Abstract
Hydrogen sulphide (H2S) 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 H2S deficiency. In this work, we reported the roles of a novel pH‐controlled H2S donor (JK‐1) in NSAID‐related gastric lesions. We found that JK‐1 could release H2S 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 H2S 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 H2S 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 H2S donors in the future.
Highlights
Stomachs can resist a variety of unimaginable lesions induced by hydrochloric acid (HCl), refluxed bile salts, alcohol etc
We further examined the levels of endogenous antioxidative defence system, reduced glutathione GSH, and found that the exposure to ASP markedly decreased the content of GSH in the mouse gastric mucosa, which was suppressed by the pre-treatment with JK-1 (Fig. 5B)
We observed its gastric protection in ASP-exposed mice and hypochloric acid (HClO)-stimulated GES-1 cells
Summary
Stomachs can resist a variety of unimaginable lesions induced by hydrochloric acid (HCl), refluxed bile salts, alcohol etc. JK-1-mediated gastric protection was further evaluated in an in vitro model, incubation of gastric mucosal epithelial (GES-1) cells with hypochloric acid (HClO), to imitate MPOdriven oxidative injury Both in vivo and in vitro studies showed that JK-1 attenuated ASP-related gastric lesions through reconstruction of endogenous gastric defence. Healthy adult male Kunming mice, weighting 20.0–25.0 g, were obtained from Guangzhou University of Chinese Medicine (Guangzhou, China) They were kept in a SPF level room, which was controlled temperature (22 Æ 2°C), humidity (65–70%) and light/dark cycle (12 hrs/ 12 hrs). After incubation of the lysate with 10 mM substrate L-cysteine and 2 mM coenzyme pyridoxal 50-phosphate for 2 hrs in reaction bottles, 400 ll of zinc acetate solution trapped H2S was collected and 40 ll of N, N-dimethyl-1,4-phenylenediamine sulphate (20 mM in 7.2 M HCl) was added, immediately followed by 40 ll of ferric chloride (30 mM in 1.2 M HCl). A probability of less than 0.05 was considered statistically significant
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