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Volume 22
Issue 9
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Int. J. Mol. Sci., Volume 22, Issue 9 (May-1 2021) – 760 articles

Cover Story (view full-size image): The EBI2 receptor regulates chemotaxis of immune cells and is involved in autoimmune diseases such as multiple sclerosis. Specifically, in the central nervous system, it is expressed in astrocytes where it regulates chemotaxis and neuroinflammatory response. Here, the expression and function of EBI2 in oligodendrocytes were demonstrated in the human brain and MO3.13 oligodendrocytes. The data showed EBI2 in oligodendrocyte progenitor cells in the human brain, temporal upregulation during MO3.13 maturation, as well as induction of chemotaxis. Antagonism of EBI2 inhibited spontaneous remyelination in organotypic cerebellar slices. These data provide alternative approaches to the regulation of oligodendrocyte biology and potential new therapeutic opportunities for demyelination diseases. View this paper
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21 pages, 2426 KiB  
Review
“Dividing and Conquering” and “Caching” in Molecular Modeling
by Xiaoyong Cao and Pu Tian
Int. J. Mol. Sci. 2021, 22(9), 5053; https://doi.org/10.3390/ijms22095053 - 10 May 2021
Cited by 5 | Viewed by 3650
Abstract
Molecular modeling is widely utilized in subjects including but not limited to physics, chemistry, biology, materials science and engineering. Impressive progress has been made in development of theories, algorithms and software packages. To divide and conquer, and to cache intermediate results have been [...] Read more.
Molecular modeling is widely utilized in subjects including but not limited to physics, chemistry, biology, materials science and engineering. Impressive progress has been made in development of theories, algorithms and software packages. To divide and conquer, and to cache intermediate results have been long standing principles in development of algorithms. Not surprisingly, most important methodological advancements in more than half century of molecular modeling are various implementations of these two fundamental principles. In the mainstream classical computational molecular science, tremendous efforts have been invested on two lines of algorithm development. The first is coarse graining, which is to represent multiple basic particles in higher resolution modeling as a single larger and softer particle in lower resolution counterpart, with resulting force fields of partial transferability at the expense of some information loss. The second is enhanced sampling, which realizes “dividing and conquering” and/or “caching” in configurational space with focus either on reaction coordinates and collective variables as in metadynamics and related algorithms, or on the transition matrix and state discretization as in Markov state models. For this line of algorithms, spatial resolution is maintained but results are not transferable. Deep learning has been utilized to realize more efficient and accurate ways of “dividing and conquering” and “caching” along these two lines of algorithmic research. We proposed and demonstrated the local free energy landscape approach, a new framework for classical computational molecular science. This framework is based on a third class of algorithm that facilitates molecular modeling through partially transferable in resolution “caching” of distributions for local clusters of molecular degrees of freedom. Differences, connections and potential interactions among these three algorithmic directions are discussed, with the hope to stimulate development of more elegant, efficient and reliable formulations and algorithms for “dividing and conquering” and “caching” in complex molecular systems. Full article
(This article belongs to the Special Issue Advances in Molecular Simulation)
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21 pages, 3391 KiB  
Article
Active Components from Cassia abbreviata Prevent HIV-1 Entry by Distinct Mechanisms of Action
by Yue Zheng, Xian-Wen Yang, Dominique Schols, Mattia Mori, Bruno Botta, Andy Chevigné, Martin Mulinge, André Steinmetz, Jean-Claude Schmit and Carole Seguin-Devaux
Int. J. Mol. Sci. 2021, 22(9), 5052; https://doi.org/10.3390/ijms22095052 - 10 May 2021
Cited by 6 | Viewed by 3115
Abstract
Cassia abbreviata is widely used in Sub-Saharan Africa for treating many diseases, including HIV-1 infection. We have recently described the chemical structures of 28 compounds isolated from an alcoholic crude extract of barks and roots of C. abbreviata, and showed that six [...] Read more.
Cassia abbreviata is widely used in Sub-Saharan Africa for treating many diseases, including HIV-1 infection. We have recently described the chemical structures of 28 compounds isolated from an alcoholic crude extract of barks and roots of C. abbreviata, and showed that six bioactive compounds inhibit HIV-1 infection. In the present study, we demonstrate that the six compounds block HIV-1 entry into cells: oleanolic acid, palmitic acid, taxifolin, piceatannol, guibourtinidol-(4α→8)-epiafzelechin, and a novel compound named as cassiabrevone. We report, for the first time, that guibourtinidol-(4α→8)-epiafzelechin and cassiabrevone inhibit HIV-1 entry (IC50 of 42.47 µM and 30.96 µM, respectively), as well as that piceatannol interacts with cellular membranes. Piceatannol inhibits HIV-1 infection in a dual-chamber assay mimicking the female genital tract, as well as HSV infection, emphasizing its potential as a microbicide. Structure-activity relationships (SAR) showed that pharmacophoric groups of piceatannol are strictly required to inhibit HIV-1 entry. By a ligand-based in silico study, we speculated that piceatannol and norartocarpetin may have a very similar mechanism of action and efficacy because of the highly comparable pharmacophoric and 3D space, while guibourtinidol-(4α→8)-epiafzelechin and cassiabrevone may display a different mechanism. We finally show that cassiabrevone plays a major role of the crude extract of CA by blocking the binding activity of HIV-1 gp120 and CD4. Full article
(This article belongs to the Collection Feature Papers in Bioactives and Nutraceuticals)
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18 pages, 6170 KiB  
Article
Proteomic Identification of Bombyx mori Organelles Using the Engineered Ascorbate Peroxidase APEX and Development of Silkworm Organelle Proteome Database (SilkOrganPDB)
by Tian Li, Chen Xu, Jinzhi Xu, Jian Luo, Bin Yu, Xianzhi Meng, Chunfeng Li, Guoqing Pan and Zeyang Zhou
Int. J. Mol. Sci. 2021, 22(9), 5051; https://doi.org/10.3390/ijms22095051 - 10 May 2021
Viewed by 2738
Abstract
Silkworm Bombyx mori is an economically important insect and a lepidopteran model. Organelle proteome is vital to understanding gene functions; however, it remains to be identified in silkworm. Here, using the engineered ascorbate peroxidase APEX, we constructed transgenic B. mori embryo cells (BmE) [...] Read more.
Silkworm Bombyx mori is an economically important insect and a lepidopteran model. Organelle proteome is vital to understanding gene functions; however, it remains to be identified in silkworm. Here, using the engineered ascorbate peroxidase APEX, we constructed transgenic B. mori embryo cells (BmE) expressing APEX-NLS, COX4-APEX, APEX-Rev, and APEX-KDEL in nucleus, mitochondrial matrix (MM), cytosol, and endoplasmic reticulum (ER), and isolated the biotin-labeled proteins using streptavidin-affinity purification, respectively. The isolated proteins were determined using LC-MS/MS and annotated by searching B. mori genomes downloaded from GenBank, SilkBase, SilkDB 2.0, and SilkDB 3.0, resulting in 842, 495, 311, and 445 organelle proteins identified, respectively. We mapped the 296 MM proteins annotated in the GenBank data to mitochondrial protein databases of the fly, human, and mouse, and found that 140 (47%) proteins are homologous to 80 fly proteins, and 65 (22%) proteins match to 31 and 29 human and mouse proteins, respectively. Protein orthology was predicted in multiple insects using OrthoMCL, producing 460 families containing 839 proteins we identified. Out of 460 families, 363 were highly conserved and found in all insects, leaving only three proteins without orthology in other insects, indicating that the identified proteins are highly conserved and probably play important roles in insects. A gene ontology enrichment analysis by clusterProfiler revealed that the nucleus proteins significantly enriched in cellular component terms of nucleus and nucleolus, the MM proteins markedly enriched in molecular function terms of nucleotide binding, and the cytosol proteins mainly enriched in biological process terms of small molecule metabolism. To facilitate the usage and analysis of our data, we developed an open-access database, Silkworm Organelle Proteome Database (SilkOrganPDB), which provides multiple modules for searching, browsing, downloading, and analyzing these proteins, including BLAST, HMMER, Organelle Proteins, Protein Locations, Sequences, Gene Ontology, Homologs, and Phylogeny. In summary, our work revealed the protein composition of silkworm BmE organelles and provided a database resource helpful for understanding the functions and evolution of these proteins. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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13 pages, 1281 KiB  
Review
The Pathogenesis of Hydrocephalus Following Aneurysmal Subarachnoid Hemorrhage
by Lu-Ting Kuo and Abel Po-Hao Huang
Int. J. Mol. Sci. 2021, 22(9), 5050; https://doi.org/10.3390/ijms22095050 - 10 May 2021
Cited by 27 | Viewed by 4928
Abstract
Hydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage (aSAH) and reportedly contributes to poor neurological outcomes. In this review, we summarize the molecular and cellular mechanisms involved in the pathogenesis of hydrocephalus following aSAH and summarize its treatment strategies. Various mechanisms have [...] Read more.
Hydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage (aSAH) and reportedly contributes to poor neurological outcomes. In this review, we summarize the molecular and cellular mechanisms involved in the pathogenesis of hydrocephalus following aSAH and summarize its treatment strategies. Various mechanisms have been implicated for the development of chronic hydrocephalus following aSAH, including alterations in cerebral spinal fluid (CSF) dynamics, obstruction of the arachnoid granulations by blood products, and adhesions within the ventricular system. Regarding molecular mechanisms that cause chronic hydrocephalus following aSAH, we carried out an extensive review of animal studies and clinical trials about the transforming growth factor-β/SMAD signaling pathway, upregulation of tenascin-C, inflammation-dependent hypersecretion of CSF, systemic inflammatory response syndrome, and immune dysregulation. To identify the ideal treatment strategy, we discuss the predictive factors of shunt-dependent hydrocephalus between surgical clipping and endovascular coiling groups. The efficacy and safety of other surgical interventions including the endoscopic removal of an intraventricular hemorrhage, placement of an external ventricular drain, the use of intraventricular or cisternal fibrinolysis, and an endoscopic third ventriculostomy on shunt dependency following aSAH were also assessed. However, the optimal treatment is still controversial, and it necessitates further investigations. A better understanding of the pathogenesis of acute and chronic hydrocephalus following aSAH would facilitate the development of treatments and improve the outcome. Full article
(This article belongs to the Special Issue Role of Cellular and Molecular Inflammation in Subarachnoid Hemorrhage)
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19 pages, 10171 KiB  
Article
Nematicidal Volatiles from Bacillus atrophaeus GBSC56 Promote Growth and Stimulate Induced Systemic Resistance in Tomato against Meloidogyne incognita
by Muhammad Ayaz, Qurban Ali, Ayaz Farzand, Abdur Rashid Khan, Hongli Ling and Xuewen Gao
Int. J. Mol. Sci. 2021, 22(9), 5049; https://doi.org/10.3390/ijms22095049 - 10 May 2021
Cited by 59 | Viewed by 4039
Abstract
Bacillus volatiles to control plant nematodes is a topic of great interest among researchers due to its safe and environmentally friendly nature. Bacillus strain GBSC56 isolated from the Tibet region of China showed high nematicidal activity against M. incognita, with 90% mortality [...] Read more.
Bacillus volatiles to control plant nematodes is a topic of great interest among researchers due to its safe and environmentally friendly nature. Bacillus strain GBSC56 isolated from the Tibet region of China showed high nematicidal activity against M. incognita, with 90% mortality as compared with control in a partition plate experiment. Pure volatiles produced by GBSC56 were identified through gas chromatography and mass spectrometry (GC-MS). Among 10 volatile organic compounds (VOCs), 3 volatiles, i.e., dimethyl disulfide (DMDS), methyl isovalerate (MIV), and 2-undecanone (2-UD) showed strong nematicidal activity with a mortality rate of 87%, 83%, and 80%, respectively, against M. incognita. The VOCs induced severe oxidative stress in nematodes, which caused rapid death. Moreover, in the presence of volatiles, the activity of antioxidant enzymes, i.e., SOD, CAT, POD, and APX, was observed to be enhanced in M. incognita-infested roots, which might reduce the adverse effect of oxidative stress-induced after infection. Moreover, genes responsible for plant growth promotion SlCKX1, SlIAA1, and Exp18 showed an upsurge in expression, while AC01 was downregulated in infested plants. Furthermore, the defense-related genes (PR1, PR5, and SlLOX1) in infested tomato plants were upregulated after treatment with MIV and 2-UD. These findings suggest that GBSC56 possesses excellent biocontrol potential against M. incognita. Furthermore, the study provides new insight into the mechanism by which GBSC56 nematicidal volatiles regulate antioxidant enzymes, the key genes involved in plant growth promotion, and the defense mechanism M. incognita-infested tomato plants use to efficiently manage root-knot disease. Full article
(This article belongs to the Special Issue Plant Secondary Metabolites in Plant Defence against Abiotic and Biotic Stresses)
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16 pages, 1936 KiB  
Article
ThHSFA1 Confers Salt Stress Tolerance through Modulation of Reactive Oxygen Species Scavenging by Directly Regulating ThWRKY4
by Ting-Ting Sun, Chao Wang, Rui Liu, Yu Zhang, Yu-Cheng Wang and Liu-Qiang Wang
Int. J. Mol. Sci. 2021, 22(9), 5048; https://doi.org/10.3390/ijms22095048 - 10 May 2021
Cited by 12 | Viewed by 2518
Abstract
Heat shock transcription factors (HSFs) play critical roles in several types of environmental stresses. However, the detailed regulatory mechanisms in response to salt stress are still largely unknown. In this study, we examined the salt-induced transcriptional responses of ThHSFA1-ThWRKY4 in Tamarix [...] Read more.
Heat shock transcription factors (HSFs) play critical roles in several types of environmental stresses. However, the detailed regulatory mechanisms in response to salt stress are still largely unknown. In this study, we examined the salt-induced transcriptional responses of ThHSFA1-ThWRKY4 in Tamarix hispida and their functions and regulatory mechanisms in salt tolerance. ThHSFA1 protein acts as an upstream regulator that can directly activate ThWRKY4 expression by binding to the heat shock element (HSE) of the ThWRKY4 promoter using yeast one-hybrid (Y1H), chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. ThHSFA1 and ThWRKY4 expression was significantly induced by salt stress and abscisic acid (ABA) treatment in the roots and leaves of T. hispida. ThHSFA1 is a nuclear-localized protein with transactivation activity at the C-terminus. Compared to nontransgenic plants, transgenic plants overexpressing ThHSFA1 displayed enhanced salt tolerance and exhibited reduced reactive oxygen species (ROS) levels and increased antioxidant enzyme activity levels under salt stress. Therefore, we further concluded that ThHSFA1 mediated the regulation of ThWRKY4 in response to salt stress in T. hispida. Full article
(This article belongs to the Section Molecular Plant Sciences)
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20 pages, 407 KiB  
Review
Epigenetics, microRNA and Metabolic Syndrome: A Comprehensive Review
by Farha Ramzan, Mark H. Vickers and Richard F. Mithen
Int. J. Mol. Sci. 2021, 22(9), 5047; https://doi.org/10.3390/ijms22095047 - 10 May 2021
Cited by 39 | Viewed by 5778
Abstract
Epigenetics refers to the DNA chemistry changes that result in the modification of gene transcription and translation independently of the underlying DNA coding sequence. Epigenetic modifications are reported to involve various molecular mechanisms, including classical epigenetic changes affecting DNA methylation and histone modifications [...] Read more.
Epigenetics refers to the DNA chemistry changes that result in the modification of gene transcription and translation independently of the underlying DNA coding sequence. Epigenetic modifications are reported to involve various molecular mechanisms, including classical epigenetic changes affecting DNA methylation and histone modifications and small RNA-mediated processes, particularly that of microRNAs. Epigenetic changes are reversible and are closely interconnected. They are recognised to play a critical role as mediators of gene regulation, and any alteration in these mechanisms has been identified to mediate various pathophysiological conditions. Moreover, genetic predisposition and environmental factors, including dietary alterations, lifestyle or metabolic status, are identified to interact with the human epigenome, highlighting the importance of epigenetic factors as underlying processes in the aetiology of various diseases such as MetS. This review will reflect on how both the classical and microRNA-regulated epigenetic changes are associated with the pathophysiology of metabolic syndrome. We will then focus on the various aspects of epigenetic-based strategies used to modify MetS outcomes, including epigenetic diet, epigenetic drugs, epigenome editing tools and miRNA-based therapies. Full article
(This article belongs to the Special Issue Metabolic Syndrome: From Molecular Mechanisms to Novel Therapies)
16 pages, 1905 KiB  
Article
Estradiol Regulates mRNA Levels of Estrogen Receptor Beta 4 and Beta 5 Isoforms and Modulates Human Granulosa Cell Apoptosis
by Alice Pierre, Anne Mayeur, Clémentine Marie, Victoria Cluzet, Jonathan Chauvin, Nelly Frydman, Michael Grynberg, Joelle Cohen-Tannoudji, Céline J. Guigon and Stéphanie Chauvin
Int. J. Mol. Sci. 2021, 22(9), 5046; https://doi.org/10.3390/ijms22095046 - 10 May 2021
Cited by 10 | Viewed by 2601
Abstract
Estrogen receptor beta (ERβ) plays a critical role in granulosa cell (GC) functions. The existence of four human ERβ splice isoforms in the ovary suggests their differential implication in 17β-estradiol (E2) actions on GC apoptosis causing follicular atresia. In this study, we investigated [...] Read more.
Estrogen receptor beta (ERβ) plays a critical role in granulosa cell (GC) functions. The existence of four human ERβ splice isoforms in the ovary suggests their differential implication in 17β-estradiol (E2) actions on GC apoptosis causing follicular atresia. In this study, we investigated whether E2 can regulate ERβ isoforms expression to fine tune its apoptotic activities in human GC. For this purpose, we measured by RT-qPCR the expression of ERβ isoforms in primary culture of human granulosa cells (hGCs) collected from patients undergoing in vitro fertilization, before and after E2 exposure. Besides, we assessed the potential role of ERβ isoforms on cell growth and apoptosis after their overexpression in a human GC line (HGrC1 cells). We confirmed that ERβ1, ERβ2, ERβ4, and ERβ5 isoform mRNAs were predominant over that of ERα in hGCs, and found that E2 selectively regulates mRNA levels of ERβ4 and ERβ5 isoforms in these cells. In addition, we demonstrated that overexpression of ERβ1 and ERβ4 in HGrC1 cells increased cell apoptosis by 225% while ERβ5 or ERβ2 had no effect. Altogether, our study revealed that E2 may influence GC fate by specifically regulating the relative abundance of ERβ isoforms mRNA to modulate the balance between pro-apoptotic and non-apoptotic ERβ isoforms. Full article
(This article belongs to the Special Issue Hormones and Receptors in Sexual Reproduction)
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16 pages, 1741 KiB  
Article
Development of an Experimental Ex Vivo Wound Model to Evaluate Antimicrobial Efficacy of Topical Formulations
by Madelene Å Andersson, Lone Bruhn Madsen, Artur Schmidtchen and Manoj Puthia
Int. J. Mol. Sci. 2021, 22(9), 5045; https://doi.org/10.3390/ijms22095045 - 10 May 2021
Cited by 25 | Viewed by 5904
Abstract
Wound infections are considered a major cause for wound-associated morbidity. There is a high demand for alternative, robust, and affordable methods that can provide relatable and reproducible results when testing topical treatments, both in research and in the pharmaceutical industry. Here we present [...] Read more.
Wound infections are considered a major cause for wound-associated morbidity. There is a high demand for alternative, robust, and affordable methods that can provide relatable and reproducible results when testing topical treatments, both in research and in the pharmaceutical industry. Here we present an ex vivo wound infection model using porcine skin and a burn wounding method, allowing for the efficacy evaluation of topical antimicrobial formulations. Utilizing this model, we demonstrate the potential of topical treatments after infecting the wounds with clinically significant bacteria, P. aeruginosa and S. aureus. We show that the method is compatible with several analytical tools used to analyze infection and antimicrobial effects. Both bacterial strains successfully infected the wound surface, as well as deeper regions of the tissue. Quantification of viable bacteria on the wound surface and in the tissue, longitudinal measurements of bioluminescence, fluorescence microscopy, and scanning electron microscopy were used to confirm the effects of antibacterial treatments. Furthermore, we show that biofilms are formed on the wound surface, indicating that the demonstrated method mirrors typical in vivo infections. Full article
(This article belongs to the Special Issue New Innovations in Wound Healing and Repair 2.0)
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18 pages, 3287 KiB  
Article
Impact of Differentiated Macrophage-Like Cells on the Transcriptional Toxicity Profile of CuO Nanoparticles in Co-Cultured Lung Epithelial Cells
by Matthias Hufnagel, Ronja Neuberger, Johanna Wall, Martin Link, Alexandra Friesen and Andrea Hartwig
Int. J. Mol. Sci. 2021, 22(9), 5044; https://doi.org/10.3390/ijms22095044 - 10 May 2021
Cited by 14 | Viewed by 3158
Abstract
To mimic more realistic lung tissue conditions, co-cultures of epithelial and immune cells are one comparatively easy-to-use option. To reveal the impact of immune cells on the mode of action (MoA) of CuO nanoparticles (NP) on epithelial cells, A549 cells as a model [...] Read more.
To mimic more realistic lung tissue conditions, co-cultures of epithelial and immune cells are one comparatively easy-to-use option. To reveal the impact of immune cells on the mode of action (MoA) of CuO nanoparticles (NP) on epithelial cells, A549 cells as a model for epithelial cells have been cultured with or without differentiated THP-1 cells, as a model for macrophages. After 24 h of submerged incubation, cytotoxicity and transcriptional toxicity profiles were obtained and compared between the cell culture systems. Dose-dependent cytotoxicity was apparent starting from 8.0 µg/cm2 CuO NP. With regard to gene expression profiles, no differences between the cell models were observed concerning metal homeostasis, oxidative stress, and DNA damage, confirming the known MoA of CuO NP, i.e., endocytotic particle uptake, intracellular particle dissolution within lysosomes with subsequent metal ion deliberation, increased oxidative stress, and genotoxicity. However, applying a co-culture of epithelial and macrophage-like cells, CuO NP additionally provoked a pro-inflammatory response involving NLRP3 inflammasome and pro-inflammatory transcription factor activation. This study demonstrates that the application of this easy-to-use advanced in vitro model is able to extend the detection of cellular effects provoked by nanomaterials by an immunological response and emphasizes the use of such models to address a more comprehensive MoA. Full article
(This article belongs to the Special Issue Interaction of Nanomaterials with the Immune System 2.0)
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11 pages, 1086 KiB  
Review
Peripheral Vascular Abnormalities in Anorexia Nervosa: A Psycho-Neuro-Immune-Metabolic Connection
by Maria Maddalena Sirufo, Lia Ginaldi and Massimo De Martinis
Int. J. Mol. Sci. 2021, 22(9), 5043; https://doi.org/10.3390/ijms22095043 - 10 May 2021
Cited by 7 | Viewed by 3176
Abstract
Immune, neuroendocrine, and autonomic nervous system dysregulation in anorexia nervosa lead to cardiovascular complications that can potentially result in increased morbidity and mortality. It is suggested that a complex non-invasive assessment of cardiovascular autonomic regulation—cardiac vagal control, sympathetic vascular activity, and cardiovascular reflex [...] Read more.
Immune, neuroendocrine, and autonomic nervous system dysregulation in anorexia nervosa lead to cardiovascular complications that can potentially result in increased morbidity and mortality. It is suggested that a complex non-invasive assessment of cardiovascular autonomic regulation—cardiac vagal control, sympathetic vascular activity, and cardiovascular reflex control—could represent a promising tool for early diagnosis, personalized therapy, and monitoring of therapeutic interventions in anorexia nervosa particularly at a vulnerable adolescent age. In this view, we recommend to consider in the diagnostic route, at least in the subset of patients with peripheral microvascular symptoms, a nailfold video-capillaroscopy as an easy not invasive tool for the early assessing of possible cardiovascular involvement. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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25 pages, 938 KiB  
Review
Recent Advances in the Use of Molecular Analyses to Inform the Diagnosis and Prognosis of Patients with Polycythaemia Vera
by Ruth Stuckey and María Teresa Gómez-Casares
Int. J. Mol. Sci. 2021, 22(9), 5042; https://doi.org/10.3390/ijms22095042 - 10 May 2021
Cited by 12 | Viewed by 3855
Abstract
Genetic studies in the past decade have improved our understanding of the molecular basis of the BCR-ABL1-negative myeloproliferative neoplasm (MPN) polycythaemia vera (PV). Such breakthroughs include the discovery of the JAK2V617F driver mutation in approximately 95% of patients with PV, as [...] Read more.
Genetic studies in the past decade have improved our understanding of the molecular basis of the BCR-ABL1-negative myeloproliferative neoplasm (MPN) polycythaemia vera (PV). Such breakthroughs include the discovery of the JAK2V617F driver mutation in approximately 95% of patients with PV, as well as some very rare cases of familial hereditary MPN caused by inherited germline mutations. Patients with PV often progress to fibrosis or acute myeloid leukaemia, both associated with very poor clinical outcome. Moreover, thrombosis and major bleeding are the principal causes of morbidity and mortality. As a result of increasingly available and economical next-generation sequencing technologies, mutational studies have revealed the prognostic relevance of a few somatic mutations in terms of thrombotic risk and risk of transformation, helping to improve the risk stratification of patients with PV. Finally, knowledge of the molecular basis of PV has helped identify targets for directed therapy. The constitutive activation of the tyrosine kinase JAK2 is targeted by ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor for PV patients who are resistant or intolerant to cytoreductive treatment with hydroxyurea. Other molecular mechanisms have also been revealed, and numerous agents are in various stages of development. Here, we will provide an update of the recent published literature on how molecular testing can improve the diagnosis and prognosis of patients with PV and present recent advances that may have prognostic value in the near future. Full article
(This article belongs to the Special Issue Myelofibrosis and Myeloproliferative Neoplasms: Molecular Basis)
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18 pages, 3682 KiB  
Article
Immunomodulatory Effects of Vitamin D Supplementation in a Deficient Population
by Mathieu Garand, Mohammed Toufiq, Parul Singh, Susie Shih Yin Huang, Sara Tomei, Rebecca Mathew, Valentina Mattei, Mariam Al Wakeel, Elham Sharif and Souhaila Al Khodor
Int. J. Mol. Sci. 2021, 22(9), 5041; https://doi.org/10.3390/ijms22095041 - 10 May 2021
Cited by 7 | Viewed by 3306
Abstract
In addition to its canonical functions, vitamin D has been proposed to be an important mediator of the immune system. Despite ample sunshine, vitamin D deficiency is prevalent (>80%) in the Middle East, resulting in a high rate of supplementation. However, the underlying [...] Read more.
In addition to its canonical functions, vitamin D has been proposed to be an important mediator of the immune system. Despite ample sunshine, vitamin D deficiency is prevalent (>80%) in the Middle East, resulting in a high rate of supplementation. However, the underlying molecular mechanisms of the specific regimen prescribed and the potential factors affecting an individual’s response to vitamin D supplementation are not well characterized. Our objective is to describe the changes in the blood transcriptome and explore the potential mechanisms associated with vitamin D3 supplementation in one hundred vitamin D-deficient women who were given a weekly oral dose (50,000 IU) of vitamin D3 for three months. A high-throughput targeted PCR, composed of 264 genes representing the important blood transcriptomic fingerprints of health and disease states, was performed on pre and post-supplementation blood samples to profile the molecular response to vitamin D3. We identified 54 differentially expressed genes that were strongly modulated by vitamin D3 supplementation. Network analyses showed significant changes in the immune-related pathways such as TLR4/CD14 and IFN receptors, and catabolic processes related to NF-kB, which were subsequently confirmed by gene ontology enrichment analyses. We proposed a model for vitamin D3 response based on the expression changes of molecules involved in the receptor-mediated intra-cellular signaling pathways and the ensuing predicted effects on cytokine production. Overall, vitamin D3 has a strong effect on the immune system, G-coupled protein receptor signaling, and the ubiquitin system. We highlighted the major molecular changes and biological processes induced by vitamin D3, which will help to further investigate the effectiveness of vitamin D3 supplementation among individuals in the Middle East as well as other regions. Full article
(This article belongs to the Special Issue Epigenomics of Complex Traits and Diseases 2.0)
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20 pages, 3291 KiB  
Article
BDNF Overexpression in the Ventral Hippocampus Promotes Antidepressant- and Anxiolytic-Like Activity in Serotonin Transporter Knockout Rats
by Danielle M. Diniz, Francesca Calabrese, Paola Brivio, Marco A. Riva, Joanes Grandjean and Judith R. Homberg
Int. J. Mol. Sci. 2021, 22(9), 5040; https://doi.org/10.3390/ijms22095040 - 10 May 2021
Cited by 10 | Viewed by 2576
Abstract
BDNF plays a pivotal role in neuroplasticity events, vulnerability and resilience to stress-related disorders, being decreased in depressive patients and increased after antidepressant treatment. BDNF was found to be reduced in patients carrying the human polymorphism in the serotonin transporter promoter region (5-HTTLPR). [...] Read more.
BDNF plays a pivotal role in neuroplasticity events, vulnerability and resilience to stress-related disorders, being decreased in depressive patients and increased after antidepressant treatment. BDNF was found to be reduced in patients carrying the human polymorphism in the serotonin transporter promoter region (5-HTTLPR). The serotonin knockout rat (SERT−/−) is one of the animal models used to investigate the underlying molecular mechanisms of depression in humans. They present decreased BDNF levels, and anxiety- and depression-like behavior. To investigate whether upregulating BDNF would ameliorate the phenotype of SERT−/− rats, we overexpressed BDNF locally into the ventral hippocampus and submitted the animals to behavioral testing. The results showed that BDNF overexpression in the vHIP of SERT−/− rats promoted higher sucrose preference and sucrose intake; on the first day of the sucrose consumption test it decreased immobility time in the forced swim test and increased the time spent in the center of a novel environment. Furthermore, BDNF overexpression altered social behavior in SERT−/− rats, which presented increased passive contact with test partner and decreased solitary behavior. Finally, it promoted decrease in plasma corticosterone levels 60 min after restraint stress. In conclusion, modulation of BDNF IV levels in the vHIP of SERT−/− rats led to a positive behavioral outcome placing BDNF upregulation in the vHIP as a potential target to new therapeutic approaches to improve depressive symptoms. Full article
(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)
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34 pages, 5889 KiB  
Article
Aberrant Early in Life Stimulation of the Stress-Response System Affects Emotional Contagion and Oxytocin Regulation in Adult Male Mice
by Giovanni Laviola, Ludovica Maria Busdraghi, Noemi Meschino, Carla Petrella and Marco Fiore
Int. J. Mol. Sci. 2021, 22(9), 5039; https://doi.org/10.3390/ijms22095039 - 10 May 2021
Cited by 11 | Viewed by 2990
Abstract
Results over the last decades have provided evidence suggesting that HPA axis dysfunction is a major risk factor predisposing to the development of psychopathological behaviour. This susceptibility can be programmed during developmental windows of marked neuroplasticity, allowing early-life adversity to convey vulnerability to [...] Read more.
Results over the last decades have provided evidence suggesting that HPA axis dysfunction is a major risk factor predisposing to the development of psychopathological behaviour. This susceptibility can be programmed during developmental windows of marked neuroplasticity, allowing early-life adversity to convey vulnerability to mental illness later in life. Besides genetic predisposition, also environmental factors play a pivotal role in this process, through embodiment of the mother’s emotions, or via nutrients and hormones transferred through the placenta and the maternal milk. The aim of the current translational study was to mimic a severe stress condition by exposing female CD-1 mouse dams to abnormal levels of corticosterone (80 µg/mL) in the drinking water either during the last week of pregnancy (PreCORT) or the first one of lactation (PostCORT), compared to an Animal Facility Rearing (AFR) control group. When tested as adults, male mice from PostCORT offspring and somewhat less the PreCORT mice exhibited a markedly increased corticosterone response to acute restraint stress, compared to perinatal AFR controls. Aberrant persistence of adolescence-typical increased interest towards novel social stimuli and somewhat deficient emotional contagion also characterised profiles in both perinatal-CORT groups. Intranasal oxytocin (0 or 20.0 µg/kg) generally managed to reduce the stress response and restore a regular behavioural phenotype. Alterations in density of glucocorticoid and mineralocorticoid receptors, oxytocin and µ- and κ-opioid receptors were found. Changes differed as a function of brain areas and the specific age window of perinatal aberrant stimulation of the HPA axis. Present results provided experimental evidence in a translational mouse model that precocious adversity represents a risk factor predisposing to the development of psychopathological behaviour. Full article
(This article belongs to the Special Issue Therapeutic Potential of Targeting the Oxytocinergic System)
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45 pages, 3448 KiB  
Review
In Vitro Liver Toxicity Testing of Chemicals: A Pragmatic Approach
by Andrés Tabernilla, Bruna dos Santos Rodrigues, Alanah Pieters, Anne Caufriez, Kaat Leroy, Raf Van Campenhout, Axelle Cooreman, Ana Rita Gomes, Emma Arnesdotter, Eva Gijbels and Mathieu Vinken
Int. J. Mol. Sci. 2021, 22(9), 5038; https://doi.org/10.3390/ijms22095038 - 10 May 2021
Cited by 18 | Viewed by 9469
Abstract
The liver is among the most frequently targeted organs by noxious chemicals of diverse nature. Liver toxicity testing using laboratory animals not only raises serious ethical questions, but is also rather poorly predictive of human safety towards chemicals. Increasing attention is, therefore, being [...] Read more.
The liver is among the most frequently targeted organs by noxious chemicals of diverse nature. Liver toxicity testing using laboratory animals not only raises serious ethical questions, but is also rather poorly predictive of human safety towards chemicals. Increasing attention is, therefore, being paid to the development of non-animal and human-based testing schemes, which rely to a great extent on in vitro methodology. The present paper proposes a rationalized tiered in vitro testing strategy to detect liver toxicity triggered by chemicals, in which the first tier is focused on assessing general cytotoxicity, while the second tier is aimed at identifying liver-specific toxicity as such. A state-of-the-art overview is provided of the most commonly used in vitro assays that can be used in both tiers. Advantages and disadvantages of each assay as well as overall practical considerations are discussed. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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13 pages, 7662 KiB  
Review
Wound Repair and Extremely Low Frequency-Electromagnetic Field: Insight from In Vitro Study and Potential Clinical Application
by Giulio Gualdi, Erica Costantini, Marcella Reale and Paolo Amerio
Int. J. Mol. Sci. 2021, 22(9), 5037; https://doi.org/10.3390/ijms22095037 - 10 May 2021
Cited by 22 | Viewed by 4249
Abstract
Wound healing is a complex, staged process. It involves extensive communication between the different cellular constituents of various compartments of the skin and its extracellular matrix (ECM). Different signaling pathways are determined by a mutual influence on each other, resulting in a dynamic [...] Read more.
Wound healing is a complex, staged process. It involves extensive communication between the different cellular constituents of various compartments of the skin and its extracellular matrix (ECM). Different signaling pathways are determined by a mutual influence on each other, resulting in a dynamic and complex crosstalk. It consists of various dynamic processes including a series of overlapping phases: hemostasis, inflammation response, new tissue formation, and tissue remodeling. Interruption or deregulation of one or more of these phases may lead to non-healing (chronic) wounds. The most important factor among local and systemic exogenous factors leading to a chronic wound is infection with a biofilm presence. In the last few years, an increasing number of reports have evaluated the effects of extremely low frequency (ELF) electromagnetic fields (EMFs) on tissue repair. Each experimental result comes from a single element of this complex process. An interaction between ELF-EMFs and healing has shown to effectively modulate inflammation, protease matrix rearrangement, neo-angiogenesis, senescence, stem-cell proliferation, and epithelialization. These effects are strictly related to the time of exposure, waveform, frequency, and amplitude. In this review, we focus on the effect of ELF-EMFs on different wound healing phases. Full article
(This article belongs to the Special Issue Non-ionizing Radiations: Biological Effects and Interaction Mechanisms)
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21 pages, 3516 KiB  
Review
Biological Activity of Selected Natural and Synthetic Terpenoid Lactones
by Alicja K. Surowiak, Lucyna Balcerzak, Stanisław Lochyński and Daniel J. Strub
Int. J. Mol. Sci. 2021, 22(9), 5036; https://doi.org/10.3390/ijms22095036 - 10 May 2021
Cited by 18 | Viewed by 3625
Abstract
Terpenoids with lactone moieties have been indicated to possess high bioactivity. Certain terpenoid lactones exist in nature, in plants and animals, but they can also be obtained by chemical synthesis. Terpenoids possessing lactone moieties are known for their cytotoxic, anti-inflammatory, antimicrobial, anticancer, and [...] Read more.
Terpenoids with lactone moieties have been indicated to possess high bioactivity. Certain terpenoid lactones exist in nature, in plants and animals, but they can also be obtained by chemical synthesis. Terpenoids possessing lactone moieties are known for their cytotoxic, anti-inflammatory, antimicrobial, anticancer, and antimalarial activities. Moreover, one terpenoid lactone, artemisinin, is used as a drug against malaria. Because of these abilities, there is constant interest in new terpenoid lactones that are both isolated and synthesized, and their biological activities have been verified. In some cases, the activity of the terpenoid lactone is specifically connected to the lactone moiety. Recent works have revealed that new terpenoid lactones can demonstrate such functions and are thus considered to be potential active agents against many diseases. Full article
(This article belongs to the Special Issue Natural and Synthetic Lactones: Isolation, Synthesis, Biotransformations and Biological Activity)
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11 pages, 696 KiB  
Review
GnRH-Related Neurohormones in the Fruit Fly Drosophila melanogaster
by David Ben-Menahem
Int. J. Mol. Sci. 2021, 22(9), 5035; https://doi.org/10.3390/ijms22095035 - 10 May 2021
Cited by 5 | Viewed by 2434
Abstract
Genomic and phylogenetic analyses of various invertebrate phyla revealed the existence of genes that are evolutionarily related to the vertebrate’s decapeptide gonadotropin-releasing hormone (GnRH) and the GnRH receptor genes. Upon the characterization of these gene products, encoding peptides and putative receptors, GnRH-related peptides [...] Read more.
Genomic and phylogenetic analyses of various invertebrate phyla revealed the existence of genes that are evolutionarily related to the vertebrate’s decapeptide gonadotropin-releasing hormone (GnRH) and the GnRH receptor genes. Upon the characterization of these gene products, encoding peptides and putative receptors, GnRH-related peptides and their G-protein coupled receptors have been identified. These include the adipokinetic hormone (AKH) and corazonin (CRZ) in insects and their cognate receptors that pair to form bioactive signaling systems, which network with additional neurotransmitters/hormones (e.g., octopamine and ecdysone). Multiple studies in the past 30 years have identified many aspects of the biology of these peptides that are similar in size to GnRH and function as neurohormones. This review briefly describes the main activities of these two neurohormones and their receptors in the fruit fly Drosophila melanogaster. The similarities and differences between Drosophila AKH/CRZ and mammalian GnRH signaling systems are discussed. Of note, while GnRH has a key role in reproduction, AKH and CRZ show pleiotropic activities in the adult fly, primarily in metabolism and stress responses. From a protein evolution standpoint, the GnRH/AKH/CRZ family nicely demonstrates the developmental process of neuropeptide signaling systems emerging from a putative common ancestor and leading to divergent activities in distal phyla. Full article
(This article belongs to the Special Issue Gonadotropin-Releasing Hormone Receptor Signaling and Functions 2.0)
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11 pages, 2470 KiB  
Communication
Targeting SIRT2 Sensitizes Melanoma Cells to Cisplatin via an EGFR-Dependent Mechanism
by Iwona Karwaciak, Anna Sałkowska, Kaja Karaś, Jarosław Dastych and Marcin Ratajewski
Int. J. Mol. Sci. 2021, 22(9), 5034; https://doi.org/10.3390/ijms22095034 - 10 May 2021
Cited by 7 | Viewed by 2627
Abstract
Melanoma cells are resistant to most anticancer chemotherapeutics. Despite poor response rates and short-term efficacy, chemotherapy remains the main approach to treating this cancer. The underlying mechanisms of the intrinsic chemoresistance of melanoma remain unclear, but elucidating these mechanisms is important to improve [...] Read more.
Melanoma cells are resistant to most anticancer chemotherapeutics. Despite poor response rates and short-term efficacy, chemotherapy remains the main approach to treating this cancer. The underlying mechanisms of the intrinsic chemoresistance of melanoma remain unclear, but elucidating these mechanisms is important to improve the efficacy of chemotherapy regimens. Increasing evidence suggests that sirtuin 2 (SIRT2) plays a key role in the response of melanoma cells to chemotherapeutics; thus, in the present study, we evaluated the impact of shRNA-mediated and pharmacological inhibition of SIRT2 on the sensitivity of melanoma cells to cisplatin, which is used in several regimens to treat melanoma patients. We found that cells with SIRT2 inhibition revealed increased sensitivity to cisplatin and exhibited increased accumulation of γ-H2AX and reduced EGFR-AKT-RAF-ERK1/2 (epidermal growth factor receptor-protein B kinase–RAF kinase-extracellular signal-regulated kinase 1/2) pathway signaling compared to control cells. Thus, our results show that sirtuin 2 inhibition increased the in vitro efficacy of cisplatin against melanoma cells. Full article
(This article belongs to the Special Issue Skin Cancer and Melanoma)
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35 pages, 7942 KiB  
Article
The Quest to Quantify Selective and Synergistic Effects of Plasma for Cancer Treatment: Insights from Mathematical Modeling
by Charlotta Bengtson and Annemie Bogaerts
Int. J. Mol. Sci. 2021, 22(9), 5033; https://doi.org/10.3390/ijms22095033 - 10 May 2021
Cited by 4 | Viewed by 2145
Abstract
Cold atmospheric plasma (CAP) and plasma-treated liquids (PTLs) have recently become a promising option for cancer treatment, but the underlying mechanisms of the anti-cancer effect are still to a large extent unknown. Although hydrogen peroxide (H2O2) has been [...] Read more.
Cold atmospheric plasma (CAP) and plasma-treated liquids (PTLs) have recently become a promising option for cancer treatment, but the underlying mechanisms of the anti-cancer effect are still to a large extent unknown. Although hydrogen peroxide (H2O2) has been recognized as the major anti-cancer agent of PTL and may enable selectivity in a certain concentration regime, the co-existence of nitrite can create a synergistic effect. We develop a mathematical model to describe the key species and features of the cellular response toward PTL. From the numerical solutions, we define a number of dependent variables, which represent feasible measures to quantify cell susceptibility in terms of the H2O2 membrane diffusion rate constant and the intracellular catalase concentration. For each of these dependent variables, we investigate the regimes of selective versus non-selective, and of synergistic versus non-synergistic effect to evaluate their potential role as a measure of cell susceptibility. Our results suggest that the maximal intracellular H2O2 concentration, which in the selective regime is almost four times greater for the most susceptible cells compared to the most resistant cells, could be used to quantify the cell susceptibility toward exogenous H2O2. We believe our theoretical approach brings novelty to the field of plasma oncology, and more broadly, to the field of redox biology, by proposing new ways to quantify the selective and synergistic anti-cancer effect of PTL in terms of inherent cell features. Full article
(This article belongs to the Special Issue Plasma Biology)
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18 pages, 12976 KiB  
Review
Molecular Imprinting Technology for Determination of Uric Acid
by Vilma Ratautaite, Urte Samukaite-Bubniene, Deivis Plausinaitis, Raimonda Boguzaite, Domas Balciunas, Almira Ramanaviciene, Grażyna Neunert and Arunas Ramanavicius
Int. J. Mol. Sci. 2021, 22(9), 5032; https://doi.org/10.3390/ijms22095032 - 10 May 2021
Cited by 33 | Viewed by 5208
Abstract
The review focuses on the overview of electrochemical sensors based on molecularly imprinted polymers (MIPs) for the determination of uric acid. The importance of robust and precise determination of uric acid is highlighted, a short description of the principles of molecular imprinting technology [...] Read more.
The review focuses on the overview of electrochemical sensors based on molecularly imprinted polymers (MIPs) for the determination of uric acid. The importance of robust and precise determination of uric acid is highlighted, a short description of the principles of molecular imprinting technology is presented, and advantages over the others affinity-based analytical methods are discussed. The review is mainly concerned with the electro-analytical methods like cyclic voltammetry, electrochemical impedance spectroscopy, amperometry, etc. Moreover, there are some scattered notes to the other electrochemistry-related analytical methods, which are capable of providing additional information and to solve some challenges that are not achievable using standard electrochemical methods. The significance of these overviewed methods is highlighted. The overview of the research that is employing MIPs imprinted with uric acid is mainly targeted to address these topics: (i) type of polymers, which are used to design uric acid imprint structures; (ii) types of working electrodes and/or other parts of signal transducing systems applied for the registration of analytical signal; (iii) the description of the uric acid extraction procedures applied for the design of final MIP-structure; (iv) advantages and disadvantages of electrochemical methods and other signal transducing methods used for the registration of the analytical signal; (vi) overview of types of interfering molecules, which were analyzed to evaluate the selectivity; (vi) comparison of analytical characteristics such as linear range, limits of detection and quantification, reusability, reproducibility, repeatability, and stability. Some insights in future development of uric acid sensors are discussed in this review. Full article
(This article belongs to the Special Issue Multidisciplinary Investigations of Nanoparticle Synthesis and Analysis for Possible Biomedical and Food Technology Applications)
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22 pages, 5620 KiB  
Article
Candida Administration in Bilateral Nephrectomy Mice Elevates Serum (1→3)-β-D-glucan That Enhances Systemic Inflammation Through Energy Augmentation in Macrophages
by Jiraphorn Issara-Amphorn, Cong Phi Dang, Wilasinee Saisorn, Kavee Limbutara and Asada Leelahavanichkul
Int. J. Mol. Sci. 2021, 22(9), 5031; https://doi.org/10.3390/ijms22095031 - 10 May 2021
Cited by 23 | Viewed by 2351
Abstract
Systemic inflammation, from gut translocation of organismal molecules, might worsen uremic complications in acute kidney injury (AKI). The monitoring of gut permeability integrity and/or organismal molecules in AKI might be clinically beneficial. Due to the less prominence of Candida albicans in human intestine [...] Read more.
Systemic inflammation, from gut translocation of organismal molecules, might worsen uremic complications in acute kidney injury (AKI). The monitoring of gut permeability integrity and/or organismal molecules in AKI might be clinically beneficial. Due to the less prominence of Candida albicans in human intestine compared with mouse gut, C. albicans were orally administered in bilateral nephrectomy (BiN) mice. Gut dysbiosis, using microbiome analysis, and gut permeability defect (gut leakage), which was determined by fluorescein isothiocyanate-dextran and intestinal tight-junction immunofluorescent staining, in mice with BiN-Candida was more severe than BiN without Candida. Additionally, profound gut leakage in BiN-Candida also resulted in gut translocation of lipopolysaccharide (LPS) and (1→3)-β-D-glucan (BG), the organismal components from gut contents, that induced more severe systemic inflammation than BiN without Candida. The co-presentation of LPS and BG in mouse serum enhanced inflammatory responses. As such, LPS with Whole Glucan Particle (WGP, a representative BG) induced more severe macrophage responses than LPS alone as determined by supernatant cytokines and gene expression of downstream signals (NFκB, Malt-1 and Syk). Meanwhile, WGP alone did not induced the responses. In parallel, WGP (with or without LPS), but not LPS alone, accelerated macrophage ATP production (extracellular flux analysis) through the upregulation of genes in mitochondria and glycolysis pathway (using RNA sequencing analysis), without the induction of cell activities. These data indicated a WGP pre-conditioning effect on cell energy augmentation. In conclusion, Candida in BiN mice accelerated gut translocation of BG that augmented cell energy status and enhanced pro-inflammatory macrophage responses. Hence, gut fungi and BG were associated with the enhanced systemic inflammation in acute uremia. Full article
(This article belongs to the Special Issue Lipopolysaccharide: Bacterial Endotoxin 2.0)
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10 pages, 1247 KiB  
Communication
Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis
by Meewhi Kim and Ilya Bezprozvanny
Int. J. Mol. Sci. 2021, 22(9), 5030; https://doi.org/10.3390/ijms22095030 - 10 May 2021
Cited by 5 | Viewed by 2491
Abstract
Apolipoprotein E (ApoE) is a protein that plays an important role in the transport of fatty acids and cholesterol and in cellular signaling. On the surface of the cells, ApoE lipoparticles bind to low density lipoprotein receptors (LDLR) that mediate the uptake of [...] Read more.
Apolipoprotein E (ApoE) is a protein that plays an important role in the transport of fatty acids and cholesterol and in cellular signaling. On the surface of the cells, ApoE lipoparticles bind to low density lipoprotein receptors (LDLR) that mediate the uptake of the lipids and downstream signaling events. There are three alleles of the human ApoE gene. Presence of ApoE4 allele is a major risk factor for developing Alzheimer’s disease (AD) and other disorders late in life, but the mechanisms responsible for biological differences between different ApoE isoforms are not well understood. We here propose that the differences between ApoE isoforms can be explained by differences in the pH-dependence of the association between ApoE3 and ApoE4 isoforms and LDL-A repeats of LDLR. As a result, the following endocytosis ApoE3-associated LDLRs are recycled back to the plasma membrane but ApoE4-containing LDLR complexes are trapped in late endosomes and targeted for degradation. The proposed mechanism is predicted to lead to a reduction in steady-state surface levels of LDLRs and impaired cellular signaling in ApoE4-expressing cells. We hope that this proposal will stimulate experimental research in this direction that allows the testing of our hypothesis. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of Neurodegenerative Diseases Targeting Early Diagnosis and Treatment)
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10 pages, 1637 KiB  
Review
Role of Carbonic Anhydrase in Cerebral Ischemia and Carbonic Anhydrase Inhibitors as Putative Protective Agents
by Irene Bulli, Ilaria Dettori, Elisabetta Coppi, Federica Cherchi, Martina Venturini, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Alessio Nocentini, Claudiu T. Supuran, Anna Maria Pugliese and Felicita Pedata
Int. J. Mol. Sci. 2021, 22(9), 5029; https://doi.org/10.3390/ijms22095029 - 10 May 2021
Cited by 11 | Viewed by 3523
Abstract
Ischemic stroke is a leading cause of death and disability worldwide. The only pharmacological treatment available to date for cerebral ischemia is tissue plasminogen activator (t-PA) and the search for successful therapeutic strategies still remains a major challenge. The loss of cerebral blood [...] Read more.
Ischemic stroke is a leading cause of death and disability worldwide. The only pharmacological treatment available to date for cerebral ischemia is tissue plasminogen activator (t-PA) and the search for successful therapeutic strategies still remains a major challenge. The loss of cerebral blood flow leads to reduced oxygen and glucose supply and a subsequent switch to the glycolytic pathway, which leads to tissue acidification. Carbonic anhydrase (CA, EC 4.2.1.1) is the enzyme responsible for converting carbon dioxide into a protons and bicarbonate, thus contributing to pH regulation and metabolism, with many CA isoforms present in the brain. Recently, numerous studies have shed light on several classes of carbonic anhydrase inhibitor (CAI) as possible new pharmacological agents for the management of brain ischemia. In the present review we summarized pharmacological, preclinical and clinical findings regarding the role of CAIs in strokes and we discuss their potential protective mechanisms. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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19 pages, 3805 KiB  
Article
TRPV1 Responses in the Cerebellum Lobules VI, VII, VIII Using Electroacupuncture Treatment for Chronic Pain and Depression Comorbidity in a Murine Model
by Bernice Lottering and Yi-Wen Lin
Int. J. Mol. Sci. 2021, 22(9), 5028; https://doi.org/10.3390/ijms22095028 - 10 May 2021
Cited by 12 | Viewed by 3057
Abstract
Depression is a prominent complex psychiatric disorder, usually complicated through expression of comorbid conditions, with chronic pain being among the most prevalent. This comorbidity is consistently associated with a poor prognosis and has been shown to negatively impact patient outcomes. With a global [...] Read more.
Depression is a prominent complex psychiatric disorder, usually complicated through expression of comorbid conditions, with chronic pain being among the most prevalent. This comorbidity is consistently associated with a poor prognosis and has been shown to negatively impact patient outcomes. With a global rise in this condition presenting itself, the importance of discovering long-term, effective, and affordable treatments is crucial. Electroacupuncture has demonstrated renowned success in its use for the treatment of pain and is a widely recognized therapy in clinical practice for the treatment of various psychosomatic disorders, most notably depression. Our study aimed to investigate the effects and mechanisms of Acid-Saline (AS) inducing states of chronic pain and depression comorbidity in the cerebellum, using the ST36 acupoint as the therapeutic intervention. Furthermore, the role of TRPV1 was relatedly explored through the use of TRPV1−/− mice (KO). The results indicated significant differences in the four behavioral tests used to characterize pain and depression states in mice. The AS and AS + SHAM group showed significant differences when compared to the Control and AS + EA groups in the von Frey and Hargreaves’s tests, as well as the Open-Field and Forced Swimming tests. This evidence was further substantiated in the protein levels observed in immunoblotting, with significant differences between the AS and AS + SHAM groups when compared to the AS + EA and AS + KO groups being identified. In addition, immunofluorescence visibly served to corroborate the quantitative outcomes. Conclusively these findings suggest that AS-induced chronic pain and depression comorbidity elicits changes in the cerebellum lobules VI, VII, VIII, which are ameliorated through the use of EA at ST36 via its action on TRPV1 and related molecular pathways. The action of TRPV1 is not singular in CPDC, which would suggest other potential targets such as acid-sensing ion channel subtype 3 (ASIC3) or voltage-gated sodium channels (Navs) that could be explored in future studies. Full article
(This article belongs to the Section Molecular Neurobiology)
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18 pages, 4608 KiB  
Article
Fitness Costs of Chlorantraniliprole Resistance Related to the SeNPF Overexpression in the Spodoptera exigua (Lepidoptera: Noctuidae)
by Changwei Gong, Xinge Yao, Qunfang Yang, Xuegui Wang, Yuming Zhang, Yumeng Wang and Litao Shen
Int. J. Mol. Sci. 2021, 22(9), 5027; https://doi.org/10.3390/ijms22095027 - 10 May 2021
Cited by 6 | Viewed by 2162
Abstract
Spodopteraexigua, a multifeeding insect pest, has developed a high level of resistance to chlorantraniliprole, which is a benzoylurea insecticide that targets the ryanodine receptors (RyRs). Herein, the resistant strain (SE-Sel) and sensitive strain (SE-Sus) were obtained by bidirectional screening for six [...] Read more.
Spodopteraexigua, a multifeeding insect pest, has developed a high level of resistance to chlorantraniliprole, which is a benzoylurea insecticide that targets the ryanodine receptors (RyRs). Herein, the resistant strain (SE-Sel) and sensitive strain (SE-Sus) were obtained by bidirectional screening for six generations. The potential oviposited eggs and oviposition rate of the SE-Sel strain were dramatically lower than those of the SE-Sus strain; on the contrary, the weights of prepupae and preadult were significantly increased. As a post-mating response, the higher number of non-oviposited eggs in the SE-Sel strain was caused by a lower mating rate. In addition, the expression levels of vitellogenin (SeVg) and its receptor (SeVgR) in the SE-Sel strain were consistently lower than those in the SE-Sus strain. An RyRI4743M mutation, contributing to the resistance to chlorantraniliprole, was located in the S3 transmembrane segments and might have affected the release of calcium ions; it led to the upregulated expression of the neuropeptide SeNPF and its receptor SeNPFR, and the mating and oviposition rate were significantly recovered when the SeNPF was knocked down though RNA interference (RNAi) in the male adult of the SE-Sel strain. Moreover, the expression of the juvenile hormone-binding proteins SeJHBWDS3 and SeJHBAN in the male adult of the SE-Sel strain was significantly decreased, which proved the existence of a fitness cost from another angle. Therefore, these results indicate that the fitness cost accompanied by chlorantraniliprole resistance in S. exigua may be related to the decrease in mating desire due to SeNPF overexpression. Full article
(This article belongs to the Section Molecular Toxicology)
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25 pages, 1520 KiB  
Review
In Pursuit of Healthy Aging: Effects of Nutrition on Brain Function
by Thayza Martins Melzer, Luana Meller Manosso, Suk-yu Yau, Joana Gil-Mohapel and Patricia S. Brocardo
Int. J. Mol. Sci. 2021, 22(9), 5026; https://doi.org/10.3390/ijms22095026 - 10 May 2021
Cited by 24 | Viewed by 14347
Abstract
Consuming a balanced, nutritious diet is important for maintaining health, especially as individuals age. Several studies suggest that consuming a diet rich in antioxidants and anti-inflammatory components such as those found in fruits, nuts, vegetables, and fish may reduce age-related cognitive decline and [...] Read more.
Consuming a balanced, nutritious diet is important for maintaining health, especially as individuals age. Several studies suggest that consuming a diet rich in antioxidants and anti-inflammatory components such as those found in fruits, nuts, vegetables, and fish may reduce age-related cognitive decline and the risk of developing various neurodegenerative diseases. Numerous studies have been published over the last decade focusing on nutrition and how this impacts health. The main objective of the current article is to review the data linking the role of diet and nutrition with aging and age-related cognitive decline. Specifically, we discuss the roles of micronutrients and macronutrients and provide an overview of how the gut microbiota-gut-brain axis and nutrition impact brain function in general and cognitive processes in particular during aging. We propose that dietary interventions designed to optimize the levels of macro and micronutrients and maximize the functioning of the microbiota-gut-brain axis can be of therapeutic value for improving cognitive functioning, particularly during aging. Full article
(This article belongs to the Special Issue The Links between Nutrition, Energy Metabolism, Aging and Cognition)
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20 pages, 5267 KiB  
Article
Dystrophin Deficiency Causes Progressive Depletion of Cardiovascular Progenitor Cells in the Heart
by Sarka Jelinkova, Yvonne Sleiman, Petr Fojtík, Franck Aimond, Amanda Finan, Gerald Hugon, Valerie Scheuermann, Deborah Beckerová, Olivier Cazorla, Marie Vincenti, Pascal Amedro, Sylvain Richard, Josef Jaros, Petr Dvorak, Alain Lacampagne, Gilles Carnac, Vladimir Rotrekl and Albano C. Meli
Int. J. Mol. Sci. 2021, 22(9), 5025; https://doi.org/10.3390/ijms22095025 - 10 May 2021
Cited by 1 | Viewed by 3804
Abstract
Duchenne muscular dystrophy (DMD) is a devastating condition shortening the lifespan of young men. DMD patients suffer from age-related dilated cardiomyopathy (DCM) that leads to heart failure. Several molecular mechanisms leading to cardiomyocyte death in DMD have been described. However, the pathological progression [...] Read more.
Duchenne muscular dystrophy (DMD) is a devastating condition shortening the lifespan of young men. DMD patients suffer from age-related dilated cardiomyopathy (DCM) that leads to heart failure. Several molecular mechanisms leading to cardiomyocyte death in DMD have been described. However, the pathological progression of DMD-associated DCM remains unclear. In skeletal muscle, a dramatic decrease in stem cells, so-called satellite cells, has been shown in DMD patients. Whether similar dysfunction occurs with cardiac muscle cardiovascular progenitor cells (CVPCs) in DMD remains to be explored. We hypothesized that the number of CVPCs decreases in the dystrophin-deficient heart with age and disease state, contributing to DCM progression. We used the dystrophin-deficient mouse model (mdx) to investigate age-dependent CVPC properties. Using quantitative PCR, flow cytometry, speckle tracking echocardiography, and immunofluorescence, we revealed that young mdx mice exhibit elevated CVPCs. We observed a rapid age-related CVPC depletion, coinciding with the progressive onset of cardiac dysfunction. Moreover, mdx CVPCs displayed increased DNA damage, suggesting impaired cardiac muscle homeostasis. Overall, our results identify the early recruitment of CVPCs in dystrophic hearts and their fast depletion with ageing. This latter depletion may participate in the fibrosis development and the acceleration onset of the cardiomyopathy. Full article
(This article belongs to the Special Issue Genetic Basis and Molecular Mechanisms of Heart Rhythm Disorders)
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2 pages, 162 KiB  
Editorial
Mastocytosis, MCAS, and Related Disorders—Diagnosis, Classification, and Therapy
by Marek Niedoszytko, Peter Valent and Bogusław Nedoszytko
Int. J. Mol. Sci. 2021, 22(9), 5024; https://doi.org/10.3390/ijms22095024 - 10 May 2021
Cited by 2 | Viewed by 2117
Abstract
Mastocytosis is a heterogeneous group of hematologic neoplasms defined by an accumulation of neoplastic mast cells (MC) in the skin, bone marrow, and other visceral organs [...] Full article
(This article belongs to the Special Issue Mastocytosis, MCAS, and Related Disorders – Diagnosis, Classification and Therapy)
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