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      Hydrogen Sulfide in Pharmacotherapy, Beyond the Hydrogen Sulfide-Donors

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          Abstract

          Hydrogen sulfide (H 2S) is one of the important biological mediators involved in physiological and pathological processes in mammals. Recently developed H 2S donors show promising effects against several pathological processes in preclinical and early clinical studies. For example, H 2S donors have been found to be effective in the prevention of gastrointestinal ulcers during anti-inflammatory treatment. Notably, there are well-established medicines used for the treatment of a variety of diseases, whose chemical structure contains sulfur moieties and may release H 2S. Hence, the therapeutic effect of these drugs may be partly the result of the release of H 2S occurring during drug metabolism and/or the effect of these drugs on the production of endogenous hydrogen sulfide. In this work, we review data regarding sulfur drugs commonly used in clinical practice that can support the hypothesis about H 2S-dependent pharmacotherapeutic effects of these drugs.

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          Most cited references217

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          H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase.

          Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine. The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H2S) is now receiving increasing attention. Here we show that H2S is physiologically generated by cystathionine gamma-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H2S levels in the serum, heart, aorta, and other tissues. Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation. CSE is physiologically activated by calcium-calmodulin, which is a mechanism for H2S formation in response to vascular activation. These findings provide direct evidence that H2S is a physiologic vasodilator and regulator of blood pressure.
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            The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener.

            Hydrogen sulfide (H(2)S) has been traditionally viewed as a toxic gas. It is also, however, endogenously generated from cysteine metabolism. We attempted to assess the physiological role of H(2)S in the regulation of vascular contractility, the modulation of H(2)S production in vascular tissues, and the underlying mechanisms. Intravenous bolus injection of H(2)S transiently decreased blood pressure of rats by 12- 30 mmHg, which was antagonized by prior blockade of K(ATP) channels. H(2)S relaxed rat aortic tissues in vitro in a K(ATP) channel-dependent manner. In isolated vascular smooth muscle cells (SMCs), H(2)S directly increased K(ATP) channel currents and hyperpolarized membrane. The expression of H(2)S-generating enzyme was identified in vascular SMCs, but not in endothelium. The endogenous production of H(2)S from different vascular tissues was also directly measured with the abundant level in the order of tail artery, aorta and mesenteric artery. Most importantly, H(2)S production from vascular tissues was enhanced by nitric oxide. Our results demonstrate that H(2)S is an important endogenous vasoactive factor and the first identified gaseous opener of K(ATP) channels in vascular SMCs.
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              H2S signals through protein S-sulfhydration.

              Hydrogen sulfide (H2S), a messenger molecule generated by cystathionine gamma-lyase, acts as a physiologic vasorelaxant. Mechanisms whereby H2S signals have been elusive. We now show that H2S physiologically modifies cysteines in a large number of proteins by S-sulfhydration. About 10 to 25% of many liver proteins, including actin, tubulin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), are sulfhydrated under physiological conditions. Sulfhydration augments GAPDH activity and enhances actin polymerization. Sulfhydration thus appears to be a physiologic posttranslational modification for proteins.
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                Author and article information

                Journal
                Biomolecules
                Biomolecules
                biomolecules
                Biomolecules
                MDPI
                2218-273X
                18 February 2020
                February 2020
                : 10
                : 2
                : 323
                Affiliations
                [1 ]Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland; ewelina.zaorska@ 123456gmail.com
                [2 ]Institute of Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, 84505 Bratislava, Slovakia; lennytomasova@ 123456gmail.com
                [3 ]Institute of Organic Chemistry, Polish Academy of Sciences Kasprzaka 44/52, 01-224 Warsaw, Poland; medyk20@ 123456gmail.com (D.K.); ryszard.ostaszewski@ 123456icho.edu.pl (R.O.)
                Author notes
                [* ]Correspondence: mufnal@ 123456wum.edu.pl ; Tel.: +48-22-116-6195
                Author information
                https://orcid.org/0000-0002-1943-0858
                https://orcid.org/0000-0003-0968-3330
                https://orcid.org/0000-0002-3032-196X
                https://orcid.org/0000-0003-0088-8284
                Article
                biomolecules-10-00323
                10.3390/biom10020323
                7072623
                32085474
                a7b9c724-ece4-4f19-bf4c-bd871cb2089a
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 December 2019
                : 14 February 2020
                Categories
                Review

                hydrogen sulfide,h2s donors,h2s pro-drugs,sulfur-containing drugs,cardiovascular,neuromodulation,anticancer drug,anti-inflammatory agents

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