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Background and Purpose: Hydrogen sulfide (H 2 S) and polysulfides (H 2 S n ) are signalling molecules that mediate various physiological responses including cytoprotection. Their oxidized metabolite sulfite (SO 3 ) is found in blood and tissues. However, its physiological role remains unclear. In this study, we investigated the cytoprotective effect of sulfite on neurons exposed to oxidative stress caused by high concentrations of the neurotransmitter glutamate, known as oxytosis.2- ) is found in blood and tissues. However, its physiological role remains unclear. In this study, we investigated the cytoprotective effect of sulfite on neurons exposed to oxidative stress caused by high concentrations of the neurotransmitter glutamate, known as oxytosis., Experimental Approach: Concentrations of sulfite as well as those of cysteine and GSH in rats were measured by HPLC. Cytoprotective effects of sulfite on primary cultures of rat neurons against oxytosis was examined by WST-8 cytoprotective and LDH cytotoxicity assays and compared with that of H 2 S, H 2 S n and thiosulfate., Key Results: Free sulfite, present at approximately 2 μM in the rat brain, converts cystine to cysteine more efficiently than H 2 S and H 2 S n and facilitates transport of cysteine into cells. Physiological concentrations of sulfite protected neurons from oxytosis and were accompanied by increased intracellular concentrations of cysteine and GSH probably due to converting extracellular cystine to cysteine, more efficiently than H 2 S and H 2 S n . In contrast, thiosulfate only slightly protected neurons from oxytosis., Conclusions and Implications: Our present data have shown sulfite to be a novel cytoprotective molecule against oxytosis, through maintaining cysteine levels in the extracellular milieu, leading to increased intracellular cysteine and GSH. Although there may be adverse clinical effects in sensitive individuals, our results provide a new insight into the therapeutic application of sulfite to neuronal diseases caused by oxidative stress., Linked Articles: This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc., (© 2018 The British Pharmacological Society.)

Hydrogen sulfide (H(2)S) is a synaptic modulator as well as a neuroprotectant in the brain. We recently showed that H(2)S protects neurons from oxidative stress by increasing the levels of glutathione (GSH), a major cellular antioxidant, by more than twice that of a control through enhancing the cystine transport. Here we show that H(2)S enhances the transport of cysteine to increase GSH production more than cystine transport and to redistribute the localization of GSH to mitochondria. The efficiency of GSH production enhanced by H(2)S is even greater by fourfold under oxidative stress by glutamate. H(2)S reinstated GSH levels in the fetal brain decreased by ischemia/reperfusion in utero. In addition, Neuro2a cells expressing a mitochondrial H(2)S-producing enzyme, 3-mercaptopyruvate sulfurtransferase (3MST), along with cysteine aminotransferase (CAT), showed significant resistance to oxidative stress. The present study shows that H(2)S protects cells from oxidative stress by two mechanisms. It enhances the production of GSH by enhancing cystine/cysteine transporters and redistributes GSH to mitochondria. H(2)S produced in mitochondria also may directly suppress oxidative stress. It provides a new mechanism of neuroprotection from oxidative stress by H(2)S.

Background: Oxidative stress has been implicated in the pathogenesis of chronic heart failure. The present study investigated whether the levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, were elevated in the serum and myocardium of patients with dilated cardiomyopathy (DCM), and furthermore whether carvedilol, a vasodilating beta-blocker with antioxidant activity, could reduce the levels., Methods and Results: Serum levels of 8-OHdG were measured by enzyme immunoassay in 56 patients with DCM and in 20 control subjects. DCM patients had significantly elevated serum levels of 8-OHdG compared with control subjects. Endomyocardial biopsy samples obtained from 12 DCM patients and 5 control subjects with normal cardiac function were studied immunohistochemically for the expression of 8-OHdG. Positive 8-OHdG staining was found in the nuclei of cardiomyocytes from DCM patients but not in those from control subjects. After treatment with carvedilol, the serum levels of 8-OHdG in DCM patients significantly decreased by 19%, together with amelioration of heart failure., Conclusions: Levels of 8-OHdG are elevated in the serum and myocardium of patients with heart failure. Treatment with carvedilol might be effective for decreasing the oxidative DNA damage.

Hydrogen sulfide (H2S) is a neuromodulator in the brain and a relaxant for smooth muscle. H2S protects primary cortical neurons from oxidative stress by increasing the intracellular concentrations of glutathione, the major antioxidant in cells. However, changes in glutathione alone are not sufficient to account for full protection in all types of nerve cells. H2S is here shown to protect an immortalized mouse hippocampal cell line from oxidative glutamate toxicity by activating ATP-dependent K+ (KATP) and Cl- channels, in addition to increasing the levels of glutathione. The present study therefore identifies a novel pathway for H2S protection from oxidative stress.

Hydrogen sulfide (H 2 S) is a signaling molecule used to modify neuronal transmission, regulate vascular tone, protect tissues from oxidative stress, sense oxygen, and generate ATP. Hydrogen polysulfides (H 2 S n) have recently been identified as signaling molecules that mediate the activation of ion channels, regulation of tumor growth, and the transcriptional regulation of oxidative stress; some of which were previously ascribed to H 2 S. Cystathionine β-synthetase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST) are known as H 2 S-producing enzymes. 3MST also produces H 2 S n and other persulfurated molecules such as cysteine persulfide, glutathione persulfide, and persulfurated proteins. The chemical interaction of H 2 S and nitric oxide (NO) also produces H 2 S n , which may be the mechanism underlying the synergistic effect of H 2 S and NO that was initially reported on vascular relaxation. H 2 S n and other persulfurated molecules elicit their effect via S-sulfuration (S-sulfhydration) of specific cysteine residues of the target proteins. This review article focuses on the production and roles of H 2 S n as well as H 2 S in the central nervous system. • Hydrogen sulfide (H 2 S) is a signaling molecule with various physiological roles. • Some functions previously reported by H 2 S have recently been ascribed to polysulfides (H 2 S n). • H 2 S n S-sulfurate (S-sulfhydrate) cysteine residues of the target proteins. • The disturbance of the signaling by H 2 S and H 2 S n may be involved in various neuronal diseases. [ABSTRACT FROM AUTHOR]

About 20 years ago, a pungent gas was found to be the physiological mediator of cognitive function and vascular tone. Since then, studies on hydrogen sulfide (H 2 S) have uncovered its numerous physiological roles such as protecting various tissues/organs from ischemia and regulating inflammation, cell growth, oxygen sensing, and senescence. These effects of H 2 S were extensively studied, and some of the corresponding mechanisms were also studied in detail. Previous studies on the synergistic interaction between H 2 S and nitric oxide (NO) have led to the discovery of several potential signaling molecules. Polysulfides are considerably potent and are one of the most active forms of H 2 S. H 2 S has a significant therapeutic potential, which is evident from the large number of novel H 2 S-donating compounds and substances developed for manipulating endogenous levels of H 2 S. The Third International Conference on H 2 S was held in Kyoto in June 2014. One hundred and sixty participants from 21 countries convened in Kyoto to report new advances, discuss conflicting findings, and make plans for future research. This article summarizes each oral presentation presented at the conference. [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]

Highlights: [•] H2S is produced by four enzymatic pathways. [•] H2S regulates synaptic transmission. [•] H2S protects neurons from oxidative stress. [•] H2S-derived polysulfides activate TRPA1 channels. [Copyright &y& Elsevier]

Highlights: [•] Polysulfide uptake induces acceleration of GSH synthesis and HO-1 expression. [•] Polysulfide possesses cytoprotective function against ROS toxicity in the cell. [•] Polysulfide-induced disulfide formation of Keap1 causes Nrf2 activation. [•] The PI3K/Akt phosphorylation pathway is activated by polysulfide. [ABSTRACT FROM AUTHOR]

Sulfur is the seventh most abundant element measurable in the human body and is supplied mainly by the intake of methionine ( Met), an indispensable amino acid found in plant and animal proteins. Met controls the initiation of protein synthesis, governs major metabolic and catalytic activities, and may undergo reversible redox processes safeguarding protein integrity. Withdrawal of Met from customary diets causes the greatest downsizing of lean body mass following either unachieved replenishment (malnutrition) or excessive losses (inflammation). These physiopathologically unrelated morbidities nevertheless stimulate comparable remethylation reactions from homocysteine, indicating that Met homeostasis benefits from high metabolic priority. Inhibition of cystathionine-β-synthase activity causes the upstream sequestration of homocysteine and the downstream drop in cysteine and glutathione. Consequently, the enzymatic production of hydrogen sulfide and the nonenzymatic reduction of elemental sulfur to hydrogen sulfide are impaired. Sulfur operates as cofactor of several enzymes critically involved in the regulation of oxidative processes. A combination of malnutrition and nutritional deprivation of sulfur maximizes the risk of cardiovascular disorders and stroke, constituting a novel clinical entity that threatens plant-eating population groups. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows that H2S has physiological functions in various tissues and organs. It includes regulation of neuronal activity, vascular tension, a release of insulin, and protection of the heart, kidney, and brain from ischemic insult. H2S is produced by enzymes from L-cysteine; cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase (3MST) along with cysteine aminotransferase. We recently discovered an additional pathway for the production of H2S from D-cysteine. D-Amino acid oxidase provides 3-mercaptopyruvate for 3MST to produce H2S. D-Cysteine protects cerebellar neurons from oxidative stress and attenuates ischemia-reperfusion injury caused in the kidney more effectively than L-cysteine. This review focuses on a novel pathway for the production of H2S and its therapeutic application especially to the renal diseases. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (HS), which is a well-known toxic gas, has been recognized as a signal molecule as well as a cytoprotectant. It is produced by three enzymes, cystathionine β-synthase, cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase along with cysteine aminotransferase. In addition to an immediate release of HS from producing enzymes, it can be stored as bound sulfane sulfur, which may release HS in response to physiological stimuli. As a signal molecule, it modulates neuronal transmission, relaxes smooth muscle, regulates release of insulin and is involved in inflammation. Because of its reputation as a toxic gas, the function as a cytoprotectant has been overlooked: the nervous system and cardiovascular system are protected from oxidative stress. In this review, enzymatic production, release mechanism and functions of HS are focused on. [ABSTRACT FROM AUTHOR]

Endogenous levels of sulfide in the brain have been measured in rats, humans and bovines in 1989 and 1990, suggesting that H2S may have a physiological function. We demonstrated in 1996 that cystathionine β-synthase can produce H2S in the brain and that H2S facilitates the induction of hippocampal long-term potentiation by enhancing the activity of NMDA receptors. The following year, we showed that another H2S-producing enzyme, cystathionine γ-lyase, is expressed in the thoracic aorta, portal vein and ileum and that H2S relaxes these tissues. We proposed that H2S may be a neuromodulator as well as a smooth muscle relaxant. In addition to a function as a signalling molecule, we demonstrated another function as a cytoprotectant in 2004. Hydrogen sulfide protects neurons from oxidative stress by reinstating the reduced glutathione levels. We recently demonstrated that a third H2S-producing enzyme, 3-mercaptopyruvate sulfurtransferase (3MST), is expressed in neurons and vascular endothelium. In addition to reinstating glutathione levels, H2S produced by 3MST, which is mainly localized to mitochondria, reduces reactive oxygen species generated in these organelles. [ABSTRACT FROM AUTHOR]

Deals with a study which examined the role of hydrogen sulfide in protecting neurons from oxidative stress. Influence of hydrogen sulfide on the production of glutathione; Effect of hydrogen sulfide on &gamma-glutamylcysteine; Significance of hydrogen sulfide to cystine transport.

The relatively high concentrations of endogenous sulfide in the mammalian brain were measured in 1989, suggesting that hydrogen sulfide (H 2 S) might have a physiological function. In 1996 we demonstrated that cystathionine β -synthase (CBS) is a H 2 S producing enzyme in the brain and that H 2 S facilitates the induction of hippocampal long-term potentiation (LTP), a synaptic model of memory, by enhancing the activity of N -methyl d -aspartate (NMDA) receptors. The following year we demonstrated that another H 2 S producing enzyme, cystathionine γ -lyase (CSE) is found in tissues including vasculature and that H 2 S relaxes them. Based on these observations we proposed that H 2 S is a neuromodulator and a smooth muscle relaxant. In addition to the function as a signaling molecule, we and others found a cytoprotective effect of this molecule; H 2 S protects neurons from oxidative stress. This finding led to the identification of the protection of various organs including the heart, pancreas, retina, and the kidney against ischemia–reperfusion injury. From our finding that the brains of CBS knockout mice was still able to produce H 2 S, we found another pathway; 3-mercaptopyruvate sulfur transferase (3MST) along with cysteine aminotransferase (CAT). 3MST produces H 2 S in the presence of thioredoxin or dihydrolipoic acid (DHLA). We recently found a novel pathway to produce H 2 S from d -cysteine, a negative control. d -Amino acid oxidase (DAO) metabolizes d -cysteine to an achiral α –keto acid, 3-mercaptopyruvate (3MP), which is further metabolized to H 2 S by 3MST. This pathway is mainly localized in the cerebellum and the kidney. The production of H 2 S from d -cysteine is 80 times more efficient than that from l -cysteine in the kidney, and the administration of d -cysteine to mice ameliorates renal ischemia–reperfusion injury more effectively than l -cysteine. These results show a therapeutic potential of d -cysteine to the renal diseases and even to the kidney transplantation. Our additional contribution to this field is the discovery of H 2 S-derived polysulfides, which exist in the brain and activate transient receptor potential ankyrin-1 (TRPA1) channels 300 times more potently than H 2 S. TRPA1 channels mediate the sensory transduction and respond to a variety of stimuli, including cold temperature, pungent compounds and environmental irritants, but its endogenous ligand has not been identified. The sulfane sulfur of polysulfides is reactive electrophile and readily transferred to a nucleophilic protein thiolate, to generate the protein persulfide (sulfhydration). The sulfhydration activity of polysulfides is much greater than H 2 S. The production of H 2 S and the physiological function of H 2 S and polysulfides will be discussed. [ABSTRACT FROM AUTHOR]

Polysulfides are a typical type of bound sulfur, which is physiologically stable form of sulfur species, derived from the hydrogen sulfide (H 2 S) that is generated endogenously in cells. We previously reported that bound sulfur protects neuronal cells from oxidative injury. In the present study, we demonstrated that polysulfides inhibited cell growth and promoted neurite outgrowth in mouse neuroblastoma Neuro2A (N2A) cells. However, Na 2 S showed no effect on neurite outgrowth in N2A cells. Furthermore, 2-APB and SKF96365, which are typical transient receptor potential (TRP) channel inhibitors, suppressed the neurite outgrowth induced by Na 2 S 4 . These new findings suggest that bound sulfur could induce neurite outgrowth and cell differentiation of N2A cells by accelerating calcium influx. [ABSTRACT FROM AUTHOR]

Polysulfide is a bound sulfur species derived from endogenous H2S. When mouse neuroblastoma, Neuro2A cells were exposed to tert-butyl hydroperoxide after treatment with polysulfide, a significant decline in cell toxicity was observed. Rapid uptake of polysulfides induced translocation of Nrf2 into the nucleus, resulting in acceleration of GSH synthesis and HO-1 expression. We demonstrated that polysulfide reversibly modified Keap1 to form oxidized dimers and induced the translocation of Nrf2. Moreover, polysulfide treatment accelerated Akt phosphorylation, which is a known pathway of Nrf2 phosphorylation. Thus, polysulfide may mediate the activation of Nrf2 signaling, thereby exerting protective effects against oxidative damage in Neuro2A cells. [ABSTRACT FROM AUTHOR]