南方医科大学学报

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (4): 718-724.doi: 10.12122/j.issn.1673-4254.2025.04.06

• • 上一篇    

退黄合剂通过调控法尼醇X受体抑制NLRP3炎症小体改善α-萘异硫氰酸酯诱导的大鼠胆汁淤积

朱正望1,2(), 王琳琳1,2, 赵静涵1,2, 马瑞雪1, 余雨春1, 蔡庆春3, 王兵4, 朱平生1,2(), 苗明三1,2   

  1. 1.河南中医药大学第一临床医学院，河南 郑州 450046
    2.豫药全产业链研发河南省协同创新中心，河南 郑州 450046
    3.河南中医药大学第三附属医院病理科，河南 郑州 450008
    4.上海交通大学医学院附属第六人民医院中医科，上海 200233
  • 收稿日期:2024-12-25 出版日期:2025-04-20 发布日期:2025-04-28
  • 通讯作者: 朱平生 E-mail:2235848407@qq.com;zhupingsheng@126.com
  • 作者简介:朱正望，在读博士研究生，E-mail: 2235848407@qq.com
  • 基金资助:
    国家自然科学基金(82074340);河南省“双一流”创建学科中医学科学研究专项(HSRP-DFCTCM-2023-1-19);河南省科技创新人才计划-杰出青年项目(154100510020)

Tuihuang Mixture improves α‑naphthylisothiocyanate-induced cholestasis in rats by inhibiting NLRP3 inflammasomes via regulating farnesoid X receptor

Zhengwang ZHU1,2(), Linlin WANG1,2, Jinghan ZHAO1,2, Ruixue MA1, Yuchun YU1, Qingchun CAI3, Bing WANG4, Pingsheng ZHU1,2(), Mingsan MIAO1,2   

  1. 1.First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou 450046, China
    2.Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou 450046, China
    3.Department of Pathology, Third Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450008, China
    4.Department of Traditional Chinese Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
  • Received:2024-12-25 Online:2025-04-20 Published:2025-04-28
  • Contact: Pingsheng ZHU E-mail:2235848407@qq.com;zhupingsheng@126.com
  • Supported by:
    National Natural Science Foundation of China(82074340)

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摘要：

目的 研究退黄合剂通过调控法尼醇X受体（FXR）抑制NLRP3炎症小体活化改善胆汁淤积的作用机制。 方法 将48只Wistar大鼠随机分为空白组、模型组、熊去氧胆酸组、退黄合剂组（12只/组），除空白组外，其余大鼠采用α-萘异硫氰酸酯（ANIT）灌胃复制胆汁淤积模型。造模后，各组大鼠分别给予相应药物灌胃。检测血清中ALT、AST、ALP、γ-GT、TBA、TBIL水平；肝组织中IL-1β、IL-18水平及mRNA表达；Western blotting和q-PCR检测肝组织中FXR、NLRP3、ASC、Caspase-1、GSDMD蛋白及mRNA表达；HE染色观察肝组织病理学变化。 结果 与空白组相比，模型组大鼠血清中ALT、AST、ALP、γ-GT、TBA、TBIL水平明显升高，肝组织中IL-1β、IL-18水平及mRNA表达明显升高，FXR蛋白及mRNA表达明显降低，NLRP3、Caspase-1蛋白及NLRP3、ASC、Caspase-1、GSDMD mRNA表达明显升高（P<0.05，P<0.01）；肝细胞排列紊乱，胆管上皮细胞增生，炎症细胞浸润。与模型组相比，退黄合剂组大鼠血清中ALT、AST、ALP、γ-GT、TBA、TBIL水平明显降低，肝组织中IL-1β、IL-18水平及mRNA表达明显降低，FXR蛋白及mRNA表达明显升高，NLRP3、ASC、Caspase-1、GSDMD 蛋白及NLRP3、ASC、Caspase-1 mRNA表达明显降低（P<0.05，P<0.01）；肝细胞损伤、胆管上皮细胞增生、炎症细胞浸润减轻。 结论 退黄合剂可有效改善胆汁淤积，其机制可能与调控FXR抑制NLRP3炎症小体活化介导的细胞焦亡有关。

关键词: 退黄合剂, 胆汁淤积, FXR, NLRP3炎症小体, 细胞焦亡

Abstract:

Objective To study the therapeutic mechanism of Tuihuang Mixture against cholestasis. Methods Forty-eight Wistar rats were randomized equally into blank group, model group, ursodeoxycholic acid group and Tuihuang Mixture group. Except for those in the blank group, all the rats were given α‑naphthylisothiocyanate (ANIT) to establish rat models of cholestasis, followed by treatments with indicated drugs or distilled water. Serum levels of ALT, AST, ALP, γ-GT, TBA and TBIL of the rats were determined, and hepatic expressions IL-1β, IL-18, FXR, NLRP3, ASC, Caspase-1 and GSDMD were detected using q-PCR, ELISA or Western blotting. Histopathological changes of the liver tissues were observed using HE staining. Results The rat models of cholestasis had significantly increased serum levels of ALT, AST, ALP, γ-GT, TBA and TBIL with increased mRNA and protein expressions of IL-1β and IL-18, decreased protein and mRNA expressions of FXR, and increased protein expressions of NLRP3 and Caspase-1 and mRNA expressions of NLRP3, ASC, Caspase-1 and GSDMD in the liver tissue, showing also irregular arrangement of liver cells, proliferation of bile duct epithelial cells and inflammatory cells infiltration. Treatment of the rat models with Tuihuang Mixture significantly decreased serum levels of ALT, AST, ALP, γ-GT, TBA and TBIL, lowered IL-1β and IL-18 and increased FXR protein and mRNA expressions, and reduced NLRP3, ASC, Caspase-1 and GSDMD proteins and NLRP3, ASC and Caspase-1 mRNA expressions in the liver tissue. Tuihuang Mixture also significantly alleviated hepatocyte injury, bile duct epithelial cell proliferation and inflammatory cell infiltration in the liver of the rat models. Conclusion Tuihuang Mixture can effectively improve cholestasis in rats possibly by inhibiting NLRP3 inflammatosome-mediated pyroptosis via regulating FXR.

Key words: Tuihuang Mixture, cholestasis, farnesoid X receptor, NLRP3 inflammasomes, cell pyroptosis