中国药物警戒 ›› 2026, Vol. 23 ›› Issue (4): 405-413.
DOI: 10.19803/j.1672-8629.20260004

• 基于斑马鱼模型的中药毒性特征研究专栏 • 上一篇    下一篇

基于斑马鱼幼鱼模型与网络药理学研究小檗碱对吴茱萸治疗炎性肠病和肝毒性的影响

徐梓轩1, 黄海丽2Δ, 李思彤1, 李嘉琪1, 陈小橹1, 林瑞超1#, 赵崇军1,*   

  1. 1北京中医药大学中药学院,中药品质评价北京市重点实验室,国家中医药管理局中药炮制技术传承基地,北京 102488;
    2广西中医药大学瑞康临床医学院,广西 南宁 530011
  • 收稿日期:2026-01-02 出版日期:2026-04-15 发布日期:2026-04-15
  • 通讯作者: *赵崇军,男,博士,助理研究员,中药安全性评价与主要活性毒性物质基础筛选研究。E-mail: 1014256537@qq.com。#为共同通信作者。
  • 作者简介:徐梓轩,男,本科,中药安全性评价研究。Δ为并列第一作者。
  • 基金资助:
    北京市自然科学基金资助项目（7252240）; 国家自然科学基金资助项目（82204753）

Effects of Berberine on the Therapeutic Efficacy of Evodiae Fructus in Inflammatory Bowel Disease and Its Hepatotoxicity: a Study Based on a Zebrafish Larval Model and Network Pharmacology

XU Zixuan1, HUANG Haili2Δ, LI Sitong1, LI Jiaqi1, CHEN Xiaolu1, LIN Ruichao1#, ZHAO Chongjun1,*   

  1. 1Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica/Traditional Chinese Medicine Processing Technology Inheritance Base of National Administration of Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China;
    2Ruikang Clinical Medical School, Guangxi University of Chinese Medicine, Nanning Guangxi 530011, China
  • Received:2026-01-02 Online:2026-04-15 Published:2026-04-15

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摘要： 目的 基于斑马鱼模型与网络药理学方法,研究小檗碱（Berberine,BBR）针对吴茱萸（Evodiae Fructus,EF）所诱导的肝毒性,以及在治疗炎症性肠病（Inflammatory Bowel Disease,IBD）过程中的“减毒增效”作用及其潜在机制。方法 从斑马鱼死亡率、肝荧光面积、肝细胞凋亡、生化指标以及肝脏病理结构等多个维度对其毒性进行评估,并观察BBR对EF肝毒性的拮抗效应。利用2,4,6-三硝基苯磺酸（TNBS)诱导的斑马鱼IBD模型,通过内吞功能、肠道巨噬细胞数量、中性粒细胞浸润以及杯状细胞黏液分泌4个关键指标评估BBR对EF治疗IBD药效的协同作用。结合网络药理学筛选EF-BBR-IBD共同靶点并解析相关通路,同时采用qRT-PCR验证核心基因的表达变化。结果 高剂量的EF致使斑马鱼出现显著的肝毒性,而BBR能够显著减轻EF引发的肝脏肿大、凋亡增加、丙氨酸氨基转移酶（ALT）/天冬氨酸氨基转移酶（AST）升高等毒性表现。在IBD模型中,EF可改善肠道内吞功能、减少中性粒细胞和巨噬细胞浸润、促进杯状细胞黏液分泌,而BBR与EF联合使用可在上述指标上实现进一步显著改善,呈现出良好的增效作用。网络药理学分析确定PI3K-Akt、TNF、VEGF等炎症与修复相关通路为潜在关键通路,核心靶点涵盖SRC、MAPK14、ptgs2a、CDK4、CDK2、KIT等。qRT-PCR结果与预测高度吻合：EF显著下调IL-1β、ptgs2a、MAPK14、SRC、CDK4等炎症相关基因,上调CDK2,而BBR可进一步强化这一下调趋势,增强EF对上述关键炎症节点的调控能力。结论 BBR能够显著拮抗EF的肝毒性,同时增强其治疗IBD的药效。其“增效”作用可能通过抑制TNF、VEGF、PI3K-Akt等炎症及血管通透性相关通路,协同下调SRC、MAPK14、IL-1β、ptgs2a、CDK4等核心靶点,进而减轻炎症、促进肠黏膜修复。本研究为EF类毒性中药的安全使用提供实验依据,也为传统药对“黄连-吴茱萸”的配伍机制提供参考,为中药减毒配伍理论的现代化研究提供新的思路。

关键词: 吴茱萸, 小檗碱, 炎症性肠病, 肝毒性, 斑马鱼

Abstract: Objective To elucidate the detoxifying and efficacy-enhancing effects of berberine (BBR), the principal active constituent of Coptidis Rhizoma, on hepatotoxicity induced by Evodiae fructus (EF) and its therapeutic efficacy against inflammatory bowel disease (IBD). Methods The hepatotoxicity of EF was evaluated in terms of zebrafish mortality, liver fluorescence areas, hepatocyte apoptosis, biochemical indices (ALT and AST), and hepatic histopathology. The antagonistic effect of BBR against EF-induced hepatotoxicity was also explored. In a TNBS-induced zebrafish IBD model, the synergistic effect of BBR on EF treatment of IBD was evaluated based on such crucial indicators as intestinal endocytic function, macrophage abundance, neutrophil infiltration, and goblet cell mucus secretion. Network pharmacology analysis was conducted to identify the shared targets and signaling pathways between EF, BBR, and IBD. Subsequently, the expressions of core genes were validated using quantitative real-time PCR (qRT-PCR). Results A high-dose of EF induced significant hepatotoxicity in zebrafish, manifested as liver enlargement, an increase in apoptosis, and elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) while berberine (BBR) markedly alleviated these toxic effects. In the IBD model, EF improved the intestinal endocytic function, reduced the infiltration of neutrophils and macrophages, and promoted the mucus secretion of goblet cells. Notably, the co-administration of BBR and EF led to significant improvements in these parameters, indicating a pronounced synergistic effect. Network pharmacology analysis identified the PI3K-Akt, TNF, and VEGF signaling pathways as potential key pathways, with core targets including SRC, MAPK14, ptgs2a, CDK4, CDK2, and KIT. The results of quantitative reverse transcription polymerase chain reaction (qRT-PCR) were highly consistent with the prediction that EF could significantly downregulate inflammation-related genes such as IL-1β, ptgs2a, MAPK14, SRC, and CDK4 while upregulating CDK2. BBR added to the downregulation of these inflammatory targets. Conclusion BBR can effectively attenuate the hepatotoxicity induced by EF while enhancing its therapeutic efficacy in IBD, possibly by inhibiting the TNF, VEGF, and PI3K-Akt signaling pathways and by synergistically downregulating such key targets as SRC, MAPK14, IL-1β, ptgs2a, and CDK4, thereby alleviating inflammation and boosting the repair of the intestinal mucosa. The study is expected to provide experimental evidence for safe applications of toxic medicines derived from EF and offers a new interpretation of the classical herbal pair Coptidis Rhizoma-EF.

Key words: Evodiae Fructus, Berberine, Inflammatory Bowel Disease, Hepatotoxicity, Zebrafish

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