Explore dual anti-inflammatory and cell protective mechanisms the mechanism of Jianwei Yuyang tablet in the treatment of alcohol-induced gastric ulcers via bioinformatics and experimental validation

Abstract

Background: Jianwei Yuyang Tablet (JWYY), a Chinese herbal formulation, has been approved for the treatment of various gastric diseases in clinic and has demonstrated significant therapeutic effects in patients with multiple types of gastric ulcers (GU).

Purpose: This study aimed to evaluate the protective effects of JWYY on alcohol-induced gastric ulcers in mice and to explore the potential mechanisms underlying its therapeutic effects.

Methods: Gastric ulcers were induced in male C57/BL6J mice through a single oral dose of 10 ml/kg alcohol. The extent of gastric mucosal injury was evaluated using ulcer index (UI) and histopathological examinations. Additionally, the levels of inflammatory biomarkers, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and malondialdehyde (MDA), were determined using enzyme-linked immunosorbent assay (ELISA). Transcriptomic sequencing (RNA-seq) and network pharmacology were used to explore the potential mechanisms underlying the therapeutic effects of JWYY in the treatment of GU. Changes in potential hub genes and pathways related to the therapeutic effects of JWYY were assessed using western blot, qRT-PCR, and immunofluorescence analyses. The protective effects of potential active ingredients were evaluated in vitro models.

Results: The administration of JWYY significantly decrease the UI and alleviated gastric hemorrhagic necrosis, submucosal edema, and destruction of epithelial cells in mouse model of GU. JWYY markedly suppressed IL-1β, TNF-α and MDA levels, and restored mucosal integrity (ZO-1 expression). RNA-seq revealed dual roles of JWYY, including the inhibition of JAK2-STAT3/NF-κB pathways to attenuate inflammation and the rescue of activation of PI3K-AKT/DNA repair pathways to enhance cell survival. Network pharmacology and UPLC-MS/MS identified quercetin, morin, naringenin, catechin as key bioactive components, which bind to JAK2/PDGFRA, decreased inflammation, reduced oxidative stress, and inhibited apoptosis in vitro.

Conclusions: This study deciphers the multi-target, multi-pathway mechanisms underline the JWYY in the treatment of alcohol-induced GU, integrating TCM principles with modern pharmacology. The identified bioactive components and pathways provide a scientific foundation for clinical usage of JWYY and indicated the important of targeting JAK-STAT/NF-κB signaling in the treatment of GU. These bioactive components not only explain the mechanism of complex TCM formulations but also can be used to improve the therapeutic efficacy.

Keywords: Gastric ulcer; JAK2-STAT3 signaling pathways; Jianwei yuyang tablet; NF-ĸB signaling pathway; Network pharmacology; RNA-seq.