scholarly journals Role of the Cation-chloride-cotransporters in Cardiovascular Disease

2020 ◽  
Author(s):  
Nur Farah Meor Azlan ◽  
Jinwei Zhang
Keyword(s):  
Cardiovascular Disease ◽  
Functional Role ◽  
Genetic Disorders ◽  
Ion Homeostasis ◽  
Cell Volume Regulation ◽  
Renal Cells ◽  
Sodium Homeostasis ◽  
Physiological Processes ◽  
Cation Chloride Cotransporters

The SLC12 family of cation-chloride-cotransporters (CCCs), comprising potassium chloride cotransporters (KCCs)-mediated Cl- extrusion relative to sodium chloride cotransporters (NKCCs)-mediated Cl- loading, play vital roles in cell volume regulation and ion homeostasis. These functions of the CCCs influence a variety of physiological processes, many of which overlap with the pathophysiology of cardiovascular disease. Although not all of the cotransporters have been linked to Mendelian genetic disorders, recent studies have provided new insights into their functional role in vascular and renal cells along with their contribution to cardiovascular diseases. Particularly, an imbalance in potassium levels promote the pathogenesis of atherosclerosis and disturbances in sodium homeostasis are one of the causes of hypertension. Recent findings even suggest hypothalamic signalling as a key signalling pathway in the pathophysiology of hypertension. In this review, we summarize and discuss the role of CCCs in cardiovascular disease with particular emphasis on knowledge gained in recent years on NKCCs and KCCs.

scholarly journals Role of the Cation-Chloride-Cotransporters in Cardiovascular Disease

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2293 ◽  
Author(s):  
Nur Farah Meor Azlan ◽  
Jinwei Zhang
Keyword(s):  
Cardiovascular Disease ◽  
Potassium Chloride ◽  
Genetic Disorders ◽  
Ion Homeostasis ◽  
Cell Volume Regulation ◽  
Renal Cells ◽  
Sodium Potassium ◽  
Physiological Processes ◽  
Cation Chloride Cotransporters

The SLC12 family of cation-chloride-cotransporters (CCCs) is comprised of potassium chloride cotransporters (KCCs), which mediate Cl− extrusion and sodium-potassium chloride cotransporters (N[K]CCs), which mediate Cl− loading. The CCCs play vital roles in cell volume regulation and ion homeostasis. The functions of CCCs influence a variety of physiological processes, many of which overlap with the pathophysiology of cardiovascular disease. Although not all of the cotransporters have been linked to Mendelian genetic disorders, recent studies have provided new insights into their functional role in vascular and renal cells in addition to their contribution to cardiovascular diseases. Particularly, an imbalance in potassium levels promotes the pathogenesis of atherosclerosis and disturbances in sodium homeostasis are one of the causes of hypertension. Recent findings suggest hypothalamic signaling as a key signaling pathway in the pathophysiology of hypertension. In this review, we summarize and discuss the role of CCCs in cardiovascular disease with particular emphasis on knowledge gained in recent years on NKCCs and KCCs.

scholarly journals Fluorinated Mannosides Inhibit Cellular Fucosylation.

2020 ◽  
Author(s):  
Johan Pijnenborg ◽  
Emiel Rossing ◽  
Marek Noga ◽  
Willem Titulaer ◽  
Raisa Veizaj ◽  
...  
Keyword(s):  
Mammalian Cell ◽  
De Novo ◽  
Genetic Disorders ◽  
Living Cells ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Inflammation ◽  
Mannose Derivatives ◽  
Potential Therapeutics

Fucose sugars are expressed on mammalian cell membranes as part of glycoconjugates and mediates essential physiological processes. The aberrant expression of fucosylated glycans has been linked to pathologies such as cancer, inflammation, infection, and genetic disorders. Tools to modulate fucose expression on living cells are needed to elucidate the biological role of fucose sugars and the development of potential therapeutics. Herein, we report a novel class of fucosylation inhibitors directly targeting de novo GDP-fucose biosynthesis. We demonstrate that cell permeable fluorinated mannoside 1-phosphate derivatives (Fucotrim I & II) are metabolic prodrugs that are metabolized to their respective GDP-mannose derivatives and efficiently inhibit cellular fucosylation.

Actin dynamics as critical ion channel regulator: ENaC and Piezo in focus

2021 ◽  
Author(s):  
Elena A. Morachevskaya ◽  
Anastasia V. Sudarikova
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Dynamic Balance ◽  
Cell Volume Regulation ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Actin Assembly ◽  
Excitable Cells ◽  
Physiological Processes

Ion channels in plasma membrane play a principal role in different physiological processes, including cell volume regulation, signal transduction and modulation of membrane potential in living cells. Actin-based cytoskeleton, which exists in a dynamic balance between monomeric and polymeric forms (globular and fibrillar actin), can be directly or indirectly involved in various cellular responses including modulation of ion channel activity. In this mini-review, we present an overview of the role of submembranous actin dynamics in the regulation of ion channels in excitable and non-excitable cells. Special attention is focused on the important data about the involvement of actin assembly/disassembly and some actin-binding proteins in the control of the Epithelial Na+ Channel (ENaC) and mechanosensitive Piezo channels whose integral activity has potential impact on membrane transport and multiple coupled cellular reactions. Growing evidence suggests that actin elements of the cytoskeleton can represent a "converging point" of various signaling pathways modulating the activity of ion transport proteins in cell membranes.

scholarly journals CHIR99021 Augmented the Function of Late Endothelial Progenitor Cells by Preventing Replicative Senescence

2021 ◽  
Vol 22 (9) ◽  
pp. 4796
Author(s):  
Vinoth Kumar Rethineswaran ◽  
Da Yeon Kim ◽  
Yeon-Ju Kim ◽  
WoongBi Jang ◽  
Seung Taek Ji ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Blood Circulation ◽  
Functional Role ◽  
Replicative Senescence ◽  
Endothelial Progenitor ◽  
Vascular Structures ◽  
Gsk 3Β

Endothelial progenitor cells (EPCs) are specialized cells in circulating blood, well known for their ability to form new vascular structures. Aging and various ailments such as diabetes, atherosclerosis and cardiovascular disease make EPCs vulnerable to decreasing in number, which affects their migration, proliferation and angiogenesis. Myocardial ischemia is also linked to a reduced number of EPCs and their endothelial functional role, which hinders proper blood circulation to the myocardium. The current study shows that an aminopyrimidine derivative compound (CHIR99021) induces the inhibition of GSK-3β in cultured late EPCs. GSK-3β inhibition subsequently inhibits mTOR by blocking the phosphorylation of TSC2 and lysosomal localization of mTOR. Furthermore, suppression of GSK-3β activity considerably increased lysosomal activation and autophagy. The activation of lysosomes and autophagy by GSK-3β inhibition not only prevented replicative senescence of the late EPCs but also directed their migration, proliferation and angiogenesis. To conclude, our results demonstrate that lysosome activation and autophagy play a crucial role in blocking the replicative senescence of EPCs and in increasing their endothelial function. Thus, the findings provide an insight towards the treatment of ischemia-associated cardiovascular diseases based on the role of late EPCs.

scholarly journals Noncoding RNAs in Cardiovascular Disease: Current Knowledge, Tools and Technologies for Investigation, and Future Directions: A Scientific Statement From the American Heart Association

2020 ◽  
Vol 13 (4) ◽  
Author(s):  
Saumya Das ◽  
Ravi Shah ◽  
Stefanie Dimmeler ◽  
Jane E. Freedman ◽  
Christopher Holley ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Noncoding Rna ◽  
Functional Role ◽  
Unmet Need ◽  
Noncoding Rnas ◽  
Rapid Expansion ◽  
Cardiovascular Development ◽  
Computational Tools ◽  
Cellular Processes

Background: The discovery that much of the non–protein-coding genome is transcribed and plays a diverse functional role in fundamental cellular processes has led to an explosion in the development of tools and technologies to investigate the role of these noncoding RNAs in cardiovascular health. Furthermore, identifying noncoding RNAs for targeted therapeutics to treat cardiovascular disease is an emerging area of research. The purpose of this statement is to review existing literature, offer guidance on tools and technologies currently available to study noncoding RNAs, and identify areas of unmet need. Methods: The writing group used systematic literature reviews (including MEDLINE, Web of Science through 2018), expert opinion/statements, analyses of databases and computational tools/algorithms, and review of current clinical trials to provide a broad consensus on the current state of the art in noncoding RNA in cardiovascular disease. Results: Significant progress has been made since the initial studies focusing on the role of miRNAs (microRNAs) in cardiovascular development and disease. Notably, recent progress on understanding the role of novel types of noncoding small RNAs such as snoRNAs (small nucleolar RNAs), tRNA (transfer RNA) fragments, and Y-RNAs in cellular processes has revealed a noncanonical function for many of these molecules. Similarly, the identification of long noncoding RNAs that appear to play an important role in cardiovascular disease processes, coupled with the development of tools to characterize their interacting partners, has led to significant mechanistic insight. Finally, recent work has characterized the unique role of extracellular RNAs in mediating intercellular communication and their potential role as biomarkers. Conclusions: The rapid expansion of tools and pipelines for isolating, measuring, and annotating these entities suggests that caution in interpreting results is warranted until these methodologies are rigorously validated. Most investigators have focused on investigating the functional role of single RNA entities, but studies suggest complex interaction between different RNA molecules. The use of network approaches and advanced computational tools to understand the interaction of different noncoding RNA species to mediate a particular phenotype may be required to fully comprehend the function of noncoding RNAs in mediating disease phenotypes.

scholarly journals Fluorinated rhamnosides inhibit cellular fucosylation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Johan F. A. Pijnenborg ◽  
Emiel Rossing ◽  
Jona Merx ◽  
Marek J. Noga ◽  
Willem H. C. Titulaer ◽  
...  
Keyword(s):  
Mammalian Cell ◽  
De Novo ◽  
Genetic Disorders ◽  
Living Cells ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Inflammation ◽  
Mannose Derivatives ◽  
Potential Therapeutics

AbstractThe sugar fucose is expressed on mammalian cell membranes as part of glycoconjugates and mediates essential physiological processes. The aberrant expression of fucosylated glycans has been linked to pathologies such as cancer, inflammation, infection, and genetic disorders. Tools to modulate fucose expression on living cells are needed to elucidate the biological role of fucose sugars and the development of potential therapeutics. Herein, we report a class of fucosylation inhibitors directly targeting de novo GDP-fucose biosynthesis via competitive GMDS inhibition. We demonstrate that cell permeable fluorinated rhamnose 1-phosphate derivatives (Fucotrim I & II) are metabolic prodrugs that are metabolized to their respective GDP-mannose derivatives and efficiently inhibit cellular fucosylation.

scholarly journals Fluorinated Mannosides Inhibit Cellular Fucosylation.

2020 ◽  
Author(s):  
Johan Pijnenborg ◽  
Emiel Rossing ◽  
Marek Noga ◽  
Willem Titulaer ◽  
Raisa Veizaj ◽  
...  
Keyword(s):  
Mammalian Cell ◽  
De Novo ◽  
Genetic Disorders ◽  
Living Cells ◽  
Aberrant Expression ◽  
Physiological Processes ◽  
Cancer Inflammation ◽  
Mannose Derivatives ◽  
Potential Therapeutics

Fucose sugars are expressed on mammalian cell membranes as part of glycoconjugates and mediates essential physiological processes. The aberrant expression of fucosylated glycans has been linked to pathologies such as cancer, inflammation, infection, and genetic disorders. Tools to modulate fucose expression on living cells are needed to elucidate the biological role of fucose sugars and the development of potential therapeutics. Herein, we report a novel class of fucosylation inhibitors directly targeting de novo GDP-fucose biosynthesis. We demonstrate that cell permeable fluorinated mannoside 1-phosphate derivatives (Fucotrim I & II) are metabolic prodrugs that are metabolized to their respective GDP-mannose derivatives and efficiently inhibit cellular fucosylation.

scholarly journals Cracking the Monoubiquitin Code of Genetic Diseases

2020 ◽  
Vol 21 (9) ◽  
pp. 3036 ◽  
Author(s):  
Raj Nayan Sewduth ◽  
Maria Francesca Baietti ◽  
Anna A. Sablina
Keyword(s):  
Genetic Disorders ◽  
Genetic Diseases ◽  
Post Translational Modification ◽  
Binding Properties ◽  
Polyubiquitin Chains ◽  
Target Proteins ◽  
Therapeutic Implications ◽  
Physiological Processes ◽  
The Stability

Ubiquitination is a versatile and dynamic post-translational modification in which single ubiquitin molecules or polyubiquitin chains are attached to target proteins, giving rise to mono- or poly-ubiquitination, respectively. The majority of research in the ubiquitin field focused on degradative polyubiquitination, whereas more recent studies uncovered the role of single ubiquitin modification in important physiological processes. Monoubiquitination can modulate the stability, subcellular localization, binding properties, and activity of the target proteins. Understanding the function of monoubiquitination in normal physiology and pathology has important therapeutic implications, as alterations in the monoubiquitin pathway are found in a broad range of genetic diseases. This review highlights a link between monoubiquitin signaling and the pathogenesis of genetic disorders.

scholarly journals Role of Exosomal MicroRNAs and Their Crosstalk with Oxidative Stress in the Pathogenesis of Osteoporosis

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Jun Lu ◽  
Yan Zhang ◽  
Jinqi Liang ◽  
Jiayu Diao ◽  
Peilong Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Tissue ◽  
Functional Role ◽  
Treatment Strategies ◽  
Related Disease ◽  
Physiological Processes ◽  
Exosomal Mirnas ◽  
Relationship Of ◽  
The Relationship

Osteoporosis (OP) is an aging-related disease involving permanent bone tissue atrophy. Most patients with OP show high levels of oxidative stress (OS), which destroys the microstructure of bone tissue and promotes disease progression. Exosomes (exos) help in the delivery of microRNAs (miRNAs) and allow intercellular communication. In OP, exosomal miRNAs modulate several physiological processes, including the OS response. In the present review, we aim to describe how exosomal miRNAs and OS contribute to OP. We first summarize the relationship of OS with OP and then detail the features of exos along with the functions of exo-related miRNAs. Further, we explore the interplay between exosomal miRNAs and OS in OP and summarize the functional role of exos in OP. Finally, we identify the advantages of exo-based miRNA delivery in treatment strategies for OP. Our review seeks to improve the current understanding of the mechanism underlying OP pathogenesis and lay the foundation for the development of novel theranostic approaches for OP.

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