarize and discuss recent findings regarding variables that modulate energy regulation in two different pathways of mitochondrial [...] Read more.
In general, metabolic flexibility refers to an organism’s capacity to adapt to metabolic changes due to differing energy demands. The aim of this work is to summarize and discuss recent findings regarding variables that modulate energy regulation in two different pathways of mitochondrial fatty metabolism: β-oxidation and fatty acid biosynthesis. We focus specifically on two diseases: very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and malonyl-CoA synthetase deficiency (acyl-CoA synthetase family member 3 (ACSF3)) deficiency, which are both characterized by alterations in metabolic flexibility. On the one hand, in a mouse model of VLCAD-deficient (VLCAD−/−) mice, the white skeletal muscle undergoes metabolic and morphologic transdifferentiation towards glycolytic muscle fiber types via the up-regulation of mitochondrial fatty acid biosynthesis (mtFAS). On the other hand, in ACSF3-deficient patients, fibroblasts show impaired mitochondrial respiration, reduced lipoylation, and reduced glycolytic flux, which are compensated for by an increased β-oxidation rate and the use of anaplerotic amino acids to address the energy needs. Here, we discuss a possible co-regulation by mtFAS and β-oxidation in the maintenance of energy homeostasis. Full article
(This article belongs to the Special Issue Energy Metabolism in Health and Disease)
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Review
Cannabidiol and the Canonical WNT/β-Catenin Pathway in Glaucoma
Int. J. Mol. Sci. 2021, 22(7), 3798; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073798 - 06 Apr 2021
Viewed by 1041
Abstract
Glaucoma is a progressive neurodegenerative disease which constitutes the main frequent cause of irreversible blindness. Recent findings have shown that oxidative stress, inflammation and glutamatergic pathway play key roles in the causes of glaucoma. Recent studies have shown a down regulation of the [...] Read more.
Glaucoma is a progressive neurodegenerative disease which constitutes the main frequent cause of irreversible blindness. Recent findings have shown that oxidative stress, inflammation and glutamatergic pathway play key roles in the causes of glaucoma. Recent studies have shown a down regulation of the WNT/β-catenin pathway in glaucoma, associated with overactivation of the GSK-3β signaling. WNT/β-catenin pathway is mainly associated with oxidative stress, inflammation and glutamatergic pathway. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa plant which possesses many therapeutic properties across a range of neuropsychiatric disorders. Since few years, CBD presents an increased interest as a possible drug in anxiolytic disorders. CBD administration is associated with increase of the WNT/β-catenin pathway and decrease of the GSK-3β activity. CBD has a lower affinity for CB1 but can act through other signaling in glaucoma, including the WNT/β-catenin pathway. CBD downregulates GSK3-β activity, an inhibitor of WNT/β-catenin pathway. Moreover, CBD was reported to suppress pro-inflammatory signaling and neuroinflammation, oxidative stress and glutamatergic pathway. Thus, this review focuses on the potential effects of cannabidiol, as a potential therapeutic strategy, on glaucoma and some of the presumed mechanisms by which this phytocannabinoid provides its possible benefit properties through the WNT/β-catenin pathway. Full article
(This article belongs to the Special Issue Towards an Understanding of Retinal Diseases and Novel Treatment)
Article
Combining Magnetic Resonance Imaging with Systemic Monocyte Evaluation for the Implementation of GBM Management
Int. J. Mol. Sci. 2021, 22(7), 3797; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073797 - 06 Apr 2021
Viewed by 769
Abstract
Magnetic resonance imaging (MRI) is the gold standard for glioblastoma (GBM) patient evaluation. Additional non-invasive diagnostic modalities are needed. GBM is heavily infiltrated with tumor-associated macrophages (TAMs) that can be found in peripheral blood. FKBP51s supports alternative-macrophage polarization. Herein, we assessed FKBP51s expression [...] Read more.
Magnetic resonance imaging (MRI) is the gold standard for glioblastoma (GBM) patient evaluation. Additional non-invasive diagnostic modalities are needed. GBM is heavily infiltrated with tumor-associated macrophages (TAMs) that can be found in peripheral blood. FKBP51s supports alternative-macrophage polarization. Herein, we assessed FKBP51s expression in circulating monocytes from 14 GBM patients. The M2 monocyte phenotype was investigated by qPCR and flow cytometry using antibodies against PD-L1, CD163, FKBP51s, and CD14. MRI assessed morphologic features of the tumors that were aligned to flow cytometry data. PD-L1 expression on circulating monocytes correlated with MRI tumor necrosis score. A wider expansion in circulating CD163/monocytes was measured. These monocytes resulted in a dramatic decrease in patients with an MRI diagnosis of complete but not partial surgical removal of the tumor. Importantly, in patients with residual tumor, most of the peripheral monocytes that in the preoperative stage were CD163/FKBP51s− had turned into CD163/FKBP51s+. After Stupp therapy, CD163/FKBP51s+ monocytes were almost absent in a case of pseudoprogression, while two patients with stable or true disease progression showed sustained levels in such circulating monocytes. Our work provides preliminary but meaningful and novel results that deserve to be confirmed in a larger patient cohort, in support of potential usefulness in GBM monitoring of CD163/FKBP51s/CD14 immunophenotype in adjunct to MRI. Full article
(This article belongs to the Special Issue Frontiers in Neuro-Oncology)
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Article
Differential Expression of Sphingolipid Metabolizing Enzymes in Spontaneously Hypertensive Rats: A Possible Substrate for Susceptibility to Brain and Kidney Damage
Int. J. Mol. Sci. 2021, 22(7), 3796; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073796 - 06 Apr 2021
Viewed by 630
Abstract
Alterations in the metabolism of sphingolipids, a class of biologically active molecules in cell membranes with direct effect on vascular homeostasis, are increasingly recognized as important determinant in different vascular disorders. However, it is not clear whether sphingolipids are implicated in the pathogenesis [...] Read more.
Alterations in the metabolism of sphingolipids, a class of biologically active molecules in cell membranes with direct effect on vascular homeostasis, are increasingly recognized as important determinant in different vascular disorders. However, it is not clear whether sphingolipids are implicated in the pathogenesis of hypertension-related cerebrovascular and renal damage. In this study, we evaluated the existence of possible abnormalities related to the sphingolipid metabolism in the brain and kidneys of two well validated spontaneously hypertensive rat strains, the stroke-prone (SHRSP) and the stroke-resistant (SHRSR) models, as compared to the normotensive Wistar Kyoto (WKY) rat strain. Our results showed a global alteration in the metabolism of sphingolipids in both cerebral and renal tissues of both hypertensive strains as compared to the normotensive rat. However, few defects, such as reduced expression of enzymes involved in the metabolism/catabolism of sphingosine-1-phosphate and in the de novo biosynthetic pathways, were exclusively detected in the SHRSP. Although further studies are necessary to fully understand the significance of these findings, they suggest that defects in specific lipid molecules and/or their related metabolic pathways may likely contribute to the pathogenesis of hypertensive target organ damage and may eventually serve as future therapeutic targets to reduce the vascular consequences of hypertension. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases)
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Article
Towards the Enhancement of Essential Oil Components’ Antimicrobial Activity Using New Zein Protein-Gated Mesoporous Silica Microdevices
Int. J. Mol. Sci. 2021, 22(7), 3795; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073795 - 06 Apr 2021
Cited by 1 | Viewed by 639
Abstract
The development of new food preservatives is essential to prevent foodborne outbreaks or food spoilage due to microbial growth, enzymatic activity or oxidation. Furthermore, new compounds that substitute the commonly used synthetic food preservatives are needed to stifle the rising problem of microbial [...] Read more.
The development of new food preservatives is essential to prevent foodborne outbreaks or food spoilage due to microbial growth, enzymatic activity or oxidation. Furthermore, new compounds that substitute the commonly used synthetic food preservatives are needed to stifle the rising problem of microbial resistance. In this scenario, we report herein, as far as we know, for the first time the use of the zein protein as a gating moiety and its application for the controlled release of essential oil components (EOCs). The design of microdevices consist of mesoporous silica particles loaded with essential oils components (thymol, carvacrol and cinnamaldehyde) and functionalized with the zein (prolamin) protein found in corn as a molecular gate. The zein protein grafted on the synthesized microdevices is degraded by the proteolytic action of bacterial enzymatic secretions with the consequent release of the loaded essential oil components efficiently inhibiting bacterial growth. The results allow us to conclude that the new microdevice presented here loaded with the essential oil component cinnamaldehyde improved the antimicrobial properties of the free compound by decreasing volatility and increasing local concentration. Full article
(This article belongs to the Special Issue Ordered Mesoporous Materials)
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Article
Excitatory Effects of Calcitonin Gene-Related Peptide (CGRP) on Superficial Sp5C Neurons in Mouse Medullary Slices
Int. J. Mol. Sci. 2021, 22(7), 3794; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073794 - 06 Apr 2021
Viewed by 633
Abstract
The neuromodulator calcitonin gene-related peptide (CGRP) is known to facilitate nociceptive transmission in the superficial laminae of the spinal trigeminal nucleus caudalis (Sp5C). The central effects of CGRP in the Sp5C are very likely to contribute to the activation of central nociceptive pathways [...] Read more.
The neuromodulator calcitonin gene-related peptide (CGRP) is known to facilitate nociceptive transmission in the superficial laminae of the spinal trigeminal nucleus caudalis (Sp5C). The central effects of CGRP in the Sp5C are very likely to contribute to the activation of central nociceptive pathways leading to attacks of severe headaches like migraine. To examine the potential impacts of CGRP on laminae I/II neurons at cellular and synaptic levels, we performed whole-cell patch-clamp recordings in juvenile mouse brainstem slices. First, we tested the effect of CGRP on cell excitability, focusing on neurons with tonically firing action potentials upon depolarizing current injection. CGRP (100 nM) enhanced tonic discharges together with membrane depolarization, an excitatory effect that was significantly reduced when the fast synaptic transmissions were pharmacologically blocked. However, CGRP at 500 nM was capable of exciting the functionally isolated cells, in a nifedipine-sensitive manner, indicating its direct effect on membrane intrinsic properties. In voltage-clamped cells, 100 nM CGRP effectively increased the frequency of excitatory synaptic inputs, suggesting its preferential presynaptic effect. Both CGRP-induced changes in cell excitability and synaptic drives were prevented by the CGRP receptor inhibitor BIBN 4096BS. Our data provide evidence that CGRP increases neuronal activity in Sp5C superficial laminae by dose-dependently promoting excitatory synaptic drive and directly enhancing cell intrinsic properties. We propose that the combination of such pre- and postsynaptic actions of CGRP might underlie its facilitation in nociceptive transmission in situations like migraine with elevated CGRP levels. Full article
(This article belongs to the Special Issue Neuropeptides, Receptors, and Behavior)
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Article
Predicting the Structure and Dynamics of Membrane Protein GerAB from Bacillus subtilis
Int. J. Mol. Sci. 2021, 22(7), 3793; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073793 - 06 Apr 2021
Viewed by 847
Abstract
Bacillus subtilis forms dormant spores upon nutrient depletion. Germinant receptors (GRs) in spore’s inner membrane respond to ligands such as L-alanine, and trigger spore germination. In B. subtilis spores, GerA is the major GR, and has three subunits, GerAA, GerAB, and GerAC. L-Alanine [...] Read more.
Bacillus subtilis forms dormant spores upon nutrient depletion. Germinant receptors (GRs) in spore’s inner membrane respond to ligands such as L-alanine, and trigger spore germination. In B. subtilis spores, GerA is the major GR, and has three subunits, GerAA, GerAB, and GerAC. L-Alanine activation of GerA requires all three subunits, but which binds L-alanine is unknown. To date, how GRs trigger germination is unknown, in particular due to lack of detailed structural information about B subunits. Using homology modelling with molecular dynamics (MD) simulations, we present structural predictions for the integral membrane protein GerAB. These predictions indicate that GerAB is an α-helical transmembrane protein containing a water channel. The MD simulations with free L-alanine show that alanine binds transiently to specific sites on GerAB. These results provide a starting point for unraveling the mechanism of L-alanine mediated signaling by GerAB, which may facilitate early events in spore germination. Full article
(This article belongs to the Section Biochemistry)
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Article
Altered microRNA Transcriptome in Cultured Human Liver Cells upon Infection with Ebola Virus
Int. J. Mol. Sci. 2021, 22(7), 3792; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073792 - 06 Apr 2021
Viewed by 752
Abstract
Ebola virus (EBOV) is a virulent pathogen, notorious for inducing life-threatening hemorrhagic fever, that has been responsible for several outbreaks in Africa and remains a public health threat. Yet, its pathogenesis is still not completely understood. Although there have been numerous studies on [...] Read more.
Ebola virus (EBOV) is a virulent pathogen, notorious for inducing life-threatening hemorrhagic fever, that has been responsible for several outbreaks in Africa and remains a public health threat. Yet, its pathogenesis is still not completely understood. Although there have been numerous studies on host transcriptional response to EBOV, with an emphasis on the clinical features, the impact of EBOV infection on post-transcriptional regulatory elements, such as microRNAs (miRNAs), remains largely unexplored. MiRNAs are involved in inflammation and immunity and are believed to be important modulators of the host response to viral infection. Here, we have used small RNA sequencing (sRNA-Seq), qPCR and functional analyses to obtain the first comparative miRNA transcriptome (miRNome) of a human liver cell line (Huh7) infected with one of the following three EBOV strains: Mayinga (responsible for the first Zaire outbreak in 1976), Makona (responsible for the West Africa outbreak in 2013–2016) and the epizootic Reston (presumably innocuous to humans). Our results highlight specific miRNA-based immunity pathways and substantial differences between the strains beyond their clinical manifestation and pathogenicity. These analyses shed new light into the molecular signature of liver cells upon EBOV infection and reveal new insights into miRNA-based virus attack and host defense strategy. Full article
(This article belongs to the Special Issue Host–Pathogen Interaction 2.0)
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Review
Ssu72 Dual-Specific Protein Phosphatase: From Gene to Diseases
Int. J. Mol. Sci. 2021, 22(7), 3791; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073791 - 06 Apr 2021
Viewed by 859
Abstract
More than 70% of eukaryotic proteins are regulated by phosphorylation. However, the mechanism of dephosphorylation that counteracts phosphorylation is less studied. Phosphatases are classified into 104 distinct groups based on substrate-specific features and the sequence homologies in their catalytic domains. Among them, dual-specificity [...] Read more.
More than 70% of eukaryotic proteins are regulated by phosphorylation. However, the mechanism of dephosphorylation that counteracts phosphorylation is less studied. Phosphatases are classified into 104 distinct groups based on substrate-specific features and the sequence homologies in their catalytic domains. Among them, dual-specificity phosphatases (DUSPs) that dephosphorylate both phosphoserine/threonine and phosphotyrosine are important for cellular homeostasis. Ssu72 is a newly studied phosphatase with dual specificity that can dephosphorylate both phosphoserine/threonine and phosphotyrosine. It is important for cell-growth signaling, metabolism, and immune activation. Ssu72 was initially identified as a phosphatase for the Ser5 and Ser7 residues of the C-terminal domain of RNA polymerase II. It prefers the cis configuration of the serine–proline motif within its substrate and regulates Pin1, different from other phosphatases. It has recently been reported that Ssu72 can regulate sister chromatid cohesion and the separation of duplicated chromosomes during the cell cycle. Furthermore, Ssu72 appears to be involved in the regulation of T cell receptor signaling, telomere regulation, and even hepatocyte homeostasis in response to a variety of stress and damage signals. In this review, we aim to summarize various functions of the Ssu72 phosphatase, their implications in diseases, and potential therapeutic indications. Full article
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Article
Argon Plasma Exposure Augments Costimulatory Ligands and Cytokine Release in Human Monocyte-Derived Dendritic Cells
Int. J. Mol. Sci. 2021, 22(7), 3790; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073790 - 06 Apr 2021
Cited by 2 | Viewed by 715
Abstract
Cold physical plasma is a partially ionized gas expelling many reactive oxygen and nitrogen species (ROS/RNS). Several plasma devices have been licensed for medical use in dermatology, and recent experimental studies suggest their putative role in cancer treatment. In cancer therapies with an [...] Read more.
Cold physical plasma is a partially ionized gas expelling many reactive oxygen and nitrogen species (ROS/RNS). Several plasma devices have been licensed for medical use in dermatology, and recent experimental studies suggest their putative role in cancer treatment. In cancer therapies with an immunological dimension, successful antigen presentation and inflammation modulation is a key hallmark to elicit antitumor immunity. Dendritic cells (DCs) are critical for this task. However, the inflammatory consequences of DCs following plasma exposure are unknown. To this end, human monocyte-derived DCs (moDCs) were expanded from isolated human primary monocytes; exposed to plasma; and their metabolic activity, surface marker expression, and cytokine profiles were analyzed. As controls, hydrogen peroxide, hypochlorous acid, and peroxynitrite were used. Among all types of ROS/RNS-mediated treatments, plasma exposure exerted the most notable increase of activation markers at 24 h such as CD25, CD40, and CD83 known to be crucial for T cell costimulation. Moreover, the treatments increased interleukin (IL)-1α, IL-6, and IL-23. Altogether, this study suggests plasma treatment augmenting costimulatory ligand and cytokine expression in human moDCs, which might exert beneficial effects in the tumor microenvironment. Full article
(This article belongs to the Special Issue Plasma Biology)
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Review
Chronic Low Grade Inflammation in Pathogenesis of PCOS
Int. J. Mol. Sci. 2021, 22(7), 3789; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073789 - 06 Apr 2021
Cited by 1 | Viewed by 1603
Abstract
Polycystic ovary syndrome (PCOS) is a one of the most common endocrine disorders, with a prevalence rate of 5–10% in reproductive aged women. It’s characterized by (1) chronic anovulation, (2) biochemical and/or clinical hyperandrogenism, and (3) polycystic ovarian morphology. PCOS has significant clinical [...] Read more.
Polycystic ovary syndrome (PCOS) is a one of the most common endocrine disorders, with a prevalence rate of 5–10% in reproductive aged women. It’s characterized by (1) chronic anovulation, (2) biochemical and/or clinical hyperandrogenism, and (3) polycystic ovarian morphology. PCOS has significant clinical implications and can lead to health problems related to the accumulation of adipose tissue, such as obesity, insulin resistance, metabolic syndrome, and type 2 diabetes. There is also evidence that PCOS patients are at higher risk of cardiovascular diseases, atherosclerosis, and high blood pressure. Several studies have reported the association between polycystic ovary syndrome (PCOS) and low-grade chronic inflammation. According to known data, inflammatory markers or their gene markers are higher in PCOS patients. Correlations have been found between increased levels of C-reactive protein (CRP), interleukin 18 (IL-18), tumor necrosis factor (TNF-α), interleukin 6 (IL-6), white blood cell count (WBC), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α) in the PCOS women compared with age- and BMI-matched controls. Women with PCOS present also elevated levels of AGEs and increased RAGE (receptor for advanced glycation end products) expression. This chronic inflammatory state is aggravating by obesity and hyperinsulinemia. There are studies describing mutual impact of hyperinsulinemia and obesity, hyperandrogenism, and inflammatory state. Endothelial cell dysfunction may be also triggered by inflammatory cytokines. Many factors involved in oxidative stress, inflammation, and thrombosis were proposed as cardiovascular risk markers showing the endothelial cell damage in PCOS. Those markers include asymmetric dimethylarginine (ADMA), C-reactive protein (CRP), homocysteine, plasminogen activator inhibitor-I (PAI-I), PAI-I activity, vascular endothelial growth factor (VEGF) etc. It was also proposed that the uterine hyperinflammatory state in polycystic ovary syndrome may be responsible for significant pregnancy complications ranging from miscarriage to placental insufficiency. In this review, we discuss the most importance evidence concerning the role of the process of chronic inflammation in pathogenesis of PCOS. Full article
(This article belongs to the Special Issue Polycystic Ovary Syndrome: From Molecular Mechanisms to Therapies)
Review
Recent Perspectives on Sex Differences in Compulsion-Like and Binge Alcohol Drinking
Int. J. Mol. Sci. 2021, 22(7), 3788; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073788 - 06 Apr 2021
Cited by 3 | Viewed by 1316
Abstract
Alcohol use disorder remains a substantial social, health, and economic problem and problem drinking levels in women have been increasing in recent years. Understanding whether and how the underlying mechanisms that drive drinking vary by sex is critical and could provide novel, more [...] Read more.
Alcohol use disorder remains a substantial social, health, and economic problem and problem drinking levels in women have been increasing in recent years. Understanding whether and how the underlying mechanisms that drive drinking vary by sex is critical and could provide novel, more targeted therapeutic treatments. Here, we examine recent results from our laboratories and others which we believe provide useful insights into similarities and differences in alcohol drinking patterns across the sexes. Findings for binge intake and aversion-resistant, compulsion-like alcohol drinking are considered, since both are likely significant contributors to alcohol problems in humans. We also describe studies regarding mechanisms that may underlie sex differences in maladaptive alcohol drinking, with some focus on the importance of nucleus accumbens (NAcb) core and shell regions, several receptor types (dopamine, orexin, AMPA-type glutamate), and possible contributions of sex hormones. Finally, we discuss how stressors such as early life stress and anxiety-like states may interact with sex differences to contribute to alcohol drinking. Together, these findings underscore the importance and critical relevance of studying female and male mechanisms for alcohol and co-morbid conditions to gain a true and clinically useful understanding of addiction and neuropsychiatric mechanisms and treatment. Full article
Article
Phosphorylation of GAPVD1 Is Regulated by the PER Complex and Linked to GAPVD1 Degradation
Int. J. Mol. Sci. 2021, 22(7), 3787; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073787 - 06 Apr 2021
Viewed by 861
Abstract
Repressor protein period (PER) complexes play a central role in the molecular oscillator mechanism of the mammalian circadian clock. While the main role of nuclear PER complexes is transcriptional repression, much less is known about the functions of cytoplasmic PER complexes. We found [...] Read more.
Repressor protein period (PER) complexes play a central role in the molecular oscillator mechanism of the mammalian circadian clock. While the main role of nuclear PER complexes is transcriptional repression, much less is known about the functions of cytoplasmic PER complexes. We found with a biochemical screen for PER2-interacting proteins that the small GTPase regulator GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1), which has been identified previously as a component of cytoplasmic PER complexes in mice, is also a bona fide component of human PER complexes. We show that in situ GAPVD1 is closely associated with casein kinase 1 delta (CSNK1D), a kinase that regulates PER2 levels through a phosphoswitch mechanism, and that CSNK1D regulates the phosphorylation of GAPVD1. Moreover, phosphorylation determines the kinetics of GAPVD1 degradation and is controlled by PER2 and a C-terminal autoinhibitory domain in CSNK1D, indicating that the regulation of GAPVD1 phosphorylation is a novel function of cytoplasmic PER complexes and might be part of the oscillator mechanism or an output function of the circadian clock. Full article
(This article belongs to the Section Molecular Biology)
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Article
Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset
Int. J. Mol. Sci. 2021, 22(7), 3786; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073786 - 06 Apr 2021
Cited by 2 | Viewed by 897
Abstract
About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown [...] Read more.
About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases. Full article
(This article belongs to the Special Issue Genetic Basis and Molecular Mechanisms of Heart Rhythm Disorders)
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Review
In Vitro Activation Early Follicles: From the Basic Science to the Clinical Perspectives
Int. J. Mol. Sci. 2021, 22(7), 3785; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073785 - 06 Apr 2021
Cited by 2 | Viewed by 991
Abstract
Development of early follicles, especially the activation of primordial follicles, is strictly modulated by a network of signaling pathways. Recent advance in ovarian physiology has been allowed the development of several therapies to improve reproductive outcomes by manipulating early folliculogenesis. Among these, in [...] Read more.
Development of early follicles, especially the activation of primordial follicles, is strictly modulated by a network of signaling pathways. Recent advance in ovarian physiology has been allowed the development of several therapies to improve reproductive outcomes by manipulating early folliculogenesis. Among these, in vitro activation (IVA) has been recently developed to extend the possibility of achieving genetically related offspring for patients with premature ovarian insufficiency and ovarian dysfunction. This method was established based on basic science studies of the intraovarian signaling pathways: the phosphoinositide 3-kinase (PI3K)/Akt and the Hippo signaling pathways. These two pathways were found to play crucial roles in folliculogenesis from the primordial follicle to the early antral follicle. Following the results of rodent experiments, IVA was implemented in clinical practice. There have been multiple recorded live births and ongoing pregnancies. Further investigations are essential to confirm the efficacy and safety of IVA before used widely in clinics. This review aimed to summarize the published literature on IVA and provide future perspectives for its improvement. Full article
(This article belongs to the Special Issue Molecular Basis of Fertility Preservation and Restoration 3.0)
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Article
Polypurine Reverse-Hoogsteen Hairpins as a Tool for Exon Skipping at the Genomic Level in Mammalian Cells
Int. J. Mol. Sci. 2021, 22(7), 3784; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073784 - 06 Apr 2021
Cited by 1 | Viewed by 629
Abstract
Therapeutic strategies for rare diseases based on exon skipping are aimed at mediating the elimination of mutated exons and restoring the reading frame of the affected protein. We explored the capability of polypurine reverse-Hoogsteen hairpins (PPRHs) to cause exon skipping in NB6 cells [...] Read more.
Therapeutic strategies for rare diseases based on exon skipping are aimed at mediating the elimination of mutated exons and restoring the reading frame of the affected protein. We explored the capability of polypurine reverse-Hoogsteen hairpins (PPRHs) to cause exon skipping in NB6 cells carrying a duplication of exon 2 of the DHFR gene that causes a frameshift abolishing DHFR activity. Methods: Different editing PPRHs were designed and transfected in NB6 cells followed by incubation in a DHFR-selective medium lacking hypoxanthine and thymidine. Surviving colonies were analyzed by DNA sequencing, RT-PCR, Western blotting and DHFR enzymatic activity. Results: Transfection of editing PPRHs originated colonies in the DHFR-selective medium. DNA sequencing results proved that the DHFR sequence in all these colonies corresponded to the wildtype sequence with just one copy of exon 2. In the edited colonies, the skipping of the additional exon was confirmed at the mRNA level, the DHFR protein was restored, and it showed high levels of DHFR activity. Conclusions: Editing-PPRHs are able to cause exon skipping at the DNA level and could be applied as a possible therapeutic tool for rare diseases. Full article
(This article belongs to the Special Issue Oligonucleotide, Therapy, and Applications 2.0)
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Article
Novel and Potent Small Molecules against Melanoma Harboring BRAF Class I/II/III Mutants for Overcoming Drug Resistance
Int. J. Mol. Sci. 2021, 22(7), 3783; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073783 - 06 Apr 2021
Cited by 1 | Viewed by 920
Abstract
Melanoma accounts for the majority of skin cancer deaths. About 50% of all melanomas are associated with BRAF mutations. BRAF mutations are classified into three classes with regard to dependency on RAF dimerization and RAS signaling. The most frequently occurring class I BRAF [...] Read more.
Melanoma accounts for the majority of skin cancer deaths. About 50% of all melanomas are associated with BRAF mutations. BRAF mutations are classified into three classes with regard to dependency on RAF dimerization and RAS signaling. The most frequently occurring class I BRAF V600 mutations are sensitive to vemurafenib whereas class II and class III mutants, non-V600 BRAF mutants are resistant to vemurafenib. Herein we report six pyrimido[4,5-d]pyrimidin-2-one derivatives possessing highly potent anti-proliferative activities on melanoma cells harboring BRAF class I/II/III mutants. Novel and most potent derivative, SIJ1777, possesses not only two-digit nanomolar potency but also 2 to 14-fold enhanced anti-proliferative activities compared with reference compound, GNF-7 against melanoma cells (SK-MEL-2, SK-MEL-28, A375, WM3670, WM3629). Moreover, SIJ1777 substantially inhibits the activation of MEK, ERK, and AKT and remarkably induces apoptosis and significantly blocks migration, invasion, and anchorage-independent growth of melanoma cells harboring BRAF class I/II/II mutations while both vemurafenib and PLX8394 have little to no effects on melanoma cells expressing BRAF class II/III mutations. Taken together, our six GNF-7 derivatives exhibit highly potent activities against melanoma cells harboring class I/II/III BRAF mutations compared with vemurafenib as well as PLX8394. Full article
(This article belongs to the Special Issue Precision Oncology in Melanoma Progression)
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Article
The Fibronectin Expression Determines the Distinct Progressions of Malignant Gliomas via Transforming Growth Factor-Beta Pathway
Int. J. Mol. Sci. 2021, 22(7), 3782; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073782 - 06 Apr 2021
Viewed by 772
Abstract
Due to the increasing incidence of malignant gliomas, particularly glioblastoma multiforme (GBM), a simple and reliable GBM diagnosis is needed to screen early the death-threaten patients. This study aimed to identify a protein that can be used to discriminate GBM from low-grade astrocytoma [...] Read more.
Due to the increasing incidence of malignant gliomas, particularly glioblastoma multiforme (GBM), a simple and reliable GBM diagnosis is needed to screen early the death-threaten patients. This study aimed to identify a protein that can be used to discriminate GBM from low-grade astrocytoma and elucidate further that it has a functional role during malignant glioma progressions. To identify proteins that display low or no expression in low-grade astrocytoma but elevated levels in GBM, glycoprotein fibronectin (FN) was particularly examined according to the mining of the Human Protein Atlas. Web-based open megadata minings revealed that FN was mainly mutated in the cBio Cancer Genomic Portal but dominantly overexpressed in the ONCOMINE (a cancer microarray database and integrated data-mining platform) in distinct tumor types. Furthermore, numerous different cancer patients with high FN indeed exhibited a poor prognosis in the PrognoScan mining, indicating that FN involves in tumor malignancy. To investigate further the significance of FN expression in glioma progression, tumor specimens from five malignant gliomas with recurrences that received at least two surgeries were enrolled and examined. The immunohistochemical staining showed that FN expression indeed determined the distinct progressions of malignant gliomas. Furthermore, the expression of vimentin (VIM), a mesenchymal protein that is strongly expressed in malignant cancers, was similar to the FN pattern. Moreover, the level of epithelial–mesenchymal transition (EMT) inducer transforming growth factor-beta (TGF-β) was almost recapitulated with the FN expression. Together, this study identifies a protein FN that can be used to diagnose GBM from low-grade astrocytoma; moreover, its expression functionally determines the malignant glioma progressions via TGF-β-induced EMT pathway. Full article
(This article belongs to the Special Issue Biochemistry, Molecular Biology and Druggability of Proteins)
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Review
Polymorphisms of Dopamine Receptor Genes and Parkinson’s Disease: Clinical Relevance and Future Perspectives
Int. J. Mol. Sci. 2021, 22(7), 3781; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073781 - 06 Apr 2021
Viewed by 747
Abstract
Parkinson’s disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the midbrain. PD is clinically characterized by a variety of motor and nonmotor symptoms, and treatment relies on dopaminergic replacement. Beyond a common pathological hallmark, PD patients may present [...] Read more.
Parkinson’s disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the midbrain. PD is clinically characterized by a variety of motor and nonmotor symptoms, and treatment relies on dopaminergic replacement. Beyond a common pathological hallmark, PD patients may present differences in both clinical progression and response to drug therapy that are partly affected by genetic factors. Despite extensive knowledge on genetic variability of dopaminergic receptors (DR), few studies have addressed their relevance as possible influencers of clinical heterogeneity in PD patients. In this review, we summarized available evidence regarding the role of genetic polymorphisms in DR as possible determinants of PD development, progression and treatment response. Moreover, we examined the role of DR in the modulation of peripheral immunity, in light of the emerging role of the peripheral immune system in PD pathophysiology. A better understanding of all these aspects represents an important step towards the development of precise and personalized disease-modifying therapies for PD. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders 3.0)
Article
Genome and Pangenome Analysis of Lactobacillus hilgardii FLUB—A New Strain Isolated from Mead
Int. J. Mol. Sci. 2021, 22(7), 3780; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073780 - 06 Apr 2021
Viewed by 811
Abstract
The production of mead holds great value for the Polish liquor industry, which is why the bacterium that spoils mead has become an object of concern and scientific interest. This article describes, for the first time, Lactobacillus hilgardii FLUB newly isolated from mead, [...] Read more.
The production of mead holds great value for the Polish liquor industry, which is why the bacterium that spoils mead has become an object of concern and scientific interest. This article describes, for the first time, Lactobacillus hilgardii FLUB newly isolated from mead, as a mead spoilage bacteria. Whole genome sequencing of L. hilgardii FLUB revealed a 3 Mbp chromosome and five plasmids, which is the largest reported genome of this species. An extensive phylogenetic analysis and digital DNA-DNA hybridization confirmed the membership of the strain in the L. hilgardii species. The genome of L. hilgardii FLUB encodes 3043 genes, 2871 of which are protein coding sequences, 79 code for RNA, and 93 are pseudogenes. L. hilgardii FLUB possesses three clustered regularly interspaced short palindromic repeats (CRISPR), eight genomic islands (44,155 bp to 6345 bp), and three (two intact and one incomplete) prophage regions. For the first time, the characteristics of the genome of this species were described and a pangenomic analysis was performed. The concept of the pangenome was used not only to establish the genetic repertoire of this species, but primarily to highlight the unique characteristics of L. hilgardii FLUB. The core of the genome of L. hilgardii is centered around genes related to the storage and processing of genetic information, as well as to carbohydrate and amino acid metabolism. Strains with such a genetic constitution can effectively adapt to environmental changes. L. hilgardii FLUB is distinguished by an extensive cluster of metabolic genes, arsenic detoxification genes, and unique surface layer proteins. Variants of MRS broth with ethanol (10–20%), glucose (2–25%), and fructose (2–24%) were prepared to test the strain’s growth preferences using Bioscreen C and the PYTHON script. L. hilgardii FLUB was found to be more resistant than a reference strain to high concentrations of alcohol (18%) and sugars (25%). It exhibited greater preference for fructose than glucose, which suggests it has a fructophilic nature. Comparative genomic analysis supported by experimental research imitating the conditions of alcoholic beverages confirmed the niche specialization of L. hilgardii FLUB to the mead environment. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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Review
Endogenous Opioid Peptides and Alternatively Spliced Mu Opioid Receptor Seven Transmembrane Carboxyl-Terminal Variants
Int. J. Mol. Sci. 2021, 22(7), 3779; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073779 - 06 Apr 2021
Cited by 1 | Viewed by 644
Abstract
There exist three main types of endogenous opioid peptides, enkephalins, dynorphins and β-endorphin, all of which are derived from their precursors. These endogenous opioid peptides act through opioid receptors, including mu opioid receptor (MOR), delta opioid receptor (DOR) and kappa opioid receptor (KOR), [...] Read more.
There exist three main types of endogenous opioid peptides, enkephalins, dynorphins and β-endorphin, all of which are derived from their precursors. These endogenous opioid peptides act through opioid receptors, including mu opioid receptor (MOR), delta opioid receptor (DOR) and kappa opioid receptor (KOR), and play important roles not only in analgesia, but also many other biological processes such as reward, stress response, feeding and emotion. The MOR gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, generating multiple splice variants or isoforms. One type of these splice variants, the full-length 7 transmembrane (TM) Carboxyl (C)-terminal variants, has the same receptor structures but contains different intracellular C-terminal tails. The pharmacological functions of several endogenous opioid peptides through the mouse, rat and human OPRM1 7TM C-terminal variants have been considerably investigated together with various mu opioid ligands. The current review focuses on the studies of these endogenous opioid peptides and summarizes the results from early pharmacological studies, including receptor binding affinity and G protein activation, and recent studies of β-arrestin2 recruitment and biased signaling, aiming to provide new insights into the mechanisms and functions of endogenous opioid peptides, which are mediated through the OPRM1 7TM C-terminal splice variants. Full article
(This article belongs to the Special Issue Opioid Receptors and Endorphinergic Systems 2.0)
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Article
Study on Demethoxycurcumin as a Promising Approach to Reverse Methicillin-Resistance of Staphylococcus aureus
Int. J. Mol. Sci. 2021, 22(7), 3778; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073778 - 06 Apr 2021
Viewed by 430
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) has always been a threatening pathogen. Research on phytochemical components that can replace antibiotics with limited efficacy may be an innovative method to solve intractable MRSA infections. The present study was devoted to investigate the antibacterial activity of the [...] Read more.
Methicillin-resistant Staphylococcus aureus (MRSA) has always been a threatening pathogen. Research on phytochemical components that can replace antibiotics with limited efficacy may be an innovative method to solve intractable MRSA infections. The present study was devoted to investigate the antibacterial activity of the natural compound demethoxycurcumin (DMC) against MRSA and explore its possible mechanism for eliminating MRSA. The minimum inhibitory concentrations (MICs) of DMC against MRSA strains was determined by the broth microdilution method, and the results showed that the MIC of DMC was 62.5 μg/mL. The synergistic effects of DMC and antibiotics were investigated by the checkerboard method and the time–kill assay. The ATP synthase inhibitors were employed to block the metabolic ability of bacteria to explore their synergistic effect on the antibacterial ability of DMC. In addition, western blot analysis and qRT-PCR were performed to detect the proteins and genes related to drug resistance and S. aureus exotoxins. As results, DMC hindered the translation of penicillin-binding protein 2a (PBP2a) and staphylococcal enterotoxin and reduced the transcription of related genes. This study provides experimental evidences that DMC has the potential to be a candidate substance for the treatment of MRSA infections. Full article
(This article belongs to the Special Issue Antimicrobial Resistance-New Insights)
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Article
Characterization of the mbsA Gene Encoding a Putative APSES Transcription Factor in Aspergillus fumigatus
Int. J. Mol. Sci. 2021, 22(7), 3777; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073777 - 06 Apr 2021
Viewed by 586
Abstract
The APSES family proteins are transcription factors (TFs) with a basic helix-loop-helix domain, known to regulate growth, development, secondary metabolism, and other biological processes in Aspergillus species. In the genome of the human opportunistic pathogenic fungus Aspergillus fumigatus, five genes predicted to [...] Read more.
The APSES family proteins are transcription factors (TFs) with a basic helix-loop-helix domain, known to regulate growth, development, secondary metabolism, and other biological processes in Aspergillus species. In the genome of the human opportunistic pathogenic fungus Aspergillus fumigatus, five genes predicted to encode APSES TFs are present. Here, we report the characterization of one of these genes, called mbsA (Afu7g05620). The deletion (Δ) of mbsA resulted in significantly decreased hyphal growth and asexual sporulation (conidiation), and lowered mRNA levels of the key conidiation genes abaA, brlA, and wetA. Moreover, ΔmbsA resulted in reduced spore germination rates, elevated sensitivity toward Nikkomycin Z, and significantly lowered transcripts levels of genes associated with chitin synthesis. The mbsA deletion also resulted in significantly reduced levels of proteins and transcripts of genes associated with the SakA MAP kinase pathway. Importantly, the cell wall hydrophobicity and architecture of the ΔmbsA asexual spores (conidia) were altered, notably lacking the rodlet layer on the surface of the ΔmbsA conidium. Comparative transcriptomic analyses revealed that the ΔmbsA mutant showed higher mRNA levels of gliotoxin (GT) biosynthetic genes, which was corroborated by elevated levels of GT production in the mutant. While the ΔmbsA mutant produced higher amount of GT, ΔmbsA strains showed reduced virulence in the murine model, likely due to the defective spore integrity. In summary, the putative APSES TF MbsA plays a multiple role in governing growth, development, spore wall architecture, GT production, and virulence, which may be associated with the attenuated SakA signaling pathway. Full article
(This article belongs to the Section Molecular Microbiology)
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Review
Application of the Antibody-Inducing Activity of Glycosphingolipids to Human Diseases
Int. J. Mol. Sci. 2021, 22(7), 3776; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073776 - 06 Apr 2021
Cited by 2 | Viewed by 718
Abstract
Glycosphingolipids (GSLs) are composed of a mono-, di-, or oligosaccharide and a ceramide and function as constituents of cell membranes. Various molecular species of GSLs have been identified in mammalian cells due to differences in the structures of oligosaccharides. The oligosaccharide structure can [...] Read more.
Glycosphingolipids (GSLs) are composed of a mono-, di-, or oligosaccharide and a ceramide and function as constituents of cell membranes. Various molecular species of GSLs have been identified in mammalian cells due to differences in the structures of oligosaccharides. The oligosaccharide structure can vary depending on cell lineage, differentiation stage, and pathology; this property can be used as a cell identification marker. Furthermore, GSLs are involved in various aspects of the immune response, such as cytokine production, immune signaling, migration of immune cells, and antibody production. GSLs containing certain structures exhibit strong immunogenicity in immunized animals and promote the production of anti-GSL antibodies. By exploiting this property, it is possible to generate antibodies that recognize the fine oligosaccharide structure of specific GSLs or glycoproteins. In our study using artificially synthesized GSLs (artGSLs), we found that several structural features are correlated with the antibody-inducing activity of GSLs. Based on these findings, we designed artGSLs that efficiently induce the production of antibodies accompanied by class switching and developed several antibodies that recognize not only certain glycan structures of GSLs but also those of glycoproteins. This review comprehensively introduces the immune activities of GSLs and their application as pharmaceuticals. Full article
(This article belongs to the Special Issue Sphingolipid Metabolism and Signaling in Diseases)
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Review
Cancer-Associated Adipocytes in Breast Cancer: Causes and Consequences
Int. J. Mol. Sci. 2021, 22(7), 3775; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073775 - 06 Apr 2021
Cited by 2 | Viewed by 828
Abstract
Breast cancer progression is highly dependent on the heterotypic interaction between tumor cells and stromal cells of the tumor microenvironment. Cancer-associated adipocytes (CAAs) are emerging as breast cancer cell partners favoring proliferation, invasion, and metastasis. This article discussed the intersection between extracellular signals [...] Read more.
Breast cancer progression is highly dependent on the heterotypic interaction between tumor cells and stromal cells of the tumor microenvironment. Cancer-associated adipocytes (CAAs) are emerging as breast cancer cell partners favoring proliferation, invasion, and metastasis. This article discussed the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation in order to appreciate the molecular pathways that have been described to drive adipocyte dedifferentiation. Moreover, recent studies on the mechanisms through which CAAs affect the progression of breast cancer were reviewed, including adipokine regulation, metabolic reprogramming, extracellular matrix remodeling, and immune cell modulation. An in-depth understanding of the complex vicious cycle between CAAs and breast cancer cells is crucial for designing novel strategies for new therapeutic interventions. Full article
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Article
Reduced Claudin-12 Expression Predicts Poor Prognosis in Cervical Cancer
Int. J. Mol. Sci. 2021, 22(7), 3774; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073774 - 06 Apr 2021
Cited by 1 | Viewed by 894
Abstract
Background: Within the claudin (CLDN) family, CLDN12 mRNA expression is altered in various types of cancer, but its clinicopathological relevance has yet to be established due to the absence of specific antibodies (Abs) with broad applications. Methods: We generated a monoclonal Ab (mAb) [...] Read more.
Background: Within the claudin (CLDN) family, CLDN12 mRNA expression is altered in various types of cancer, but its clinicopathological relevance has yet to be established due to the absence of specific antibodies (Abs) with broad applications. Methods: We generated a monoclonal Ab (mAb) against human/mouse CLDN12 and verified its specificity. By performing immunohistochemical staining and semiquantification, we evaluated the relationship between CLDN12 expression and clinicopathological parameters in tissues from 138 cases of cervical cancer. Results: Western blot and immunohistochemical analyses revealed that the established mAb selectively recognized the CLDN12 protein. Twenty six of the 138 cases (18.8%) showed low CLDN12 expression, and the disease-specific survival (DSS) and recurrence-free survival rates were significantly decreased compared with those in the high CLDN12 expression group. We also demonstrated, via univariable and multivariable analyses, that the low CLDN12 expression represents a significant prognostic factor for the DSS of cervical cancer patients (HR 3.412, p = 0.002 and HR 2.615, p = 0.029, respectively). Conclusions: It can be concluded that a reduced CLDN12 expression predicts a poor outcome for cervical cancer. The novel anti-CLDN12 mAb could be a valuable tool to evaluate the biological relevance of the CLDN12 expression in diverse cancer types and other diseases. Full article
(This article belongs to the Section Biochemistry)
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Review
Corticosteroids for COVID-19 Therapy: Potential Implications on Tuberculosis
Int. J. Mol. Sci. 2021, 22(7), 3773; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073773 - 06 Apr 2021
Cited by 3 | Viewed by 1312
Abstract
On 11 March 2020, the World Health Organization announced the Corona Virus Disease-2019 (COVID-19) as a global pandemic, which originated in China. At the host level, COVID-19, caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), affects the respiratory system, with the clinical [...] Read more.
On 11 March 2020, the World Health Organization announced the Corona Virus Disease-2019 (COVID-19) as a global pandemic, which originated in China. At the host level, COVID-19, caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), affects the respiratory system, with the clinical symptoms ranging from mild to severe or critical illness that often requires hospitalization and oxygen support. There is no specific therapy for COVID-19, as is the case for any common viral disease except drugs to reduce the viral load and alleviate the inflammatory symptoms. Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb), also primarily affects the lungs and has clinical signs similar to pulmonary SARS-CoV-2 infection. Active TB is a leading killer among infectious diseases and adds to the burden of the COVID-19 pandemic worldwide. In immunocompetent individuals, primary Mtb infection can also lead to a non-progressive, asymptomatic latency. However, latent Mtb infection (LTBI) can reactivate symptomatic TB disease upon host immune-suppressing conditions. Importantly, the diagnosis and treatment of TB are hampered and admixed with COVID-19 control measures. The US-Center for Disease Control (US-CDC) recommends using antiviral drugs, Remdesivir or corticosteroid (CST), such as dexamethasone either alone or in-combination with specific recommendations for COVID-19 patients requiring hospitalization or oxygen support. However, CSTs can cause immunosuppression, besides their anti-inflammatory properties. The altered host immunity during COVID-19, combined with CST therapy, poses a significant risk for new secondary infections and/or reactivation of existing quiescent infections, such as LTBI. This review highlights CST therapy recommendations for COVID-19, various types and mechanisms of action of CSTs, the deadly combination of two respiratory infectious diseases COVID-19 and TB. It also discusses the importance of screening for LTBI to prevent TB reactivation during corticosteroid therapy for COVID-19. Full article
(This article belongs to the Collection Feature Papers in Molecular Pharmacology)
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Review
Manmade Electromagnetic Fields and Oxidative Stress—Biological Effects and Consequences for Health
Int. J. Mol. Sci. 2021, 22(7), 3772; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073772 - 06 Apr 2021
Cited by 5 | Viewed by 5342
Abstract
Concomitant with the ever-expanding use of electrical appliances and mobile communication systems, public and occupational exposure to electromagnetic fields (EMF) in the extremely-low-frequency and radiofrequency range has become a widely debated environmental risk factor for health. Radiofrequency (RF) EMF and extremely-low-frequency (ELF) MF [...] Read more.
Concomitant with the ever-expanding use of electrical appliances and mobile communication systems, public and occupational exposure to electromagnetic fields (EMF) in the extremely-low-frequency and radiofrequency range has become a widely debated environmental risk factor for health. Radiofrequency (RF) EMF and extremely-low-frequency (ELF) MF have been classified as possibly carcinogenic to humans (Group 2B) by the International Agency for Research on Cancer (IARC). The production of reactive oxygen species (ROS), potentially leading to cellular or systemic oxidative stress, was frequently found to be influenced by EMF exposure in animals and cells. In this review, we summarize key experimental findings on oxidative stress related to EMF exposure from animal and cell studies of the last decade. The observations are discussed in the context of molecular mechanisms and functionalities relevant to health such as neurological function, genome stability, immune response, and reproduction. Most animal and many cell studies showed increased oxidative stress caused by RF-EMF and ELF-MF. In order to estimate the risk for human health by manmade exposure, experimental studies in humans and epidemiological studies need to be considered as well. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Genotoxicity)
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