董跨, 唐莹莹, 蒋嘉瑞, 黄幼媚, 谷丽华, 丁丽丽, 李冠成, 熊爱珍, 杨莉, 王峥涛. 泽泻改善胆管结扎致小鼠肝纤维化的药效与机制研究J. 药学学报, 2025, 60(5): 1454-1463. DOI: 10.16438/j.0513-4870.2024-1104
引用本文: 董跨, 唐莹莹, 蒋嘉瑞, 黄幼媚, 谷丽华, 丁丽丽, 李冠成, 熊爱珍, 杨莉, 王峥涛. 泽泻改善胆管结扎致小鼠肝纤维化的药效与机制研究J. 药学学报, 2025, 60(5): 1454-1463. DOI: 10.16438/j.0513-4870.2024-1104
DONG Kua, TANG Ying-ying, JIANG Jia-rui, HUANG You-mei, GU Li-hua, DING Li-li, LI Guan-cheng, XIONG Ai-zhen, YANG Li, WANG Zheng-tao. Study on the hepatoprotective effects and mechanism of Alismatis Rhizoma extracts in bile duct ligation-induced liver fibrosis in miceJ. Acta Pharmaceutica Sinica, 2025, 60(5): 1454-1463. DOI: 10.16438/j.0513-4870.2024-1104
Citation: DONG Kua, TANG Ying-ying, JIANG Jia-rui, HUANG You-mei, GU Li-hua, DING Li-li, LI Guan-cheng, XIONG Ai-zhen, YANG Li, WANG Zheng-tao. Study on the hepatoprotective effects and mechanism of Alismatis Rhizoma extracts in bile duct ligation-induced liver fibrosis in miceJ. Acta Pharmaceutica Sinica, 2025, 60(5): 1454-1463. DOI: 10.16438/j.0513-4870.2024-1104

泽泻改善胆管结扎致小鼠肝纤维化的药效与机制研究

Study on the hepatoprotective effects and mechanism of Alismatis Rhizoma extracts in bile duct ligation-induced liver fibrosis in mice

  • 摘要: 肝纤维化是由多种致病因素导致的慢性肝损伤, 造成胶原在内的细胞外基质过度堆积, 是多数慢性肝病进展过程中常见的病理改变, 然而迄今尚无公认特异有效的药物用于肝纤维化的临床治疗。因此本文研究中药泽泻对胆管结扎(bile duct ligation, BDL) 诱导的肝纤维化的改善作用, 并初步探讨其潜在的药理作用机制。动物实验方案经上海中医药大学实验动物福利与伦理委员会审查(批准号: PZSHUTCM2303280007), 符合实验动物福利与伦理相关规范。对小鼠进行胆管结扎以诱导肝纤维化模型, 并设立假手术组(Sham组)、模型组(BDL组)、泽泻醇提物保护组(BDL+EE)、泽泻水提物保护组(BDL+WE)、奥贝胆酸保护组(BDL+OCA)。结果表明, 泽泻可明显改善胆管结扎诱导的肝纤维化: 泽泻提取物可显著降低肝纤维化小鼠血清谷丙转氨酶、谷草转氨酶活性、碱性磷酸酶、谷氨酰转移酶及总胆汁酸水平, 改善胆汁淤积、胶原沉积、炎性细胞浸润、肝组织坏死等病理状况, 其中醇提物药效优于水提物。进一步考察泽泻醇提物改善胆管结扎诱导小鼠肝纤维化的量-效关系, 并探讨其作用机制, 发现泽泻醇提物可缓解胆管结扎致肝纤维化小鼠体内血清和肝脏胆汁酸代谢失衡, 调节肝组织内胆汁酸代谢关键核受体法尼醇X受体(farnesoid X receptor, FXR) 及其下游靶基因小异二聚体伴侣(small heterodimer partner, SHP)、胆固醇7-羟化酶(cholesterol 7-alpha hydroxylase, CYP7A1)、胆盐输出泵(bile salt export pump, BSEP) 的mRNA表达; 体外进一步证实泽泻醇提物中4种主要三萜可在转录水平激活FXR。本研究表明泽泻在临床上防治肝纤维化的应用提供了理论依据。

     

    Abstract: Liver fibrosis is a chronic liver injury caused by various pathogenic factors, leading to excessive accumulation of extracellular matrix such as collagen. It represents a common pathological hallmark during the progression of most chronic liver diseases. However, there is currently no universally recognized specific and effective drug for the clinical treatment of liver fibrosis. Therefore, this study investigates the effects of Alisma Rhizoma on bile duct ligation (BDL)-induced liver fibrosis and explores the potential pharmacological mechanisms. The animal experimental protocol was reviewed and approved by the Animal Welfare and Ethics Committee of Shanghai University of Traditional Chinese Medicine (registration No. PZSHUTCM2303280007), in compliance with relevant animal welfare and ethical standards. Mice were subjected to BDL to induce liver fibrosis. Mice were divided into five groups: sham operation group (Sham), model group (BDL), ethanol extract protection group (BDL+EE, 1.6 g·kg-1), water extract protection group (BDL+WE, 4.0 g·kg-1), obeticholic acid protection group (BDL+OCA, 10 mg·kg-1). The results showed that both of EE and WE could attenuate BDL-induced liver fibrosis as evident by reduced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT) activities, total bile acids (TBA) levels, and improved pathological conditions such as cholestasis, collagen deposition, inflammatory cell infiltration, and liver tissue necrosis. Notably, EE showed better efficacy than WE. Further studies showed that EE improved liver fibrosis dose dependently. EE treatment impaired the bile acids homeostasis in serum and liver, and recovered the hepatic mRNA expression of farnesoid X receptor (FXR) as well as the downstream genes including small heterodimer partner (SHP), cholesterol 7-alpha hydroxylase (CYP7A1) and bile salt export pump (BSEP). Further study also proved that the four major triterpenes in EE increased the transcriptional activities of FXR in vitro. This study provides a theoretical basis for the clinical application of Alisma Rhizoma in the prevention and treatment of liver fibrosis.

     

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