Biomolecules

18 pages, 1612 KiB

Open AccessArticle

A Set of 17 microRNAs Common for Brain and Cerebrospinal Fluid Differentiates Primary Central Nervous System Lymphoma from Non-Malignant Brain Tumors

by Maria Sromek, Grzegorz Rymkiewicz, Agnieszka Paziewska, Lukasz Michal Szafron, Maria Kulecka, Michalina Zajdel, Mariusz Kulinczak, Michalina Dabrowska, Aneta Balabas, Zbigniew Bystydzienski, Magdalena Chechlinska and Jan Konrad Siwicki

Biomolecules 2021, 11(9), 1395; https://doi.org/10.3390/biom11091395 - 21 Sep 2021

Cited by 2 | Viewed by 2399

Abstract

The diagnosis of primary central nervous system (CNS) lymphoma, which is predominantly of the diffuse large B-cell lymphoma type (CNS DLBCL), is challenging. MicroRNAs (miRs) are gene expression-regulating non-coding RNAs that are potential biomarkers. We aimed to distinguish miR expression patterns differentiating CNS [...] Read more.

The diagnosis of primary central nervous system (CNS) lymphoma, which is predominantly of the diffuse large B-cell lymphoma type (CNS DLBCL), is challenging. MicroRNAs (miRs) are gene expression-regulating non-coding RNAs that are potential biomarkers. We aimed to distinguish miR expression patterns differentiating CNS DLBCL and non-malignant CNS diseases with tumor presentation (n-ML). Next generation sequencing-based miR profiling of cerebrospinal fluids (CSFs) and brain tumors was performed. Sample source-specific (CSF vs. brain tumor) miR patterns were revealed. Even so, a set of 17 miRs differentiating CNS DLBCL from n-ML, no matter if assessed in CSF or in a tumor, was identified. Along with the results of pathway analyses, this suggests their pathogenic role in CNS DLBCL. A combination of just four of those miRs (miR-16-5p, miR-21-5p, miR-92a-3p, and miR-423-5p), assessed in CSFs, discriminated CNS DLBCL from n-ML samples with 100% specificity and 67.0% sensitivity. Analyses of paired CSF-tumor samples from patients with CNS DLBCL showed significantly lower CSF levels of miR-26a, and higher CSF levels of miR-15a-5p, miR-15b-5p, miR-19a-3p, miR-106b-3p, miR-221-3p, and miR-423-5p. Noteworthy, the same miRs belonged to the abovementioned set differentiating CNS DLBCL from non-malignant CNS diseases. Our results not only add to the basic knowledge, but also hold significant translational potential. Full article

(This article belongs to the Special Issue MicroRNAs - Small Molecules with Great Potential in Tumorigenesis)

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15 pages, 797 KiB

Open AccessReview

The Underappreciated Role of Epithelial Mesenchymal Transition in Chronic Obstructive Pulmonary Disease and Its Strong Link to Lung Cancer

by Malik Quasir Mahmood, Shakti D. Shukla, Chris Ward and Eugene Haydn Walters

Biomolecules 2021, 11(9), 1394; https://doi.org/10.3390/biom11091394 - 21 Sep 2021

Cited by 19 | Viewed by 3408

Abstract

The World Health Organisation reported COPD to be the third leading cause of death globally in 2019, and in 2020, the most common cause of cancer death was lung cancer; when these linked conditions are added together they come near the top of [...] Read more.

The World Health Organisation reported COPD to be the third leading cause of death globally in 2019, and in 2020, the most common cause of cancer death was lung cancer; when these linked conditions are added together they come near the top of the leading causes of mortality. The cell-biological program termed epithelial-to-mesenchymal transition (EMT) plays an important role in organ development, fibrosis and cancer progression. Over the past decade there has emerged a substantial literature that also links EMT specifically to the pathophysiology of chronic obstructive pulmonary disease (COPD) as primarily an airway fibrosis disease; COPD is a recognised strong independent risk factor for the development of lung cancer, over and above the risks associated with smoking. In this review, our primary focus is to highlight these linkages and alert both the COPD and lung cancer fields to these complex interactions. We emphasise the need for inter-disciplinary attention and research focused on the likely crucial roles of EMT (and potential for its inhibition) with recognition of its strategic place mechanistically in both COPD and lung cancer. As part of this we discuss the future potential directions for novel therapeutic opportunities, including evidence-based strategic repurposing of currently used familiar/approved medications. Full article

(This article belongs to the Special Issue EMT and Cancer)

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29 pages, 8078 KiB

Open AccessFeature PaperReview

The Surprising Story of Fusicoccin: A Wilt-Inducing Phytotoxin, a Tool in Plant Physiology and a 14-3-3-Targeted Drug

by Mauro Marra, Lorenzo Camoni, Sabina Visconti, Anna Fiorillo and Antonio Evidente

Biomolecules 2021, 11(9), 1393; https://doi.org/10.3390/biom11091393 - 21 Sep 2021

Cited by 21 | Viewed by 2967

Abstract

Fusicoccin is the α glucoside of a carbotricyclic diterpene, produced by the fungus Phomopsis amygdali (previously classified as Fusicoccum amygdali), the causal agent of almond and peach canker disease. A great interest in this molecule started when it was discovered that it [...] Read more.

Fusicoccin is the α glucoside of a carbotricyclic diterpene, produced by the fungus Phomopsis amygdali (previously classified as Fusicoccum amygdali), the causal agent of almond and peach canker disease. A great interest in this molecule started when it was discovered that it brought about an irreversible stomata opening of higher plants, thereby inducing the wilting of their leaves. Since then, several studies were carried out to elucidate its biological activity, biosynthesis, structure, structure-activity relationships and mode of action. After sixty years of research and more than 1800 published articles, FC is still the most studied phytotoxin and one of the few whose mechanism of action has been elucidated in detail. The ability of FC to stimulate several fundamental plant processes depends on its ability to activate the plasma membrane H⁺-ATPase, induced by eliciting the association of 14-3-3 proteins, a class of regulatory molecules widespread in eukaryotes. This discovery renewed interest in FC and prompted more recent studies aimed to ascertain the ability of the toxin to influence the interaction between 14-3-3 proteins and their numerous client proteins in animals, involved in the regulation of basic cellular processes and in the etiology of different diseases, including cancer. This review covers the different aspects of FC research partially treated in different previous reviews, starting from its discovery in 1964, with the aim to outline the extraordinary pathway which led this very uncommon diterpenoid to evolve from a phytotoxin into a tool in plant physiology and eventually into a 14-3-3-targeted drug. Full article

(This article belongs to the Special Issue State-of-the-Art Isolation, Chemical and Biological Characterization, Synthesis and Formulation of Natural Products in Italy 2020–2021)

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20 pages, 4946 KiB

Open AccessArticle

The HMGB Protein KlIxr1, a DNA Binding Regulator of Kluyveromyces lactis Gene Expression Involved in Oxidative Metabolism, Growth, and dNTP Synthesis

by Agustín Rico-Díaz, Aída Barreiro-Alonso, Cora Rey-Souto, Manuel Becerra, Mónica Lamas-Maceiras, M. Esperanza Cerdán and Ángel Vizoso-Vázquez

Biomolecules 2021, 11(9), 1392; https://doi.org/10.3390/biom11091392 - 21 Sep 2021

Cited by 2 | Viewed by 2374

Abstract

In the traditional fermentative model yeast Saccharomyces cerevisiae, ScIxr1 is an HMGB (High Mobility Group box B) protein that has been considered as an important regulator of gene transcription in response to external changes like oxygen, carbon source, or nutrient availability. [...] Read more.

In the traditional fermentative model yeast Saccharomyces cerevisiae, ScIxr1 is an HMGB (High Mobility Group box B) protein that has been considered as an important regulator of gene transcription in response to external changes like oxygen, carbon source, or nutrient availability. Kluyveromyces lactis is also a useful eukaryotic model, more similar to many human cells due to its respiratory metabolism. We cloned and functionally characterized by different methodologies KlIXR1, which encodes a protein with only 34.4% amino acid sequence similarity to ScIxr1. Our data indicate that both proteins share common functions, including their involvement in the response to hypoxia or oxidative stress induced by hydrogen peroxide or metal treatments, as well as in the control of key regulators for maintenance of the dNTP (deoxyribonucleotide triphosphate) pool and ribosome synthesis. KlIxr1 is able to bind specific regulatory DNA sequences in the promoter of its target genes, which are well conserved between S. cerevisiae and K. lactis. Oppositely, we found important differences between ScIrx1 and KlIxr1 affecting cellular responses to cisplatin or cycloheximide in these yeasts, which could be dependent on specific and non-conserved domains present in these two proteins. Full article

(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)

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17 pages, 5023 KiB

Open AccessArticle

First Dye-Decolorizing Peroxidase from an Ascomycetous Fungus Secreted by Xylaria grammica

by Virginia Kimani, René Ullrich, Enrico Büttner, Robert Herzog, Harald Kellner, Nico Jehmlich, Martin Hofrichter and Christiane Liers

Biomolecules 2021, 11(9), 1391; https://doi.org/10.3390/biom11091391 - 21 Sep 2021

Cited by 7 | Viewed by 2315

Abstract

Background: Fungal DyP-type peroxidases have so far been described exclusively for basidiomycetes. Moreover, peroxidases from ascomycetes that oxidize Mn²⁺ ions are yet not known. Methods: We describe here the physicochemical, biocatalytic, and molecular characterization of a DyP-type peroxidase (DyP, EC 1.11.1.19) from [...] Read more.

Background: Fungal DyP-type peroxidases have so far been described exclusively for basidiomycetes. Moreover, peroxidases from ascomycetes that oxidize Mn²⁺ ions are yet not known. Methods: We describe here the physicochemical, biocatalytic, and molecular characterization of a DyP-type peroxidase (DyP, EC 1.11.1.19) from an ascomycetous fungus. Results: The enzyme oxidizes classic peroxidase substrates such as 2,6-DMP but also veratryl alcohol and notably Mn²⁺ to Mn³⁺ ions, suggesting a physiological function of this DyP in lignin modification. The K_M value (49 µM) indicates that Mn²⁺ ions bind with high affinity to the XgrDyP protein but their subsequent oxidation into reactive Mn³⁺ proceeds with moderate efficiency compared to MnPs and VPs. Mn²⁺ oxidation was most effective at an acidic pH (between 4.0 and 5.0) and a hypothetical surface exposed an Mn²⁺ binding site comprising three acidic amino acids (two aspartates and one glutamate) could be localized within the hypothetical XgrDyP structure. The oxidation of Mn²⁺ ions is seemingly supported by four aromatic amino acids that mediate an electron transfer from the surface to the heme center. Conclusions: Our findings shed new light on the possible involvement of DyP-type peroxidases in lignocellulose degradation, especially by fungi that lack prototypical ligninolytic class II peroxidases. Full article

(This article belongs to the Special Issue Fungal Metabolism - Enzymes and Bioactive Compounds)

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18 pages, 5954 KiB

Open AccessReview

Cyclophilins and Their Functions in Abiotic Stress and Plant–Microbe Interactions

by Przemysław Olejnik, Cezary Jerzy Mądrzak and Katarzyna Nuc

Biomolecules 2021, 11(9), 1390; https://doi.org/10.3390/biom11091390 - 21 Sep 2021

Cited by 12 | Viewed by 2753

Abstract

Plants have developed a variety of mechanisms and regulatory pathways to change their gene expression profiles in response to abiotic stress conditions and plant–microbe interactions. The plant–microbe interaction can be pathogenic or beneficial. Stress conditions, both abiotic and pathogenic, negatively affect the growth, [...] Read more.

Plants have developed a variety of mechanisms and regulatory pathways to change their gene expression profiles in response to abiotic stress conditions and plant–microbe interactions. The plant–microbe interaction can be pathogenic or beneficial. Stress conditions, both abiotic and pathogenic, negatively affect the growth, development, yield and quality of plants, which is very important for crops. In contrast, the plant–microbe interaction could be growth-promoting. One of the proteins involved in plant response to stress conditions and plant–microbe interactions is cyclophilin. Cyclophilins (CyPs), together with FK506-binding proteins (FKBPs) and parvulins, belong to a big family of proteins with peptidyl-prolyl cis-trans isomerase activity (Enzyme Commission (EC) number 5.2.1.8). Genes coding for proteins with the CyP domain are widely expressed in all organisms examined, including bacteria, fungi, animals, and plants. Their different forms can be found in the cytoplasm, endoplasmic reticulum, nucleus, chloroplast, mitochondrion and in the phloem space. They are involved in numerous processes, such as protein folding, cellular signaling, mRNA processing, protein degradation and apoptosis. In the past few years, many new functions, and molecular mechanisms for cyclophilins have been discovered. In this review, we aim to summarize recent advances in cyclophilin research to improve our understanding of their biological functions in plant defense and symbiotic plant–microbe interactions. Full article

(This article belongs to the Collection Cellular and Molecular Mechanisms Governing Stress Response in Plants)

25 pages, 2696 KiB

Open AccessReview

Mechanosensitivity in Pulmonary Circulation: Pathophysiological Relevance of Stretch-Activated Channels in Pulmonary Hypertension

by Solène Barbeau, Guillaume Gilbert, Guillaume Cardouat, Isabelle Baudrimont, Véronique Freund-Michel, Christelle Guibert, Roger Marthan, Pierre Vacher, Jean-François Quignard and Thomas Ducret

Biomolecules 2021, 11(9), 1389; https://doi.org/10.3390/biom11091389 - 21 Sep 2021

Cited by 17 | Viewed by 3939

Abstract

A variety of cell types in pulmonary arteries (endothelial cells, fibroblasts, and smooth muscle cells) are continuously exposed to mechanical stimulations such as shear stress and pulsatile blood pressure, which are altered under conditions of pulmonary hypertension (PH). Most functions of such vascular [...] Read more.

A variety of cell types in pulmonary arteries (endothelial cells, fibroblasts, and smooth muscle cells) are continuously exposed to mechanical stimulations such as shear stress and pulsatile blood pressure, which are altered under conditions of pulmonary hypertension (PH). Most functions of such vascular cells (e.g., contraction, migration, proliferation, production of extracellular matrix proteins, etc.) depend on a key event, i.e., the increase in intracellular calcium concentration ([Ca²⁺]_i) which results from an influx of extracellular Ca²⁺ and/or a release of intracellular stored Ca²⁺. Calcium entry from the extracellular space is a major step in the elevation of [Ca²⁺]_i, involving a variety of plasmalemmal Ca²⁺ channels including the superfamily of stretch-activated channels (SAC). A common characteristic of SAC is that their gating depends on membrane stretch. In general, SAC are non-selective Ca²⁺-permeable cation channels, including proteins of the TRP (Transient Receptor Potential) and Piezo channel superfamily. As membrane mechano-transducers, SAC convert physical forces into biological signals and hence into a cell response. Consequently, SAC play a major role in pulmonary arterial calcium homeostasis and, thus, appear as potential novel drug targets for a better management of PH. Full article

(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)

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30 pages, 8651 KiB

Open AccessEditor’s ChoiceArticle

Multifunctionality of Nanosized Calcium Apatite Dual-Doped with Li⁺/Eu³⁺ Ions Related to Cell Culture Studies and Cytotoxicity Evaluation In Vitro

by Paulina Sobierajska, Blazej Pozniak, Marta Tikhomirov, Julia Miller, Lucyna Mrowczynska, Agata Piecuch, Justyna Rewak-Soroczynska, Agata Dorotkiewicz-Jach, Zuzanna Drulis-Kawa and Rafal J. Wiglusz

Biomolecules 2021, 11(9), 1388; https://doi.org/10.3390/biom11091388 - 21 Sep 2021

Cited by 10 | Viewed by 2802

Abstract

Li⁺/Eu³⁺ dual-doped calcium apatite analogues were fabricated using a microwave stimulated hydrothermal technique. XRPD, FT-IR, micro-Raman spectroscopy, TEM and SAED measurements indicated that obtained apatites are single-phased, crystallize with a hexagonal structure, have similar morphology and nanometric size as well [...] Read more.

Li⁺/Eu³⁺ dual-doped calcium apatite analogues were fabricated using a microwave stimulated hydrothermal technique. XRPD, FT-IR, micro-Raman spectroscopy, TEM and SAED measurements indicated that obtained apatites are single-phased, crystallize with a hexagonal structure, have similar morphology and nanometric size as well as show red luminescence. Lithium effectively modifies the local symmetry of optical active sites and, thus, affects the emission efficiency. Moreover, the hydrodynamic size and surface charge of the nanoparticles have been extensively studied. The protein adsorption (lysozyme, LSZ; bovine serum albumin, BSA) on the nanoparticle surface depended on the type of cationic dopant (Li⁺, Eu³⁺) and anionic group (OH⁻, Cl⁻, F⁻) of the apatite matrix. Interaction with LSZ resulted in a positive zeta potential, and the nanoparticles had the lowest hydrodynamic size in this protein medium. The cytotoxicity assessment was carried out on the human osteosarcoma cell line (U2OS), murine macrophages (J774.E), as well as human red blood cells (RBCs). The studied apatites were not cytotoxic to RBCs and J774.E cells; however, at higher concentrations of nanoparticles, cytotoxicity was observed against the U2OS cell line. No antimicrobial activity was detected against Gram-negative bacteria with one exception for P. aeruginosa treated with Li⁺-doped fluorapatite. Full article

(This article belongs to the Section Biological and Bio- Materials)

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12 pages, 1013 KiB

Open AccessArticle

Common Metabolites in Two Different Hypertensive Mouse Models: A Serum and Urine Metabolome Study

by Gaurav Baranwal, Rachel Pilla, Bethany L. Goodlett, Aja K. Coleman, Cristina M. Arenaz, Arul Jayaraman, Joseph M. Rutkowski, Robert C. Alaniz and Brett M. Mitchell

Biomolecules 2021, 11(9), 1387; https://doi.org/10.3390/biom11091387 - 21 Sep 2021

Cited by 4 | Viewed by 3263

Abstract

Recent metabolomics studies have identified a wide array of microbial metabolites and metabolite pathways that are significantly altered in hypertension. However, whether these metabolites play an active role in pathogenesis of hypertension or are altered because of this has yet to be determined. [...] Read more.

Recent metabolomics studies have identified a wide array of microbial metabolites and metabolite pathways that are significantly altered in hypertension. However, whether these metabolites play an active role in pathogenesis of hypertension or are altered because of this has yet to be determined. In the current study, we hypothesized that metabolite changes common between hypertension models may unify hypertension’s pathophysiology with respect to metabolites. We utilized two common mouse models of experimental hypertension: L-arginine methyl ester hydrochloride (L-NAME)/high-salt-diet-induced hypertension (LSHTN) and angiotensin II induced hypertension (AHTN). To identify common metabolites that were altered across both models, we performed untargeted global metabolomics analysis in serum and urine and the resulting data were analyzed using MetaboAnalyst software and compared to control mice. A total of 41 serum metabolites were identified as being significantly altered in any hypertensive model compared to the controls. Of these compounds, 14 were commonly changed in both hypertensive groups, with 4 significantly increased and 10 significantly decreased. In the urine, six metabolites were significantly altered in any hypertensive group with respect to the control; however, none of them were common between the hypertensive groups. These findings demonstrate that a modest, but potentially important, number of serum metabolites are commonly altered between experimental hypertension models. Further studies of the newly identified metabolites from this untargeted metabolomics analysis may lead to a greater understanding of the association between gut dysbiosis and hypertension. Full article

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15 pages, 2057 KiB

Open AccessReview

Galectins in Endothelial Cell Biology and Angiogenesis: The Basics

by Victor L. Thijssen

Biomolecules 2021, 11(9), 1386; https://doi.org/10.3390/biom11091386 - 20 Sep 2021

Cited by 18 | Viewed by 3608

Abstract

Angiogenesis, the growth of new blood vessels out of existing vessels, is a complex and tightly regulated process. It is executed by the cells that cover the inner surface of the vasculature, i.e., the endothelial cells. During angiogenesis, these cells adopt different phenotypes, [...] Read more.

Angiogenesis, the growth of new blood vessels out of existing vessels, is a complex and tightly regulated process. It is executed by the cells that cover the inner surface of the vasculature, i.e., the endothelial cells. During angiogenesis, these cells adopt different phenotypes, which allows them to proliferate and migrate, and to form tube-like structures that eventually result in the generation of a functional neovasculature. Multiple internal and external cues control these processes and the galectin protein family was found to be indispensable for proper execution of angiogenesis. Over the last three decades, several members of this glycan-binding protein family have been linked to endothelial cell functioning and to different steps of the angiogenesis cascade. This review provides a basic overview of our current knowledge regarding galectins in angiogenesis. It covers the main findings with regard to the endothelial expression of galectins and highlights their role in endothelial cell function and biology. Full article

(This article belongs to the Special Issue Cell Biology of Galectins)

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10 pages, 1426 KiB

Open AccessArticle

The Effect of a Synthetic Estrogen, Ethinylestradiol, on the hERG Block by E-4031

by Fumiya Tamura, Shintaro Sugimoto, Mana Sugimoto, Kazuho Sakamoto, Masahiko Yamaguchi, Takeshi Suzuki, Keiichi Fukuda, Masaki Ieda and Junko Kurokawa

Biomolecules 2021, 11(9), 1385; https://doi.org/10.3390/biom11091385 - 20 Sep 2021

Cited by 2 | Viewed by 2579

Abstract

Inhibition of K⁺-conductance through the human ether-a-go-go related gene (hERG) channel leads to QT prolongation and is associated with cardiac arrhythmias. We previously reported that physiological concentrations of some estrogens partially suppress the hERG channel currents by interacting with the S6 [...] Read more.

Inhibition of K⁺-conductance through the human ether-a-go-go related gene (hERG) channel leads to QT prolongation and is associated with cardiac arrhythmias. We previously reported that physiological concentrations of some estrogens partially suppress the hERG channel currents by interacting with the S6 residue F656 and increase the sensitivity of hERG blockade by E-4031. Although these studies suggested that clinically used synthetic estrogens with similar structures have the marked potential to alter hERG functions, the hERG interactions with synthetic estrogens have not been assessed. We therefore examined whether ethinylestradiol (EE2), a synthetic estrogen used in oral contraceptives, affects hERG function and blockade by drugs. Supratherapeutic concentrations of EE2 did not alter amplitudes or kinetics of the hERG currents elicited by train pulses at 20 mV (0.1 Hz). On the other hand, EE2 at therapeutic concentrations reduced the degree of hERG current suppression by E-4031. The administration of EE2 followed by E-4031 blockade reversed the current suppression, suggesting that the interaction of EE2 and E-4031 alters hERG at the drug-binding site. The effects of EE2 on hERG blockade raised the possibility that other estrogens, including synthetic estrogens, can alter hERG blockade by drugs that cause QT prolongation and ventricular arrhythmias. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

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15 pages, 1566 KiB

Open AccessReview

Cyclodextrins as Anti-inflammatory Agents: Basis, Drugs and Perspectives

by Silvia Lucia Appleton, Silvia Navarro-Orcajada, Francisco Juan Martínez-Navarro, Fabrizio Caldera, José Manuel López-Nicolás, Francesco Trotta and Adrián Matencio

Biomolecules 2021, 11(9), 1384; https://doi.org/10.3390/biom11091384 - 19 Sep 2021

Cited by 15 | Viewed by 3499

Abstract

Inflammation is a biological response of the immune system to harmful stimuli. Importantly, inflammation is also a hallmark of several human diseases such as cancer or diabetes. Novel drugs to treat this response are constantly researched, but the formulation is usually forgotten. Cyclodextrins [...] Read more.

Inflammation is a biological response of the immune system to harmful stimuli. Importantly, inflammation is also a hallmark of several human diseases such as cancer or diabetes. Novel drugs to treat this response are constantly researched, but the formulation is usually forgotten. Cyclodextrins (CDs) are a well-known excipient for complexing and drug delivery. Anti-inflammatory drugs and bioactive compounds with similar activities have been favored from these CD processes. CDs also illustrate anti-inflammatory activity per se. This review tried to describe the capacities of CDs in this field, and is divided into two parts: Firstly, a short description of the inflammation disease (causes, symptoms, treatment) is explained; secondly, the effects of different CDs alone or forming inclusion complexes with drugs or bioactive compounds are discussed. Full article

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16 pages, 4440 KiB

Open AccessArticle

PAQR6 Upregulation Is Associated with AR Signaling and Unfavorite Prognosis in Prostate Cancers

by Min Yang, Jean Chong Li, Chang Tao, Sa Wu, Bin Liu, Qiang Shu, Benyi Li and Runzhi Zhu

Biomolecules 2021, 11(9), 1383; https://doi.org/10.3390/biom11091383 - 18 Sep 2021

Cited by 12 | Viewed by 2604

Abstract

Progesterone-induced rapid non-genomic signaling events have been confirmed through several membrane progesterone receptors (mPR). Some mPRs were reported to correlate with cancer progression and patient prognosis. In this study, we conducted a comprehensive analysis of all progesterone receptor (PGR)-related genes in prostate cancer [...] Read more.

Progesterone-induced rapid non-genomic signaling events have been confirmed through several membrane progesterone receptors (mPR). Some mPRs were reported to correlate with cancer progression and patient prognosis. In this study, we conducted a comprehensive analysis of all progesterone receptor (PGR)-related genes in prostate cancer tissues and examined the correlations of their expression levels with disease progression and patient survival outcomes. We utilized multiple RNA-seq and cDNA microarray datasets to analyze gene expression profiles and performed logistics aggression and Kaplan-Meier survival analysis after stratifying patients based on tumor stages and Gleason scores. We also used NCBI GEO datasets to examine gene expression patterns in individual cell types of the prostate gland and to determine the androgen-induced alteration of gene expression. Spearman coefficient analysis was conducted to access the correlation of target gene expression with treatment responses and disease progression status. The classic PGR was mainly expressed in stromal cells and progestin and adipoQ receptor (PAQR) genes were the predominant genes in prostate epithelial cells. Progesterone receptor membrane component-1 (PGRMC1) was significantly higher than PGRMC2 in all prostate cell types. In prostate cancer tissues, PAQR6 expression was significantly upregulated, while all other genes were largely downregulated compared to normal prostate tissues. Although both PAQR6 upregulation and PAQR5 downregulation were significantly correlated with tumor pathological stages, only PAQR6 upregulation was associated with Gleason score, free-prostate-specific antigen (fPSA)/total-PSA (tPSA) ratio, and patient overall survival outcomes. In addition, PAQR6 upregulation and PGR/PGRMC1 downregulation were significantly associated with a quick relapse. Conversely, in neuroendocrinal prostate cancer (NEPC) tissues, PAQR6 expression was significantly lower, but PAQR7/8 expression was higher than castration-resistant prostate cancer (CRPC) tissues. PAQR8 expression was positively correlated with androgen receptor (AR) score and AR-V7 expression levels but inversely correlated with NEPC score in metastatic CRPC tumors. This study provides detailed expression profiles of membrane progesterone receptor genes in primary cancer, CRPC, and NEPC tissues. PAQR6 upregulation in primary cancer tissues is a novel prognostic biomarker for disease progression, overall, and progression-free survival in prostate cancers. PAQR8 expression in CRPC tissues is a biomarker for AR activation. Full article

(This article belongs to the Special Issue Molecular Signaling in Prostate Development and Prostate Cancer)

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20 pages, 18302 KiB

Open AccessArticle

Mechanistic Target of Rapamycin Complex 1 Signaling Links Hypoxia to Increased IGFBP-1 Phosphorylation in Primary Human Decidualized Endometrial Stromal Cells

by Pinki Nandi, Chloe E. Jang, Kyle Biggar, Chidambra D. Halari, Thomas Jansson and Madhulika B. Gupta

Biomolecules 2021, 11(9), 1382; https://doi.org/10.3390/biom11091382 - 18 Sep 2021

Cited by 3 | Viewed by 2422

Abstract

Insulin-like growth factor-1 (IGF-1) bioavailability in pregnancy is governed by IGF binding protein (IGFBP-1) and its phosphorylation, which enhances the affinity of IGFBP-1 for the growth factor. The decidua is the predominant source of maternal IGFBP-1; however, the mechanisms regulating decidual IGFBP-1 secretion/phosphorylation [...] Read more.

Insulin-like growth factor-1 (IGF-1) bioavailability in pregnancy is governed by IGF binding protein (IGFBP-1) and its phosphorylation, which enhances the affinity of IGFBP-1 for the growth factor. The decidua is the predominant source of maternal IGFBP-1; however, the mechanisms regulating decidual IGFBP-1 secretion/phosphorylation are poorly understood. Using decidualized primary human endometrial stromal cells (HESCs) from first-trimester placenta, we tested the hypothesis that mTORC1 signaling mechanistically links hypoxia to decidual IGFBP-1 secretion/phosphorylation. Hypoxia inhibited mechanistic target of rapamycin (mTORC1) (p-P70-S6K/Thr389, −47%, p = 0.038; p-4E-BP1/Thr70, −55%, p = 0.012) and increased IGFBP-1 (total, +35%, p = 0.005; phosphorylated, Ser101/+82%, p = 0.018; Ser119/+88%, p = 0.039; Ser 169/+157%, p = 0.019). Targeted parallel reaction monitoring-mass spectrometry (PRM-MS) additionally demonstrated markedly increased dual IGFBP-1 phosphorylation (pSer98+Ser101; pSer169+Ser174) in hypoxia. IGFBP-1 hyperphosphorylation inhibited IGF-1 receptor autophosphorylation/ Tyr1135 (−29%, p = 0.002). Furthermore, silencing of tuberous sclerosis complex 2 (TSC2) activated mTORC1 (p-P70-S6K/Thr389, +68%, p = 0.038; p-4E-BP1/Thr70, +30%, p = 0.002) and reduced total/site-specific IGFBP-1 phosphorylation. Importantly, TSC2 siRNA prevented inhibition of mTORC1 and the increase in secretion/site-specific IGFBP-1 phosphorylation in hypoxia. PRM-MS indicated concomitant changes in protein kinase autophosphorylation (CK2/Tyr182; PKC/Thr497; PKC/Ser657). Overall, mTORC1 signaling mechanistically links hypoxia to IGFBP-1 secretion/phosphorylation in primary HESC, implicating decidual mTORC1 inhibition as a novel mechanism linking uteroplacental hypoxia to fetal growth restriction. Full article

(This article belongs to the Collection TOR Signaling Pathway)

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13 pages, 1947 KiB

Open AccessArticle

The Effects of Fibrinogen’s Interactions with Its Neuronal Receptors, Intercellular Adhesion Molecule-1 and Cellular Prion Protein

by Nurul Sulimai, Jason Brown and David Lominadze

Biomolecules 2021, 11(9), 1381; https://doi.org/10.3390/biom11091381 - 18 Sep 2021

Cited by 7 | Viewed by 6456

Abstract

Neuroinflammatory diseases, such as Alzheimer’s disease (AD) and traumatic brain injury (TBI), are associated with the extravascular deposition of the fibrinogen (Fg) derivative fibrin and are accompanied with memory impairment. We found that during the hyperfibrinogenemia that typically occurs during AD and TBI, [...] Read more.

Neuroinflammatory diseases, such as Alzheimer’s disease (AD) and traumatic brain injury (TBI), are associated with the extravascular deposition of the fibrinogen (Fg) derivative fibrin and are accompanied with memory impairment. We found that during the hyperfibrinogenemia that typically occurs during AD and TBI, extravasated Fg was associated with amyloid beta and astrocytic cellular prion protein (PrP^C). These effects coincided with short-term memory (STM) reduction and neurodegeneration. However, the mechanisms of a direct Fg–neuron interaction and its functional role in neurodegeneration are still unclear. Cultured mouse brain neurons were treated with Fg in the presence or absence of function-blockers of its receptors, PrP^C or intercellular adhesion molecule-1 (ICAM-1). Associations of Fg with neuronal PrP^C and ICAM-1 were characterized. The expression of proinflammatory marker interleukin 6 (IL-6) and the generation of reactive oxygen species (ROS), mitochondrial superoxide, and nitrite in neurons were assessed. Fg-induced neuronal death was also evaluated. A strong association of Fg with neuronal PrP^C and ICAM-1, accompanied with overexpression of IL-6 and enhanced generation of ROS, mitochondrial superoxide, and nitrite as well as the resulting neuronal death, was found. These effects were reduced by blocking the function of neuronal PrP^C and ICAM-1, suggesting that the direct interaction of Fg with its neuronal receptors can induce overexpression of IL-6 and increase the generation of ROS, nitrite, and mitochondrial superoxide, ultimately leading to neuronal death. These effects can be a mechanism of neurodegeneration and the resultant memory reduction seen during TBI and AD. Full article

(This article belongs to the Special Issue Prions and Prion-Like Mechanisms in Disease and Biological Function)

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30 pages, 2095 KiB

Open AccessEditor’s ChoiceReview

Stress-Induced Epstein-Barr Virus Reactivation

by Daniel G. Sausen, Maimoona S. Bhutta, Elisa S. Gallo, Harel Dahari and Ronen Borenstein

Biomolecules 2021, 11(9), 1380; https://doi.org/10.3390/biom11091380 - 18 Sep 2021

Cited by 39 | Viewed by 11814

Abstract

Epstein-Barr virus (EBV) is typically found in a latent, asymptomatic state in immunocompetent individuals. Perturbations of the host immune system can stimulate viral reactivation. Furthermore, there are a myriad of EBV-associated illnesses including various cancers, post-transplant lymphoproliferative disease, and autoimmune conditions. A thorough [...] Read more.

Epstein-Barr virus (EBV) is typically found in a latent, asymptomatic state in immunocompetent individuals. Perturbations of the host immune system can stimulate viral reactivation. Furthermore, there are a myriad of EBV-associated illnesses including various cancers, post-transplant lymphoproliferative disease, and autoimmune conditions. A thorough understanding of this virus, and the interplay between stress and the immune system, is essential to establish effective treatment. This review will provide a summary of the interaction between both psychological and cellular stressors resulting in EBV reactivation. It will examine mechanisms by which EBV establishes and maintains latency and will conclude with a brief overview of treatments targeting EBV. Full article

(This article belongs to the Special Issue Epstein-Barr Virus Disease Mechanisms and Stress Responses)

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19 pages, 10882 KiB

Open AccessArticle

Molecular Biology Networks and Key Gene Regulators for Inflammatory Biomarkers Shared by Breast Cancer Development: Multi-Omics Systems Analysis

by Su Yon Jung, Jeanette C. Papp, Matteo Pellegrini, Herbert Yu and Eric M. Sobel

Biomolecules 2021, 11(9), 1379; https://doi.org/10.3390/biom11091379 - 18 Sep 2021

Cited by 2 | Viewed by 2448

Abstract

As key inflammatory biomarkers C-reactive protein (CRP) and interleukin-6 (IL6) play an important role in the pathogenesis of non-inflammatory diseases, including specific cancers, such as breast cancer (BC). Previous genome-wide association studies (GWASs) have neither explained the large proportion of genetic heritability nor [...] Read more.

As key inflammatory biomarkers C-reactive protein (CRP) and interleukin-6 (IL6) play an important role in the pathogenesis of non-inflammatory diseases, including specific cancers, such as breast cancer (BC). Previous genome-wide association studies (GWASs) have neither explained the large proportion of genetic heritability nor provided comprehensive understanding of the underlying regulatory mechanisms. We adopted an integrative genomic network approach by incorporating our previous GWAS data for CRP and IL6 with multi-omics datasets, such as whole-blood expression quantitative loci, molecular biologic pathways, and gene regulatory networks to capture the full range of genetic functionalities associated with CRP/IL6 and tissue-specific key drivers (KDs) in gene subnetworks. We applied another systematic genomics approach for BC development to detect shared gene sets in enriched subnetworks across BC and CRP/IL6. We detected the topmost significant common pathways across CRP/IL6 (e.g., immune regulatory; chemokines and their receptors; interferon γ, JAK-STAT, and ERBB4 signaling), several of which overlapped with BC pathways. Further, in gene–gene interaction networks enriched by those topmost pathways, we identified KDs—both well-established (e.g., JAK1/2/3, STAT3) and novel (e.g., CXCR3, CD3D, CD3G, STAT6)—in a tissue-specific manner, for mechanisms shared in regulating CRP/IL6 and BC risk. Our study may provide robust, comprehensive insights into the mechanisms of CRP/IL6 regulation and highlight potential novel genetic targets as preventive and therapeutic strategies for associated disorders, such as BC. Full article

(This article belongs to the Section Molecular Genetics)

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18 pages, 1072 KiB

Open AccessArticle

Prognostic Impact of Genetic Variants of MECP2 and TIRAP on Clinical Outcomes of Systemic Lupus Erythematosus with and without Nephritis

by Safaa I. Tayel, Nashwa M. Muharram, Dina S. Fotoh, Hany S. Elbarbary, Huda I. Abd-Elhafiz, Eman A. El-Masry, Ahmed E. Taha and Shimaa E. Soliman

Biomolecules 2021, 11(9), 1378; https://doi.org/10.3390/biom11091378 - 18 Sep 2021

Cited by 4 | Viewed by 2336

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune illness with a growing prevalence in many populations. Few studies have examined genetic predisposition to SLE, so we aimed to examine the clinical impact of the genetic polymorphisms MECP2 rs2734647and TIRAP rs8177374 on the outcomes [...] Read more.

Systemic lupus erythematosus (SLE) is a chronic autoimmune illness with a growing prevalence in many populations. Few studies have examined genetic predisposition to SLE, so we aimed to examine the clinical impact of the genetic polymorphisms MECP2 rs2734647and TIRAP rs8177374 on the outcomes and therapeutic precision of SLE with and without nephritis. This study included 110 SLE patients—divided into 63 with lupus nephritis (LN), and 47 without nephritis—and 100 controls. Laboratory measurements including CRP, ESR, ACR, CBC, anti-ds-DNA, vitamin A, C3, and C4 were carried out, along with genotyping of MECP2 rs2734647and TIRAP rs8177374 by real-time PCR and sequencing. Treg %, vitamin A, C3, and C4 were lower, whereas Th17 % was higher, in patients vs. controls (p < 0.001). The T allele of MECP2 rs2734647 was higher in LN than in non-nephritis and control subjects. Moreover, the T allele of TIRAP rs8177374 was higher in LN than in non-nephritis and control subjects. The MECP2 and TIRAP genes could play a role in predisposition to SLE, and can also predict disease progress to nephritis, helping to personalize medicine. Full article

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16 pages, 1547 KiB

Open AccessArticle

Interaction of Linear Polyelectrolytes with Proteins: Role of Specific Charge–Charge Interaction and Ionic Strength

by Julia Bukala, Prabhusrinivas Yavvari, Jacek J. Walkowiak, Matthias Ballauff and Marie Weinhart

Biomolecules 2021, 11(9), 1377; https://doi.org/10.3390/biom11091377 - 17 Sep 2021

Cited by 5 | Viewed by 2204

Abstract

We present a thermodynamic study of the interaction of synthetic, linear polyelectrolytes with bovine serum albumin (BSA). All polyelectrolytes are based on poly(allyl glycidyl ether) which has been modified by polymer-analogous reaction with anionic (-SO₃Na), cationic (-NH₃Cl or -NHMe [...] Read more.

We present a thermodynamic study of the interaction of synthetic, linear polyelectrolytes with bovine serum albumin (BSA). All polyelectrolytes are based on poly(allyl glycidyl ether) which has been modified by polymer-analogous reaction with anionic (-SO₃Na), cationic (-NH₃Cl or -NHMe₂Cl) or zwitterionic groups (-NMe₂(CH₂)₃SO₃). While the anionic polymer shows a very weak interaction, the zwitterionic polymer exhibits no interaction with BSA (pI = 4.7) under the applied pH = 7.4, ionic strength (I = 23–80 mM) and temperature conditions (T = 20–37 °C). A strong binding, however, was observed for the polycations bearing primary amino or tertiary dimethyl amino groups, which could be analysed in detail by isothermal titration calorimetry (ITC). The analysis was done using an expression which describes the free energy of binding, ΔG_b, as the function of the two decisive variables, temperature, T, and salt concentration, c_s. The underlying model splits ΔG_b into a term related to counterion release and a term related to water release. While the number of released counter ions is similar for both systems, the release of bound water is more important for the primary amine compared to the tertiary N,N-dimethyl amine presenting polymer. This finding is further traced back to a closer contact of the polymers’ protonated primary amino groups in the complex with oppositely charged moieties of BSA as compared to the bulkier protonated tertiary amine groups. We thus present an investigation that quantifies both driving forces for electrostatic binding, namely counterion release and change of hydration, which contribute to a deeper understanding with direct impact on future advancements in the biomedical field. Full article

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12 pages, 933 KiB

Open AccessArticle

The Aldehyde Dehydrogenase ALDH2*2 Allele, Associated with Alcohol Drinking Behavior, Dates Back to Prehistoric Times

by Chih-Lang Lin, Rong-Nan Chien, Li-Wei Chen, Ting-Shuo Huang, Yu-Chiau Shyu, Chau-Ting Yeh and Kung-Hao Liang

Biomolecules 2021, 11(9), 1376; https://doi.org/10.3390/biom11091376 - 17 Sep 2021

Cited by 3 | Viewed by 2368

Abstract

Human alcohol-consumption behavior is partly genetically encoded. The alcohol consumption of 987 residents in Keelung, Taiwan, was evaluated by using the Alcohol Use Disorder Identification Test (AUDIT). We assessed ~750,000 genomic variants of 71 residents who drank hazardously (AUDIT score ≥ 8) and [...] Read more.

Human alcohol-consumption behavior is partly genetically encoded. The alcohol consumption of 987 residents in Keelung, Taiwan, was evaluated by using the Alcohol Use Disorder Identification Test (AUDIT). We assessed ~750,000 genomic variants of 71 residents who drank hazardously (AUDIT score ≥ 8) and 126 residents who did not drink in their daily lives (AUDIT score = 0), using high-density single nucleotide polymorphism (SNP) arrays. The rs671 G > A manifests the highest significance of the association with drinking behavior (Fisher’s exact P = 8.75 × 10⁻⁹). It is a pleiotropic, non-synonymous variant in the aldehyde dehydrogenase 2 (ALDH2) gene. The minor allele “A”, commonly known as ALDH2*2, is associated with non-drinkers. Intriguingly, identity-by-descent haplotypes encompassing genomic regions with a median length of 1.6 (0.6–2.0) million nucleotide bases were found in all study participants with either heterozygous or homozygous ALDH2*2 (n = 81 and 13, respectively). We also analyzed a public-domain dataset with genome-wide genotypes of 2000 participants in Guangzhou, a coastal city in Southern China. Among them, 175 participants have homozygous ALDH2*2 genotype, and again, long ALDH2*2-carrying haplotypes were found in all 175 participants without exceptions. The median length of the ALDH2*2-carrying haplotype is 1.7 (0.5–2.8) million nucleotide bases. The haplotype lengths in the Keelung and Guangzhou cohorts combined indicate that the origin of the ALDH2*2 allele dates back to 7935 (7014–9381) years ago. In conclusion, the rs671 G > A is the leading genomic variant associated with the long-term drinking behavior among residents of Keelung, Taiwan. The ALDH2*2 allele has been in Asian populations since prehistoric times. Full article

(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)

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5 pages, 551 KiB

Open AccessCommentary

Strategies to Protect Dialysis Patients against Bisphenol A

by Borja Quiroga

Biomolecules 2021, 11(9), 1375; https://doi.org/10.3390/biom11091375 - 17 Sep 2021

Cited by 4 | Viewed by 1693

Abstract

Bisphenol A (BPA), also known as 2,2,-bis(4-hydroxyphenyl) propane, is a common component of plastics worldwide. However, it has been shown to act as an endocrine disruptor with some hormonal functions. Furthermore, high levels of BPA have been related to the development of cardiovascular [...] Read more.

Bisphenol A (BPA), also known as 2,2,-bis(4-hydroxyphenyl) propane, is a common component of plastics worldwide. However, it has been shown to act as an endocrine disruptor with some hormonal functions. Furthermore, high levels of BPA have been related to the development of cardiovascular events and the activation of carcinogenesis pathways. Patients with chronic kidney disease (CKD) have higher serum concentrations of BPA due to their impaired renal function. This situation is aggravated in CKD patients requiring dialysis, because the BPA content of dialysis devices (such as, for example, the filters) is added to the lack of excretion. In addition to the development of BPA-free dialysis filters, some techniques can contribute to the reduction of BPA levels in these patients. The aim of this review is to illustrate the impact of BPA on dialysis patients and suggest some strategies to reduce its inherent risks. Full article

(This article belongs to the Special Issue Bisphenol A: An Environmental Factor with an Emerging Role in the Pathophysiology of Renal and Cardiovascular Diseases)

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13 pages, 1580 KiB

Open AccessArticle

Opposing Actions of Octopamine and Tyramine on Honeybee Vision

by Felix Schilcher, Markus Thamm, Martin Strube-Bloss and Ricarda Scheiner

Biomolecules 2021, 11(9), 1374; https://doi.org/10.3390/biom11091374 - 17 Sep 2021

Cited by 7 | Viewed by 3016

Abstract

The biogenic amines octopamine and tyramine are important neurotransmitters in insects and other protostomes. They play a pivotal role in the sensory responses, learning and memory and social organisation of honeybees. Generally, octopamine and tyramine are believed to fulfil similar roles as their [...] Read more.

The biogenic amines octopamine and tyramine are important neurotransmitters in insects and other protostomes. They play a pivotal role in the sensory responses, learning and memory and social organisation of honeybees. Generally, octopamine and tyramine are believed to fulfil similar roles as their deuterostome counterparts epinephrine and norepinephrine. In some cases opposing functions of both amines have been observed. In this study, we examined the functions of tyramine and octopamine in honeybee responses to light. As a first step, electroretinography was used to analyse the effect of both amines on sensory sensitivity at the photoreceptor level. Here, the maximum receptor response was increased by octopamine and decreased by tyramine. As a second step, phototaxis experiments were performed to quantify the behavioural responses to light following treatment with either amine. Octopamine increased the walking speed towards different light sources while tyramine decreased it. This was independent of locomotor activity. Our results indicate that tyramine and octopamine act as functional opposites in processing responses to light. Full article

(This article belongs to the Special Issue Insect Receptors: Biochemical, Physiological and Molecular Studies)

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14 pages, 3202 KiB

Open AccessArticle

Dual Blockade of Lactate/GPR81 and PD-1/PD-L1 Pathways Enhances the Anti-Tumor Effects of Metformin

by Shaomeng Chen, Xiuman Zhou, Xin Yang, Wanqiong Li, Shuzhen Li, Zheng Hu, Chen Ling, Ranran Shi, Juan Liu, Guanyu Chen, Nazi Song, Xianxing Jiang, Xinghua Sui and Yanfeng Gao

Biomolecules 2021, 11(9), 1373; https://doi.org/10.3390/biom11091373 - 17 Sep 2021

Cited by 22 | Viewed by 4280

Abstract

Metformin is a widely used antidiabetic drug for cancer prevention and treatment. However, the overproduction of lactic acid and its inefficiency in cancer therapy limit its application. Here, we demonstrate the synergistic effects of the lactate/GPR81 blockade (3-hydroxy-butyrate, 3-OBA) and metformin on inhibiting [...] Read more.

Metformin is a widely used antidiabetic drug for cancer prevention and treatment. However, the overproduction of lactic acid and its inefficiency in cancer therapy limit its application. Here, we demonstrate the synergistic effects of the lactate/GPR81 blockade (3-hydroxy-butyrate, 3-OBA) and metformin on inhibiting cancer cells growth in vitro. Simultaneously, this combination could inhibit glycolysis and OXPHOS metabolism, as well as inhibiting tumor growth and reducing serum lactate levels in tumor-bearing mice. Interestingly, we observed that this combination could enhance the functions of Jurkat cells in vitro and CD8⁺ T cells in vivo. In addition, considering that 3-OBA could recover the inhibitory effects of metformin on PD-1 expression, we further determined the dual blockade effects of PD-1/PD-L1 and lactate/GPR81 on the antitumor activity of metformin. Our results suggested that this dual blockade strategy could remarkably enhance the anti-tumor effects of metformin, or even lead to tumor regression. In conclusion, our study has proposed a novel and robust strategy for a future application of metformin in cancer treatment. Full article

(This article belongs to the Special Issue Repurposing Drugs for Anti-Cancer Therapy)

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15 pages, 1618 KiB

Open AccessReview

The Immunological Therapeutic Strategies for Controlling Multiple Sclerosis: Considerations during the COVID-19 Pandemic

by Maryam Azimzadeh, Nora Möhn, Sajjad Ghane Ezabadi, Zahra Moghimi Esfandabadi, Alireza Soleimani, Elaheh Ranjbar, Maliheh Jahromi, Reihaneh Seyedebrahimi, Thomas Skripuletz and Farshad Moharrami Kasmaie

Biomolecules 2021, 11(9), 1372; https://doi.org/10.3390/biom11091372 - 17 Sep 2021

Cited by 3 | Viewed by 3134

Abstract

A growing body of evidence initially suggested that patients with multiple sclerosis (MS) might be more susceptible to coronavirus disease 2019 (COVID-19). Moreover, it was speculated that patients with MS treated with immunosuppressive drugs might be at risk to develop a severe diseases [...] Read more.

A growing body of evidence initially suggested that patients with multiple sclerosis (MS) might be more susceptible to coronavirus disease 2019 (COVID-19). Moreover, it was speculated that patients with MS treated with immunosuppressive drugs might be at risk to develop a severe diseases course after infection with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2). However, the recently published data have shown that MS patients do not have a higher risk for severe COVID-19. Although there is no indication that patients with MS and immunomodulatory/immunosuppressive therapy are generally at a higher risk of severe COVID-19, it is currently being emphasized that the hazards of poorly treated MS may outweigh the putative COVID-19 dangers. In this review, we discuss the challenges and considerations for MS patients in the COVID-19 pandemic. Full article

(This article belongs to the Special Issue The Molecular Mechanisms and Therapeutics in Multiple Sclerosis)

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17 pages, 329 KiB

Open AccessReview

Replacement of the Trabecular Meshwork Cells—A Way Ahead in IOP Control?

by Xiaochen Fan, Emine K. Bilir, Olivia A. Kingston, Rachel A. Oldershaw, Victoria R. Kearns, Colin E. Willoughby and Carl M. Sheridan

Biomolecules 2021, 11(9), 1371; https://doi.org/10.3390/biom11091371 - 16 Sep 2021

Cited by 9 | Viewed by 4033

Abstract

Glaucoma is one of the leading causes of vision loss worldwide, characterised with irreversible optic nerve damage and progressive vision loss. Primary open-angle glaucoma (POAG) is a subset of glaucoma, characterised by normal anterior chamber angle and raised intraocular pressure (IOP). Reducing IOP [...] Read more.

Glaucoma is one of the leading causes of vision loss worldwide, characterised with irreversible optic nerve damage and progressive vision loss. Primary open-angle glaucoma (POAG) is a subset of glaucoma, characterised by normal anterior chamber angle and raised intraocular pressure (IOP). Reducing IOP is the main modifiable factor in the treatment of POAG, and the trabecular meshwork (TM) is the primary site of aqueous humour outflow (AH) and the resistance to outflow. The structure and the composition of the TM are key to its function in regulating AH outflow. Dysfunction and loss of the TM cells found in the natural ageing process and more so in POAG can cause abnormal extracellular matrix (ECM) accumulation, increased TM stiffness, and increased IOP. Therefore, repair or regeneration of TM’s structure and function is considered as a potential treatment for POAG. Cell transplantation is an attractive option to repopulate the TM cells in POAG, but to develop a cell replacement approach, various challenges are still to be addressed. The choice of cell replacement covers autologous or allogenic approaches, which led to investigations into TM progenitor cells, induced pluripotent stem cells (iPSCs), and mesenchymal stem cells (MSCs) as potential stem cell source candidates. However, the potential plasticity and the lack of definitive cell markers for the progenitor and the TM cell population compound the biological challenge. Morphological and differential gene expression of TM cells located within different regions of the TM may give rise to different cell replacement or regenerative approaches. As such, this review describes the different approaches taken to date investigating different cell sources and their differing cell isolation and differentiation methodologies. In addition, we highlighted how these approaches were evaluated in different animal and ex vivo model systems and the potential of these methods in future POAG treatment. Full article

(This article belongs to the Special Issue Cellular Therapies for Glaucoma)

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14 pages, 5895 KiB

Open AccessArticle

Establishment of a Drug Screening Model for Cardiac Complications of Acute Renal Failure

by Shuyi Liao, Wenmin Yang, Ting Yu, Lu Dai, Xiaoliang Liu, Jiangping Zhang, Jinghong Zhao and Chi Liu

Biomolecules 2021, 11(9), 1370; https://doi.org/10.3390/biom11091370 - 16 Sep 2021

Cited by 3 | Viewed by 2489

Abstract

Acute renal failure (ARF) is a clinical critical syndrome with rapid and severe decline of renal function. Complications of ARF, especially its cardiac complications (cardiorenal syndrome type 3, CRS-3), are the main causes of death in patients with ARF. However, the shortage and [...] Read more.

Acute renal failure (ARF) is a clinical critical syndrome with rapid and severe decline of renal function. Complications of ARF, especially its cardiac complications (cardiorenal syndrome type 3, CRS-3), are the main causes of death in patients with ARF. However, the shortage and limited efficacy of therapeutic drugs make it significant to establish new large-scale drug screening models. Based on the Nitroreductase/Metronidazole (NTR/MTZ) cell ablation system, we constructed a Tg(cdh17:Dendra2-NTR) transgenic zebrafish line, which can specifically ablate renal tubular epithelial cells. The absence of renal tubular epithelial cells can lead to ARF in zebrafish larvae. The ARF symptoms, such as heart enlargement, slow heart rate and blood stasis, are similar to the clinical manifestations of human CRS-3. Furthermore, two therapeutic drugs (digoxin and enalapril) commonly used in the clinical treatment of heart failure were also effective in alleviating the symptoms of CRS-3 in zebrafish, which proved the effectiveness of this model. Drug screening further discovered a potential drug candidate, α-lipoic acid, which can effectively alleviate the symptoms of CRS-3 through its antioxidant function. Accordingly, we established a new ARF model of zebrafish, which laid a foundation for large-scale screening of new therapeutic drugs for its complications. Full article

(This article belongs to the Special Issue Fish as Simple Models for Human Disease and Drug Screen)

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23 pages, 2274 KiB

Open AccessFeature PaperReview

The Role of Intracellular Trafficking of Notch Receptors in Ligand-Independent Notch Activation

by Judith Hounjet and Marc Vooijs

Biomolecules 2021, 11(9), 1369; https://doi.org/10.3390/biom11091369 - 16 Sep 2021

Cited by 12 | Viewed by 4004

Abstract

Aberrant Notch signaling has been found in a broad range of human malignancies. Consequently, small molecule inhibitors and antibodies targeting Notch signaling in human cancers have been developed and tested; however, these have failed due to limited anti-tumor efficacy because of dose-limiting toxicities [...] Read more.

Aberrant Notch signaling has been found in a broad range of human malignancies. Consequently, small molecule inhibitors and antibodies targeting Notch signaling in human cancers have been developed and tested; however, these have failed due to limited anti-tumor efficacy because of dose-limiting toxicities in normal tissues. Therefore, there is an unmet need to discover novel regulators of malignant Notch signaling, which do not affect Notch signaling in healthy tissues. This review provides a comprehensive overview of the current knowledge on the role of intracellular trafficking in ligand-independent Notch receptor activation, the possible mechanisms involved, and possible therapeutic opportunities for inhibitors of intracellular trafficking in Notch targeting. Full article

(This article belongs to the Special Issue Notch Signalling and Cell Fate)

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10 pages, 518 KiB

Open AccessArticle

Further Findings Concerning Endothelial Damage in COVID-19 Patients

by Monica Gelzo, Sara Cacciapuoti, Biagio Pinchera, Annunziata De Rosa, Gustavo Cernera, Filippo Scialò, Marika Comegna, Mauro Mormile, Gabriella Fabbrocini, Roberto Parrella, Gaetano Corso, Ivan Gentile and Giuseppe Castaldo

Biomolecules 2021, 11(9), 1368; https://doi.org/10.3390/biom11091368 - 16 Sep 2021

Cited by 7 | Viewed by 2165

Abstract

Systemic vascular damage with micro/macro-thrombosis is a typical feature of severe COVID-19. However, the pathogenesis of this damage and its predictive biomarkers remain poorly defined. For this reason, in this study, serum monocyte chemotactic protein (MCP)-2 and P- and E-selectin levels were analyzed [...] Read more.

Systemic vascular damage with micro/macro-thrombosis is a typical feature of severe COVID-19. However, the pathogenesis of this damage and its predictive biomarkers remain poorly defined. For this reason, in this study, serum monocyte chemotactic protein (MCP)-2 and P- and E-selectin levels were analyzed in 204 patients with COVID-19. Serum MCP-2 and P-selectin were significantly higher in hospitalized patients compared with asymptomatic patients. Furthermore, MCP-2 increased with the WHO stage in hospitalized patients. After 1 week of hospitalization, MCP-2 levels were significantly reduced, while P-selectin increased in patients in WHO stage 3 and decreased in patients in WHO stages 5–7. Serum E-selectin was not significantly different between asymptomatic and hospitalized patients. The lower MCP-2 levels after 1 week suggest that endothelial damage triggered by monocytes occurs early in COVID-19 disease progression. MCP-2 may also predict COVID-19 severity. The increase in P-selectin levels, which further increased in mild patients and reduced in severe patients after 1 week of hospitalization, suggests that the inactive form of the protein produced by the cleavage of the active protein from the platelet membrane is present. This may be used to identify a subset of patients that would benefit from targeted therapies. The unchanged levels of E-selectin in these patients suggest that endothelial damage is less relevant. Full article

(This article belongs to the Special Issue State-of-the-Art on COVID-19 Disease in Italy- The Pathologist’s Experience)

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20 pages, 895 KiB

Open AccessReview

Exocytosis in Astrocytes

by Aleksandra Mielnicka and Piotr Michaluk

Biomolecules 2021, 11(9), 1367; https://doi.org/10.3390/biom11091367 - 16 Sep 2021

Cited by 9 | Viewed by 4989

Abstract

Until recently, astrocytes were thought to be a part of a simple “brain glue” providing only a supporting role for neurons. However, the discoveries of the last two decades have proven astrocytes to be dynamic partners participating in brain metabolism and actively influencing [...] Read more.

Until recently, astrocytes were thought to be a part of a simple “brain glue” providing only a supporting role for neurons. However, the discoveries of the last two decades have proven astrocytes to be dynamic partners participating in brain metabolism and actively influencing communication between neurons. The means of astrocyte-neuron communication are diverse, although regulated exocytosis has received the most attention but also caused the most debate. Similar to most of eukaryotic cells, astrocytes have a complex range of vesicular organelles which can undergo exocytosis as well as intricate molecular mechanisms that regulate this process. In this review, we focus on the components needed for regulated exocytosis to occur and summarise the knowledge about experimental evidence showing its presence in astrocytes. Full article

(This article belongs to the Special Issue Astroglia in Physiology, Pathology and Therapy)

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12 pages, 22452 KiB

Open AccessArticle

Bioguided Isolation of Cyclopenin Analogues as Potential SARS-CoV-2 M^pro Inhibitors from Penicillium citrinum TDPEF34

by Bathini Thissera, Ahmed M. Sayed, Marwa H. A. Hassan, Sayed F. Abdelwahab, Ngozi Amaeze, Valeria T. Semler, Faizah N. Alenezi, Mohammed Yaseen, Hani A. Alhadrami, Lassaad Belbahri and Mostafa E. Rateb

Biomolecules 2021, 11(9), 1366; https://doi.org/10.3390/biom11091366 - 15 Sep 2021

Cited by 10 | Viewed by 3085

Abstract

SARS-CoV-2 virus mutations might increase its virulence, and thus the severity and duration of the ongoing pandemic. Global drug discovery campaigns have successfully developed several vaccines to reduce the number of infections by the virus. However, finding a small molecule pharmaceutical that is [...] Read more.

SARS-CoV-2 virus mutations might increase its virulence, and thus the severity and duration of the ongoing pandemic. Global drug discovery campaigns have successfully developed several vaccines to reduce the number of infections by the virus. However, finding a small molecule pharmaceutical that is effective in inhibiting SARS-CoV-2 remains a challenge. Natural products are the origin of many currently used pharmaceuticals and, for this reason, a library of in-house fungal extracts were screened to assess their potential to inhibit the main viral protease M^pro in vitro. The extract of Penicillium citrinum, TDPEF34, showed potential inhibition and was further analysed to identify potential M^pro inhibitors. Following bio-guided isolation, a series of benzodiazepine alkaloids cyclopenins with good-to-moderate activity against SARS-CoV-2 M^pro were identified. The mode of enzyme inhibition of these compounds was predicted by docking and molecular dynamic simulation. Compounds 1 (isolated as two conformers of S- and R-isomers), 2, and 4 were found to have promising in vitro inhibitory activity towards M^pro, with an IC₅₀ values range of 0.36–0.89 µM comparable to the positive control GC376. The in silico investigation revealed compounds to achieve stable binding with the enzyme active site through multiple H-bonding and hydrophobic interactions. Additionally, the isolated compounds showed very good drug-likeness and ADMET properties. Our findings could be utilized in further in vitro and in vivo investigations to produce anti-SARS-CoV-2 drug candidates. These findings also provide critical structural information that could be used in the future for designing potent M^pro inhibitors. Full article

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