A unique reaction between H2S and a selenenyl sulfide containing benzoate ester template was discovered. This reaction could be specifically triggered by H2S and lead to ester bond cleavage. The reaction was not affected by the presence of thiols such as glutathione and cysteine. With this reaction, a series of fluorescent probes were synthesized and evaluated. The probes exhibited high sensitivity/selectivity for H2S in both buffers and cells.
Abstract Hydrogen sulfide (H 2 S) is an important signaling molecule whose up‐ and down‐regulation have specific biological consequences. Although significant advances in H 2 S up‐regulation, by the development of H 2 S donors, have been achieved in recent years, precise H 2 S down‐regulation is still challenging. The lack of potent/specific inhibitors for H 2 S‐producing enzymes contributes to this problem. We expect the development of H 2 S scavengers is an alternative approach to address this problem. Since chemical sensors and scavengers of H 2 S share the same criteria, we constructed a H 2 S sensor database, which summarizes key parameters of reported sensors. Data‐driven analysis led to the selection of 30 potential compounds. Further evaluation of these compounds identified a group of promising scavengers, based on the sulfonyl azide template. The efficiency of these scavengers in in vitro and in vivo experiments was demonstrated.
Significance: Hydrogen sulfide (H2S) plays critical roles in redox biology, and its regulatory effects are tightly controlled by its cellular location and concentration. The imbalance of H2S is believed to contribute to some pathological processes. Recent Advances: Downregulation of H2S requires chemical tools such as inhibitors of H2S-producing enzymes and H2S scavengers. Recent efforts have discovered some promising inhibitors and scavengers. These advances pave the road toward better understanding of the functions of H2S. Critical Issues: Precise H2S downregulation is challenging. The potency and specificity of current inhibitors are still far from ideal. H2S-producing enzymes are involved in complex sulfur metabolic pathways and ubiquitously present in biological matrices. The inhibition of these enzymes can cause unwanted side effects. H2S scavengers allow targeted H2S clearance, but their options are still limited. In addition, the scavenging process often results in biologically active by-products. Future Directions: Further development of potent and specific inhibitors for H2S-producing enzymes is needed. Scavengers that can rapidly and selectively remove H2S while generating biocompatible by-products are needed. Potential therapeutic applications of scavengers and inhibitors are worth exploring. Antioxid. Redox Signal. 36, 294-308.
Abstract Hydrogen sulphide (H 2 S) serves as a vital gastric mucosal defence under acid condition. Non‐steroidal anti‐inflammatory drugs (NSAIDs) are among widely prescribed medications with effects of antipyresis, analgesia and anti‐inflammation. However, their inappropriate use causes gastric lesions and endogenous H 2 S deficiency. In this work, we reported the roles of a novel pH‐controlled H 2 S donor (JK‐1) in NSAID‐related gastric lesions. We found that JK‐1 could release H 2 S under mild acidic pH and increase solution pH value. Intragastrical administration of aspirin (ASP), one of NSAIDs, to mice elicited significant gastric lesions, evidenced by mucosal festering and bleeding. It also led to infiltration of inflammatory cells and resultant releases of IL‐6 and TNF‐α, as well as oxidative injury including myeloperoxidase (MPO) induction and GSH depletion. In addition, the ASP administration statistically inhibited H 2 S generation in gastric mucosa, while up‐regulated cyclooxygenase (COX)‐2 and cystathionine gamma lyase (CSE) expression. Importantly, these adverse effects of ASP were prevented by the intragastrical pre‐administration of JK‐1. However, JK‐1 alone did not markedly alter the property of mouse stomachs. Furthermore, in vitro cellular experiments showed the exposure of gastric mucosal epithelial (GES‐1) cells to HClO, imitating MPO‐driven oxidative injury, decreased cell viability, increased apoptotic rate and damaged mitochondrial membrane potential, which were reversed by pre‐treatment with JK‐1. In conclusion, JK‐1 was proved to be an acid‐sensitive H 2 S donor and could attenuate ASP‐related gastric lesions through reconstruction of endogenous gastric defence. This work indicates the possible treatment of adverse effects of NSAIDs with pH‐controlled H 2 S donors in the future.
Reported is a one-pot synthesis of 3-substituted benzisothiazoles from ortho-mercaptoacylphenones by an in situ S-nitrosation procedure. The starting materials, readily prepared from thiosalicylic acids, are transformed into the unstable S-nitroso intermediates A, which upon treatment with EtPPh2 undergo an aza-Wittig reaction to produce the products in overall poor to very good yield. i-PentylONO proved to be the best oxidant for the formation of the S-nitroso intermediates without effecting the oxidation of EtPPh2.
Abstract The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.
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