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Open accessJournal ArticleDOI: 10.1161/CIRCULATIONAHA.120.051877

Mapping the Endothelial Cell S-Sulfhydrome Highlights the Crucial Role of Integrin Sulfhydration in Vascular Function

02 Mar 2021-Circulation (Lippincott Williams & WilkinsHagerstown, MD)-Vol. 143, Iss: 9, pp 935-948
Abstract: Background: In vascular endothelial cells, cysteine metabolism by the cystathionine γ lyase (CSE), generates hydrogen sulfide–related sulfane sulfur compounds (H2Sn), that exert their biological ac...

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Topics: Cystathionine gamma-lyase (66%), Cystathionine beta synthase (60%), Cysteine metabolism (56%) ... show more

8 results found

Open accessJournal ArticleDOI: 10.3390/CELLS10020220
Csaba Szabó1Institutions (1)
22 Jan 2021-Cells
Abstract: Hydrogen sulfide (H2S) has a long history as toxic gas and environmental hazard; inhibition of cytochrome c oxidase (mitochondrial Complex IV) is viewed as a primary mode of its cytotoxic action. However, studies conducted over the last two decades unveiled multiple biological regulatory roles of H2S as an endogenously produced mammalian gaseous transmitter. Cystathionine -lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST) are currently viewed as the principal mammalian H2S-generating enzymes. In contrast to its inhibitory (toxicological) mitochondrial effects, at lower (physiological) concentrations, H2S serves as a stimulator of electron transport in mammalian mitochondria, by acting as an electron donor-with sulfide:quinone oxidoreductase (SQR) being the immediate electron acceptor. The mitochondrial roles of H2S are significant in various cancer cells, many of which exhibit high expression and partial mitochondrial localization of various H2S producing enzymes. In addition to the stimulation of mitochondrial ATP production, the roles of endogenous H2S in cancer cells include the maintenance of mitochondrial organization (protection against mitochondrial fission) and the maintenance of mitochondrial DNA repair (via the stimulation of the assembly of mitochondrial DNA repair complexes). The current article overviews the state-of-the-art knowledge regarding the mitochondrial functions of endogenously produced H2S in cancer cells.

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Topics: Mitochondrial DNA repair (68%), Mitochondrial fission (67%), Mitochondrion (59%) ... show more

12 Citations

Open accessJournal ArticleDOI: 10.3390/ANTIOX10030383
Kevin M Casin1, John W. Calvert1Institutions (1)
04 Mar 2021-Antioxidants
Abstract: Cardiovascular disease is the leading cause of death in the U.S. While various studies have shown the beneficial impact of exogenous hydrogen sulfide (H2S)-releasing drugs, few have demonstrated the influence of endogenous H2S production. Modulating the predominant enzymatic sources of H2S-cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase-is an emerging and promising research area. This review frames the discussion of harnessing endogenous H2S within the context of a non-ischemic form of cardiomyopathy, termed diabetic cardiomyopathy, and heart failure. Also, we examine the current literature around therapeutic interventions, such as intermittent fasting and exercise, that stimulate H2S production.

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Topics: Cardiomyopathy (50%)

5 Citations

Open accessJournal ArticleDOI: 10.3390/ANTIOX10030486
19 Mar 2021-Antioxidants
Abstract: The vascular endothelium consists of a single layer of squamous endothelial cells (ECs) lining the inner surface of blood vessels. Nowadays, it is no longer considered as a simple barrier between the blood and vessel wall, but a central hub to control blood flow homeostasis and fulfill tissue metabolic demands by furnishing oxygen and nutrients. The endothelium regulates the proper functioning of vessels and microcirculation, in terms of tone control, blood fluidity, and fine tuning of inflammatory and redox reactions within the vessel wall and in surrounding tissues. This multiplicity of effects is due to the ability of ECs to produce, process, and release key modulators. Among these, gasotransmitters such as nitric oxide (NO) and hydrogen sulfide (H2S) are very active molecules constitutively produced by endotheliocytes for the maintenance and control of vascular physiological functions, while their impairment is responsible for endothelial dysfunction and cardiovascular disorders such as hypertension, atherosclerosis, and impaired wound healing and vascularization due to diabetes, infections, and ischemia. Upregulation of H2S producing enzymes and administration of H2S donors can be considered as innovative therapeutic approaches to improve EC biology and function, to revert endothelial dysfunction or to prevent cardiovascular disease progression. This review will focus on the beneficial autocrine/paracrine properties of H2S on ECs and the state of the art on H2S potentiating drugs and tools.

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Topics: Endothelium (63%), Endothelial dysfunction (58%), Microcirculation (54%) ... show more

4 Citations

Open accessJournal ArticleDOI: 10.3390/IJMS22042193
Abstract: Integrins represent the biologically and medically significant family of cell adhesion molecules that govern a wide range of normal physiology. The activities of integrins in cells are dynamically controlled via activation-dependent conformational changes regulated by the balance of intracellular activators, such as talin and kindlin, and inactivators, such as Shank-associated RH domain interactor (SHARPIN) and integrin cytoplasmic domain-associated protein 1 (ICAP-1). The activities of integrins are alternatively controlled by homotypic lateral association with themselves to induce integrin clustering and/or by heterotypic lateral engagement with tetraspanin and syndecan in the same cells to modulate integrin adhesiveness. It has recently emerged that integrins are expressed not only in cells but also in exosomes, important entities of extracellular vesicles secreted from cells. Exosomal integrins have received considerable attention in recent years, and they are clearly involved in determining the tissue distribution of exosomes, forming premetastatic niches, supporting internalization of exosomes by target cells and mediating exosome-mediated transfer of the membrane proteins and associated kinases to target cells. A growing body of evidence shows that tumor and immune cell exosomes have the ability to alter endothelial characteristics (proliferation, migration) and gene expression, some of these effects being facilitated by vesicle-bound integrins. As endothelial metabolism is now thought to play a key role in tumor angiogenesis, we also discuss how tumor cells and their exosomes pleiotropically modulate endothelial functions in the tumor microenvironment.

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Topics: Exosome (64%), Integrin (59%), Tumor microenvironment (57%) ... show more

2 Citations

Open accessJournal ArticleDOI: 10.20892/J.ISSN.2095-3941.2021.0004
Jie Liang1, Xiao Zhao1, Xiao Zhao2Institutions (2)
Abstract: Nanomaterial-based delivery vehicles such as lipid-based, polymer-based, inorganics-based, and bio-inspired vehicles often carry distinct and attractive advantages in the development of therapeutic cancer vaccines. Based on various delivery vehicles, specifically designed nanomaterials-based vaccines are highly advantageous in boosting therapeutic and prophylactic antitumor immunities. Specifically, therapeutic vaccines featuring unique properties have made major contributions to the enhancement of antigen immunogenicity, encapsulation efficiency, biocompatibility, and stability, as well as promoting antigen cross-presentation and specific CD8+ T cell responses. However, for clinical applications, tumor-associated antigen-derived vaccines could be an obstacle, involving immune tolerance and deficiency of tumor specificities, in achieving maximum therapeutic indices. However, when using bioinformatics predictions with emerging innovations of in silico tools, neoantigen-based therapeutic vaccines might become potent personalized vaccines for tumor treatments. In this review, we summarize the development of preclinical therapeutic cancer vaccines and the advancements of nanomaterial-based delivery vehicles for cancer immunotherapies, which provide the basis for a personalized vaccine delivery platform. Moreover, we review the existing challenges and future perspectives of nanomaterial-based personalized vaccines for novel tumor immunotherapies.

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Topics: Cancer vaccine (58%)

1 Citations


72 results found

Open accessJournal ArticleDOI: 10.1093/NAR/GKR483
Chen Xie1, Xizeng Mao2, Jiaju Huang2, Yang Ding2  +6 moreInstitutions (2)
Abstract: High-throughput experimental technologies often identify dozens to hundreds of genes related to, or changed in, a biological or pathological process. From these genes one wants to identify biological pathways that may be involved and diseases that may be implicated. Here, we report a web server, KOBAS 2.0, which annotates an input set of genes with putative pathways and disease relationships based on mapping to genes with known annotations. It allows for both ID mapping and cross-species sequence similarity mapping. It then performs statistical tests to identify statistically significantly enriched pathways and diseases. KOBAS 2.0 incorporates knowledge across 1327 species from 5 pathway databases (KEGG PATHWAY, PID, BioCyc, Reactome and Panther) and 5 human disease databases (OMIM, KEGG DISEASE, FunDO, GAD and NHGRI GWAS Catalog). KOBAS 2.0 can be accessed at

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Topics: KEGG (53%), Pelvic inflammatory disease (52%)

2,269 Citations

Journal ArticleDOI: 10.1038/NATURE03952
15 Sep 2005-Nature
Abstract: Shear stress is a fundamental determinant of vascular homeostasis, regulating vascular remodelling, cardiac development and atherogenesis, but the mechanisms of transduction are poorly understood. Previous work showed that the conversion of integrins to a high-affinity state mediates a subset of shear responses, including cell alignment and gene expression. Here we investigate the pathway upstream of integrin activation. PECAM-1 (which directly transmits mechanical force), vascular endothelial cell cadherin (which functions as an adaptor) and VEGFR2 (which activates phosphatidylinositol-3-OH kinase) comprise a mechanosensory complex. Together, these receptors are sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, PECAM-1-knockout mice do not activate NF-kappaB and downstream inflammatory genes in regions of disturbed flow. Therefore, this mechanosensing pathway is required for the earliest-known events in atherogenesis.

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Topics: Vascular remodelling in the embryo (55%), Signal transduction (53%), Cell signaling (52%) ... show more

1,387 Citations

Open accessJournal ArticleDOI: 10.1038/NRM3896
Abstract: Soft connective tissues at steady state are dynamic; resident cells continually read environmental cues and respond to them to promote homeostasis, including maintenance of the mechanical properties of the extracellular matrix (ECM) that are fundamental to cellular and tissue health. The mechanosensing process involves assessment of the mechanics of the ECM by the cells through integrins and the actomyosin cytoskeleton, and is followed by a mechanoregulation process, which includes the deposition, rearrangement or removal of the ECM to maintain overall form and function. Progress towards understanding the molecular, cellular and tissue-level effects that promote mechanical homeostasis has helped to identify key questions for future research.

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1,112 Citations

Open accessJournal ArticleDOI: 10.1038/NATURE13701
Jing Li1, Bing Hou1, Sarka Tumova1, Katsuhiko Muraki2  +25 moreInstitutions (5)
13 Nov 2014-Nature
Abstract: The mechanisms by which physical forces regulate endothelial cells to determine the complexities of vascular structure and function are enigmatic. Studies of sensory neurons have suggested Piezo proteins as subunits of Ca(2+)-permeable non-selective cationic channels for detection of noxious mechanical impact. Here we show Piezo1 (Fam38a) channels as sensors of frictional force (shear stress) and determinants of vascular structure in both development and adult physiology. Global or endothelial-specific disruption of mouse Piezo1 profoundly disturbed the developing vasculature and was embryonic lethal within days of the heart beating. Haploinsufficiency was not lethal but endothelial abnormality was detected in mature vessels. The importance of Piezo1 channels as sensors of blood flow was shown by Piezo1 dependence of shear-stress-evoked ionic current and calcium influx in endothelial cells and the ability of exogenous Piezo1 to confer sensitivity to shear stress on otherwise resistant cells. Downstream of this calcium influx there was protease activation and spatial reorganization of endothelial cells to the polarity of the applied force. The data suggest that Piezo1 channels function as pivotal integrators in vascular biology.

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Topics: Angiogenesis (54%), Mechanosensitive ion channel (53%), PIEZO1 (53%)

521 Citations

Open accessJournal ArticleDOI: 10.1101/CSHPERSPECT.A005066
Martin A. Schwartz1Institutions (1)
Abstract: Integrins bind extracellular matrix fibrils and associate with intracellular actin filaments through a variety of cytoskeletal linker proteins to mechanically connect intracellular and extracellular structures. Each component of the linkage from the cytoskeleton through the integrin-mediated adhesions to the extracellular matrix therefore transmits forces that may derive from both intracellular, myosin-generated contractile forces and forces from outside the cell. These forces activate a wide range of signaling pathways and genetic programs to control cell survival, fate, and behavior. Additionally, cells sense the physical properties of their surrounding environment through forces exerted on integrin-mediated adhesions. This article first summarizes current knowledge about regulation of cell function by mechanical forces acting through integrin-mediated adhesions and then discusses models for mechanotransduction and sensing of environmental forces.

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520 Citations