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      Hydrogen Sulfide as a Novel Regulatory Factor in Liver Health and Disease

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          Abstract

          Hydrogen sulfide (H 2S), a colorless gas smelling of rotten egg, has long been recognized as a toxic gas and environment pollutant. However, increasing evidence suggests that H 2S acts as a novel gasotransmitter and plays important roles in a variety of physiological and pathological processes in mammals. H 2S is involved in many hepatic functions, including the regulation of oxidative stress, glucose and lipid metabolism, vasculature, mitochondrial function, differentiation, and circadian rhythm. In addition, H 2S contributes to the pathogenesis and treatment of a number of liver diseases, such as hepatic fibrosis, liver cirrhosis, liver cancer, hepatic ischemia/reperfusion injury, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, hepatotoxicity, and acute liver failure. In this review, the biosynthesis and metabolism of H 2S in the liver are summarized and the role and mechanism of H 2S in liver health and disease are further discussed.

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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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            Hydrogen sulfide is an endogenous stimulator of angiogenesis.

            The goal of the current study was to investigate the role of exogenous and endogenous hydrogen sulfide (H(2)S) on neovascularization and wound healing in vitro and in vivo. Incubation of endothelial cells (ECs) with H(2)S enhanced their angiogenic potential, evidenced by accelerated cell growth, migration, and capillary morphogenesis on Matrigel. Treatment of chicken chorioallantoic membranes (CAMS) with H(2)S increased vascular length. Exposure of ECs to H(2)S resulted in increased phosphorylation of Akt, ERK, and p38. The K(ATP) channel blocker glibenclamide or the p38 inhibitor SB203580 abolished H(2)S-induced EC motility. Since glibenclamide inhibited H(2)S-triggered p38 phosphorylation, we propose that K(ATP) channels lay upstream of p38 in this process. When CAMs were treated with H(2)S biosynthesis inhibitors dl-propylargylglycine or beta-cyano-L-alanine, a reduction in vessel length and branching was observed, indicating that H(2)S serves as an endogenous stimulator of the angiogenic response. Stimulation of ECs with vascular endothelial growth factor (VEGF) increased H(2)S release, while pharmacological inhibition of H(2)S production or K(ATP) channels or silencing of cystathionine gamma-lyase (CSE) attenuated VEGF signaling and migration of ECs. These results implicate endothelial H(2)S synthesis in the pro-angiogenic action of VEGF. Aortic rings isolated from CSE knockout mice exhibited markedly reduced microvessel formation in response to VEGF when compared to wild-type littermates. Finally, in vivo, topical administration of H(2)S enhanced wound healing in a rat model, while wound healing was delayed in CSE(-/-) mice. We conclude that endogenous and exogenous H(2)S stimulates EC-related angiogenic properties through a K(ATP) channel/MAPK pathway.
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              Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer.

              The physiological functions of hydrogen sulfide (H2S) include vasorelaxation, stimulation of cellular bioenergetics, and promotion of angiogenesis. Analysis of human colon cancer biopsies and patient-matched normal margin mucosa revealed the selective up-regulation of the H2S-producing enzyme cystathionine-β-synthase (CBS) in colon cancer, resulting in an increased rate of H2S production. Similarly, colon cancer-derived epithelial cell lines (HCT116, HT-29, LoVo) exhibited selective CBS up-regulation and increased H2S production, compared with the nonmalignant colonic mucosa cells, NCM356. CBS localized to the cytosol, as well as the mitochondrial outer membrane. ShRNA-mediated silencing of CBS or its pharmacological inhibition with aminooxyacetic acid reduced HCT116 cell proliferation, migration, and invasion; reduced endothelial cell migration in tumor/endothelial cell cocultures; and suppressed mitochondrial function (oxygen consumption, ATP turnover, and respiratory reserve capacity), as well as glycolysis. Treatment of nude mice with aminooxyacetic acid attenuated the growth of patient-derived colon cancer xenografts and reduced tumor blood flow. Similarly, CBS silencing of the tumor cells decreased xenograft growth and suppressed neovessel density, suggesting a role for endogenous H2S in tumor angiogenesis. In contrast to CBS, silencing of cystathionine-γ-lyase (the expression of which was unchanged in colon cancer) did not affect tumor growth or bioenergetics. In conclusion, H2S produced from CBS serves to (i) maintain colon cancer cellular bioenergetics, thereby supporting tumor growth and proliferation, and (ii) promote angiogenesis and vasorelaxation, consequently providing the tumor with blood and nutritients. The current findings identify CBS-derived H2S as a tumor growth factor and anticancer drug target.
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                Author and article information

                Contributors
                Journal
                Oxid Med Cell Longev
                Oxid Med Cell Longev
                OMCL
                Oxidative Medicine and Cellular Longevity
                Hindawi
                1942-0900
                1942-0994
                2019
                20 January 2019
                : 2019
                : 3831713
                Affiliations
                1School of Basic Medical Sciences, Henan University, Kaifeng, Henan 475004, China
                2Henan International Joint Laboratory for Nuclear Protein Regulation, Henan University, Kaifeng, Henan 475004, China
                3The First Affiliated Hospital of Henan University, Kaifeng, Henan 475001, China
                4Center for Precision Medicine, Zhengzhou University, Zhengzhou, Henan 450052, China
                5Institute for Innovative Drug Design and Evaluation, School of Pharmacy, Henan University, Kaifeng, Henan 475004, China
                Author notes

                Academic Editor: Claudia Penna

                Author information
                http://orcid.org/0000-0001-6739-8437
                http://orcid.org/0000-0003-2151-082X
                http://orcid.org/0000-0003-0690-4206
                Article
                10.1155/2019/3831713
                6360590
                30805080
                c3e20d4a-d85a-4cdd-ae49-fa3441bdfa36
                Copyright © 2019 Dong-Dong Wu et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 July 2018
                : 29 November 2018
                Funding
                Funded by: Henan University
                Award ID: yqpy20170044
                Funded by: Science Foundation of Kaifeng City
                Award ID: 1703016
                Award ID: 1608004
                Funded by: Education Department of Henan Province
                Award ID: 15A310017
                Funded by: Science and Technology Department, Henan Province
                Award ID: 172102410019
                Award ID: 182102310335
                Funded by: National Natural Science Foundation of China
                Award ID: 81670088
                Award ID: U1504817
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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