南方医科大学学报

南方医科大学学报 ›› 2026, Vol. 46 ›› Issue (7): 1487-1497.doi: 10.12122/j.issn.1673-4254.2026.07.03

• • 上一篇    

异香草酸激活PPARγ通路改善线粒体功能缓解葡聚糖硫酸钠诱导的小鼠溃疡性结肠炎

乔通1,3(), 张龙涛1,3, 章雨1, 黄菊2, 李晴晴1, 耿志军2, 胡建国1,2, 李静1,2()   

  1. 1.蚌埠医科大学第一附属医院，检验科，安徽 蚌埠 233030
    2.蚌埠医科大学第一附属医院，炎症相关性疾病基础与转化研究安徽省重点实验室，安徽 蚌埠 233004，安徽 蚌埠 233030
    3.蚌埠医科大学第一附属医院，蚌埠医科大学基础医学院免疫学教研室，安徽 蚌埠 233030
  • 收稿日期:2025-12-29 出版日期:2026-07-20 发布日期:2026-07-20
  • 通讯作者: 李静 E-mail:qt1231126@163.com;lijingbyfy@bbmu.edu.cn
  • 作者简介:乔 通，在读硕士研究生，E-mail: qt1231126@163.com
  • 基金资助:
    安徽省卫生健康委科研项目(AHWJ2024Aa40007);安徽省临床医学研究转化专项(202427b10020093);安徽省临床医学研究转化专项(202427b10020088);蚌埠医科大学研究生创新计划项目(Byycx25004)

Isovanillic acid alleviates dextran sulfate sodium-induced ulcerative colitis in mice by improving mitochondrial function via activating the PPARγ pathway

Tong QIAO1,3(), Longtao ZHANG1,3, Yu ZHANG1, Ju HUANG2, Qingqing LI1, Zhijun GENG2, Jianguo HU1,2, Jing Li1,2()   

  1. 1.Department of Clinical Laboratory, First Affiliated Hospital of Bengbu Medical University
    2.Anhui Key Laboratory of Basic and Translational Research on Inflammatory Related Diseases, Bengbu 233004, China
    3.Department of Immunology, School of Basic Medical Sciences, Bengbu Medical University, Bengbu 233030, China
  • Received:2025-12-29 Online:2026-07-20 Published:2026-07-20
  • Contact: Jing Li E-mail:qt1231126@163.com;lijingbyfy@bbmu.edu.cn

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摘要：

目的 探讨异香草酸（IVA）对葡聚糖硫酸钠（DSS）诱导的小鼠溃疡性结肠炎（UC）的保护作用及其潜在机制。 方法 将48只C57BL/6雄性小鼠随机分为6组（n=8）：对照组（Con）、DSS模型组（DSS）、IVA低剂量组（IVA-L，50 mg/kg）、IVA中剂量组（IVA-M，100 mg/kg）、IVA高剂量组（IVA-H，150 mg/kg）及阳性对照组（5-ASA，100 mg/kg）。除对照组自由饮水外，其余各组自第1天起自由饮用2.5% DSS溶液至第7天，第8天更换为普通水。各干预组每日灌胃相应剂量的IVA或5-ASA（溶于含0.1% DMSO的生理盐水，100 μL/只），对照组及DSS组灌胃等体积溶剂。第10天处死动物，取结肠组织进行后续检测。实验期间监测小鼠体质量，评估疾病活动指数（DAI）；处死小鼠后检测结肠长度，进行结肠组织病理学评分；采用免疫荧光、Western blotting、TUNEL染色、JC-1染色等，分别评估IVA对DSS诱导小鼠和NCM460细胞模型的屏障功能、细胞凋亡及线粒体功能的影响；并结合网络药理学分析其潜在作用通路。 结果 与Con组相比，DSS组小鼠体质量下降（P<0.05），DAI评分升高（P<0.05），结肠长度缩短（P<0.05），结肠组织中白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β）水平升高（P<0.05），结肠黏膜结构破坏、炎细胞浸润增加、杯状细胞减少；而经IVA干预后上述指标呈剂量依赖性改善（P<0.05）。与DSS组相比，IVA-M组紧密连接蛋白ZO-1和Claudin-1表达升高（P<0.05），肠上皮细胞凋亡率降低（P<0.05），Bax、C-caspase3表达下调，Bcl-2表达上调（P<0.05），TOMM20阳性细胞数增加，线粒体呼吸链复合体Ⅰ、Ⅳ活性升高（P<0.05）。在NCM460细胞中，与C-Con组相比，C-DSS组线粒体膜电位下降，复合体Ⅰ、Ⅳ活性降低（P<0.05），细胞凋亡率增加（P<0.05），ZO-1、Claudin-1表达下降（P<0.05）；与C-DSS组相比，C-IVA组上述指标均显著改善（P<0.05）。网络药理学分析提示PPARγ通路为潜在作用靶点。Western blotting结果显示，IVA-M组和C-IVA组PPARγ蛋白表达水平均高于相应模型组（P<0.05）。加入PPARγ拮抗剂GW9662后，与C-IVA组相比，C-IVA+GW9662组线粒体膜电位下降，复合体Ⅰ、Ⅳ活性降低（P<0.05），细胞凋亡率升高（P<0.05），Bcl-2表达降低，Bax、C-caspase3表达升高（P<0.05），ZO-1、Claudin-1表达降低（P<0.05）。 结论 IVA通过激活PPARγ通路，改善线粒体功能，抑制炎症与细胞凋亡，从而缓解DSS诱导的结肠炎，具有成为UC治疗候选药物的潜力。

关键词: 异香草酸, 溃疡性结肠炎, 线粒体功能, PPARγ通路, 肠屏障, 细胞凋亡

Abstract:

Objective To investigate the protective effect of isovanillic acid (IVA) against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice and its underlying mechanism. Methods Forty-eight male C57BL/6 mice were randomly divided into 6 groups (n=8), including a control group and 5 DSS model groups with daily gavage of saline containing 0.1% DMSO, low-, medium- or high-dose IVA (50, 100, and 150 mg/kg, respectively), or 5-ASA (100 mg/kg) for 10 days. Body weight and disease activity index (DAI) of the mice were monitored, and colon length and pathologies were assessed after the treatments. Immunofluorescence staining, Western blotting, TUNEL staining, and JC-1 staining were used to evaluate the effects of IVA on barrier function, apoptosis, and mitochondrial function in the mouse models and DSS-induced NCM460 cells. Network pharmacology was employed to predict potential signaling pathways. Results The DSS-treated mice showed significantly decreased body weight, increased DAI score, shortened colon length, elevated colonic IL-6 and IL-1β expressions, and severe mucosal damage. IVA, especially at the medium and high doses, obviously improved these changes. Treatment with medium-dose IVA-M significantly increased colonic expressions of ZO-1 and claudin-1, decreased intestinal epithelial cell apoptosis rate and expressions of Bax and cleaved caspase-3, and increased Bcl-2 expression, TOMM20-positive cell counts, and activities of mitochondrial respiratory chain complexes I and IV. In NCM460 cells, IVA treatment obviously reversed DSS-induced mitochondrial impairment, reduced epithelial cell apoptosis, and enhanced expressions of ZO-1 and claudin-1. Network pharmacology analysis suggested that IVA potentially targeted the PPARγ pathway, which was confirmed by increased PPARγ protein expression in IVA-treated mice and NCM460 cells. Treatment with the PPARγ antagonist GW9662 significantly attenuated the protective effect of IVA in DSS-induced NCM460 cells. Conclusion IVA alleviates DSS-induced colitis in mice by protecting mitochondrial function via activating the PPARγ pathway and suppressing inflammation and apoptosis.

Key words: isovanillic acid, ulcerative colitis, mitochondrial functions, PPARγ pathway, intestinal barrier, cell apoptosis