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Hydrogen sulfide (H2S) has been demonstrated to have physiological roles such as neuromodulation, vascular tone regulation, cytoprotection, oxygen sensing, inflammatory regulation, and cell growth. Recently, hydrogen polysulfides (H2Sn) have been found to be produced by 3-mercaptopyruvate sulfurtransferase and to regulate the activity of ion channels, tumor suppressers, and protein kinases. Furthermore, some of the effects previously reported to be mediated by H2S are now ascribed to H2Sn. Cysteine persulfide and cysteine polysulfide may also be involved in cellular redox regulation. The chemical interaction between H2S and nitric oxide (NO) can also produce H2Sn, nitroxyl, and nitrosopersulfide, suggesting their involvement in the reactions previously thought to be mediated by NO alone. This Forum focuses on and critically discusses the recent progress in the study of H2Sn, H2S, and NO as well as other per- or polysulfide species. Antioxid. Redox Signal. 00, 000-000. [ABSTRACT FROM AUTHOR]

Significance: Hydrogen sulfide (H2S) has been recognized as a signaling molecule as well as a cytoprotectant. It modulates neurotransmission, regulates vascular tone, and protects various tissues and organs, including neurons, the heart, and kidneys, from oxidative stress and ischemia-reperfusion injury. H2S is produced from l-cysteine by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST) along with cysteine aminotransferase. Recent Advances: In addition to these enzymes, we recently identified a novel pathway to produce H2S from d-cysteine, which involves d-amino acid oxidase (DAO) along with 3MST. These enzymes are localized in the cytoplasm, mitochondria, and peroxisomes. However, some enzymes translocate to organelles under specific conditions. Moreover, H2S-derived potential signaling molecules such as polysulfides and HSNO have been identified. Critical Issues: The physiological stimulations, which trigger the production of H2S and its derivatives and maintain their local levels, remain unclear. Future Directions: Understanding the regulation of the H2S production and H2S-derived signaling molecules and the specific stimuli that induce their release will provide new insights into the biology of H2S and therapeutic development in diseases involving these substances. Antioxid. Redox Signal. 22, 362-376. [ABSTRACT FROM AUTHOR]

It has been almost two decades since the first demonstration of hydrogen sulfide (H2S) as a physiological mediator of cognitive function and vascular tone. H2S is physiologically important because it protects various organs from ischemia-reperfusion injury besides regulating inflammation, oxygen sensing, cell growth, and senescence. The production, metabolism, and regulation of H2S have been studied extensively. H2S modulates target proteins through sulfhydration (or sulfuration) or by the reduction of cysteine disulfide bonds. A large number of novel H2S-donating compounds are being developed owing to the therapeutic potential of H2S. Recently, polysulfides, rather than H2S, have been identified as molecules that sulfhydrate (or sulfurate) their target proteins. Antioxid. Redox Signal. 22, 347-349. [ABSTRACT FROM AUTHOR]