Explore the vast range of titles available.

Hydrogen sulfide is a highly toxic gas—second only to carbon monoxide as a cause of inhalational deaths. Its mechanism of toxicity is only partially known and no specific therapy exists for sulfide poisoning. We show in several cell types, including human inducible pluripotent stem cell (hiPSC)-derived neurons, that sulfide inhibited complex IV of the mitochondrial respiratory chain and induced apoptosis. Sulfide increased hydroxyl radical production in isolated mouse heart mitochondria and F 2 -isoprostanes in brains and hearts of mice. The vitamin B 12 analog cobinamide reversed the cellular toxicity of sulfide and rescued Drosophila melanogaster and mice from lethal exposures of hydrogen sulfide gas. Cobinamide worked through two distinct mechanisms: direct reversal of complex IV inhibition and neutralization of sulfide-generated reactive oxygen species. We conclude that sulfide produces a high degree of oxidative stress in cells and tissues and that cobinamide has promise as a first specific treatment for sulfide poisoning.

Key Points Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H 2 S) are labile gaseous mediators that have multiple biological functions in tumour cells and in the host tissue. Each of these gases is produced by specific enzyme systems and regulates (among other aspects) cell viability, cell division, mitochondrial activity, angiogenesis and vascular tone. Upregulation of the various gasotransmitter-producing enzymes occurs in many tumours. Most commonly, NO is overproduced by upregulation of inducible NO synthase (iNOS); CO is overproduced by haem oxygenase 1 (HO1); and H 2 S is overproduced by cystathionine-β-synthase (CBS). Selective genetic silencing or pharmacological inhibition of iNOS, HO1 or CBS has been shown to exert anticancer effects in various in vitro and in vivo models. Many of these approaches also sensitize the tumour to chemotherapy and/or radiotherapy. Because of the bell-shaped pharmacological character of the gasotransmitters, not only inhibition of gasotransmitter biosynthesis, but also elevation of gasotransmitter levels beyond a certain threshold can exert antitumour effects; preclinical data show that tumour-targeted NO donors, CO donors or CO inhalation therapy, and H 2 S donors of various classes exert antitumour effects. Although the clinical translation of the findings of gasotransmitters in the field of tumour biology has been slow, several compounds can be identified that may be suitable for clinical repurposing and translational research activity. The gasotransmitters nitric oxide, carbon monoxide and hydrogen sulfide are involved in a large number of physiological processes. In this Review, the author explains how, in cancer, each of these gaseous mediators exhibits a biphasic pharmacological character, whereby increasing or decreasing gasotransmitter concentrations in the tumour can exert antitumour effects. The three endogenous gaseous transmitters — nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H 2 S) — regulate a number of key biological functions. Emerging data have revealed several new mechanisms for each of these three gasotransmitters in tumour biology. It is now appreciated that they show bimodal pharmacological character in cancer, in that not only the inhibition of their biosynthesis but also elevation of their concentration beyond a certain threshold can exert anticancer effects. This Review discusses the role of each gasotransmitter in cancer and the effects of pharmacological agents — some of which are in early-stage clinical studies — that modulate the levels of each gasotransmitter. A clearer understanding of the pharmacological character of these three gases and the mechanisms underlying their biological effects is expected to guide further clinical translation.

Key Points Hydrogen sulphide (H 2 S), together with nitric oxide and carbon monoxide, belongs to a family of labile biological mediators called gasotransmitters. H 2 S has long been known as a toxic gas emanating from sewers and as a by-product of industrial processes; however, the biological processes of sulphide and its metabolism and fate in biological systems is now beginning to be understood. H 2 S is synthesized endogenously in numerous mammalian tissues by two enzymes responsible for metabolizing L -cysteine — cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGS). CBS is the predominant H 2 S-generating enzyme in the brain and nervous system. CSE is mainly expressed in the liver and in the vascular and non-vascular smooth muscle. Other sources of H 2 S include enterobacterial flora and inorganic sources. H 2 S exerts numerous biological effects on various biological targets, leading to responses that range from cytotoxic effects (due to free radical and oxidant generation) to cytoprotective (antinecrotic or anti-apoptotic) actions. In particular, H 2 S has been specifically shown to exert a pharmacological effect on potassium-opened ATP (K ATP ) channels. These opposing effects have been demonstrated in various animal models. Inhibition of sulphide in animal models of haemorrhagic shock has been demonstrated to accelerate the recovery of mean arterial pressure. H 2 S can also induce a suspended-animated-like state in mice — whether this can be achieved in larger animals remains to be seen. Protection from lethal hypoxic insult, myocardial injury and inflammation has also been shown. The options that could be explored to utilize this knowledge for therapeutic purposes are discussed. Two main pathways are considered viable: the development of inhibitors of CBS or CSE, and the development of H 2 S or H 2 S-releasing compounds. In this rapidly emerging field, there are still many unknowns — including the relationship of H 2 S with the other two gasotransmitters — however, further studies are likely to yield a number of therapeutic possibilities, and early stage drug candidates are already in development. Hydrogen sulphide (H 2 S) is increasingly being recognized as an important signalling molecule in the cardiovascular and nervous systems. This article overviews the physiology and biochemistry of H 2 S, summarizes the effects of H 2 S inhibitors or H 2 S donors in animal models of disease and discusses the likely options and paths for the therapeutic exploitation of H 2 S. Hydrogen sulphide (H 2 S) is increasingly being recognized as an important signalling molecule in the cardiovascular and nervous systems. The production of H 2 S from L -cysteine is catalysed primarily by two enzymes, cystathionine γ-lyase and cystathionine β-synthase. Evidence is accumulating to demonstrate that inhibitors of H 2 S production or therapeutic H 2 S donor compounds exert significant effects in various animal models of inflammation, reperfusion injury and circulatory shock. H 2 S can also induce a reversible state of hypothermia and suspended-animation-like state in rodents. This article overviews the physiology and biochemistry of H 2 S, summarizes the effects of H 2 S inhibitors or H 2 S donors in animal models of disease and outlines the potential options for the therapeutic exploitation of H 2 S.

Background Emerging studies have demonstrated the important physiological and pathophysiological roles of hydrogen sulphide (H 2 S) as a gasotransmitter for NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-associated neuroinflammation in the central nervous system. However, the effects of H 2 S on neuroinflammation after intracerebral haemorrhage (ICH), especially on the NLRP3 inflammasome, remain unknown. Methods We employed a Sprague–Dawley rat of collagenase-induced ICH in the present study. The time course of H 2 S content and the spatial expression of cystathionine-β-synthase (CBS) after ICH, the effects of endogenous and exogenous H 2 S after ICH, the effects of endogenous and exogenous H 2 S on NLRP3 inflammasome activation under P2X7 receptor (P2X7R) overexpression after ICH, and the involvement of the P2X7R in the mechanism by which microglia-derived H 2 S prevented NLRP3 inflammasome activation were investigated. Results We found ICH induced significant downregulation of endogenous H 2 S production in the brain, which may be the result of decreasing in CBS, the predominant cerebral H 2 S-generating enzyme. Administration of S -adenosyl- l -methionine (SAM), a CBS-specific agonist, or sodium hydrosulfide (NaHS), a classical exogenous H 2 S donor, not only restored brain and plasma H 2 S content but also attenuated brain oedema, microglial accumulation and neurological deficits at 1 day post-ICH by inhibiting the P2X7R/NLRP3 inflammasome cascade. Endogenous H 2 S production, which was derived mainly by microglia and above treatments, was verified by adenovirus-overexpressed P2X7R and in vitro primary microglia studies. Conclusions These results indicated endogenous H 2 S synthesis was impaired after ICH, which plays a pivotal role in the P2X7R/NLRP3 inflammasome-associated neuroinflammatory response in the pathogenesis of secondary brain injury. Maintaining appropriate H 2 S concentrations in the central nervous system may represent a potential therapeutic strategy for managing post-ICH secondary brain injury and associated neurological deficits.

Of the numerous gaseous substances that can act as signaling molecules, the best characterized are nitric oxide, carbon monoxide and hydrogen sulfide. Contributions of each of these low molecular weight substances, alone or in combination, to maintenance of gastrointestinal mucosal integrity have been established. There is considerable overlap in the actions of these gases in modulating mucosal defense and responses to injury, and in some instances they act in a cooperative manner. Each also play important roles in regulating inflammatory and repair processes throughout the gastrointestinal tract. In recent years, significant progress has been made in the development of novel anti-inflammatory and cytoprotective drugs that exploit the beneficial activities of one or more of these gaseous mediators.

Adipose tissue hormone leptin induces endothelium-dependent vasorelaxation mediated by nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHF). Previously it has been demonstrated that in short-term obesity the NO-dependent and the EDHF-dependent components of vascular effect of leptin are impaired and up-regulated, respectively. Herein we examined the mechanism of the EDHF-dependent vasodilatory effect of leptin and tested the hypothesis that alterations of acute vascular effects of leptin in obesity are accounted for by chronic hyperleptinemia. The study was performed in 5 groups of rats: (1) control, (2) treated with exogenous leptin for 1 week to induce hyperleptinemia, (3) obese, fed highly-palatable diet for 4 weeks, (4) obese treated with pegylated superactive rat leptin receptor antagonist (PEG-SRLA) for 1 week, (5) fed standard chow and treated with PEG-SRLA. Acute effect of leptin on isometric tension of mesenteric artery segments was measured ex vivo. Leptin relaxed phenylephrine-preconstricted vascular segments in NO- and EDHF-dependent manner. The NO-dependent component was impaired and the EDHF-dependent component was increased in the leptin-treated and obese groups and in the latter group both these effects were abolished by PEG-SRLA. The EDHF-dependent vasodilatory effect of leptin was blocked by either the inhibitor of cystathionine γ-lyase, propargylglycine, or a hydrogen sulfide (H2S) scavenger, bismuth (III) subsalicylate. The results indicate that NO deficiency is compensated by the up-regulation of EDHF in obese rats and both effects are accounted for by chronic hyperleptinemia. The EDHF-dependent component of leptin-induced vasorelaxation is mediated, at least partially, by H2S.

Constipation due to colonic contractility disorders is the predominant gastrointestinal symptom in diabetics. Hydrogen sulfide (H 2 S) is an intestinal contractile agent at low concentrations and a relaxant at high concentrations. Cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and sulfate-reducing bacteria (SRB) are among the factors that produce H 2 S. This study investigated the effects of H 2 S production inhibitors on colonic motility indices in mice with diabetic-induced constipation. Fifty-six mice were randomly allocated into four groups, including control, diabetic constipation (DC), disulfiram, and propargylglycine (PAG). Diabetes was induced using streptozotocin (STZ), followed by the administration of disulfiram and PAG. Blood and colon tissue samples were collected for analysis at the end of the study period. Measurements included body weight, blood glucose level, fecal parameters, and intestinal transit ratio (ITR). The gene expression levels of CBS, CSE, Bcl-2 antagonist/killer (BAK), and B-cell lymphoma 2 (BCL2) were measured, along with myosin light chain (MLC) protein expression. H 2 S and gastrin levels, as well as the SRB content, were analyzed. Additionally, acetylcholinesterase (AChE) expression in colon tissue was evaluated. Histological assessment of the colon was also performed. Disulfiram and PAG administration improved the fecal pellet number and water content in mice with DC. H 2 S inhibition decreased CBS and CSE gene expression, and improved SRB levels, ITR, and histological factors. The results of this study demonstrated that H 2 S is an effective and key factor in regulating colonic motility in mice with DC. In the future, inhibitors of H 2 S production may be used to manage the digestive complications associated with DC.

Background/Aims: Overproliferation of mesangial cells was believed to play an important role in the progress of diabetic nephropathy, one of the primary complications of diabetes. Hydrogen sulfide (H 2 S), a well-known and pungent gas with the distinctive smell of rotten eggs, was discovered to play a protective role in diabetic nephropathy. Methods: MTT assay was used to examine the viability of mesangial cells. Small interfering RNA was used to knock down the expression of TLR4 while specific inhibitor LY294002 to suppress the function of PI3K. H 2 S generation rate was determined by a H 2 S micro-respiration sensor. Results: Glucose of 25mM induced significant mesangial cells proliferation, which was accomplished by significantly inhibited endogenous H 2 S synthesis. And exogenous H 2 S treatment by NaHS markedly mitigated the overproliferation of mouse mesangial cells. Furthermore, it was found that H 2 S deficiency could result in TLR4 activation. And H 2 S supplementation remarkably inhibited TLR4 expression and curbed the mesangial cell overproliferation. Besides, PI3K/Akt pathway inhibition also significantly ameliorated the cell overproliferation. Conclusion: High glucose (HG) induces mouse mesangial cell overproliferation via inhibition of hydrogen sulfide synthesis in a TLR-4-dependent manner. And PI3K/Akt pathway might also play a vital part in the HG-induced mesangial cell overproliferation.

Hydrogen sulfide (H 2 S), an endogenous gaseous signal molecule, exhibits protective effect against ischemic injury. However, its underlying mechanism is not fully understood. We have recently reported that exogenous H 2 S decreases the accumulation of autophagic vacuoles in mouse brain with ischemia/reperfusion (I/R) injury. To further investigate whether this H 2 S-induced reduction of autophagic vacuoles is caused by the decreased autophagosome synthesis and/or the increased autophagic degradation inautophagic flux, we performed in vitro and in vivo studies using SH-SY5Y cells for the oxygen and glucose deprivation/reoxygenation (OGD/R) and mice for the cerebral I/R, respectively. NaHS (a donor of H 2 S) treatment significantly increased cell viability and reduced cerebral infarct volume. NaHS treatment reduced the OGD/R-induced elevation in LC3-II (an autophagic marker), which was completely reversed by co-treatment with an autophagic flux inhibitor bafilomycin A 1 (BafA1). However, H 2 S did not affect the OGD/R-induced increase of the ULK1 self-association and decrease of the ATG13 phosphorylation, which are the critical steps for the initiation of autophagosome formation. Cerebral I/R injury caused an increase in LC3-II, a decrease in p62 and the accumulation of autophagosomes in the cortex and the hippocampus, which were inhibited by NaHS treatment. This H 2 S-induced decline of LC3-II in ischemic brain was reversed by BafA1. Moreover, BafA1 treatment abolished the protection of H 2 S on the cerebral infarction. Collectively, the neuroprotection of exogenous H 2 S against ischemia/hypoxia and reperfusion/reoxygenation injury is mediated by the enhancement of autophagic degradation.

Hydrogen sulfide (H 2 S) has been traditionally known for its toxic effects on living organisms. The role of H 2 S in the homeostatic regulation of pancreatic insulin metabolism has been unclear. The present study is aimed at elucidating the effect of endogenously produced H 2 S on pancreatic insulin release and its role in diabetes development. Diabetes development in Zucker diabetic fatty (ZDF) rats was evaluated in comparison with Zucker fatty (ZF) and Zucker lean (ZL) rats. Pancreatic H 2 S production and insulin release were also assayed. It was found that H 2 S was generated in rat pancreas islets, catalyzed predominantly by cystathionine γ -lyase (CSE). Pancreatic CSE expression and H 2 S production were greater in ZDF rats than in ZF or ZL rats. ZDF rats exhibited reduced serum insulin level, hyperglycemia, and insulin resistance. Inhibition of pancreatic H 2 S production in ZDF rats by intraperitoneal injection of DL-propargylglycine (PPG) for 4 weeks increased serum insulin level, lowered hyperglycemia, and reduced hemoglobin A1c level ( P <0.05). Although in ZF rats it also reduced pancreatic H 2 S production and serum H 2 S level, PPG treatment did not alter serum insulin and glucose level. Finally, H 2 S significantly increased K ATP channel activity in freshly isolated rat pancreatic β -cells. It appears that insulin release is impaired in ZDF because of abnormally high pancreatic production of H 2 S. New therapeutic approach for diabetes management can be devised based on our observation by inhibiting endogenous H 2 S production from pancreas.