RNA Editing as a Therapeutic Approach for Retinal Gene Therapy Requiring Long Coding Sequences
Chlorinated Tryptophans—How Does Arabidopsis Deal With Them?
ERK5 Nucleo-Cytoplasmic Shuttling as a Novel Target for Anticancer Therapy
Immunological Aspects of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Gastric Carcinogenesis
Healthspan Maintenance and Prevention of Parkinson’s-like Phenotypes with Hydroxytyrosol and Oleuropein Aglycone in C. elegans

Journal Description

International Journal of Molecular Sciences — Open Access Journal

International Journal of Molecular Sciences (ISSN 1422-0067; CODEN: IJMCFK; ISSN 1661-6596 for printed edition) is an international peer-reviewed open access journal providing an advanced forum for biochemistry, molecular and cell biology, molecular biophysics, molecular medicine, and all aspects of molecular research in chemistry, and is published semi-monthly online by MDPI. The Australian Society of Plant Scientists (ASPS), Epigenetics Society, European Calcium Society (ECS), European Chitin Society (EUCHIS), Spanish Society for Cell Biology (SEBC) and Signal Transduction Society (STS) are affiliated with IJMS and their members receive a discount on the article processing charges.

Open Access free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed by the Science Citation Index Expanded (Web of Science), MEDLINE (PubMed), Scopus and other databases.
Rapid Publication: manuscripts are peer-reviewed and a first decision provided to authors approximately 13.4 days after submission; acceptance to publication is undertaken in 2.2 days (median values for papers published in this journal in the first half of 2020).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Testimonials: See what our authors say about the IJMS.

Impact Factor: 4.556 (2019) ; 5-Year Impact Factor: 4.653 (2019)

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Latest Articles

Open AccessArticle

Effect of Heat Stress on Seed Protein Composition and Ultrastructure of Protein Storage Vacuoles in the Cotyledonary Parenchyma Cells of Soybean Genotypes That Are Either Tolerant or Sensitive to Elevated Temperatures

James R. Smith and

Int. J. Mol. Sci. 2020, 21(13), 4775; https://doi.org/10.3390/ijms21134775 (registering DOI) - 05 Jul 2020

Abstract

High growth temperatures negatively affect soybean (Glycine max (L.) Merr) yields and seed quality. Soybean plants, heat stressed during seed development, produce seed that exhibit wrinkling, discoloration, poor seed germination, and have an increased potential for incidence of pathogen infection and an overall decrease in economic value. Soybean breeders have identified a heat stress tolerant exotic landrace genotype, which has been used in traditional hybridization to generate experimental genotypes, with improved seed yield and heat tolerance. Here, we have investigated the seed protein composition and ultrastructure of cotyledonary parenchyma cells of soybean genotypes that are either susceptible or tolerant to high growth temperatures. Biochemical analyses of seed proteins isolated from heat-tolerant and heat-sensitive genotypes produced under 28/22 °C (control), 36/24 °C (moderate), and 42/26 °C (extreme) day/night temperatures revealed that the accumulation in soybean seeds of lipoxygenase, the β-subunit of β-conglycinin, sucrose binding protein and Bowman-Birk protease inhibitor were negatively impacted by extreme heat stress in both genotypes, but these effects were less pronounced in the heat-tolerant genotype. Western blot analysis showed elevated accumulation of heat shock proteins (HSP70 and HSP17.6) in both lines in response to elevated temperatures during seed fill. Transmission electron microscopy showed that heat stress caused dramatic structural changes in the storage parenchyma cells. Extreme heat stress disrupted the structure and the membrane integrity of protein storage vacuoles, organelles that accumulate seed storage proteins. The detachment of the plasma membrane from the cell wall (plasmolysis) was commonly observed in the cells of the sensitive line. In contrast, these structural changes were less pronounced in the tolerant genotype, even under extreme heat stress, cells, for the most part, retained their structural integrity. The results of our study demonstrate the contrasting effects of heat stress on the seed protein composition and ultrastructural alterations that contribute to the tolerant genotype’s ability to tolerate high temperatures during seed development. Full article

(This article belongs to the Special Issue Mechanisms of Drought, Temperature and Salinity Tolerance in Plants)

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Open AccessArticle

Reproducible Large-Scale Isolation of Exosomes from Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells and Their Application in Acute Kidney Injury

Jun Ho Lee ,

Dae Hyun Ha ,

Byong Seung Cho and

Int. J. Mol. Sci. 2020, 21(13), 4774; https://doi.org/10.3390/ijms21134774 (registering DOI) - 05 Jul 2020

Abstract

Acute kidney injury (AKI) is a fatal medical episode caused by sudden kidney damage or failure, leading to the death of patients within a few hours or days. Previous studies demonstrated that exosomes derived from various mesenchymal stem/stromal cells (MSC-exosomes) have positive effects on renal injuries in multiple experimental animal models of kidney diseases including AKI. However, the mass production of exosomes is a challenge not only in preclinical studies with large animals but also for successful clinical applications. In this respect, tangential flow filtration (TFF) is suitable for good manufacturing practice (GMP)-compliant large-scale production of high-quality exosomes. Until now, no studies have been reported on the use of TFF, but rather ultracentrifugation has been almost exclusively used, to isolate exosomes for AKI therapeutic application in preclinical studies. Here, we demonstrated the reproducible large-scale production of exosomes derived from adipose tissue-derived MSC (ASC-exosomes) using TFF and the lifesaving effect of the ASC-exosomes in a lethal model of cisplatin-induced rat AKI. Our results suggest the possibility of large-scale stable production of ASC-exosomes without loss of function and their successful application in life-threatening diseases. Full article

(This article belongs to the Special Issue Kidney Injury: From Molecular Basis to Therapies 2.0)

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Open AccessReview

The Impact of Single-Cell Genomics on Adipose Tissue Research

Alana Deutsch ,

Daorong Feng ,

Jeffrey E. Pessin and

Kosaku Shinoda

Int. J. Mol. Sci. 2020, 21(13), 4773; https://doi.org/10.3390/ijms21134773 (registering DOI) - 05 Jul 2020

Abstract

Adipose tissue is an important regulator of whole-body metabolism and energy homeostasis. The unprecedented growth of obesity and metabolic disease worldwide has required paralleled advancements in research on this dynamic endocrine organ system. Single-cell RNA sequencing (scRNA-seq), a highly meticulous methodology used to dissect tissue heterogeneity through the transcriptional characterization of individual cells, is responsible for facilitating critical advancements in this area. The unique investigative capabilities achieved by the combination of nanotechnology, molecular biology, and informatics are expanding our understanding of adipose tissue’s composition and compartmentalized functional specialization, which underlie physiologic and pathogenic states, including adaptive thermogenesis, adipose tissue aging, and obesity. In this review, we will summarize the use of scRNA-seq and single-nuclei RNA-seq (snRNA-seq) in adipocyte biology and their applications to obesity and diabetes research in the hopes of increasing awareness of the capabilities of this technology and acting as a catalyst for its expanded use in further investigation. Full article

(This article belongs to the Special Issue Adipogenesis and Adipose Tissue Metabolism 2.0)

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Open AccessArticle

Indonesian Ginger (Bangle) Extract Promotes Neurogenesis of Human Neural Stem Cells through WNT Pathway Activation

Kazumi Hirano ,

Miwa Kubo ,

Yoshiyasu Fukuyama and

Masakazu Namihira

Int. J. Mol. Sci. 2020, 21(13), 4772; https://doi.org/10.3390/ijms21134772 (registering DOI) - 05 Jul 2020

Abstract

Indonesian ginger (Zingiber purpureum Rosc.), also known as Bangle, exhibits neurotrophic effects on cultured murine cortical neurons and in the adult mouse brain, but the underlying mechanisms remain unknown. Here, using human fetal neural stem cells (hfNSCs) as a model system for in vitro human neurogenesis, we show that Bangle extracts activate canonical WNT/β-catenin signaling. Bangle extract-treatment of hfNSCs not only promoted neuronal differentiation, but also accelerated neurite outgrowth from immature neurons. Furthermore, Bangle extracts induced expression of neurogenic genes and WNT signaling-target genes, and facilitated the accumulation of β-catenin in nuclei of hfNSC. Interestingly, altered histone modifications were also observed in Bangle-treated hfNSCs. Together, these findings demonstrate that Bangle contributes to hfNSC neurogenesis by WNT pathway and epigenetic regulation. Full article

(This article belongs to the Special Issue The Mechanistic Link between Cell Therapy and Neurorehabilitation)

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Open AccessArticle

Aspirin Induces Mitochondrial Ca²⁺Remodeling in Tumor Cells via ROS‒Depolarization‒Voltage-Gated Ca²⁺ Entry

Itsuho Fujikawa ,

Takashi Ando ,

Manami Suzuki-Karasaki ,

Miki Suzuki-Karasaki ,

Toyoko Ochiai and

Yoshihiro Suzuki-Karasaki

Int. J. Mol. Sci. 2020, 21(13), 4771; https://doi.org/10.3390/ijms21134771 (registering DOI) - 05 Jul 2020

Abstract

Aspirin (acetylsalicylic acid) and its metabolite salicylate, have an anti-melanoma effect by evoking mitochondrial dysfunction through poorly understood mechanisms. Depolarization of the plasma membrane potential leads to voltage-gated Ca²⁺ entry (VGCE) and caspase-3 activation. In the present study, we investigated the role of depolarization and VGCE in aspirin’s anti-melanoma effect. Aspirin and to a lesser extent, salicylate (≥2.5 mM) induced a rapid (within seconds) depolarization, while they caused comparable levels of depolarization with a lag of 2~4 h. Reactive oxygen species (ROS) generation also occurred in the two-time points, and antioxidants abolished the early ROS generation and depolarization. At the same concentrations, the two drugs induced apoptotic and necrotic cell death in a caspase-independent manner, and antioxidants and Ca²⁺channel blockers prevented cell death. Besides ROS generation, reduced mitochondrial Ca²⁺ (Ca²⁺_m) and mitochondrial membrane potential preceded cell death. Moreover, the cells expressed the Ca_v1.2 isoform of l-type Ca²⁺channel, and knockdown of Ca_v1.2 abolished the decrease in Ca²⁺_m. Our findings suggest that aspirin and salicylate induce Ca²⁺_m remodeling, mitochondrial dysfunction, and cell death via ROS-dependent depolarization and VGCE activation. Full article

(This article belongs to the Special Issue Mitochondrial Functions, Alterations and Dynamics in Cancer)

Open AccessReview

Effects of Lipids and Lipoproteins on Mesenchymal Stem Cells Used in Cardiac Tissue Regeneration

Lin Kang ,

Hsiang-Chun Lee and

Int. J. Mol. Sci. 2020, 21(13), 4770; https://doi.org/10.3390/ijms21134770 (registering DOI) - 05 Jul 2020

Abstract

Mesenchymal stem cells (MSCs) have two characteristics of interest for this paper: the ability to self-renew, and the potential for multiple-lineage differentiation into various cells. MSCs have been used in cardiac tissue regeneration for over a decade. Adult cardiac tissue regeneration ability is quite low; it cannot repair itself after injury, as the heart cells are replaced by fibroblasts and lose function. It is therefore important to search for a feasible way to repair and restore heart function through stem cell therapy. Stem cells can differentiate and provide a source of progenitor cells for cardiomyocytes, endothelial cells, and supporting cells. Studies have shown that the concentrations of blood lipids and lipoproteins affect cardiovascular diseases, such as atherosclerosis, hypertension, and obesity. Furthermore, the MSC lipid profiles, such as the triglyceride and cholesterol content, have been revealed by lipidomics, as well as their correlation with MSC differentiation. Abnormal blood lipids can cause serious damage to internal organs, especially heart tissue. In the past decade, the accumulated literature has indicated that lipids/lipoproteins affect stem cell behavior and biological functions, including their multiple lineage capability, and in turn affect the outcome of regenerative medicine. This review will focus on the effect of lipids/lipoproteins on MSC cardiac regenerative medicine, as well as the effect of lipid-lowering drugs in promoting cardiomyogenesis-associated MSC differentiation. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 2.0)

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Open AccessArticle

Aquatic Mosses as Adaptable Bio-Filters for Heavy Metal Removal from Contaminated Water

Francesco P. Fanizzi and

Gian-Pietro Di Sansebastiano

Int. J. Mol. Sci. 2020, 21(13), 4769; https://doi.org/10.3390/ijms21134769 (registering DOI) - 05 Jul 2020

Abstract

Heavy metals (HMs) are released into the environment by many human activities and persist in water even after remediation. The efficient filtration of solubilized HMs is extremely difficult. Phytoremediation appears a convenient tool to remove HMs from polluted water, but it is limited by the choice of plants able to adapt to filtration of polluted water in terms of space and physiological needs. Biomasses are often preferred. Aquatic moss biomasses, thanks to gametophyte characteristics, can act as live filtering material. The potential for phytoremediation of Hypnales aquatic mosses has been poorly investigated compared to aquatic macrophytes. Their potential is usually indicated as a tool for bioindication and environmental monitoring more than for pollutant removal. When phytoremediation has been considered, insufficient attention has been paid to the adaptability of biomasses to different needs. In this study the heavy metal uptake of moss Taxiphyllum barbieri grown in two different light conditions, was tested with high concentrations of elements such as Pb, Cd, Zn, Cu, As, and Cr. This moss produces dense mats with few culture needs. The experimental design confirmed the capacity of the moss to accumulate HMs accordingly to their physiology and then demonstrated that a significant proportion of HMs was accumulated within a few hours. In addition to the biosorption effect, an evident contribution of the active simplistic mass can be evidenced. These reports of HM accumulation within short time intervals, show how this moss is particularly suitable as an adaptable bio-filter, representing a new opportunity for water eco-sustainable remediation. Full article

(This article belongs to the Special Issue Molecular Research on Bryophytes)

Open AccessReview

Role of Macrophages and Microglia in Zebrafish Regeneration

Susanna R. Var and

Christine A. Byrd-Jacobs

Int. J. Mol. Sci. 2020, 21(13), 4768; https://doi.org/10.3390/ijms21134768 (registering DOI) - 05 Jul 2020

Abstract

Currently, there is no treatment for recovery of human nerve function after damage to the central nervous system (CNS), and there are limited regenerative capabilities in the peripheral nervous system. Since fish are known for their regenerative abilities, understanding how these species modulate inflammatory processes following injury has potential translational importance for recovery from damage and disease. Many diseases and injuries involve the activation of innate immune cells to clear damaged cells. The resident immune cells of the CNS are microglia, the primary cells that respond to infection and injury, and their peripheral counterparts, macrophages. These cells serve as key modulators of development and plasticity and have been shown to be important in the repair and regeneration of structure and function after injury. Zebrafish are an emerging model for studying macrophages in regeneration after injury and microglia in neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. These fish possess a high degree of neuroanatomical, neurochemical, and emotional/social behavioral resemblance with humans, serving as an ideal simulator for many pathologies. This review explores literature on macrophage and microglial involvement in facilitating regeneration. Understanding innate immune cell behavior following damage may help to develop novel methods for treating toxic and chronic inflammatory processes that are seen in trauma and disease. Full article

(This article belongs to the Special Issue Fish Immunology)

Open AccessReview

Could Protons and Carbon Ions Be the Silver Bullets Against Pancreatic Cancer?

Carine Michiels and

Int. J. Mol. Sci. 2020, 21(13), 4767; https://doi.org/10.3390/ijms21134767 (registering DOI) - 04 Jul 2020

Abstract

Pancreatic cancer is a very aggressive cancer type associated with one of the poorest prognostics. Despite several clinical trials to combine different types of therapies, none of them resulted in significant improvements for patient survival. Pancreatic cancers demonstrate a very broad panel of resistance mechanisms due to their biological properties but also their ability to remodel the tumour microenvironment. Radiotherapy is one of the most widely used treatments against cancer but, up to now, its impact remains limited in the context of pancreatic cancer. The modern era of radiotherapy proposes new approaches with increasing conformation but also more efficient effects on tumours in the case of charged particles. In this review, we highlight the interest in using charged particles in the context of pancreatic cancer therapy and the impact of this alternative to counteract resistance mechanisms. Full article

(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer 2.0)

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Open AccessReview

Caffeine: An Overview of Its Beneficial Effects in Experimental Models and Clinical Trials of Parkinson’s Disease

Giovanni Schepici ,

Serena Silvestro ,

Placido Bramanti and

Emanuela Mazzon

Int. J. Mol. Sci. 2020, 21(13), 4766; https://doi.org/10.3390/ijms21134766 (registering DOI) - 04 Jul 2020

Abstract

Parkinson’s Disease (PD) is a neurological disease characterized by the progressive degeneration of the nigrostriatal dopaminergic pathway with consequent loss of neurons in the substantia nigra pars compacta and dopamine depletion. The cytoplasmic inclusions of α-synuclein (α-Syn), known as Lewy bodies, are the cytologic hallmark of PD. The presence of α-Syn aggregates causes mitochondrial degeneration, responsible for the increase in oxidative stress and consequent neurodegeneration. PD is a progressive disease that shows a complicated pathogenesis. The current therapies are used to alleviate the symptoms of the disease without changing its clinical course. Recently, phytocompounds with neuroprotective effects and antioxidant properties such as caffeine have aroused the interest of researchers. The purpose of this review is to summarize the preclinical studies present in the literature and clinical trials recorded in ClinicalTrial.gov, aimed at illustrating the effects of caffeine used as a nutraceutical compound combined with the current PD therapies. Therefore, the preventive effects of caffeine in the neurodegeneration of dopaminergic neurons encourage the use of this alkaloid as a supplement to reduce the progress of the PD. Full article

(This article belongs to the collection Neuroprotective Strategies)

Open AccessArticle

Absolute Binding Free Energy Calculations for Highly Flexible Protein MDM2 and Its Inhibitors

Nidhi Singh and

Wenjin Li

Int. J. Mol. Sci. 2020, 21(13), 4765; https://doi.org/10.3390/ijms21134765 (registering DOI) - 04 Jul 2020

Abstract

Reliable prediction of binding affinities for ligand-receptor complex has been the primary goal of a structure-based drug design process. In this respect, alchemical methods are evolving as a popular choice to predict the binding affinities for biomolecular complexes. However, the highly flexible protein-ligand systems pose a challenge to the accuracy of binding free energy calculations mostly due to insufficient sampling. Herein, integrated computational protocol combining free energy perturbation based absolute binding free energy calculation with free energy landscape method was proposed for improved prediction of binding free energy for flexible protein-ligand complexes. The proposed method is applied to the dataset of various classes of p53-MDM2 ( murine double minute 2) inhibitors. The absolute binding free energy calculations for MDMX (murine double minute X) resulted in a mean absolute error value of 0.816 kcal/mol while it is 3.08 kcal/mol for MDM2, a highly flexible protein compared to MDMX. With the integration of the free energy landscape method, the mean absolute error for MDM2 is improved to 1.95 kcal/mol. Full article

(This article belongs to the Section Molecular Informatics)

Open AccessArticle

BMP-Induced MicroRNA-101 Expression Regulates Vascular Smooth Muscle Cell Migration

Nanju Park and

Hara Kang

Int. J. Mol. Sci. 2020, 21(13), 4764; https://doi.org/10.3390/ijms21134764 (registering DOI) - 04 Jul 2020

Abstract

Proliferation and migration of vascular smooth muscle cells (VSMCs) are implicated in blood vessel development, maintenance of vascular homeostasis, and pathogenesis of vascular disorders. MicroRNAs (miRNAs) mediate the regulation of VSMC functions in response to microenvironmental signals. Because a previous study reported that miR-101, a tumor-suppressive miRNA, is a critical regulator of cell proliferation in vascular disease, we hypothesized that miR-101 controls important cellular processes in VSMCs. The present study aimed to elucidate the effects of miR-101 on VSMC function and its molecular mechanisms. We revealed that miR-101 regulates VSMC proliferation and migration. We showed that miR-101 expression is induced by bone morphogenetic protein (BMP) signaling, and we identified dedicator of cytokinesis 4 (DOCK4) as a novel target of miR-101. Our results suggest that the BMP–miR-101–DOCK4 axis mediates the regulation of VSMC function. Our findings help further the understanding of vascular physiology and pathology. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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Open AccessArticle

The Differential Effect of Carbon Dots on Gene Expression and DNA Methylation of Human Embryonic Lung Fibroblasts as a Function of Surface Charge and Dose

Michal Sima ,

Jiri Klema ,

Jan Belza ,

Jan Topinka and

Pavel Rossner, Jr.

Int. J. Mol. Sci. 2020, 21(13), 4763; https://doi.org/10.3390/ijms21134763 (registering DOI) - 04 Jul 2020

Abstract

This study presents a toxicological evaluation of two types of carbon dots (CD), similar in size (<10 nm) but differing in surface charge. Whole-genome mRNA and miRNA expression (RNAseq), as well as gene-specific DNA methylation changes, were analyzed in human embryonic lung fibroblasts (HEL 12469) after 4 h and 24 h exposure to concentrations of 10 and 50 µg/mL (for positive charged CD; pCD) or 10 and 100 µg/mL (for negative charged CD, nCD). The results showed a distinct response for the tested nanomaterials (NMs). The exposure to pCD induced the expression of a substantially lower number of mRNAs than those to nCD, with few commonly differentially expressed genes between the two CDs. For both CDs, the number of deregulated mRNAs increased with the dose and exposure time. The pathway analysis revealed a deregulation of processes associated with immune response, tumorigenesis and cell cycle regulation, after exposure to pCD. For nCD treatment, pathways relating to cell proliferation, apoptosis, oxidative stress, gene expression, and cycle regulation were detected. The expression of miRNAs followed a similar pattern: more pronounced changes after nCD exposure and few commonly differentially expressed miRNAs between the two CDs. For both CDs the pathway analysis based on miRNA-mRNA interactions, showed a deregulation of cancer-related pathways, immune processes and processes involved in extracellular matrix interactions. DNA methylation was not affected by exposure to any of the two CDs. In summary, although the tested CDs induced distinct responses on the level of mRNA and miRNA expression, pathway analyses revealed a potential common biological impact of both NMs independent of their surface charge. Full article

(This article belongs to the Special Issue Mechanisms of Cellular Toxicity of Nanoparticles)

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Open AccessArticle

Extracellular Matrix Stiffness and Composition Regulate the Myofibroblast Differentiation of Vaginal Fibroblasts

Alejandra M. Ruiz-Zapata ,

Andrea Heinz ,

Manon H. Kerkhof ,

Cindy van de Westerlo-van Rijt ,

Christian E. H. Schmelzer ,

Reinout Stoop ,

Kirsten B. Kluivers and

Egbert Oosterwijk

Int. J. Mol. Sci. 2020, 21(13), 4762; https://doi.org/10.3390/ijms21134762 (registering DOI) - 04 Jul 2020

Abstract

Fibroblast to myofibroblast differentiation is a key feature of wound-healing in soft tissues, including the vagina. Vaginal fibroblasts maintain the integrity of the vaginal wall tissues, essential to keep pelvic organs in place and avoid pelvic organ prolapse (POP). The micro-environment of vaginal tissues in POP patients is stiffer and has different extracellular matrix (ECM) composition than healthy vaginal tissues. In this study, we employed a series of matrices with known stiffnesses, as well as vaginal ECMs, in combination with vaginal fibroblasts from POP and healthy tissues to investigate how matrix stiffness and composition regulate myofibroblast differentiation in vaginal fibroblasts. Stiffness was positively correlated to production of α-smooth muscle actin (α-SMA). Vaginal ECMs induced myofibroblast differentiation as both α-SMA and collagen gene expressions were increased. This differentiation was more pronounced in cells seeded on POP-ECMs that were stiffer than those derived from healthy tissues and had higher collagen and elastin protein content. We showed that stiffness and ECM content regulate vaginal myofibroblast differentiation. We provide preliminary evidence that vaginal fibroblasts might recognize POP-ECMs as scar tissues that need to be remodeled. This is fundamentally important for tissue repair, and provides a rational basis for POP disease modelling and therapeutic innovations in vaginal reconstruction. Full article

(This article belongs to the Section Biochemistry)

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Open AccessReview

Role of Extracellular Matrix in Pathophysiology of Patent Ductus Arteriosus: Emphasis on Vascular Remodeling

Ting-Yi Lin ,

Jwu-Lai Yeh and

Jong-Hau Hsu

Int. J. Mol. Sci. 2020, 21(13), 4761; https://doi.org/10.3390/ijms21134761 (registering DOI) - 04 Jul 2020

Abstract

The ductus arteriosus (DA) is a shunt vessel between the aorta and the pulmonary artery during the fetal period that is essential for the normal development of the fetus. Complete closure usually occurs after birth but the vessel might remain open in certain infants, as patent ductus arteriosus (PDA), causing morbidity or mortality. The mechanism of DA closure is a complex process involving an orchestration of cell–matrix interaction between smooth muscle cells (SMC), endothelial cells, and extracellular matrix (ECM). ECM is defined as the noncellular component secreted by cells that consists of macromolecules such as elastin, collagens, proteoglycan, hyaluronan, and noncollagenous glycoproteins. In addition to its role as a physical scaffold, ECM mediates diverse signaling that is critical in development, maintenance, and repair in the cardiovascular system. In this review, we aim to outline the current understandings of ECM and its role in the pathophysiology of PDA, with emphasis on DA remodeling and highlight future outlooks. The molecular diversity and plasticity of ECM present a rich array of potential therapeutic targets for the management of PDA. Full article

(This article belongs to the Special Issue Extracellular Matrix in Heart Disease)

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Open AccessReview

Choroid Plexus: The Orchestrator of Long-Range Signalling Within the CNS

Karol Kaiser and

Vitezslav Bryja

Int. J. Mol. Sci. 2020, 21(13), 4760; https://doi.org/10.3390/ijms21134760 (registering DOI) - 04 Jul 2020

Abstract

Cerebrospinal fluid (CSF) is the liquid that fills the brain ventricles. CSF represents not only a mechanical brain protection but also a rich source of signalling factors modulating diverse processes during brain development and adulthood. The choroid plexus (CP) is a major source of CSF and as such it has recently emerged as an important mediator of extracellular signalling within the brain. Growing interest in the CP revealed its capacity to release a broad variety of bioactive molecules that, via CSF, regulate processes across the whole central nervous system (CNS). Moreover, CP has been also recognized as a sensor, responding to altered composition of CSF associated with changes in the patterns of CNS activity. In this review, we summarize the recent advances in our understanding of the CP as a signalling centre that mediates long-range communication in the CNS. By providing a detailed account of the CP secretory repertoire, we describe how the CP contributes to the regulation of the extracellular environment—in the context of both the embryonal as well as the adult CNS. We highlight the role of the CP as an important regulator of CNS function that acts via CSF-mediated signalling. Further studies of CP–CSF signalling hold the potential to provide key insights into the biology of the CNS, with implications for better understanding and treatment of neuropathological conditions. Full article

(This article belongs to the Special Issue Choroid Plexus: Novel Functions for an Old Structure)

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Open AccessReview

Signaling Pathways that Control Muscle Mass

Anna Vainshtein and

Marco Sandri

Int. J. Mol. Sci. 2020, 21(13), 4759; https://doi.org/10.3390/ijms21134759 (registering DOI) - 04 Jul 2020

Abstract

The loss of skeletal muscle mass under a wide range of acute and chronic maladies is associated with poor prognosis, reduced quality of life, and increased mortality. Decades of research indicate the importance of skeletal muscle for whole body metabolism, glucose homeostasis, as well as overall health and wellbeing. This tissue’s remarkable ability to rapidly and effectively adapt to changing environmental cues is a double-edged sword. Physiological adaptations that are beneficial throughout life become maladaptive during atrophic conditions. The atrophic program can be activated by mechanical, oxidative, and energetic distress, and is influenced by the availability of nutrients, growth factors, and cytokines. Largely governed by a transcription-dependent mechanism, this program impinges on multiple protein networks including various organelles as well as biosynthetic and quality control systems. Although modulating muscle function to prevent and treat disease is an enticing concept that has intrigued research teams for decades, a lack of thorough understanding of the molecular mechanisms and signaling pathways that control muscle mass, in addition to poor transferability of findings from rodents to humans, has obstructed efforts to develop effective treatments. Here, we review the progress made in unraveling the molecular mechanisms responsible for the regulation of muscle mass, as this continues to be an intensive area of research. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

Open AccessReview

Lipid Signaling in Ocular Neovascularization

Ryo Terao and

Hiroki Kaneko

Int. J. Mol. Sci. 2020, 21(13), 4758; https://doi.org/10.3390/ijms21134758 (registering DOI) - 04 Jul 2020

Abstract

Vasculogenesis and angiogenesis play a crucial role in embryonic development. Pathological neovascularization in ocular tissues can lead to vision-threatening vascular diseases, including proliferative diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, choroidal neovascularization, and corneal neovascularization. Neovascularization involves various cellular processes and signaling pathways and is regulated by angiogenic factors such as vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF). Modulating these circuits may represent a promising strategy to treat ocular neovascular diseases. Lipid mediators derived from membrane lipids are abundantly present in most tissues and exert a wide range of biological functions by regulating various signaling pathways. In particular, glycerophospholipids, sphingolipids, and polyunsaturated fatty acids exert potent pro-angiogenic or anti-angiogenic effects, according to the findings of numerous preclinical and clinical studies. In this review, we summarize the current knowledge regarding the regulation of ocular neovascularization by lipid mediators and their metabolites. A better understanding of the effects of lipid signaling in neovascularization may provide novel therapeutic strategies to treat ocular neovascular diseases and other human disorders. Full article

(This article belongs to the Special Issue Recent Advancements in Research and Therapy of Ocular Neovascular Diseases)

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Open AccessArticle

Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570

Stig Linder and

Int. J. Mol. Sci. 2020, 21(13), 4757; https://doi.org/10.3390/ijms21134757 (registering DOI) - 04 Jul 2020

Abstract

The proteasome is a validated target of cancer therapeutics. Inhibition of proteasome activity results in the activation of the unfolded protein response (UPR) characterized by phosphorylation of eukaryotic initiation factor 2α (eIF2α), global translational arrest, and increased expression of the proapoptotic CHOP (C/EBP homologous protein) protein. Defects in the UPR response has been reported to result in altered sensitivity of tumor cells to proteasome inhibitors. Here, we characterized the effects of the deubiquitinase (DUB) inhibitor VLX1570 on protein homeostasis, both at the level of the UPR and on protein translation, in acute lymphoblastic leukemia (ALL). Similar to the 20S inhibitor bortezomib, VLX1570 induced accumulation of polyubiquitinated proteins and increased expression of the chaperone Grp78/Bip in ALL cells. Both compounds induced cleavage of PARP (Poly (ADP-ribose) polymerase) in ALL cells, consistent with induction of apoptosis. However, and in contrast to bortezomib, VLX1570 treatment resulted in limited induction of the proapoptotic CHOP protein. Translational inhibition was observed by both bortezomib and VLX1570. We report that in distinction to bortezomib, suppression of translation by VXL1570 occurred at the level of elongation. Increased levels of Hsc70/Hsp70 proteins were observed on polysomes following exposure to VLX1570, possibly suggesting defects in nascent protein folding. Our findings demonstrate apoptosis induction in ALL cells that appears to be uncoupled from CHOP induction, and show that VLX1570 suppresses protein translation by a mechanism distinct from that of bortezomib. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias 2.0)

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Open AccessReview

Role of Human Leukocyte Antigens at the Feto-Maternal Interface in Normal and Pathological Pregnancy: An Update

Rita Franco ,

Giovanni Scambia and

Int. J. Mol. Sci. 2020, 21(13), 4756; https://doi.org/10.3390/ijms21134756 (registering DOI) - 04 Jul 2020

Abstract

The successful maternal tolerance of the semi-allogeneic fetus provides an apparent immunologic paradox. Indeed, deep invasion of placental trophoblast cells into maternal uterine tissue and the following growth of the fetus have to be tolerated by a pregnant woman’s immune system. Among the various possible protective mechanisms that may be involved in human pregnancy, the expression of a non-classical pattern of human leukocyte antigen (HLA) class I molecules and the complete lack of expression of HLA class II molecules in placental tissues seem to be the most relevant mechanisms of fetal escape from maternal immune recognition. The importance of HLA molecules in fetal toleration by the maternal immune system is highlighted by pregnancy complications occurring in cases of abnormal HLA molecule expression at the maternal–fetal interface. In this review, we summarize evidences about the role of placental HLA molecules in normal and pathological pregnancies. Full article

(This article belongs to the Special Issue Reproductive Immunology: Immunoregulatory Mechanisms during Healthy and Pathological Pregnancies)

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