大豆苷元通过靶向ESR1，激活PI3K/AKT/CREB信号通路，减轻乙醇诱导的大鼠急性胃损伤

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-05-23 DOI:10.1016/j.phymed.2025.156887

Tao Jiang , Shengyi Du , Zexin Wang , Qichao Hu , Lingshun Zeng , Yuan Chen , Xiyue Tan , Yi Zeng , Lingping Fu , Fangli Hu , Kun Xiao , Xiao Ma , Jinhao Zeng , Yanling Zhao

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引用次数: 0

摘要

酒精性胃溃疡（GU）是最常见的上消化道疾病之一，严重影响患者的生活质量和健康。大豆苷元（Daidzein， DAI）是存在于大豆和其他可食用植物中的主要活性化合物之一，据报道对谷氨酸具有潜在的治疗作用。目的探讨DAI减轻大鼠酒精性急性GU的可能机制。方法采用免疫荧光法（IF）、细胞热移法（CETSA）、透射电镜（TEM）、免疫组化（IHC）、免疫印迹法（WB）、实时荧光定量PCR （RT- qPCR）等实验技术，建立体外和体内酒精性谷氨酰胺模型，评价DAI的保护作用。接下来，采用网络药理学、虚拟筛选和分子动力学模拟来确定DAI对GU治疗作用的潜在靶点和机制。最后，在大鼠模型和GES-1细胞模型中验证了PI3K/AKT/CREB信号通路的激活。结果dai可以减轻炎症、氧化应激和细胞凋亡，同时减轻H + /K + - atp酶和EGFR的减少，从而恢复胃屏障。在体外和体内模型中，DAI均与ESR1的关键残基（Leu387A、Arg394A、His524A和Glu353A）稳定结合，并随后激活PI3K/AKT/CREB信号通路。值得注意的是，Fulvestrant（一种选择性ESR1抑制剂）和LY294002（一种PI3K抑制剂）都取消了这一途径的激活。结论dai通过靶向ESR1激活PI3K/AKT/CREB信号通路，抑制细胞凋亡，保护粘膜完整性。本研究阐明了DAI治疗GU的作用机制及临床价值，为其作为胃粘膜保护剂在药物开发和膳食补充剂中的应用提供参考。

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Daidzein alleviates ethanol-induced acute gastric injury in rats by targeting ESR1 and activating the PI3K/AKT/CREB signaling pathway

Background

Alcohol-induced gastric ulcers (GU) rank among the most prevalent upper gastrointestinal diseases, severely impacting patients’ quality of life and health. Daidzein (DAI), one of the primary active compounds present in soybeans and other edible plants, has been reported to exert potential therapeutic effects on GU.

Purpose

This study sought to explore the potential mechanisms through which DAI alleviates alcohol-induced acute GU in rats.

Methods

In this study, in vitro and in vivo models of alcohol-induced GU were established and employed a range of experimental techniques, including Immunofluorescence (IF), Cellular thermal shift assay (CETSA), Transmission Electron Microscopy (TEM), Immunohistochemistry (IHC), Western Blotting (WB), and Real-time quantitative PCR (RT- qPCR), to assess the protective effects of DAI. Next, network pharmacology, virtual screening, and molecular dynamics simulations were employed to identify the potential targets and mechanisms responsible for DAI’s therapeutic action on GU. Finally, the activation of the PI3K/AKT/CREB signaling pathway was validated in both a rat model and a GES-1 cell model.

Results

DAI was shown to alleviate inflammation, oxidative stress, and apoptosis, while mitigating the reduction of H⁺/K⁺-ATPase and EGFR, thereby restoring the gastric barrier. In both in vitro and in vivo models, DAI showed stable binding to key residues of ESR1 (Leu387A, Arg394A, His524A, and Glu353A), and subsequently activated the PI3K/AKT/CREB signaling pathway. Notably, Fulvestrant (a selective ESR1 inhibitor) and LY294002 (a PI3K inhibitor) both abrogated the activation of this pathway.

Conclusion

DAI inhibited apoptosis and preserved mucosal integrity by targeting ESR1 to activate the PI3K/AKT/CREB signaling pathway. The research elucidated the mechanisms and clinical value of DAI in the treatment of GU, offering a reference for its application as a gastric mucosal protectant in drug development and dietary supplements.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.