Hydrogen sulfide (H2S) is synthesized in the body from L-cysteine by several enzymes including cystathionine-gamma-lyase (CSE). To date, there is little information about the potential role of H2S in inflammation. We have now investigated the part played by H2S in endotoxin-induced inflammation in the mouse. E. coli lipopolysaccharide (LPS) administration produced a dose (10 and 20 mg/kg ip)- and time (6 and 24 h)-dependent increase in plasma H2S concentration. LPS (10 mg/kg ip, 6 h) increased plasma H2S concentration from 34.1 +/- 0.7 microM to 40.9 +/- 0.6 microM (n=6, P<0.05) while H2S formation from added L-cysteine was increased in both liver and kidney. CSE gene expression was also increased in both liver (94.2+/-2.7%, n=6, P<0.05) and kidney (77.5+/-3.2%, n=6, P<0.05). LPS injection also elevated lung (148.2+/-2.6%, n=6, P<0.05) and kidney (78.8+/-8.2%, n=6, P<0.05) myeloperoxidase (MPO, a marker of tissue neutrophil infiltration) activity alongside histological evidence of lung, liver, and kidney tissue inflammatory damage. Plasma nitrate/nitrite (NOx) concentration was additionally elevated in a time- and dose-dependent manner in LPS-injected animals. To examine directly the possible proinflammatory effect of H2S, mice were administered sodium hydrosulfide (H2S donor drug, 14 micromol/kg ip) that resulted in marked histological signs of lung inflammation, increased lung and liver MPO activity, and raised plasma TNF-alpha concentration (4.6+/-1.4 ng/ml, n=6). In contrast, DL-propargylglycine (CSE inhibitor, 50 mg/kg ip), exhibited marked anti-inflammatory activity as evidenced by reduced lung and liver MPO activity, and ameliorated lung and liver tissue damage. In separate experiments, we also detected significantly higher (150.5+/-43.7 microM c.f. 43.8+/-5.1 microM, n=5, P<0.05) plasma H2S levels in humans with septic shock. These findings suggest that H2S exhibits proinflammatory activity in endotoxic shock and suggest a new approach to the development of novel drugs for this condition.

Moore PK. Hydrogen sulfide and its possible roles in myocardial ischemia in experimental rats. J Appl Physiol 102: [261][262][263][264][265][266][267][268] 2007. First published October 12, 2006; doi:10.1152/japplphysiol.00096.2006.-The role of hydrogen sulfide (H 2S) in myocardial infarction (MI) has not been previously studied. We therefore investigated the effect of H 2S in a rat model of MI in vivo. Animals were randomly divided into three groups (n ϭ 80) and received either vehicle, 14 mol/kg of sodium hydrosulfide (NaHS), or 50 mg/kg propargylglycine (PAG) everyday for 1 wk before surgery, and the treatment was continued for a further 2 days after MI when the animals were killed. The mortality was 35% in vehicletreated, 40% in PAG-treated, and 27.5% in NaHS-treated (P Ͻ 0.05 vs. vehicle) groups. Infarct size was 52.9 Ϯ 3.5% in vehicle-treated, 62.9 Ϯ 7.6% in PAG-treated, and 43.4 Ϯ 2.8% in NaHS-treated (P Ͻ 0.05 vs. vehicle) groups. Plasma H 2S concentration was significantly increased after MI (59.2 Ϯ 7.16 M) compared with the baseline concentration (i.e., 38.2 Ϯ 2.07 M before MI; P Ͻ 0.05). Elevated plasma H 2S after MI was abolished by treatment of animals with PAG (39.2 Ϯ 5.02 M). We further showed for the first time cystathioninegamma-lyase protein localization in the myocardium of the infarct area by using immunohistochemical staining. In the hypoxic vascular smooth muscle cells, we found that cell death was increased under the stimuli of hypoxia but that the increased cell death was attenuated by the pretreatment of NaHS (71 Ϯ 1.2% cell viability in hypoxic vehicle vs. 95 Ϯ 2.3% in nonhypoxic control; P Ͻ 0.05). In conclusion, endogenous H 2 S was cardioprotective in the rat model of MI. PAG reduced endogenous H 2S production after MI by inhibiting cystathionine-gamma-lyase. The results suggest that H 2S might provide a novel approach to the treatment of MI.cardioprotection; gasomediator; cardiac protection; ischemic animal model FOR MANY YEARS, HYDROGEN SULFIDE (H 2 S) has been considered solely as a broad-spectrum environmental toxicant with effects on many major organ systems, including the lung, brain, and kidney (2, 11). However, the possible physiological role(s) of H 2 S in the cardiovascular system have only recently come to light. It has been suggested that H 2 S interferes with cardiovascular function as a result of anoxia rather than a direct action on cardiac myocytes or vascular smooth muscle cells (13). However, this possibility now appears less certain in light of more recent research. The localization of H 2 S-generating enzymes and the detection of biologically significant levels of H 2 S in plasma and tissue homogenate from animals have recently been reported (20). Endogenous H 2 S is formed locally by the activity of two pyridoxal-5Ј-phosphate-dependent enzymes, namely cystathionine ␤-synthase and cystathionine ␥-lyase (CSE), each of which utilize L-cysteine as substrate (17). Although cystathionine ␤-synthase does not appear to play a major role in generating H 2 S in cardiovasc...

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Hydrogen sulfide (H2S) is now recognized as a third gaseous mediator along with nitric oxide (NO) and carbon monoxide (CO), though it was originally considered as a malodorous and toxic gas. H2S is produced endogenously from cysteine by three enzymes in mammalian tissues. An increasing body of evidence suggests the involvement of H2S in different physiological and pathological processes. Recent studies have shown that H2S has the potential to protect the heart against myocardial infarction, arrhythmia, hypertrophy, fibrosis, ischemia-reperfusion injury, and heart failure. Some mechanisms, such as antioxidative action, preservation of mitochondrial function, reduction of apoptosis, anti-inflammatory responses, angiogenic actions, regulation of ion channel, and interaction with NO, could be responsible for the cardioprotective effect of H2S. Although several mechanisms have been identified, there is a need for further research to identify the specific molecular mechanism of cardioprotection in different cardiac diseases. Therefore, insight into the molecular mechanisms underlying H2S action in the heart may promote the understanding of pathophysiology of cardiac diseases and lead to new therapeutic targets based on modulation of H2S production.

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Recently, intense interest has focused on the antioxidant properties of natural products. In particular, Chinese herbal medicines (CHM) have become hot topics for life science researchers since many are reported to possess cardioprotective compounds, many of which remain to be identified. Indeed, the exact mechanisms by which CHM work remain unknown. Although many of these herbal remedies are undoubtedly efficacious, few have been scientifically investigated for their active chemical constituents and biological activities. We have previously reported higher activities of antioxidant defence enzymes such as superoxide dismutase, catalase, glutathione peroxidase and glutathione S-transferases in the liver of rats treated with the herb Salvia miltiorrhiza in a model of acute myocardial infarction. Using well established in vitro antioxidant assays employing 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and diphenyl-l-picrylhydrazyl (DPPH) we have shown that in addition to elevating endogenous antioxidant enzyme activity, Salvia miltiorrhiza and other CHM traditionally used for cardiovascular disorders (such as Rhizoma ligustici, Herba leonuri, Radix achyranthis bidentatae, and Camellia sinensis) contain potent antioxidant moieties in addition to their phenolic constituents. Furthermore, these novel non-phenolic components are effective inhibitors of oxidative reactions mediated by the inflammatory oxidants, peroxynitrite,hypochlorous acid and hydroxyl radical as well as iron-dependent lipid peroxidation. In this review, we discuss the various antioxidant properties of CHM in the context of their biochemical mechanisms.

BackgroundS-propargyl-cysteine (SPRC), an H2S donor, is a structural analogue of S-allycysteine (SAC). It was investigated for its potential anti-cancer effect on SGC-7901 gastric cancer cells and the possible mechanisms that may be involved.Methods and FindingsSPRC treatment significantly decreased cell viability, suppressed the proliferation and migration of SPRC-7901 gastric cancer cells, was pro-apoptotic as well as caused cell cycle arrest at the G1/S phase. In an in vivo study, intra-peritoneal injection of 50 mg/kg and 100 mg/kg of SPRC significantly reduced tumor weights and tumor volumes of gastric cancer implants in nude mice, with a tumor growth inhibition rate of 40–75%. SPRC also induced a pro-apoptotic effect in cancer tissues and elevated the expressions of p53 and Bax in tumors and cells. SPRC treatment also increased protein expression of cystathione-γ-lyase (CSE) in cells and tumors, and elevated H2S levels in cell culture media, plasma and tumoral CSE activity of gastric cancer-induced nude mice by 2, 2.3 and 1.4 fold, respectively. Most of the anti-cancer functions of SPRC on cells and tumors were significantly suppressed by PAG, an inhibitor of CSE activity.ConclusionsTaken together, the results of our study provide insights into a novel anti-cancer effect of H2S as well as of SPRC on gastric cancer through inducing the activity of a new target, CSE.