期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 10, 页码 -出版社
MDPI
DOI: 10.3390/ijms22105211
关键词
hydrogen sulfide prodrugs; BW-HS-101; non-steroidal anti-inflammatory drugs; gastrotoxicity; molecular gastroenterology; gastrointestinal pharmacology
资金
- Jagiellonian University Medical College (Poland) [N41/DBS/000106]
- Brains and Behaviors pre-doctoral fellowship program
- Georgia Research Alliance Eminent Scholar endowment
- Georgia State University
The study showed that BW-HS-101 can prevent drug-induced gastric mucosal damage, reduce DNA oxidation, decrease systemic and gastric mucosal inflammation, and increase the expression of SOCS3, EGF, and HMOX-1. The gastroprotective effects of this H2S prodrug may depend on endogenous NO rather than CO activity and may be mediated by cytoprotective and anti-inflammatory pathways involving SOCS3 and EGF.
Hydrogen sulfide (H2S) is an endogenously produced molecule with anti-inflammatory and cytoprotective properties. We aimed to investigate for the first time if a novel, esterase-sensitive H2S-prodrug, BW-HS-101 with the ability to release H2S in a controllable manner, prevents gastric mucosa against acetylsalicylic acid-induced gastropathy on microscopic and molecular levels. Wistar rats were pretreated intragastrically with vehicle, BW-HS-101 (0.5-50 mu mol/kg) or its analogue without the ability to release H2S, BW-iHS-101 prior to ASA administration (125 mg/kg, intragastrically). BW-HS-101 was administered alone or in combination with nitroarginine (L-NNA, 20 mg/kg, intraperitoneally) or zinc protoporphyrin IX (10 mg/kg, intraperitoneally). Gastroprotective effects of BW-HS-101 were additionally evaluated against necrotic damage induced by intragastrical administration of 75% ethanol. Gastric mucosal damage was assessed microscopically, and gastric blood flow was determined by laser flowmetry. Gastric mucosal DNA oxidation and PGE(2) concentration were assessed by ELISA. Serum and/or gastric protein concentrations of IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-6, IL-10, IL-13, VEGF, GM-CSF, IFN-gamma, TNF-alpha, and EGF were determined by a microbeads/fluorescent-based multiplex assay. Changes in gastric mucosal iNOS, HMOX-1, SOCS3, IL1-R1, IL1-R2, TNF-R2, COX-1, and COX-2 mRNA were assessed by real-time PCR. BW-HS-101 or BW-iHS-101 applied at a dose of 50 mu mol/kg protected gastric mucosa against ASA-induced gastric damage and prevented a decrease in the gastric blood flow level. H2S prodrug decreased DNA oxidation, systemic and gastric mucosal inflammation with accompanied upregulation of SOCS3, and EGF and HMOX-1 expression. Pharmacological inhibition of nitric oxide (NO) synthase but not carbon monoxide (CO)/heme oxygenase (HMOX) activity by L-NNA or ZnPP, respectively, reversed the gastroprotective effect of BW-HS-101. BW-HS-101 also protected against ethanol-induced gastric injury formation. We conclude that BW-HS-101, due to its ability to release H2S in a controllable manner, prevents gastric mucosa against drugs-induced gastropathy, inflammation and DNA oxidation, and upregulate gastric microcirculation. Gastroprotective effects of this H2S prodrug involves endogenous NO but not CO activity and could be mediated by cytoprotective and anti-inflammatory SOCS3 and EGF pathways.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据