Dan-Shen-Yin against ethanol-induced chronic gastric mucosal injury in rats by inhibiting apoptosis via IP3R-controlled calcium release.

J Ethnopharmacol

National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Jinghai District, Tianjin 301617, P. R. China; Science and Technology Project of Haihe Laboratory of Modern Chinese Medicine, Tianjin 301617, China. Electronic address:

Published: January 2025

Ethnopharmacological Relevance: The pathogenesis of alcoholic gastric injury has long been a significant topic in the medical field. Dan-Shen-Yin (DSY), a classic traditional Chinese medicine formula, has been shown to alleviate gastric mucosal injury and to treat stomachaches in clinical settings. However, the mechanism by which DSY against alcoholic gastric injury requires further investigation.

Aim Of The Study: This study aimed to explore the effect and mechanism of DSY in preventing alcohol-induced gastric mucosal injury.

Materials And Methods: The Rat model of alcohol-induced gastric injury (AIGI) was established by gavage with 56% ethanol for 1 month. The protective effect of DSY against AIGI was confirmed. Serum non-targeted metabolomics and gastric tissue transcriptomics were employed to explore the potential mechanisms of DSY in treating alcoholic gastric injury, followed by further verification via Western blotting (WB), Histopathological and Immunohistochemical etc. Additionally, an ionomycin-induced calcium overload model and an ethanol-induced injury model in gastric epithelial cells (GES-1) were established for in vitro experiments. The active ingredients of DSY were screened using flow cytometry, laser confocal microscopy, and molecular docking techniques.

Results: Transcriptome analysis indicated that elevated calcium levels were a key pathological change in the gastric tissue of AIGI rats. DSY was found to inhibit the activation of the phosphatidylinositol signaling pathway and reduce calcium levels in serum and gastric tissue. Inositol trisphosphate receptor (IP3R) was identified as a significant potential target of DSY in AIGI rats, where IP3R was activated. Both in vivo(AIGI rats) and in vitro experiments(GES-1 Cell) demonstrated that DSY effectively inhibited the activation of IP3R-mediated calcium signaling pathway (downregulated IP3R, Grp75, VDAC1) and alleviated apoptosis (downregulated Caspase 9, Caspase 3, Cytc, Bax and upregulated Bcl-XL, Bcl-2) caused by elevated calcium levels. Furthermore, compounds including salvianolic acid A, salvianolic acid B, lithospermic acid, and isoorientin from DSY were successfully identified as possessing anti-apoptotic activity and inhibiting IP3R expression.

Conclusion: This study suggested that calcium levels were a key pathological change in AIGI rats. DSY could inhibit the activation of the phosphatidylinositol signaling pathway, reduce calcium levels, and inhibit IP3R to repair mitochondrial apoptosis. Salvianolic acid a, salvianolic acid b, lithospermic acid, and isoorientin were potential active ingredients for the treatment of alcoholic gastric injury.

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Source
http://dx.doi.org/10.1016/j.jep.2025.119413DOI Listing

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