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      Hydrogen Sulfide and Cellular Redox Homeostasis

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          Abstract

          Intracellular redox imbalance is mainly caused by overproduction of reactive oxygen species (ROS) or weakness of the natural antioxidant defense system. It is involved in the pathophysiology of a wide array of human diseases. Hydrogen sulfide (H 2S) is now recognized as the third “gasotransmitters” and proved to exert a wide range of physiological and cytoprotective functions in the biological systems. Among these functions, the role of H 2S in oxidative stress has been one of the main focuses over years. However, the underlying mechanisms for the antioxidant effect of H 2S are still poorly comprehended. This review presents an overview of the current understanding of H 2S specially focusing on the new understanding and mechanisms of the antioxidant effects of H 2S based on recent reports. Both inhibition of ROS generation and stimulation of antioxidants are discussed. H 2S-induced S-sulfhydration of key proteins (e.g., p66Shc and Keap1) is also one of the focuses of this review.

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          The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities.

          Jan Lewerenz, Sandra J Hewett, Ying Huang … (2013)
          The antiporter system x(c)(-) imports the amino acid cystine, the oxidized form of cysteine, into cells with a 1:1 counter-transport of glutamate. It is composed of a light chain, xCT, and a heavy chain, 4F2 heavy chain (4F2hc), and, thus, belongs to the family of heterodimeric amino acid transporters. Cysteine is the rate-limiting substrate for the important antioxidant glutathione (GSH) and, along with cystine, it also forms a key redox couple on its own. Glutamate is a major neurotransmitter in the central nervous system (CNS). By phylogenetic analysis, we show that system x(c)(-) is a rather evolutionarily new amino acid transport system. In addition, we summarize the current knowledge regarding the molecular mechanisms that regulate system x(c)(-), including the transcriptional regulation of the xCT light chain, posttranscriptional mechanisms, and pharmacological inhibitors of system x(c)(-). Moreover, the roles of system x(c)(-) in regulating GSH levels, the redox state of the extracellular cystine/cysteine redox couple, and extracellular glutamate levels are discussed. In vitro, glutamate-mediated system x(c)(-) inhibition leads to neuronal cell death, a paradigm called oxidative glutamate toxicity, which has successfully been used to identify neuroprotective compounds. In vivo, xCT has a rather restricted expression pattern with the highest levels in the CNS and parts of the immune system. System x(c)(-) is also present in the eye. Moreover, an elevated expression of xCT has been reported in cancer. We highlight the diverse roles of system x(c)(-) in the regulation of the immune response, in various aspects of cancer and in the eye and the CNS.
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            The Haber-Weiss reaction and mechanisms of toxicity.

            James Kehrer (2000)
            The concept that the highly reactive hydroxyl radical (HO) could be generated from an interaction between superoxide (O(2)(-)) and hydrogen peroxide (H(2)O(2)) was proposed (with Joseph Weiss) in Professor Haber's final paper published in 1934. Until it was recognized that free radicals are produced in biological systems, this finding seemed to have no relevance to biology. However, following the discovery that O(2)(-) was a normal cellular metabolite, it was quickly recognized that the Haber-Weiss reaction (O(2)(-)+H(2)O(2) -->HO+O(2)+HO(-)) might provide a means to generate more toxic radicals. Although the basic reaction has a second order rate constant of zero in aqueous solution and thus cannot occur in biological systems, the ability of iron salts to serve as catalysts was discussed by these authors. Because transition metal ions, particularly iron, are present at low levels in biological systems, this pathway (commonly referred to as the iron-catalyzed Haber-Weiss reaction) has been widely postulated to account for the in vivo generation of the highly reactive HO. Recent data documenting the importance of redox regulation of various cellular signaling pathways makes it clear that free radicals are essential for normal cellular function. However, this also makes it obvious that disruptions of free radical production or defenses at many different levels can lead to adverse effects on cells. While the generation of HO, which is by far the most reactive oxygen species, is generally indicative of an overtly toxic event, it is through studies at this level that we have reached a better understanding of free radicals as both signaling molecules and toxic species.
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              Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions.

              Nilkantha Sen, Bindu D. Paul, Moataz M. Gadalla … (2012)
              Nuclear factor κB (NF-κB) is an antiapoptotic transcription factor. We show that the antiapoptotic actions of NF-κB are mediated by hydrogen sulfide (H(2)S) synthesized by cystathionine gamma-lyase (CSE). TNF-α treatment triples H(2)S generation by stimulating binding of SP1 to the CSE promoter. H(2)S generated by CSE stimulates DNA binding and gene activation of NF-κB, processes that are abolished in CSE-deleted mice. As CSE deletion leads to decreased glutathione levels, resultant oxidative stress may contribute to alterations in CSE mutant mice. H(2)S acts by sulfhydrating the p65 subunit of NF-κB at cysteine-38, which promotes its binding to the coactivator ribosomal protein S3 (RPS3). Sulfhydration of p65 predominates early after TNF-α treatment, then declines and is succeeded by a reciprocal enhancement of p65 nitrosylation. In CSE mutant mice, antiapoptotic influences of NF-κB are markedly diminished. Thus, sulfhydration of NF-κB appears to be a physiologic determinant of its antiapoptotic transcriptional activity. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oxid Med Cell Longev
                Journal ID (iso-abbrev): Oxid Med Cell Longev
                Journal ID (publisher-id): OMCL
                Title: Oxidative Medicine and Cellular Longevity
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 1942-0900
                ISSN (Electronic): 1942-0994
                Publication date (Print): 2016
                Publication date (Electronic): 5 January 2016
                Volume: 2016
                Electronic Location Identifier: 6043038
                Affiliations
                1Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan 421001, China
                2Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang, Hunan 421001, China
                3Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
                Author notes
                *Zhi-Zhong Xie: zhizhongx@ 123456126.com and

                Academic Editor: Rodrigo Franco

                Article
                DOI: 10.1155/2016/6043038
                PMC ID: 4736422
                PubMed ID: 26881033
                SO-VID: 804ed825-2854-40ca-a895-5ac47425e3ae
                Copyright © Copyright © 2016 Zhi-Zhong Xie et al.
                License:

                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
                Date received : 26 September 2015
                Date revision received : 23 November 2015
                Date accepted : 1 December 2015
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Molecular medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine

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