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《工程(英文)》 >> 2021年 第7卷 第9期 doi: 10.1016/j.eng.2020.12.016

基于整合临床和动物实验的小分子筛选平台揭示经典方剂茵陈蒿汤治疗黄疸证显效状态下的活性化合物及潜在作用靶点

a National Chinmedomics Research Center & National TCM Key Laboratory of Serum Pharmacochemistry, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin 150040, China
b State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
c National Engineering Laboratory for the Development of Southwestern Endangered Medicinal Materials, Guangxi Botanical Garden of Medicinal Plant, Nanning 530023, China

# These authors contributed equally to this work.

收稿日期: 2019-10-07 修回日期: 2020-10-12 录用日期: 2020-12-29 发布日期: 2021-03-04

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摘要

中药方剂化学组成高度复杂,其药理作用具有多成分、多靶点的特点,使得阐明其生物活性化合物极具挑战性。茵陈蒿汤被广泛用于治疗黄疸相关疾病。尽管近年来茵陈蒿汤的药效及活性成分被不断证实,但仍然缺乏对其效应成分、效应机制和功能靶点的深入系统分析,尤其是临床研究方面。本研究建立了一个整合临床和动物实验平台用于发现茵陈蒿汤的活性化合物和潜在靶点。首先采用基于超高效液相色谱-四极杆飞行时间质谱(UPLC-Q-ToF-MS)技术的代谢组学方法结合中药血清药物化学方法揭示茵陈蒿汤的血清代谢谱和化学成分谱。此外,通过网络药理学和智能途径分析平台构建化合物-靶标-通路关联网络。最终发现茵陈蒿汤中8 个活性小分子与5 个核心靶点极度相关,并通过酶联免疫吸附测定实验进行生物学验证。结果表明茵陈蒿汤通过靶向胆固醇7α-羟化酶(CYP7A1)、多药耐药相关蛋白2(ABCC2)、多药耐药相关蛋白3(ABCC3)、尿苷二磷酸葡萄糖醛酸基转移酶1A1(UGT1A1)和法尼醇X受体(FXR)来调节包括初级胆汁酸生物合成、卟啉和叶绿素代谢以及胆汁分泌在内的代谢通路,从而发挥利胆退黄的作用。该整合策略可以成功地用于中药方剂活性小分子及其作用靶点的发现。

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