Biomolecules

36 pages, 1810 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial HMG-Box Containing Proteins: From Biochemical Properties to the Roles in Human Diseases

by Veronika Vozáriková, Nina Kunová, Jacob A. Bauer, Ján Frankovský, Veronika Kotrasová, Katarína Procházková, Vladimíra Džugasová, Eva Kutejová, Vladimír Pevala, Jozef Nosek and Ľubomír Tomáška

Biomolecules 2020, 10(8), 1193; https://doi.org/10.3390/biom10081193 - 16 Aug 2020

Cited by 13 | Viewed by 5993

Abstract

Mitochondrial DNA (mtDNA) molecules are packaged into compact nucleo-protein structures called mitochondrial nucleoids (mt-nucleoids). Their compaction is mediated in part by high-mobility group (HMG)-box containing proteins (mtHMG proteins), whose additional roles include the protection of mtDNA against damage, the regulation of gene expression [...] Read more.

Mitochondrial DNA (mtDNA) molecules are packaged into compact nucleo-protein structures called mitochondrial nucleoids (mt-nucleoids). Their compaction is mediated in part by high-mobility group (HMG)-box containing proteins (mtHMG proteins), whose additional roles include the protection of mtDNA against damage, the regulation of gene expression and the segregation of mtDNA into daughter organelles. The molecular mechanisms underlying these functions have been identified through extensive biochemical, genetic, and structural studies, particularly on yeast (Abf2) and mammalian mitochondrial transcription factor A (TFAM) mtHMG proteins. The aim of this paper is to provide a comprehensive overview of the biochemical properties of mtHMG proteins, the structural basis of their interaction with DNA, their roles in various mtDNA transactions, and the evolutionary trajectories leading to their rapid diversification. We also describe how defects in the maintenance of mtDNA in cells with dysfunctional mtHMG proteins lead to different pathologies at the cellular and organismal level. Full article

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

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16 pages, 5690 KiB

Open AccessEditor’s ChoiceReview

Peroxisomal Cofactor Transport

by Anastasija Plett, Lennart Charton and Nicole Linka

Biomolecules 2020, 10(8), 1174; https://doi.org/10.3390/biom10081174 - 12 Aug 2020

Cited by 15 | Viewed by 5499

Abstract

Peroxisomes are eukaryotic organelles that are essential for growth and development. They are highly metabolically active and house many biochemical reactions, including lipid metabolism and synthesis of signaling molecules. Most of these metabolic pathways are shared with other compartments, such as Endoplasmic reticulum [...] Read more.

Peroxisomes are eukaryotic organelles that are essential for growth and development. They are highly metabolically active and house many biochemical reactions, including lipid metabolism and synthesis of signaling molecules. Most of these metabolic pathways are shared with other compartments, such as Endoplasmic reticulum (ER), mitochondria, and plastids. Peroxisomes, in common with all other cellular organelles are dependent on a wide range of cofactors, such as adenosine 5′-triphosphate (ATP), Coenzyme A (CoA), and nicotinamide adenine dinucleotide (NAD). The availability of the peroxisomal cofactor pool controls peroxisome function. The levels of these cofactors available for peroxisomal metabolism is determined by the balance between synthesis, import, export, binding, and degradation. Since the final steps of cofactor synthesis are thought to be located in the cytosol, cofactors must be imported into peroxisomes. This review gives an overview about our current knowledge of the permeability of the peroxisomal membrane with the focus on ATP, CoA, and NAD. Several members of the mitochondrial carrier family are located in peroxisomes, catalyzing the transfer of these organic cofactors across the peroxisomal membrane. Most of the functions of these peroxisomal cofactor transporters are known from studies in yeast, humans, and plants. Parallels and differences between the transporters in the different organisms are discussed here. Full article

(This article belongs to the Special Issue Mitochondrial Transport Proteins)

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39 pages, 7906 KiB

Open AccessEditor’s ChoiceReview

Interplay between Cell-Surface Receptors and Extracellular Matrix in Skin

by Svenja Kleiser and Alexander Nyström

Biomolecules 2020, 10(8), 1170; https://doi.org/10.3390/biom10081170 - 11 Aug 2020

Cited by 29 | Viewed by 6520

Abstract

Skin consists of the epidermis and dermis, which are connected by a specialized basement membrane—the epidermal basement membrane. Both the epidermal basement membrane and the underlying interstitial extracellular matrix (ECM) created by dermal fibroblasts contain distinct network-forming macromolecules. These matrices play various roles [...] Read more.

Skin consists of the epidermis and dermis, which are connected by a specialized basement membrane—the epidermal basement membrane. Both the epidermal basement membrane and the underlying interstitial extracellular matrix (ECM) created by dermal fibroblasts contain distinct network-forming macromolecules. These matrices play various roles in order to maintain skin homeostasis and integrity. Within this complex interplay of cells and matrices, cell surface receptors play essential roles not only for inside-out and outside-in signaling, but also for establishing mechanical and biochemical properties of skin. Already minor modulations of this multifactorial cross-talk can lead to severe and systemic diseases. In this review, major epidermal and dermal cell surface receptors will be addressed with respect to their interactions with matrix components as well as their roles in fibrotic, inflammatory or tumorigenic skin diseases. Full article

(This article belongs to the Special Issue Desiphering the Network of Cell Receptors and Matrix in Health and Disease)

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15 pages, 1246 KiB

Open AccessEditor’s ChoiceArticle

Targeting Endothelial Dysfunction in Eight Extreme-Critically Ill Patients with COVID-19 Using the Anti-Adrenomedullin Antibody Adrecizumab (HAM8101)

by Mahir Karakas, Dominik Jarczak, Martin Becker, Kevin Roedl, Marylyn M. Addo, Frauke Hein, Andreas Bergmann, Jens Zimmermann, Tim-Philipp Simon, Gernot Marx, Marc Lütgehetmann, Axel Nierhaus and Stefan Kluge

Biomolecules 2020, 10(8), 1171; https://doi.org/10.3390/biom10081171 - 11 Aug 2020

Cited by 24 | Viewed by 7404

Abstract

Recently, the stabilization of the endothelium has been explicitly identified as a therapeutic goal in coronavirus disease 2019 (COVID-19). Adrecizumab (HAM8101) is a first-in-class humanized monoclonal anti-Adrenomedullin (anti-ADM) antibody, targeting the sepsis- and inflammation-based vascular and capillary leakage. Within a “treatment on a [...] Read more.

Recently, the stabilization of the endothelium has been explicitly identified as a therapeutic goal in coronavirus disease 2019 (COVID-19). Adrecizumab (HAM8101) is a first-in-class humanized monoclonal anti-Adrenomedullin (anti-ADM) antibody, targeting the sepsis- and inflammation-based vascular and capillary leakage. Within a “treatment on a named-patient basis” approach, Adrecizumab was administered to eight extreme-critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). The patients received a single dose of Adrecizumab, which was administered between 1 and 3 days after the initiation of mechanical ventilation. The SOFA (median 12.5) and SAPS-II (median 39) scores clearly documented the population at highest risk. Moreover, six of the patients suffered from acute renal failure, of whom five needed renal replacement therapy. The length of follow-up ranged between 13 and 27 days. Following the Adrecizumab administration, one patient in the low-dose group died at day 4 due to fulminant pulmonary embolism, while four were in stable condition, and three were discharged from the intensive care unit (ICU). Within 12 days, the SOFA score, as well as the disease severity score (range 0–16, mirroring critical resources in the ICU, with higher scores indicating more severe illness), decreased in five out of the seven surviving patients (in all high-dose patients). The PaO2/FiO2 increased within 12 days, while the inflammatory parameters C-reactive protein, procalcitonin, and interleukin-6 decreased. Importantly, the mortality was lower than expected and calculated by the SOFA score. In conclusion, in this preliminary uncontrolled case series of eight shock patients with life-threatening COVID-19 and ARDS, the administration of Adrecizumab was followed by a favorable outcome. Although the non-controlled design and the small sample size preclude any definitive statement about the potential efficacy of Adrecizumab in critically ill COVID-19 patients, the results of this case series are encouraging. Full article

(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)

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19 pages, 1272 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial Pyruvate Carrier Function in Health and Disease across the Lifespan

by Jane L. Buchanan and Eric B. Taylor

Biomolecules 2020, 10(8), 1162; https://doi.org/10.3390/biom10081162 - 8 Aug 2020

Cited by 28 | Viewed by 6394

Abstract

As a nodal mediator of pyruvate metabolism, the mitochondrial pyruvate carrier (MPC) plays a pivotal role in many physiological and pathological processes across the human lifespan, from embryonic development to aging-associated neurodegeneration. Emerging research highlights the importance of the MPC in diverse conditions, [...] Read more.

As a nodal mediator of pyruvate metabolism, the mitochondrial pyruvate carrier (MPC) plays a pivotal role in many physiological and pathological processes across the human lifespan, from embryonic development to aging-associated neurodegeneration. Emerging research highlights the importance of the MPC in diverse conditions, such as immune cell activation, cancer cell stemness, and dopamine production in Parkinson’s disease models. Whether MPC function ameliorates or contributes to disease is highly specific to tissue and cell type. Cell- and tissue-specific differences in MPC content and activity suggest that MPC function is tightly regulated as a mechanism of metabolic, cellular, and organismal control. Accordingly, recent studies on cancer and diabetes have identified protein–protein interactions, post-translational processes, and transcriptional factors that modulate MPC function. This growing body of literature demonstrates that the MPC and other mitochondrial carriers comprise a versatile and dynamic network undergirding the metabolism of health and disease. Full article

(This article belongs to the Special Issue Mitochondrial Transport Proteins)

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24 pages, 1431 KiB

Open AccessEditor’s ChoiceReview

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

by Amanda B. Abildgaard, Sarah K. Gersing, Sven Larsen-Ledet, Sofie V. Nielsen, Amelie Stein, Kresten Lindorff-Larsen and Rasmus Hartmann-Petersen

Biomolecules 2020, 10(8), 1141; https://doi.org/10.3390/biom10081141 - 4 Aug 2020

Cited by 30 | Viewed by 6670

Abstract

Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together [...] Read more.

Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together to facilitate degradation of misfolded and toxic protein species through the 26S proteasome. However, the underlying mechanisms are complex and remain partly unclear. Here, we provide an overview of the current knowledge on the co-chaperones that directly take part in targeting and delivery of PQC substrates for degradation. While J-domain proteins (JDPs) target substrates for the heat shock protein 70 (HSP70) chaperones, nucleotide-exchange factors (NEFs) deliver HSP70-bound substrates to the proteasome. So far, three NEFs have been established in proteasomal delivery: HSP110 and the ubiquitin-like (UBL) domain proteins BAG-1 and BAG-6, the latter acting as a chaperone itself and carrying its substrates directly to the proteasome. A better understanding of the individual delivery pathways will improve our ability to regulate the triage, and thus regulate the fate of aberrant proteins involved in cell stress and disease, examples of which are given throughout the review. Full article

(This article belongs to the Special Issue Ubiquitin-Like Modifiers and Their Diverse Impact on Cell Signaling)

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16 pages, 1884 KiB

Open AccessEditor’s ChoiceReview

Implication of Hyperhomocysteinemia in Blood Retinal Barrier (BRB) Dysfunction

by Amany Tawfik, Yara A. Samra, Nehal M. Elsherbiny and Mohamed Al-Shabrawey

Biomolecules 2020, 10(8), 1119; https://doi.org/10.3390/biom10081119 - 29 Jul 2020

Cited by 44 | Viewed by 7262

Abstract

Elevated plasma homocysteine (Hcy) level, known as hyperhomocysteinemia (HHcy) has been linked to different systemic and neurological diseases, well-known as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and has been identified as a risk factor for several ocular disorders, such [...] Read more.

Elevated plasma homocysteine (Hcy) level, known as hyperhomocysteinemia (HHcy) has been linked to different systemic and neurological diseases, well-known as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and has been identified as a risk factor for several ocular disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Different mechanisms have been proposed to explain HHcy-induced visual dysfunction, including oxidative stress, upregulation of inflammatory mediators, retinal ganglion cell apoptosis, and extracellular matrix remodeling. Our previous studies using in vivo and in vitro models of HHcy have demonstrated that Hcy impairs the function of both inner and outer blood retinal barrier (BRB). Dysfunction of BRB is a hallmark of vision loss in DR and AMD. Our findings highlighted oxidative stress, ER stress, inflammation, and epigenetic modifications as possible mechanisms of HHcy-induced BRB dysfunction. In addition, we recently reported HHcy-induced brain inflammation as a mechanism of blood–brain barrier (BBB) dysfunction and pathogenesis of Alzheimer’s disease (AD). Moreover, we are currently investigating the activation of glutamate receptor N-methyl-d-aspartate receptor (NMDAR) as the molecular mechanism for HHcy-induced BRB dysfunction. This review focuses on the studied effects of HHcy on BRB and the controversial role of HHcy in the pathogenesis of aging neurological diseases such as DR, AMD, and AD. We also highlight the possible mechanisms for such deleterious effects of HHcy. Full article

(This article belongs to the Special Issue Homocysteine: Biochemistry, Molecular Biology, and Role in Disease)

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19 pages, 2046 KiB

Open AccessEditor’s ChoiceArticle

Protein–Protein Interactions Mediated by Intrinsically Disordered Protein Regions Are Enriched in Missense Mutations

by Eric T. C. Wong, Victor So, Mike Guron, Erich R. Kuechler, Nawar Malhis, Jennifer M. Bui and Jörg Gsponer

Biomolecules 2020, 10(8), 1097; https://doi.org/10.3390/biom10081097 - 24 Jul 2020

Cited by 25 | Viewed by 6063

Abstract

Because proteins are fundamental to most biological processes, many genetic diseases can be traced back to single nucleotide variants (SNVs) that cause changes in protein sequences. However, not all SNVs that result in amino acid substitutions cause disease as each residue is under [...] Read more.

Because proteins are fundamental to most biological processes, many genetic diseases can be traced back to single nucleotide variants (SNVs) that cause changes in protein sequences. However, not all SNVs that result in amino acid substitutions cause disease as each residue is under different structural and functional constraints. Influential studies have shown that protein–protein interaction interfaces are enriched in disease-associated SNVs and depleted in SNVs that are common in the general population. These studies focus primarily on folded (globular) protein domains and overlook the prevalent class of protein interactions mediated by intrinsically disordered regions (IDRs). Therefore, we investigated the enrichment patterns of missense mutation-causing SNVs that are associated with disease and cancer, as well as those present in the healthy population, in structures of IDR-mediated interactions with comparisons to classical globular interactions. When comparing the different categories of interaction interfaces, division of the interface regions into solvent-exposed rim residues and buried core residues reveal distinctive enrichment patterns for the various types of missense mutations. Most notably, we demonstrate a strong enrichment at the interface core of interacting IDRs in disease mutations and its depletion in neutral ones, which supports the view that the disruption of IDR interactions is a mechanism underlying many diseases. Intriguingly, we also found an asymmetry across the IDR interaction interface in the enrichment of certain missense mutation types, which may hint at an increased variant tolerance and urges further investigations of IDR interactions. Full article

(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases)

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19 pages, 4801 KiB

Open AccessEditor’s ChoiceArticle

Glutenin and Gliadin, a Piece in the Puzzle of their Structural Properties in the Cell Described through Monte Carlo Simulations

by Joel Markgren, Mikael Hedenqvist, Faiza Rasheed, Marie Skepö and Eva Johansson

Biomolecules 2020, 10(8), 1095; https://doi.org/10.3390/biom10081095 - 23 Jul 2020

Cited by 34 | Viewed by 6501

Abstract

Gluten protein crosslinking is a predetermined process where specific intra- and intermolecular disulfide bonds differ depending on the protein and cysteine motif. In this article, all-atom Monte Carlo simulations were used to understand the formation of disulfide bonds in gliadins and low molecular [...] Read more.

Gluten protein crosslinking is a predetermined process where specific intra- and intermolecular disulfide bonds differ depending on the protein and cysteine motif. In this article, all-atom Monte Carlo simulations were used to understand the formation of disulfide bonds in gliadins and low molecular weight glutenin subunits (LMW-GS). The two intrinsically disordered proteins appeared to contain mostly turns and loops and showed “self-avoiding walk” behavior in water. Cysteine residues involved in intramolecular disulfide bonds were located next to hydrophobic peptide sections in the primary sequence. Hydrophobicity of neighboring peptide sections, synthesis chronology, and amino acid chain flexibility were identified as important factors in securing the specificity of intramolecular disulfide bonds formed directly after synthesis. The two LMW-GS cysteine residues that form intermolecular disulfide bonds were positioned next to peptide sections of lower hydrophobicity, and these cysteine residues are more exposed to the cytosolic conditions, which influence the crosslinking behavior. In addition, coarse-grained Monte Carlo simulations revealed that the protein folding is independent of ionic strength. The potential molecular behavior associated with disulfide bonds, as reported here, increases the biological understanding of seed storage protein function and provides opportunities to tailor their functional properties for different applications. Full article

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15 pages, 583 KiB

Open AccessEditor’s ChoiceReview

Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

by Taku Fujimura and Setsuya Aiba

Biomolecules 2020, 10(8), 1087; https://doi.org/10.3390/biom10081087 - 22 Jul 2020

Cited by 43 | Viewed by 4733

Abstract

Tumor-associated macrophages (TAMs) have been detected in most skin cancers. TAMs produce various chemokines and angiogenic factors that promote tumor development, along with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated neutrophils. TAMs generated from monocytes [...] Read more.

Tumor-associated macrophages (TAMs) have been detected in most skin cancers. TAMs produce various chemokines and angiogenic factors that promote tumor development, along with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated neutrophils. TAMs generated from monocytes develop into functional, fully activated macrophages, and TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment. Since TAMs express PD1 to maintain the immunosuppressive M2 phenotype by PD1/PD-L1 signaling from tumor cells, and the blockade of PD1/PD-L1 signaling by anti-PD1 antibodies (Abs) activate and re-polarize TAMs into immunoreactive M1 phenotypes, TAMs represent a potential target for anti-PD1 Abs. The main population of TAMs comprises CD163⁺ M2 macrophages, and CD163⁺ TAMs release soluble (s)CD163 and several proinflammatory chemokines (CXCL5, CXCL10, CCL19, etc.) as a result of TAM activation to induce an immunosuppressive tumor microenvironment together with other immunosuppressive cells. Since direct blockade of PD1/PD-L1 signaling between tumor cells and tumor-infiltrating T cells (both effector T cells and Tregs) is mandatory for inducing an anti-immune response by anti-PD1 Abs, anti-PD1 Abs need to reach the tumor microenvironment to induce anti-immune responses in the tumor-bearing host. Taken together, TAM-related factors could offer a biomarker for anti-PD1 Ab-based immunotherapy. Understanding the crosstalk between TAMs and immunosuppressive cells is important for optimizing PD1 Ab-based immunotherapy. Full article

(This article belongs to the Collection Recent Advances in Cancer Immunotherapy)

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14 pages, 1156 KiB

Open AccessEditor’s ChoiceReview

Analytical Methods for the Determination of Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) in Biological Samples, Plants and Foods

by Maroula G. Kokotou

Biomolecules 2020, 10(8), 1092; https://doi.org/10.3390/biom10081092 - 22 Jul 2020

Cited by 21 | Viewed by 5498

Abstract

Fatty acid esters of hydroxy fatty acids (FAHFAs) constitute a class of recently identified novel lipids exhibiting anti-diabetic and anti-inflammatory effects. Due to their high biological significance, a tremendous effort has been devoted to the development of analytical methods for the detection and [...] Read more.

Fatty acid esters of hydroxy fatty acids (FAHFAs) constitute a class of recently identified novel lipids exhibiting anti-diabetic and anti-inflammatory effects. Due to their high biological significance, a tremendous effort has been devoted to the development of analytical methods for the detection and quantitation of FAHFAs during the last five years. The analysis of FAHFAs is very challenging due to the great number of possible regio-isomers arising from the great number of possible combinations of FAs with HFAs, and the low abundancies of FAHFAs in biological samples. The aim of this review article is to summarize all the cutting-edge analytical methodologies for the determination of FAHFAs in biological samples, plant tissues and food matrices, with emphasis on extraction and analysis steps. All the analytical methodologies rely on the use of liquid chromatography–mass spectrometry (LC-MS), providing high sensitivity due to the MS detection. Powerful and robust analytical methodologies may highly contribute in studying FAHFAs levels under various biomedical conditions, and facilitate our understanding of the role of these lipid species in physiological and pathological conditions. Full article

(This article belongs to the Collection Bioactive Lipids in Inflammation, Diabetes and Cancer)

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19 pages, 2016 KiB

Open AccessEditor’s ChoiceReview

The Disordered Cellular Multi-Tasker WIP and Its Protein–Protein Interactions: A Structural View

by Chana G. Sokolik, Nasrin Qassem and Jordan H. Chill

Biomolecules 2020, 10(7), 1084; https://doi.org/10.3390/biom10071084 - 21 Jul 2020

Cited by 8 | Viewed by 4560

Abstract

WASp-interacting protein (WIP), a regulator of actin cytoskeleton assembly and remodeling, is a cellular multi-tasker and a key member of a network of protein–protein interactions, with significant impact on health and disease. Here, we attempt to complement the well-established understanding of WIP function [...] Read more.

WASp-interacting protein (WIP), a regulator of actin cytoskeleton assembly and remodeling, is a cellular multi-tasker and a key member of a network of protein–protein interactions, with significant impact on health and disease. Here, we attempt to complement the well-established understanding of WIP function from cell biology studies, summarized in several reviews, with a structural description of WIP interactions, highlighting works that present a molecular view of WIP’s protein–protein interactions. This provides a deeper understanding of the mechanisms by which WIP mediates its biological functions. The fully disordered WIP also serves as an intriguing example of how intrinsically disordered proteins (IDPs) exert their function. WIP consists of consecutive small functional domains and motifs that interact with a host of cellular partners, with a striking preponderance of proline-rich motif capable of interactions with several well-recognized binding partners; indeed, over 30% of the WIP primary structure are proline residues. We focus on the binding motifs and binding interfaces of three important WIP segments, the actin-binding N-terminal domain, the central domain that binds SH3 domains of various interaction partners, and the WASp-binding C-terminal domain. Beyond the obvious importance of a more fundamental understanding of the biology of this central cellular player, this approach carries an immediate and highly beneficial effect on drug-design efforts targeting WIP and its binding partners. These factors make the value of such structural studies, challenging as they are, readily apparent. Full article

(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases)

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18 pages, 991 KiB

Open AccessEditor’s ChoiceReview

The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier

by Joséphine Zangari, Francesco Petrelli, Benoît Maillot and Jean-Claude Martinou

Biomolecules 2020, 10(7), 1068; https://doi.org/10.3390/biom10071068 - 17 Jul 2020

Cited by 93 | Viewed by 26312

Abstract

Pyruvate, the end product of glycolysis, plays a major role in cell metabolism. Produced in the cytosol, it is oxidized in the mitochondria where it fuels the citric acid cycle and boosts oxidative phosphorylation. Its sole entry point into mitochondria is through the [...] Read more.

Pyruvate, the end product of glycolysis, plays a major role in cell metabolism. Produced in the cytosol, it is oxidized in the mitochondria where it fuels the citric acid cycle and boosts oxidative phosphorylation. Its sole entry point into mitochondria is through the recently identified mitochondrial pyruvate carrier (MPC). In this review, we report the latest findings on the physiology of the MPC and we discuss how a dysfunctional MPC can lead to diverse pathologies, including neurodegenerative diseases, metabolic disorders, and cancer. Full article

(This article belongs to the Special Issue Mitochondrial Transport Proteins)

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15 pages, 1172 KiB

Open AccessEditor’s ChoiceReview

The Hippo Pathway in Cardiac Regeneration and Homeostasis: New Perspectives for Cell-Free Therapy in the Injured Heart

by Mingjie Zheng, Joan Jacob, Shao-Hsi Hung and Jun Wang

Biomolecules 2020, 10(7), 1024; https://doi.org/10.3390/biom10071024 - 10 Jul 2020

Cited by 24 | Viewed by 6022

Abstract

Intractable cardiovascular diseases are leading causes of mortality around the world. Adult mammalian hearts have poor regenerative capacity and are not capable of self-repair after injury. Recent studies of cell-free therapeutics such as those designed to stimulate endogenous cardiac regeneration have uncovered new [...] Read more.

Intractable cardiovascular diseases are leading causes of mortality around the world. Adult mammalian hearts have poor regenerative capacity and are not capable of self-repair after injury. Recent studies of cell-free therapeutics such as those designed to stimulate endogenous cardiac regeneration have uncovered new feasible therapeutic avenues for cardiac repair. The Hippo pathway, a fundamental pathway with pivotal roles in cell proliferation, survival and differentiation, has tremendous potential for therapeutic manipulation in cardiac regeneration. In this review, we summarize the most recent studies that have revealed the function of the Hippo pathway in heart regeneration and homeostasis. In particular, we discuss the molecular mechanisms of how the Hippo pathway maintains cardiac homeostasis by directing cardiomyocyte chromatin remodeling and regulating the cell-cell communication between cardiomyocytes and non-cardiomyocytes in the heart. Full article

(This article belongs to the Special Issue Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration)

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15 pages, 503 KiB

Open AccessEditor’s ChoiceReview

Dopamine D3 Receptor Heteromerization: Implications for Neuroplasticity and Neuroprotection

by Federica Bono, Veronica Mutti, Chiara Fiorentini and Cristina Missale

Biomolecules 2020, 10(7), 1016; https://doi.org/10.3390/biom10071016 - 9 Jul 2020

Cited by 31 | Viewed by 8550

Abstract

The dopamine (DA) D3 receptor (D3R) plays a pivotal role in the control of several functions, including motor activity, rewarding and motivating behavior and several aspects of cognitive functions. Recently, it has been reported that the D3R is also involved in the regulation [...] Read more.

The dopamine (DA) D3 receptor (D3R) plays a pivotal role in the control of several functions, including motor activity, rewarding and motivating behavior and several aspects of cognitive functions. Recently, it has been reported that the D3R is also involved in the regulation of neuronal development, in promoting structural plasticity and in triggering key intracellular events with neuroprotective potential. A new role for D3R-dependent neurotransmission has thus been proposed both in preserving DA neuron homeostasis in physiological conditions and in preventing pathological alterations that may lead to neurodegeneration. Interestingly, there is evidence that nicotinic acetylcholine receptors (nAChR) located on DA neurons also provide neurotrophic support to DA neurons, an effect requiring functional D3R and suggesting the existence of a positive cross-talk between these receptor systems. Increasing evidence suggests that, as with the majority of G protein-coupled receptors (GPCR), the D3R directly interacts with other receptors to form new receptor heteromers with unique functional and pharmacological properties. Among them, we recently identified a receptor heteromer containing the nAChR and the D3R as the molecular effector of nicotine-mediated neurotrophic effects. This review summarizes the functional and pharmacological characteristics of D3R, including the capability to form active heteromers as pharmacological targets for specific neurodegenerative disorders. In particular, the molecular and functional features of the D3R-nAChR heteromer will be especially discussed since it may represent a possible key etiologic effector for DA-related pathologies, such as Parkinson’s disease (PD), and a target for drug design. Full article

(This article belongs to the Special Issue Dopamine Receptor in Health and Diseases)

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13 pages, 1624 KiB

Open AccessEditor’s ChoiceReview

Biogenesis of Mitochondrial Metabolite Carriers

by Patrick Horten, Lilia Colina-Tenorio and Heike Rampelt

Biomolecules 2020, 10(7), 1008; https://doi.org/10.3390/biom10071008 - 7 Jul 2020

Cited by 34 | Viewed by 6003

Abstract

Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize the majority of the cellular ATP. Like almost all mitochondrial proteins, carriers have to be imported into mitochondria from the cytosol. Carrier precursors [...] Read more.

Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize the majority of the cellular ATP. Like almost all mitochondrial proteins, carriers have to be imported into mitochondria from the cytosol. Carrier precursors utilize a specialized translocation pathway dedicated to the biogenesis of carriers and related proteins, the carrier translocase of the inner membrane (TIM22) pathway. After recognition and import through the mitochondrial outer membrane via the translocase of the outer membrane (TOM) complex, carrier precursors are ushered through the intermembrane space by hexameric TIM chaperones and ultimately integrated into the inner membrane by the TIM22 carrier translocase. Recent advances have shed light on the mechanisms of TOM translocase and TIM chaperone function, uncovered an unexpected versatility of the machineries, and revealed novel components and functional crosstalk of the human TIM22 translocase. Full article

(This article belongs to the Special Issue Mitochondrial Transport Proteins)

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40 pages, 1674 KiB

Open AccessEditor’s ChoiceReview

JAK-Inhibitors for the Treatment of Rheumatoid Arthritis: A Focus on the Present and an Outlook on the Future

by Jacopo Angelini, Rossella Talotta, Rossana Roncato, Giulia Fornasier, Giorgia Barbiero, Lisa Dal Cin, Serena Brancati and Francesco Scaglione

Biomolecules 2020, 10(7), 1002; https://doi.org/10.3390/biom10071002 - 5 Jul 2020

Cited by 137 | Viewed by 16011

Abstract

Janus kinase inhibitors (JAKi) belong to a new class of oral targeted disease-modifying drugs which have recently revolutionized the therapeutic panorama of rheumatoid arthritis (RA) and other immune-mediated diseases, placing alongside or even replacing conventional and biological drugs. JAKi are characterized by a [...] Read more.

Janus kinase inhibitors (JAKi) belong to a new class of oral targeted disease-modifying drugs which have recently revolutionized the therapeutic panorama of rheumatoid arthritis (RA) and other immune-mediated diseases, placing alongside or even replacing conventional and biological drugs. JAKi are characterized by a novel mechanism of action, consisting of the intracellular interruption of the JAK-STAT pathway crucially involved in the immune response. The aim of this narrative review is to globally report the most relevant pharmacological features and clinical outcomes of the developed and incoming JAKi for RA, based on the available preclinical and clinical evidence. A total of 219 papers, including narrative and systematic reviews, randomized controlled trials (RCTs), observational studies, case reports, guidelines, and drug factsheets, were selected. The efficacy and safety profile of both the first generation JAKi (baricitinib and tofacitinib) and the second generation JAKi (upadacitinib, filgotinib, peficitinib, decernotinib and itacitinib) were compared and discussed. Results from RCTs and real-life data are encouraging and outline a rapid onset of the pharmacologic effects, which are maintained during the time. Their efficacy and safety profile are comparable or superior to those of biologic agents and JAKi proved to be efficacious when given as monotherapy. Finally, the manufacturing of JAKi is relatively easier and cheaper than that of biologics, thus increasing the number of compounds being formulated and tested for clinical use. Full article

(This article belongs to the Special Issue Pathogenesis of Arthritis)

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25 pages, 1070 KiB

Open AccessEditor’s ChoiceReview

Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology

by Massimo Bonora, Simone Patergnani, Daniela Ramaccini, Giampaolo Morciano, Gaia Pedriali, Asrat Endrias Kahsay, Esmaa Bouhamida, Carlotta Giorgi, Mariusz R. Wieckowski and Paolo Pinton

Biomolecules 2020, 10(7), 998; https://doi.org/10.3390/biom10070998 - 4 Jul 2020

Cited by 104 | Viewed by 11082

Abstract

Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner mitochondrial membrane (IMM) to low-molecular-weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse [...] Read more.

Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner mitochondrial membrane (IMM) to low-molecular-weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate outer-mitochondrial-membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade and caspase-independent cell-death mechanisms. The induction of MPT is mostly dependent on mitochondrial reactive oxygen species (ROS) and Ca²⁺, but is also dependent on the metabolic stage of the affected cell and signaling events. Therefore, since its discovery in the late 1970s, the role of MPT in human pathology has been heavily investigated. Here, we summarize the most significant findings corroborating a role for MPT in the etiology of a spectrum of human diseases, including diseases characterized by acute or chronic loss of adult cells and those characterized by neoplastic initiation. Full article

(This article belongs to the Special Issue Mitochondrial Transport Proteins)

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34 pages, 1376 KiB

Open AccessEditor’s ChoiceReview

UPF1-Mediated RNA Decay—Danse Macabre in a Cloud

by Daria Lavysh and Gabriele Neu-Yilik

Biomolecules 2020, 10(7), 999; https://doi.org/10.3390/biom10070999 - 4 Jul 2020

Cited by 25 | Viewed by 7097

Abstract

Nonsense-mediated RNA decay (NMD) is the prototype example of a whole family of RNA decay pathways that unfold around a common central effector protein called UPF1. While NMD in yeast appears to be a linear pathway, NMD in higher eukaryotes is a multifaceted [...] Read more.

Nonsense-mediated RNA decay (NMD) is the prototype example of a whole family of RNA decay pathways that unfold around a common central effector protein called UPF1. While NMD in yeast appears to be a linear pathway, NMD in higher eukaryotes is a multifaceted phenomenon with high variability with respect to substrate RNAs, degradation efficiency, effector proteins and decay-triggering RNA features. Despite increasing knowledge of the mechanistic details, it seems ever more difficult to define NMD and to clearly distinguish it from a growing list of other UPF1-mediated RNA decay pathways (UMDs). With a focus on mammalian NMD, we here critically examine the prevailing NMD models and the gaps and inconsistencies in these models. By exploring the minimal requirements for NMD and other UMDs, we try to elucidate whether they are separate and definable pathways, or rather variations of the same phenomenon. Finally, we suggest that the operating principle of the UPF1-mediated decay family could be considered similar to that of a computing cloud providing a flexible infrastructure with rapid elasticity and dynamic access according to specific user needs. Full article

(This article belongs to the Special Issue Ribonucleoprotein Particles (RNPs): From Structure to Function)

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22 pages, 8209 KiB

Open AccessEditor’s ChoiceReview

Cell-Adhesion Properties of β-Subunits in the Regulation of Cardiomyocyte Sodium Channels

by Samantha C. Salvage, Christopher L.-H. Huang and Antony P. Jackson

Biomolecules 2020, 10(7), 989; https://doi.org/10.3390/biom10070989 - 1 Jul 2020

Cited by 23 | Viewed by 6870

Abstract

Voltage-gated sodium (Nav) channels drive the rising phase of the action potential, essential for electrical signalling in nerves and muscles. The Nav channel α-subunit contains the ion-selective pore. In the cardiomyocyte, Nav1.5 is the main Nav channel α-subunit isoform, with a smaller expression [...] Read more.

Voltage-gated sodium (Nav) channels drive the rising phase of the action potential, essential for electrical signalling in nerves and muscles. The Nav channel α-subunit contains the ion-selective pore. In the cardiomyocyte, Nav1.5 is the main Nav channel α-subunit isoform, with a smaller expression of neuronal Nav channels. Four distinct regulatory β-subunits (β1–4) bind to the Nav channel α-subunits. Previous work has emphasised the β-subunits as direct Nav channel gating modulators. However, there is now increasing appreciation of additional roles played by these subunits. In this review, we focus on β-subunits as homophilic and heterophilic cell-adhesion molecules and the implications for cardiomyocyte function. Based on recent cryogenic electron microscopy (cryo-EM) data, we suggest that the β-subunits interact with Nav1.5 in a different way from their binding to other Nav channel isoforms. We believe this feature may facilitate trans-cell-adhesion between β1-associated Nav1.5 subunits on the intercalated disc and promote ephaptic conduction between cardiomyocytes. Full article

(This article belongs to the Special Issue Trafficking of Cardiac Ion Channels – Mechanisms and Alterations Leading to Disease)

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32 pages, 2345 KiB

Open AccessEditor’s ChoiceReview

Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation

by Yves Jossin

Biomolecules 2020, 10(6), 964; https://doi.org/10.3390/biom10060964 - 26 Jun 2020

Cited by 136 | Viewed by 12275

Abstract

During embryonic development and adulthood, Reelin exerts several important functions in the brain including the regulation of neuronal migration, dendritic growth and branching, dendritic spine formation, synaptogenesis and synaptic plasticity. As a consequence, the Reelin signaling pathway has been associated with several human [...] Read more.

During embryonic development and adulthood, Reelin exerts several important functions in the brain including the regulation of neuronal migration, dendritic growth and branching, dendritic spine formation, synaptogenesis and synaptic plasticity. As a consequence, the Reelin signaling pathway has been associated with several human brain disorders such as lissencephaly, autism, schizophrenia, bipolar disorder, depression, mental retardation, Alzheimer’s disease and epilepsy. Several elements of the signaling pathway are known. Core components, such as the Reelin receptors very low-density lipoprotein receptor (VLDLR) and Apolipoprotein E receptor 2 (ApoER2), Src family kinases Src and Fyn, and the intracellular adaptor Disabled-1 (Dab1), are common to most but not all Reelin functions. Other downstream effectors are, on the other hand, more specific to defined tasks. Reelin is a large extracellular protein, and some aspects of the signal are regulated by its processing into smaller fragments. Rather than being inhibitory, the processing at two major sites seems to be fulfilling important physiological functions. In this review, I describe the various cellular events regulated by Reelin and attempt to explain the current knowledge on the mechanisms of action. After discussing the shared and distinct elements of the Reelin signaling pathway involved in neuronal migration, dendritic growth, spine development and synaptic plasticity, I briefly outline the data revealing the importance of Reelin in human brain disorders. Full article

(This article belongs to the Special Issue Reelin, a Hub Protein during Nervous System Development?)

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28 pages, 1235 KiB

Open AccessEditor’s ChoiceReview

The NRF2/KEAP1 Axis in the Regulation of Tumor Metabolism: Mechanisms and Therapeutic Perspectives

by Emiliano Panieri, Pelin Telkoparan-Akillilar, Sibel Suzen and Luciano Saso

Biomolecules 2020, 10(5), 791; https://doi.org/10.3390/biom10050791 - 20 May 2020

Cited by 60 | Viewed by 8014

Abstract

The NRF2/KEAP1 pathway is a fundamental signaling cascade that controls multiple cytoprotective responses through the induction of a complex transcriptional program that ultimately renders cancer cells resistant to oxidative, metabolic and therapeutic stress. Interestingly, accumulating evidence in recent years has indicated that metabolic [...] Read more.

The NRF2/KEAP1 pathway is a fundamental signaling cascade that controls multiple cytoprotective responses through the induction of a complex transcriptional program that ultimately renders cancer cells resistant to oxidative, metabolic and therapeutic stress. Interestingly, accumulating evidence in recent years has indicated that metabolic reprogramming is closely interrelated with the regulation of redox homeostasis, suggesting that the disruption of NRF2 signaling might represent a valid therapeutic strategy against a variety of solid and hematologic cancers. These aspects will be the focus of the present review. Full article

(This article belongs to the Special Issue Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches)

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32 pages, 1311 KiB

Open AccessEditor’s ChoiceReview

Carbapenemases: Transforming Acinetobacter baumannii into a Yet More Dangerous Menace

by Maria Soledad Ramirez, Robert A. Bonomo and Marcelo E. Tolmasky

Biomolecules 2020, 10(5), 720; https://doi.org/10.3390/biom10050720 - 6 May 2020

Cited by 166 | Viewed by 15049

Abstract

Acinetobacter baumannii is a common cause of serious nosocomial infections. Although community-acquired infections are observed, the vast majority occur in people with preexisting comorbidities. A. baumannii emerged as a problematic pathogen in the 1980s when an increase in virulence, difficulty in treatment due [...] Read more.

Acinetobacter baumannii is a common cause of serious nosocomial infections. Although community-acquired infections are observed, the vast majority occur in people with preexisting comorbidities. A. baumannii emerged as a problematic pathogen in the 1980s when an increase in virulence, difficulty in treatment due to drug resistance, and opportunities for infection turned it into one of the most important threats to human health. Some of the clinical manifestations of A. baumannii nosocomial infection are pneumonia; bloodstream infections; lower respiratory tract, urinary tract, and wound infections; burn infections; skin and soft tissue infections (including necrotizing fasciitis); meningitis; osteomyelitis; and endocarditis. A. baumannii has an extraordinary genetic plasticity that results in a high capacity to acquire antimicrobial resistance traits. In particular, acquisition of resistance to carbapenems, which are among the antimicrobials of last resort for treatment of multidrug infections, is increasing among A. baumannii strains compounding the problem of nosocomial infections caused by this pathogen. It is not uncommon to find multidrug-resistant (MDR, resistance to at least three classes of antimicrobials), extensively drug-resistant (XDR, MDR plus resistance to carbapenems), and pan-drug-resistant (PDR, XDR plus resistance to polymyxins) nosocomial isolates that are hard to treat with the currently available drugs. In this article we review the acquired resistance to carbapenems by A. baumannii. We describe the enzymes within the OXA, NDM, VIM, IMP, and KPC groups of carbapenemases and the coding genes found in A. baumannii clinical isolates. Full article

(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)

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30 pages, 1274 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Novel Applications of Mesenchymal Stem Cell-Derived Exosomes for Myocardial Infarction Therapeutics

by Sho Joseph Ozaki Tan, Juliana Ferreria Floriano, Laura Nicastro, Costanza Emanueli and Francesco Catapano

Biomolecules 2020, 10(5), 707; https://doi.org/10.3390/biom10050707 - 2 May 2020

Cited by 69 | Viewed by 8149

Abstract

Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity globally, representing approximately a third of all deaths every year. The greater part of these cases is represented by myocardial infarction (MI), or heart attack as it is better known, which occurs [...] Read more.

Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity globally, representing approximately a third of all deaths every year. The greater part of these cases is represented by myocardial infarction (MI), or heart attack as it is better known, which occurs when declining blood flow to the heart causes injury to cardiac tissue. Mesenchymal stem cells (MSCs) are multipotent stem cells that represent a promising vector for cell therapies that aim to treat MI due to their potent regenerative effects. However, it remains unclear the extent to which MSC-based therapies are able to induce regeneration in the heart and even less clear the degree to which clinical outcomes could be improved. Exosomes, which are small extracellular vesicles (EVs) known to have implications in intracellular communication, derived from MSCs (MSC-Exos), have recently emerged as a novel cell-free vector that is capable of conferring cardio-protection and regeneration in target cardiac cells. In this review, we assess the current state of research of MSC-Exos in the context of MI. In particular, we place emphasis on the mechanisms of action by which MSC-Exos accomplish their therapeutic effects, along with commentary on the current difficulties faced with exosome research and the ongoing clinical applications of stem-cell derived exosomes in different medical contexts. Full article

(This article belongs to the Special Issue Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration)

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82 pages, 15127 KiB

Open AccessEditor’s ChoiceReview

Cystathionine-β-synthase: Molecular Regulation and Pharmacological Inhibition

by Karim Zuhra, Fiona Augsburger, Tomas Majtan and Csaba Szabo

Biomolecules 2020, 10(5), 697; https://doi.org/10.3390/biom10050697 - 30 Apr 2020

Cited by 167 | Viewed by 16038

Abstract

Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen [...] Read more.

Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H₂S), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects. This article overviews the current information on the expression, tissue distribution, physiological roles, and biochemistry of CBS, followed by a comprehensive overview of direct and indirect approaches to inhibit the enzyme. Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used “CBS inhibitors” (e.g., aminooxyacetic acid) and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models. Full article

(This article belongs to the Special Issue H₂S, Polysulfides, and Enzymes: Physiological and Pathological Aspects)

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12 pages, 1039 KiB

Open AccessEditor’s ChoiceArticle

A Fluorescence-Based Method to Measure ADP/ATP Exchange of Recombinant Adenine Nucleotide Translocase in Liposomes

by Jürgen Kreiter, Eric Beitz and Elena E. Pohl

Biomolecules 2020, 10(5), 685; https://doi.org/10.3390/biom10050685 - 29 Apr 2020

Cited by 12 | Viewed by 5400

Abstract

Several mitochondrial proteins, such as adenine nucleotide translocase (ANT), aspartate/glutamate carrier, dicarboxylate carrier, and uncoupling proteins 2 and 3, are suggested to have dual transport functions. While the transport of charge (protons and anions) is characterized by an alteration in membrane conductance, investigating [...] Read more.

Several mitochondrial proteins, such as adenine nucleotide translocase (ANT), aspartate/glutamate carrier, dicarboxylate carrier, and uncoupling proteins 2 and 3, are suggested to have dual transport functions. While the transport of charge (protons and anions) is characterized by an alteration in membrane conductance, investigating substrate transport is challenging. Currently, mainly radioactively labeled substrates are used, which are very expensive and require stringent precautions during their preparation and use. We present and evaluate a fluorescence-based method using Magnesium Green (MgGr^TM), a Mg²⁺-sensitive dye suitable for measurement in liposomes. Given the different binding affinities of Mg²⁺ for ATP and ADP, changes in their concentrations can be detected. We obtained an ADP/ATP exchange rate of 3.49 ± 0.41 mmol/min/g of recombinant ANT1 reconstituted into unilamellar liposomes, which is comparable to values measured in mitochondria and proteoliposomes using a radioactivity assay. ADP/ATP exchange calculated from MgGr^TM fluorescence solely depends on the ANT1 content in liposomes and is inhibited by the ANT-specific inhibitors, bongkrekic acid and carboxyatractyloside. The application of MgGr^TM to investigate ADP/ATP exchange rates contributes to our understanding of ANT function in mitochondria and paves the way for the design of other substrate transport assays. Full article

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19 pages, 4219 KiB

Open AccessEditor’s ChoiceArticle

Computational Investigations on the Binding Mode of Ligands for the Cannabinoid-Activated G Protein-Coupled Receptor GPR18

by Alexander Neumann, Viktor Engel, Andhika B. Mahardhika, Clara T. Schoeder, Vigneshwaran Namasivayam, Katarzyna Kieć-Kononowicz and Christa E. Müller

Biomolecules 2020, 10(5), 686; https://doi.org/10.3390/biom10050686 - 29 Apr 2020

Cited by 19 | Viewed by 6771

Abstract

GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆⁹-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still [...] Read more.

GPR18 is an orphan G protein-coupled receptor (GPCR) expressed in cells of the immune system. It is activated by the cannabinoid receptor (CB) agonist ∆⁹-tetrahydrocannabinol (THC). Several further lipids have been proposed to act as GPR18 agonists, but these results still require unambiguous confirmation. In the present study, we constructed a homology model of the human GPR18 based on an ensemble of three GPCR crystal structures to investigate the binding modes of the agonist THC and the recently reported antagonists which feature an imidazothiazinone core to which a (substituted) phenyl ring is connected via a lipophilic linker. Docking and molecular dynamics simulation studies were performed. As a result, a hydrophobic binding pocket is predicted to accommodate the imidazothiazinone core, while the terminal phenyl ring projects towards an aromatic pocket. Hydrophobic interaction of Cys251 with substituents on the phenyl ring could explain the high potency of the most potent derivatives. Molecular dynamics simulation studies suggest that the binding of imidazothiazinone antagonists stabilizes transmembrane regions TM1, TM6 and TM7 of the receptor through a salt bridge between Asp118 and Lys133. The agonist THC is presumed to bind differently to GPR18 than to the distantly related CB receptors. This study provides insights into the binding mode of GPR18 agonists and antagonists which will facilitate future drug design for this promising potential drug target. Full article

(This article belongs to the Collection In Silico Drug Design for GPCRs: Big Data for Small Molecule Discovery)

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21 pages, 1138 KiB

Open AccessEditor’s ChoiceReview

Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment

by Eun Seong Hwang and Seon Beom Song

Biomolecules 2020, 10(5), 687; https://doi.org/10.3390/biom10050687 - 29 Apr 2020

Cited by 94 | Viewed by 25831

Abstract

Nicotinamide (NAM) at doses far above those recommended for vitamins is suggested to be effective against a wide spectrum of diseases and conditions, including neurological dysfunctions, depression and other psychological disorders, and inflammatory diseases. Recent increases in public awareness on possible pro-longevity effects [...] Read more.

Nicotinamide (NAM) at doses far above those recommended for vitamins is suggested to be effective against a wide spectrum of diseases and conditions, including neurological dysfunctions, depression and other psychological disorders, and inflammatory diseases. Recent increases in public awareness on possible pro-longevity effects of nicotinamide adenine dinucleotide (NAD⁺) precursors have caused further growth of NAM consumption not only for clinical treatments, but also as a dietary supplement, raising concerns on the safety of its long-term use. However, possible adverse effects and their mechanisms are poorly understood. High-level NAM administration can exert negative effects through multiple routes. For example, NAM by itself inhibits poly(ADP-ribose) polymerases (PARPs), which protect genome integrity. Elevation of the NAD⁺ pool alters cellular energy metabolism. Meanwhile, high-level NAM alters cellular methyl metabolism and affects methylation of DNA and proteins, leading to changes in cellular transcriptome and proteome. Also, methyl metabolites of NAM, namely methylnicotinamide, are predicted to play roles in certain diseases and conditions. In this review, a collective literature search was performed to provide a comprehensive list of possible adverse effects of NAM and to provide understanding of their underlying mechanisms and assessment of the raised safety concerns. Our review assures safety in current usage level of NAM, but also finds potential risks for epigenetic alterations associated with chronic use of NAM at high doses. It also suggests directions of the future studies to ensure safer application of NAM. Full article

(This article belongs to the Special Issue Nicotinamide in Health and Diseases)

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17 pages, 728 KiB

Open AccessEditor’s ChoiceReview

The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors

by Evangelos Koustas, Panagiotis Sarantis, Athanasios G. Papavassiliou and Michalis V. Karamouzis

Biomolecules 2020, 10(5), 666; https://doi.org/10.3390/biom10050666 - 25 Apr 2020

Cited by 36 | Viewed by 6156

Abstract

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary [...] Read more.

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors. Full article

(This article belongs to the Collection Recent Advances in Cancer Immunotherapy)

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21 pages, 3351 KiB

Open AccessEditor’s ChoiceArticle

Discovering the RNA-Binding Proteome of Plant Leaves with an Improved RNA Interactome Capture Method

by Marcel Bach-Pages, Felix Homma, Jiorgos Kourelis, Farnusch Kaschani, Shabaz Mohammed, Markus Kaiser, Renier A. L. van der Hoorn, Alfredo Castello and Gail M. Preston

Biomolecules 2020, 10(4), 661; https://doi.org/10.3390/biom10040661 - 24 Apr 2020

Cited by 70 | Viewed by 16546

Abstract

RNA-binding proteins (RBPs) play a crucial role in regulating RNA function and fate. However, the full complement of RBPs has only recently begun to be uncovered through proteome-wide approaches such as RNA interactome capture (RIC). RIC has been applied to various cell lines [...] Read more.

RNA-binding proteins (RBPs) play a crucial role in regulating RNA function and fate. However, the full complement of RBPs has only recently begun to be uncovered through proteome-wide approaches such as RNA interactome capture (RIC). RIC has been applied to various cell lines and organisms, including plants, greatly expanding the repertoire of RBPs. However, several technical challenges have limited the efficacy of RIC when applied to plant tissues. Here, we report an improved version of RIC that overcomes the difficulties imposed by leaf tissue. Using this improved RIC method in Arabidopsis leaves, we identified 717 RBPs, generating a deep RNA-binding proteome for leaf tissues. While 75% of these RBPs can be linked to RNA biology, the remaining 25% were previously not known to interact with RNA. Interestingly, we observed that a large number of proteins related to photosynthesis associate with RNA in vivo, including proteins from the four major photosynthetic supercomplexes. As has previously been reported for mammals, a large proportion of leaf RBPs lack known RNA-binding domains, suggesting unconventional modes of RNA binding. We anticipate that this improved RIC method will provide critical insights into RNA metabolism in plants, including how cellular RBPs respond to environmental, physiological and pathological cues. Full article

(This article belongs to the Special Issue Ribonucleoprotein Particles (RNPs): From Structure to Function)

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15 pages, 1210 KiB

Open AccessEditor’s ChoiceReview

Antimicrobial and Antibiofilm Peptides

by Angela Di Somma, Antonio Moretta, Carolina Canè, Arianna Cirillo and Angela Duilio

Biomolecules 2020, 10(4), 652; https://doi.org/10.3390/biom10040652 - 23 Apr 2020

Cited by 189 | Viewed by 13231

Abstract

The increasing onset of multidrug-resistant bacteria has propelled microbiology research towards antimicrobial peptides as new possible antibiotics from natural sources. Antimicrobial peptides are short peptides endowed with a broad range of activity against both Gram-positive and Gram-negative bacteria and are less prone to [...] Read more.

The increasing onset of multidrug-resistant bacteria has propelled microbiology research towards antimicrobial peptides as new possible antibiotics from natural sources. Antimicrobial peptides are short peptides endowed with a broad range of activity against both Gram-positive and Gram-negative bacteria and are less prone to trigger resistance. Besides their activity against planktonic bacteria, many antimicrobial peptides also show antibiofilm activity. Biofilms are ubiquitous in nature, having the ability to adhere to virtually any surface, either biotic or abiotic, including medical devices, causing chronic infections that are difficult to eradicate. The biofilm matrix protects bacteria from hostile environments, thus contributing to the bacterial resistance to antimicrobial agents. Biofilms are very difficult to treat, with options restricted to the use of large doses of antibiotics or the removal of the infected device. Antimicrobial peptides could represent good candidates to develop new antibiofilm drugs as they can act at different stages of biofilm formation, on disparate molecular targets and with various mechanisms of action. These include inhibition of biofilm formation and adhesion, downregulation of quorum sensing factors, and disruption of the pre-formed biofilm. This review focuses on the proprieties of antimicrobial and antibiofilm peptides, with a particular emphasis on their mechanism of action, reporting several examples of peptides that over time have been shown to have activity against biofilm. Full article

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15 pages, 2041 KiB

Open AccessEditor’s ChoiceArticle

Role of 3-Mercaptopyruvate Sulfurtransferase in the Regulation of Proliferation and Cellular Bioenergetics in Human Down Syndrome Fibroblasts

by Theodora Panagaki, Elisa B. Randi and Csaba Szabo

Biomolecules 2020, 10(4), 653; https://doi.org/10.3390/biom10040653 - 23 Apr 2020

Cited by 31 | Viewed by 5385

Abstract

Down syndrome (trisomy of human chromosome 21) is a common genetic disorder. Overproduction of the gaseous mediator hydrogen sulfide (H₂S) has been implicated in the pathogenesis of neurological and metabolic deficits associated with Down syndrome. Several lines of data indicate that [...] Read more.

Down syndrome (trisomy of human chromosome 21) is a common genetic disorder. Overproduction of the gaseous mediator hydrogen sulfide (H₂S) has been implicated in the pathogenesis of neurological and metabolic deficits associated with Down syndrome. Several lines of data indicate that an important enzyme responsible for H₂S overproduction in Down syndrome is cystathionine-β-synthase (CBS), an enzyme localized on chromosome 21. The current study explored the possibility that a second H₂S-producing enzyme, 3-mercaptopyruvate sulfurtransferase (3-MST), may also contribute to the development of functional deficits of Down syndrome cells. Western blotting analysis demonstrated a significantly higher level of 3-MST protein expression in human Down syndrome fibroblasts compared to cells from healthy control individuals; the excess 3-MST was mainly localized to the mitochondrial compartment. Pharmacological inhibition of 3-MST activity improved mitochondrial electron transport and oxidative phosphorylation parameters (but did not affect the suppressed glycolytic parameters) and enhanced cell proliferation in Down syndrome cells (but not in healthy control cells). The findings presented in the current report suggest that in addition to the indisputable role of CBS, H₂S produced from 3-MST may also contribute to the development of mitochondrial metabolic and functional impairments in Down syndrome cells. Full article

(This article belongs to the Special Issue H₂S, Polysulfides, and Enzymes: Physiological and Pathological Aspects)

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41 pages, 3186 KiB

Open AccessEditor’s ChoiceReview

Phenolic Compounds Exerting Lipid-Regulatory, Anti-Inflammatory and Epigenetic Effects as Complementary Treatments in Cardiovascular Diseases

by Laura Toma, Gabriela Maria Sanda, Loredan Stefan Niculescu, Mariana Deleanu, Anca Volumnia Sima and Camelia Sorina Stancu

Biomolecules 2020, 10(4), 641; https://doi.org/10.3390/biom10040641 - 21 Apr 2020

Cited by 59 | Viewed by 8303

Abstract

Atherosclerosis is the main process behind cardiovascular diseases (CVD), maladies which continue to be responsible for up to 70% of death worldwide. Despite the ongoing development of new and potent drugs, their incomplete efficacy, partial intolerance and numerous side effects make the search [...] Read more.

Atherosclerosis is the main process behind cardiovascular diseases (CVD), maladies which continue to be responsible for up to 70% of death worldwide. Despite the ongoing development of new and potent drugs, their incomplete efficacy, partial intolerance and numerous side effects make the search for new alternatives worthwhile. The focus of the scientific world turned to the potential of natural active compounds to prevent and treat CVD. Essential for effective prevention or treatment based on phytochemicals is to know their mechanisms of action according to their bioavailability and dosage. The present review is focused on the latest data about phenolic compounds and aims to collect and correlate the reliable existing knowledge concerning their molecular mechanisms of action to counteract important risk factors that contribute to the initiation and development of atherosclerosis: dyslipidemia, and oxidative and inflammatory-stress. The selection of phenolic compounds was made to prove their multiple benefic effects and endorse them as CVD remedies, complementary to allopathic drugs. The review also highlights some aspects that still need clear scientific explanations and draws up some new molecular approaches to validate phenolic compounds for CVD complementary therapy in the near future. Full article

(This article belongs to the Special Issue Phytochemical Omics in Medicinal Plants)

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19 pages, 762 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Photobiomodulation for Parkinson’s Disease in Animal Models: A Systematic Review

by Farzad Salehpour and Michael R Hamblin

Biomolecules 2020, 10(4), 610; https://doi.org/10.3390/biom10040610 - 15 Apr 2020

Cited by 55 | Viewed by 8795

Abstract

Photobiomodulation (PBM) might be an effective treatment for Parkinson’s disease (PD) in human patients. PBM of the brain uses red or near infrared light delivered from a laser or an LED at relatively low power densities, onto the head (or other body parts) [...] Read more.

Photobiomodulation (PBM) might be an effective treatment for Parkinson’s disease (PD) in human patients. PBM of the brain uses red or near infrared light delivered from a laser or an LED at relatively low power densities, onto the head (or other body parts) to stimulate the brain and prevent degeneration of neurons. PD is a progressive neurodegenerative disease involving the loss of dopamine-producing neurons in the substantia nigra deep within the brain. PD is a movement disorder that also shows various other symptoms affecting the brain and other organs. Treatment involves dopamine replacement therapy or electrical deep brain stimulation. The present systematic review covers reports describing the use of PBM to treat laboratory animal models of PD, in an attempt to draw conclusions about the best choice of parameters and irradiation techniques. There have already been clinical trials of PBM reported in patients, and more are expected in the coming years. PBM is particularly attractive as it is a non-pharmacological treatment, without any major adverse effects (and very few minor ones). Full article

(This article belongs to the Special Issue Photobiomodulation for Parkinson's Disease)

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18 pages, 1234 KiB

Open AccessEditor’s ChoiceReview

High-Density Lipoproteins Are Bug Scavengers

by Olivier Meilhac, Sébastien Tanaka and David Couret

Biomolecules 2020, 10(4), 598; https://doi.org/10.3390/biom10040598 - 12 Apr 2020

Cited by 62 | Viewed by 7874

Abstract

Lipoproteins were initially defined according to their composition (lipids and proteins) and classified according to their density (from very low- to high-density lipoproteins—HDLs). Whereas their capacity to transport hydrophobic lipids in a hydrophilic environment (plasma) is not questionable, their primitive function of cholesterol [...] Read more.

Lipoproteins were initially defined according to their composition (lipids and proteins) and classified according to their density (from very low- to high-density lipoproteins—HDLs). Whereas their capacity to transport hydrophobic lipids in a hydrophilic environment (plasma) is not questionable, their primitive function of cholesterol transporter could be challenged. All lipoproteins are reported to bind and potentially neutralize bacterial lipopolysaccharides (LPS); this is particularly true for HDL particles. In addition, HDL levels are drastically decreased under infectious conditions such as sepsis, suggesting a potential role in the clearance of bacterial material and, particularly, LPS. Moreover, "omics" technologies have unveiled significant changes in HDL composition in different inflammatory states, ranging from acute inflammation occurring during septic shock to low-grade inflammation associated with moderate endotoxemia such as periodontal disease or obesity. In this review, we will discuss HDL modifications associated with exposure to pathogens including bacteria, viruses and parasites, with a special focus on sepsis and the potential of HDL therapy in this context. Low-grade inflammation associated with atherosclerosis, periodontitis or metabolic syndrome may also highlight the protective role of HDLs in theses pathologies by other mechanisms than the reverse transport of cholesterol. Full article

(This article belongs to the Special Issue High-Density Lipoprotein (HDL): The Role of Reverse Cholesterol Transport in Human Health and Disease)

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21 pages, 2361 KiB

Open AccessEditor’s ChoiceReview

New Opportunities for Endometrial Health by Modifying Uterine Microbial Composition: Present or Future?

by Nerea M. Molina, Alberto Sola-Leyva, Maria Jose Saez-Lara, Julio Plaza-Diaz, Aleksandra Tubić-Pavlović, Barbara Romero, Ana Clavero, Juan Mozas-Moreno, Juan Fontes and Signe Altmäe

Biomolecules 2020, 10(4), 593; https://doi.org/10.3390/biom10040593 - 11 Apr 2020

Cited by 137 | Viewed by 17867

Abstract

Current knowledge suggests that the uterus harbours its own microbiota, where the microbes could influence the uterine functions in health and disease; however, the core uterine microbial composition and the host-microbial relationships remain to be fully elucidated. Different studies are indicating, based on [...] Read more.

Current knowledge suggests that the uterus harbours its own microbiota, where the microbes could influence the uterine functions in health and disease; however, the core uterine microbial composition and the host-microbial relationships remain to be fully elucidated. Different studies are indicating, based on next-generation sequencing techniques, that microbial dysbiosis could be associated with several gynaecological disorders, such as endometriosis, chronic endometritis, dysfunctional menstrual bleeding, endometrial cancer, and infertility. Treatments using antibiotics and probiotics and/or prebiotics for endometrial microbial dysbiosis are being applied. Nevertheless there is no unified protocol for assessing the endometrial dysbiosis and no optimal treatment protocol for the established dysbiosis. With this review we outline the microbes (mostly bacteria) identified in the endometrial microbiome studies, the current treatments offered for bacterial dysbiosis in the clinical setting, and the future possibilities such as pro- and prebiotics and microbial transplants for modifying uterine microbial composition. Full article

(This article belongs to the Special Issue Relevant Biomolecules for Germ Cells and Fertilization)

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15 pages, 1105 KiB

Open AccessEditor’s ChoiceReview

Methionine Dependence of Cancer

by Peter Kaiser

Biomolecules 2020, 10(4), 568; https://doi.org/10.3390/biom10040568 - 8 Apr 2020

Cited by 162 | Viewed by 11893

Abstract

Tumorigenesis is accompanied by the reprogramming of cellular metabolism. The shift from oxidative phosphorylation to predominantly glycolytic pathways to support rapid growth is well known and is often referred to as the Warburg effect. However, other metabolic changes and acquired needs that distinguish [...] Read more.

Tumorigenesis is accompanied by the reprogramming of cellular metabolism. The shift from oxidative phosphorylation to predominantly glycolytic pathways to support rapid growth is well known and is often referred to as the Warburg effect. However, other metabolic changes and acquired needs that distinguish cancer cells from normal cells have also been discovered. The dependence of cancer cells on exogenous methionine is one of them and is known as methionine dependence or the Hoffman effect. This phenomenon describes the inability of cancer cells to proliferate when methionine is replaced with its metabolic precursor, homocysteine, while proliferation of non-tumor cells is unaffected by these conditions. Surprisingly, cancer cells can readily synthesize methionine from homocysteine, so their dependency on exogenous methionine reflects a general need for altered metabolic flux through pathways linked to methionine. In this review, an overview of the field will be provided and recent discoveries will be discussed. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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22 pages, 3501 KiB

Open AccessEditor’s ChoiceArticle

SUMOylation Protects FASN Against Proteasomal Degradation in Breast Cancer Cells Treated with Grape Leaf Extract

by Andrea Floris, Michael Mazarei, Xi Yang, Aaron Elias Robinson, Jennifer Zhou, Antonio Barberis, Guy D’hallewin, Emanuela Azara, Ylenia Spissu, Ainhoa Iglesias-Ara, Sandro Orrù and Maria Lauda Tomasi

Biomolecules 2020, 10(4), 529; https://doi.org/10.3390/biom10040529 - 31 Mar 2020

Cited by 32 | Viewed by 5253

Abstract

Existing therapeutic strategies for breast cancer are limited by tumor recurrence and drug-resistance. Antioxidant plant-derived compounds such as flavonoids reduce adverse outcomes and have been identified as a potential source of antineoplastic agent with less undesirable side effects. Here, we describe the novel [...] Read more.

Existing therapeutic strategies for breast cancer are limited by tumor recurrence and drug-resistance. Antioxidant plant-derived compounds such as flavonoids reduce adverse outcomes and have been identified as a potential source of antineoplastic agent with less undesirable side effects. Here, we describe the novel regulation of fatty-acid synthase (FASN), the key enzyme in de novo fatty-acid synthesis, whereby Vitis vinifera L. cv Vermentino leaf hydroalcoholic extract lowers its protein stability that is regulated by small ubiquitin-like modifier (SUMO)ylation. The phenolic compounds characterization was performed by liquid chromatography–mass spectrometry (LC–MS), whereas mass spectrometry (LC–MS/MS), Western blotting/co-immunoprecipitation (Co-IP) and RT-PCR, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clonogenicity assays, and FACS analysis were used to measure the expression of targets and tumorigenicity. Vermentino extract exhibits antitumorigenic effects, and we went on to determine that FASN and ubiquitin-conjugating enzyme 9 (UBC9), the sole E2 enzyme required for SUMOylation, were significantly reduced. Moreover, FASN was found SUMOylated in human breast cancer tissues and cell lines, and lack of SUMOylation caused by SUMO2 silencing reduced FASN protein stability. These results suggest that SUMOylation protects FASN against proteasomal degradation and may exert oncogenic activity through alteration of lipid metabolism, whereas Vermentino extract inhibits these effects which supports the additional validation of the therapeutic value of this compound in breast cancer. Full article

(This article belongs to the Section Molecular Biology)

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15 pages, 3382 KiB

Open AccessEditor’s ChoiceArticle

A Novel NAD-RNA Decapping Pathway Discovered by Synthetic Light-Up NAD-RNAs

by Florian Abele, Katharina Höfer, Patrick Bernhard, Julia Grawenhoff, Maximilian Seidel, André Krause, Sara Kopf, Martin Schröter and Andres Jäschke

Biomolecules 2020, 10(4), 513; https://doi.org/10.3390/biom10040513 - 28 Mar 2020

Cited by 15 | Viewed by 8112

Abstract

The complexity of the transcriptome is governed by the intricate interplay of transcription, RNA processing, translocation, and decay. In eukaryotes, the removal of the 5’-RNA cap is essential for the initiation of RNA degradation. In addition to the canonical 5’-N7-methyl guanosine cap in [...] Read more.

The complexity of the transcriptome is governed by the intricate interplay of transcription, RNA processing, translocation, and decay. In eukaryotes, the removal of the 5’-RNA cap is essential for the initiation of RNA degradation. In addition to the canonical 5’-N7-methyl guanosine cap in eukaryotes, the ubiquitous redox cofactor nicotinamide adenine dinucleotide (NAD) was identified as a new 5’-RNA cap structure in prokaryotic and eukaryotic organisms. So far, two classes of NAD-RNA decapping enzymes have been identified, namely Nudix enzymes that liberate nicotinamide mononucleotide (NMN) and DXO-enzymes that remove the entire NAD cap. Herein, we introduce 8-(furan-2-yl)-substituted NAD-capped-RNA (^FurNAD-RNA) as a new research tool for the identification and characterization of novel NAD-RNA decapping enzymes. These compounds are found to be suitable for various enzymatic reactions that result in the release of a fluorescence quencher, either nicotinamide (NAM) or nicotinamide mononucleotide (NMN), from the RNA which causes a fluorescence turn-on. ^FurNAD-RNAs allow for real-time quantification of decapping activity, parallelization, high-throughput screening and identification of novel decapping enzymes in vitro. Using ^FurNAD-RNAs, we discovered that the eukaryotic glycohydrolase CD38 processes NAD-capped RNA in vitro into ADP-ribose-modified-RNA and nicotinamide and therefore might act as a decapping enzyme in vivo. The existence of multiple pathways suggests that the decapping of NAD-RNA is an important and regulated process in eukaryotes. Full article

(This article belongs to the Special Issue Nicotinamide in Health and Diseases)

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18 pages, 2976 KiB

Open AccessEditor’s ChoiceArticle

Activation of α7 Nicotinic Acetylcholine Receptor Upregulates HLA-DR and Macrophage Receptors: Potential Role in Adaptive Immunity and in Preventing Immunosuppression

by Andrei E. Siniavin, Maria A. Streltsova, Denis S. Kudryavtsev, Irina V. Shelukhina, Yuri N. Utkin and Victor I. Tsetlin

Biomolecules 2020, 10(4), 507; https://doi.org/10.3390/biom10040507 - 27 Mar 2020

Cited by 32 | Viewed by 5948

Abstract

Immune response during sepsis is characterized by hyper-inflammation followed by immunosuppression. The crucial role of macrophages is well-known for both septic stages, since they are involved in immune homeostasis and inflammation, their dysfunction being implicated in immunosuppression. The cholinergic anti-inflammatory pathway mediated by [...] Read more.

Immune response during sepsis is characterized by hyper-inflammation followed by immunosuppression. The crucial role of macrophages is well-known for both septic stages, since they are involved in immune homeostasis and inflammation, their dysfunction being implicated in immunosuppression. The cholinergic anti-inflammatory pathway mediated by macrophage α7 nicotinic acetylcholine receptor (nAChR) represents possible drug target. Although α7 nAChR activation on macrophages reduces the production of proinflammatory cytokines, the role of these receptors in immunological changes at the cellular level is not fully understood. Using α7 nAChR selective agonist PNU 282,987, we investigated the influence of α7 nAChR activation on the expression of cytokines and, for the first time, of the macrophage membrane markers: cluster of differentiation 14 (CD14), human leukocyte antigen-DR (HLA-DR), CD11b, and CD54. Application of PNU 282,987 to THP-1Mϕ (THP-1 derived macrophages) cells led to inward ion currents and Ca²⁺ increase in cytoplasm showing the presence of functionally active α7 nAChR. Production of cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-10 was estimated in classically activated macrophages (M1) and treatment with PNU 282,987 diminished IL-10 expression. α7 nAChR activation on THP-1Mϕ, THP-1M1, and monocyte-derived macrophages (MDMs) increased the expression of HLA-DR, CD54, and CD11b molecules, but decreased CD14 receptor expression, these effects being blocked by alpha (α)-bungarotoxin. Thus, PNU 282,987 enhances the macrophage-mediated immunity via α7 nAChR by regulating expression of their membrane receptors and of cytokines, both playing an important role in preventing immunosuppressive states. Full article

(This article belongs to the Special Issue Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data)

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24 pages, 1776 KiB

Open AccessEditor’s ChoiceReview

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

by Miguel Fontecha-Barriuso, Diego Martin-Sanchez, Julio Manuel Martinez-Moreno, Maria Monsalve, Adrian Mario Ramos, Maria Dolores Sanchez-Niño, Marta Ruiz-Ortega, Alberto Ortiz and Ana Belen Sanz

Biomolecules 2020, 10(2), 347; https://doi.org/10.3390/biom10020347 - 24 Feb 2020

Cited by 195 | Viewed by 25065

Abstract

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and [...] Read more.

Chronic kidney disease (CKD) is one of the fastest growing causes of death worldwide, emphasizing the need to develop novel therapeutic approaches. CKD predisposes to acute kidney injury (AKI) and AKI favors CKD progression. Mitochondrial derangements are common features of both AKI and CKD and mitochondria-targeting therapies are under study as nephroprotective agents. PGC-1α is a master regulator of mitochondrial biogenesis and an attractive therapeutic target. Low PGC-1α levels and decreased transcription of its gene targets have been observed in both preclinical AKI (nephrotoxic, endotoxemia, and ischemia-reperfusion) and in experimental and human CKD, most notably diabetic nephropathy. In mice, PGC-1α deficiency was associated with subclinical CKD and predisposition to AKI while PGC-1α overexpression in tubular cells protected from AKI of diverse causes. Several therapeutic strategies may increase kidney PGC-1α activity and have been successfully tested in animal models. These include AMP-activated protein kinase (AMPK) activators, phosphodiesterase (PDE) inhibitors, and anti-TWEAK antibodies. In conclusion, low PGC-1α activity appears to be a common feature of AKI and CKD and recent characterization of nephroprotective approaches that increase PGC-1α activity may pave the way for nephroprotective strategies potentially effective in both AKI and CKD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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34 pages, 7528 KiB

Open AccessEditor’s ChoiceReview

Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging

by Simona Neri and Rosa Maria Borzì

Biomolecules 2020, 10(2), 340; https://doi.org/10.3390/biom10020340 - 21 Feb 2020

Cited by 87 | Viewed by 10294

Abstract

Mesenchymal stem/stromal cells (MSCs) are a reservoir for tissue homeostasis and repair that age during organismal aging. Beside the fundamental in vivo role of MSCs, they have also emerged in the last years as extremely promising therapeutic agents for a wide variety of [...] Read more.

Mesenchymal stem/stromal cells (MSCs) are a reservoir for tissue homeostasis and repair that age during organismal aging. Beside the fundamental in vivo role of MSCs, they have also emerged in the last years as extremely promising therapeutic agents for a wide variety of clinical conditions. MSC use frequently requires in vitro expansion, thus exposing cells to replicative senescence. Aging of MSCs (both in vivo and in vitro) can affect not only their replicative potential, but also their properties, like immunomodulation and secretory profile, thus possibly compromising their therapeutic effect. It is therefore of critical importance to unveil the underlying mechanisms of MSC senescence and to define shared methods to assess MSC aging status. The present review will focus on current scientific knowledge about MSC aging mechanisms, control and effects, including possible anti-aging treatments. Full article

(This article belongs to the Special Issue New Targets and Strategies in Regenerative Medicine)

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24 pages, 7685 KiB

Open AccessEditor’s ChoiceArticle

Loss of Elongator- and KEOPS-Dependent tRNA Modifications Leads to Severe Growth Phenotypes and Protein Aggregation in Yeast

by Leticia Pollo-Oliveira, Roland Klassen, Nick Davis, Akif Ciftci, Jo Marie Bacusmo, Maria Martinelli, Michael S. DeMott, Thomas J. Begley, Peter C. Dedon, Raffael Schaffrath and Valérie de Crécy-Lagard

Biomolecules 2020, 10(2), 322; https://doi.org/10.3390/biom10020322 - 18 Feb 2020

Cited by 19 | Viewed by 6862

Abstract

Modifications found in the Anticodon Stem Loop (ASL) of tRNAs play important roles in regulating translational speed and accuracy. Threonylcarbamoyl adenosine (t⁶A37) and 5-methoxycarbonyl methyl-2-thiouridine (mcm⁵s²U34) are critical ASL modifications that have been linked to several human [...] Read more.

Modifications found in the Anticodon Stem Loop (ASL) of tRNAs play important roles in regulating translational speed and accuracy. Threonylcarbamoyl adenosine (t⁶A37) and 5-methoxycarbonyl methyl-2-thiouridine (mcm⁵s²U34) are critical ASL modifications that have been linked to several human diseases. The model yeast Saccharomyces cerevisiae is viable despite the absence of both modifications, growth is however greatly impaired. The major observed consequence is a subsequent increase in protein aggregates and aberrant morphology. Proteomic analysis of the t⁶A-deficient strain (sua5 mutant) revealed a global mistranslation leading to protein aggregation without regard to physicochemical properties or t⁶A-dependent or biased codon usage in parent genes. However, loss of sua5 led to increased expression of soluble proteins for mitochondrial function, protein quality processing/trafficking, oxidative stress response, and energy homeostasis. These results point to a global function for t⁶A in protein homeostasis very similar to mcm⁵/s²U modifications. Full article

(This article belongs to the Collection RNA Modifications)

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21 pages, 2655 KiB

Open AccessEditor’s ChoiceReview

Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology

by Shuya Kasai, Sunao Shimizu, Yota Tatara, Junsei Mimura and Ken Itoh

Biomolecules 2020, 10(2), 320; https://doi.org/10.3390/biom10020320 - 17 Feb 2020

Cited by 389 | Viewed by 26511

Abstract

Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence [...] Read more.

Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence has shown that mitochondrial ROS (mtROS) activate Nrf2, often mediated by certain protein kinases, and induce the expression of antioxidant genes and genes involved in mitochondrial quality/quantity control. Mild physiological stress, such as caloric restriction and exercise, elicits beneficial effects through a process known as “mitohormesis”. Exercise induces NOX4 expression in the heart, which activates Nrf2 and increases endurance capacity. Mice transiently depleted of SOD2 or overexpressing skeletal muscle-specific UCP1 exhibit Nrf2-mediated antioxidant gene expression and PGC1α-mediated mitochondrial biogenesis. ATF4 activation may induce a transcriptional program that enhances NADPH synthesis in the mitochondria and might cooperate with the Nrf2 antioxidant system. In response to severe oxidative stress, Nrf2 induces Klf9 expression, which represses mtROS-eliminating enzymes to enhance cell death. Nrf2 is inactivated in certain pathological conditions, such as diabetes, but Keap1 down-regulation or mtROS elimination rescues Nrf2 expression and improves the pathology. These reports aid us in understanding the roles of Nrf2 in pathophysiological alterations involving mtROS. Full article

(This article belongs to the Special Issue Emerging Role of Mitochondrial Reactive Oxygen Species in Cellular Signaling)

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24 pages, 2267 KiB

Open AccessEditor’s ChoiceReview

p53’s Extended Reach: The Mutant p53 Secretome

by Evangelos Pavlakis and Thorsten Stiewe

Biomolecules 2020, 10(2), 307; https://doi.org/10.3390/biom10020307 - 15 Feb 2020

Cited by 45 | Viewed by 10808

Abstract

p53 suppresses tumorigenesis by activating a plethora of effector pathways. While most of these operate primarily inside of cells to limit proliferation and survival of incipient cancer cells, many extend to the extracellular space. In particular, p53 controls expression and secretion of numerous [...] Read more.

p53 suppresses tumorigenesis by activating a plethora of effector pathways. While most of these operate primarily inside of cells to limit proliferation and survival of incipient cancer cells, many extend to the extracellular space. In particular, p53 controls expression and secretion of numerous extracellular factors that are either soluble or contained within extracellular vesicles such as exosomes. As part of the cellular secretome, they execute key roles in cell-cell communication and extracellular matrix remodeling. Mutations in the p53-encoding TP53 gene are the most frequent genetic alterations in cancer cells, and therefore, have profound impact on the composition of the tumor cell secretome. In this review, we discuss how the loss or dominant-negative inhibition of wild-type p53 in concert with a gain of neomorphic properties observed for many mutant p53 proteins, shapes a tumor cell secretome that creates a supportive microenvironment at the primary tumor site and primes niches in distant organs for future metastatic colonization. Full article

(This article belongs to the Special Issue Recent Advances in p53)

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15 pages, 1351 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Allogeneic CAR-T Cells

by Dong Wook Kim and Je-Yoel Cho

Biomolecules 2020, 10(2), 263; https://doi.org/10.3390/biom10020263 - 10 Feb 2020

Cited by 97 | Viewed by 12315

Abstract

In recent decades, great advances have been made in the field of tumor treatment. Especially, cell-based therapy targeting tumor associated antigen (TAA) has developed tremendously. T cells were engineered to have the ability to attack tumor cells by generating CAR constructs consisting of [...] Read more.

In recent decades, great advances have been made in the field of tumor treatment. Especially, cell-based therapy targeting tumor associated antigen (TAA) has developed tremendously. T cells were engineered to have the ability to attack tumor cells by generating CAR constructs consisting of genes encoding scFv, a co-stimulatory domain (CD28 or TNFRSF9), and CD247 signaling domains for T cell proliferation and activation. Principally, CAR-T cells are activated by recognizing TAA by scFv on the T cell surface, and then signaling domains inside cells connected by scFv are subsequently activated to induce downstream signaling pathways involving T cell proliferation, activation, and production of cytokines. Many efforts have been made to increase the efficacy and persistence and also to decrease T cell exhaustion. Overall, allogeneic and universal CAR-T generation has attracted much attention because of their wide and prompt usage for patients. In this review, we summarized the current techniques for generation of allogeneic and universal CAR-T cells along with their disadvantages and limitations that still need to be overcome. Full article

(This article belongs to the Special Issue Advances in Antibody Therapy of Cancer)

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18 pages, 2426 KiB

Open AccessEditor’s ChoiceArticle

Proteomic Analysis of Human Serum from Patients with Chronic Kidney Disease

by Yulia Romanova, Alexander Laikov, Maria Markelova, Rania Khadiullina, Alfiz Makseev, Milausha Hasanova, Albert Rizvanov, Svetlana Khaiboullina and Ilnur Salafutdinov

Biomolecules 2020, 10(2), 257; https://doi.org/10.3390/biom10020257 - 7 Feb 2020

Cited by 47 | Viewed by 7012

Abstract

Chronic kidney disease (CKD) is an important public health problem in the world. The aim of our research was to identify novel potential serum biomarkers of renal injury. ELISA assay showed that cytokines and chemokines IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, [...] Read more.

Chronic kidney disease (CKD) is an important public health problem in the world. The aim of our research was to identify novel potential serum biomarkers of renal injury. ELISA assay showed that cytokines and chemokines IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12 (p70), IL-13, IL-15, IL-17, Eotaxin, FGFb, G-CSF, GM-CSF, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-1bb, RANTES, TNF-α and VEGF were significantly higher (R > 0.6, p value < 0.05) in the serum of patients with CKD compared to healthy subjects, and they were positively correlated with well-established markers (urea and creatinine). The multiple reaction monitoring (MRM) quantification method revealed that levels of HSP90B2, AAT, IGSF22, CUL5, PKCE, APOA4, APOE, APOA1, CCDC171, CCDC43, VIL1, Antigen KI-67, NKRF, APPBP2, CAPRI and most complement system proteins were increased in serum of CKD patients compared to the healthy group. Among complement system proteins, the C8G subunit was significantly decreased three-fold in patients with CKD. However, only AAT and HSP90B2 were positively correlated with well-established markers and, therefore, could be proposed as potential biomarkers for CKD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury and Repair)

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14 pages, 1400 KiB

Open AccessEditor’s ChoiceReview

Copper Ions and Parkinson’s Disease: Why Is Homeostasis So Relevant?

by Marco Bisaglia and Luigi Bubacco

Biomolecules 2020, 10(2), 195; https://doi.org/10.3390/biom10020195 - 29 Jan 2020

Cited by 154 | Viewed by 11337

Abstract

The involvement of copper in numerous physiological processes makes this metal ion essential for human life. Alterations in copper homeostasis might have deleterious consequences, and several neurodegenerative disorders, including Parkinson’s disease (PD), have been associated with impaired copper levels. In the present review, [...] Read more.

The involvement of copper in numerous physiological processes makes this metal ion essential for human life. Alterations in copper homeostasis might have deleterious consequences, and several neurodegenerative disorders, including Parkinson’s disease (PD), have been associated with impaired copper levels. In the present review, we describe the molecular mechanisms through which copper can exert its toxicity, by considering how it can interfere with other cellular processes known to play a role in PD, such as dopamine metabolism, oxidative stress, and α-synuclein aggregation. The recent experimental evidence that associates copper deficiency and the formation of superoxide dismutase 1 (SOD1) aggregates with the progression of PD is also discussed together with its therapeutic implication. Overall, the recent discoveries described in this review show how either copper deficiency or excessive levels can promote detrimental effects, highlighting the importance of preserving copper homeostasis and opening unexplored therapeutic avenues in the definition of novel disease-modifying drugs. Full article

(This article belongs to the Special Issue Potential Molecular Targets for Disease—Modifying Therapeutic Strategies in Parkinson’s Disease)

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16 pages, 1861 KiB

Open AccessFeature PaperEditor’s ChoiceReview

FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions

by Paula Tapial Martínez, Pilar López Navajas and Daniel Lietha

Biomolecules 2020, 10(2), 179; https://doi.org/10.3390/biom10020179 - 24 Jan 2020

Cited by 145 | Viewed by 13678

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase with key roles in the regulation of cell adhesion migration, proliferation and survival. In cancer FAK is a major driver of invasion and metastasis and its upregulation is associated with poor patient prognosis. FAK [...] Read more.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase with key roles in the regulation of cell adhesion migration, proliferation and survival. In cancer FAK is a major driver of invasion and metastasis and its upregulation is associated with poor patient prognosis. FAK is autoinhibited in the cytosol, but activated upon localisation into a protein complex, known as focal adhesion complex. This complex forms upon cell adhesion to the extracellular matrix (ECM) at the cytoplasmic side of the plasma membrane at sites of ECM attachment. FAK is anchored to the complex via multiple sites, including direct interactions with specific membrane lipids and connector proteins that attach focal adhesions to the actin cytoskeleton. In migrating cells, the contraction of actomyosin stress fibres attached to the focal adhesion complex apply a force to the complex, which is likely transmitted to the FAK protein, causing stretching of the FAK molecule. In this review we discuss the current knowledge of the FAK structure and how specific structural features are involved in the regulation of FAK signalling. We focus on two major regulatory mechanisms known to contribute to FAK activation, namely interactions with membrane lipids and stretching forces applied to FAK, and discuss how they might induce structural changes that facilitate FAK activation. Full article

(This article belongs to the Special Issue Focal Adhesion Kinase and Its Role in Cell, Molecular Biology, Cell Mechanics, and Bioengineering)

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21 pages, 11760 KiB

Open AccessEditor’s ChoiceReview

The Genetics of Thoracic Aortic Aneurysms and Dissection: A Clinical Perspective

by Nicolai P. Ostberg, Mohammad A. Zafar, Bulat A. Ziganshin and John A. Elefteriades

Biomolecules 2020, 10(2), 182; https://doi.org/10.3390/biom10020182 - 24 Jan 2020

Cited by 100 | Viewed by 11908

Abstract

Thoracic aortic aneurysm and dissection (TAAD) affects many patients globally and has high mortality rates if undetected. Once thought to be solely a degenerative disease that afflicted the aorta due to high pressure and biomechanical stress, extensive investigation of the heritability and natural [...] Read more.

Thoracic aortic aneurysm and dissection (TAAD) affects many patients globally and has high mortality rates if undetected. Once thought to be solely a degenerative disease that afflicted the aorta due to high pressure and biomechanical stress, extensive investigation of the heritability and natural history of TAAD has shown a clear genetic basis for the disease. Here, we review both the cellular mechanisms and clinical manifestations of syndromic and non-syndromic TAAD. We particularly focus on genes that have been linked to dissection at diameters <5.0 cm, the current lower bound for surgical intervention. Genetic screening tests to identify patients with TAAD associated mutations that place them at high risk for dissection are also discussed. Full article

(This article belongs to the Special Issue Genetics of Cardiovascular Disorders)

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