Wumei Wan ameliorates ulcerative colitis in rats by modulating the inflammation-pyroptosis-intestinal stem cell axis.

IF 5.4 2区医学 Q1 CHEMISTRY, MEDICINAL

Journal of ethnopharmacology Pub Date : 2025-09-24 DOI:10.1016/j.jep.2025.120645

Yao Zhang, Fei Ge, Haonan Qu, Caihong Zhao, Jingzhe Gu, Qianwei Xu, Huiling Lei, Jian Liu, Xiaojing Wang, Yuanyuan Chu, Xue Yu, Di Zhang, Dongmei Zhang, Shujing Zhang, Ke Han, Meng Chen

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引用次数: 0

Abstract

Ethnopharmacological relevance: Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease primarily characterised by persistent disruption of the colonic epithelial barrier. Despite the proven clinical efficacy of the traditional Chinese medicine formulation Wumei Wan (WMW), its pharmacological mechanisms remain inadequately understood.

Aim of the study: This study aims to elucidate the therapeutic mechanisms through which WMW promotes the repair of colonic epithelial barrier damage in UC.

Methods: UC was induced in rats via dextran sulfate sodium (DSS), followed by treatment with low- and high-dose WMW or the positive control 5-ASA. Therapeutic effects of WMW on colonic barrier damage were assessed using conventional indices and serum biomarkers. Mechanistic insights were derived through network pharmacology analysis and transcriptome sequencing (RNA-seq), with experimental validation performed using reverse transcription quantitative PCR, Western blot analysis, and immunofluorescence (IF).

Results: Both high- and low-dose WMW improved serum biomarkers associated with intestinal barrier function (endotoxin, diamine oxidase, and D-lactate), alongside conventional metrics such as disease activity index, ZO-1, and MUC2 expression. Network pharmacology and RNA-seq analyses identified key therapeutic mechanisms, including modulation of pyroptosis, regeneration of LGR5⁺ intestinal stem cells (ISCs), and regulation of inflammatory signalling pathways. Experimental validation confirmed that WMW inhibited pyroptosis-associated proteins (NAIP5, NAIP6, NLRC4, GSDMD-N, caspase-1 p20, IL1β, and IL18) while promoting ISC regeneration via upregulation of LGR5, ASCL2, and IL11RA1, with co-localisation of LGR5 and IL11RA1-a novel finding. Additionally, WMW suppressed phosphorylation of JAK2/STAT3 pathway components (p-JAK2 and p-STAT3) and elements of the STING1/IRF3 pathway (p-STING1, p-IRF3, and p-NF-κB p65), offering moderate complementary regulation of inflammatory pathways in UC.

Conclusions: WMW mitigates UC-associated epithelial barrier dysfunction through a multifaceted mechanism involving inhibition of NAIP5/6-NLRC4 pathway-mediated epithelial pyroptosis, enhancement of ASCL2/IL11RA1-dependent LGR5⁺ ISC regeneration, and suppression of JAK-STAT and STING1/IRF3 inflammatory signalling. This polypharmacological action, driven by WMW's complex phytochemical composition, underscores therapeutic potential of multi-target herbal medicines in addressing the multifactorial pathogenesis of UC.

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乌梅丸通过调节炎症-焦热-肠干细胞轴改善大鼠溃疡性结肠炎。

民族药理学相关性：溃疡性结肠炎（UC）是一种慢性、复发性炎症性肠病，主要特征是结肠上皮屏障的持续破坏。中药乌梅丸的临床疗效已得到证实，但其药理机制尚不清楚。研究目的：本研究旨在阐明WMW促进UC结肠上皮屏障损伤修复的治疗机制。方法：采用葡聚糖硫酸钠（DSS）诱导大鼠UC，然后分别给予低、高剂量WMW或阳性对照5-ASA。采用常规指标和血清生物标志物评价WMW对结肠屏障损伤的治疗效果。通过网络药理学分析和转录组测序（RNA-seq）获得机制见解，并使用反转录定量PCR， Western blot分析和免疫荧光（IF）进行实验验证。结果：高剂量和低剂量WMW均改善了与肠屏障功能相关的血清生物标志物（内毒素、二胺氧化酶和d -乳酸），以及疾病活动性指数、ZO-1和MUC2表达等常规指标。网络药理学和RNA-seq分析确定了关键的治疗机制，包括焦亡的调节、LGR5+肠干细胞（ISCs）的再生和炎症信号通路的调节。实验验证证实，WMW抑制了焦热相关蛋白（NAIP5, NAIP6, NLRC4, GSDMD-N, caspase-1 p20， IL1β和IL18），同时通过上调LGR5， ASCL2和IL11RA1促进ISC再生，LGR5和IL11RA1共定位-这是一个新发现。此外，WMW抑制JAK2/STAT3通路组分（p-JAK2和p-STAT3）和STING1/IRF3通路组分（p-STING1、p-IRF3和p-NF-κB p65）的磷酸化，为UC炎症通路提供适度的互补调节。结论：WMW通过多方面的机制减轻uc相关的上皮屏障功能障碍，包括抑制NAIP5/6-NLRC4途径介导的上皮焦亡，增强ASCL2/ il11ra1依赖性LGR5+ ISC再生，抑制JAK-STAT和STING1/IRF3炎症信号。这种由WMW复杂的植物化学成分驱动的多药理作用强调了多靶点草药在解决UC多因素发病机制方面的治疗潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of ethnopharmacology 医学-全科医学与补充医学

CiteScore

10.30

自引率

5.60%

发文量

967

审稿时长

77 days

期刊介绍： The Journal of Ethnopharmacology is dedicated to the exchange of information and understandings about people''s use of plants, fungi, animals, microorganisms and minerals and their biological and pharmacological effects based on the principles established through international conventions. Early people confronted with illness and disease, discovered a wealth of useful therapeutic agents in the plant and animal kingdoms. The empirical knowledge of these medicinal substances and their toxic potential was passed on by oral tradition and sometimes recorded in herbals and other texts on materia medica. Many valuable drugs of today (e.g., atropine, ephedrine, tubocurarine, digoxin, reserpine) came into use through the study of indigenous remedies. Chemists continue to use plant-derived drugs (e.g., morphine, taxol, physostigmine, quinidine, emetine) as prototypes in their attempts to develop more effective and less toxic medicinals.