基于网络毒理学和代谢组学的青蒿琥酯心脏毒性作用机制研究  

Toxicity Mechanism of Artesunate-Induced Cardiotoxic Injury:Based on Network Toxicology and Serum Metabolomics

作　　者：陈璐璐[1] 袁祯爽 刘婕[1] 马瑜瑾 江涛[1] 李映 姜宏卫[1] Chen Lulu;Yuan Zhenshuang;Liu Jie;Ma Yujin;Jiang Tao;Li Ying;Jiang Hongwei(The First Affiliated Hospital,College of Clinical Medicine of Henan University of Science and Technology,Luoyang 471003,China;College of Chinese Materia Medica,Beijing University of Chinese Medicine,Beijing 100029,China)

机构地区：[1]河南科技大学临床医学院、河南科技大学第一附属医院,洛阳471003 [2]北京中医药大学中药学院,北京100029

出　　处：《世界科学技术-中医药现代化》2023年第12期3808-3828,共21页Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology

基　　金：洛阳市医疗卫生科技计划项目(1920008A):双氢青蒿素在2型糖尿病中的应用及疗效评价,负责人:姜宏卫;河南省医学科技攻关计划联合共建项目(LHGJ20200570):双氢青蒿素通过抑制TGF-β/Smads信号通路改善db/db小鼠糖尿病肾病纤维化,负责人:刘婕;国家重点研发计划(2018YFC1311705):重大慢病流行病学监测大数据平台构建和关键技术研究,负责人:姜宏卫。

摘　　要：目的运用网络毒理学和血清非靶向代谢组学研究青蒿琥酯致心脏毒性作用机制。方法运用网络毒理学挖掘青蒿琥酯致心脏毒性关键靶点及信号通路;选用C57BL/6J健康小鼠灌胃给予青蒿琥酯后,观察经毒性暴露小鼠的心脏病理形态和血清生化指标以评价其毒性作用;运用血清非靶向代谢组学技术筛选青蒿琥酯致心脏毒性相关内源性代谢物,并进一步富集其毒性所干扰的关键代谢通路。结果通过网络毒理学分析共获取青蒿琥酯心脏毒性作用靶点包括AKT1、EGFR、CASP3、VEGFA等64个,以及Apoptosis、PI3K-Akt、FoxO等165条信号通路,血清代谢组学分析显示青蒿琥酯引发心脏毒性所影响的血清代谢物包括溶血磷脂酰胆碱、溶血磷脂酰乙醇胺、吲哚乙醛等,所富集的代谢通路为甘油磷脂代谢和色氨酸代谢。结论青蒿琥酯600 mg·kg^(-1)给药1周后可诱发C57BL/6J小鼠的心脏毒性,其诱发的毒性机制与甘油磷脂代谢失调及色氨酸代谢紊乱有关,本研究为青蒿琥酯引发药源性心脏毒性的早期预测和评价提供了参考依据。Objective This study aimed to investigate the mechanism of artesunate-induced cardiotoxicity by using network toxicology and serum untargeted metabolomics.Methods The key targets and signaling pathways of artesunateinduced cardiotoxicity were expored by network toxicology technique.The toxic effect of artesunate on Healthy C57BL/6J mice was evaluated according to the pathological morphology of the heart and the levels of serum biochemical indexes included LDH and CKMB.Serum untargeted metabolomics analysis was combined with multivariate statistical analysis to search the key endogenous metabolites of artesunate cardiotoxic injury and related metabolic pathways.Results 64 targets including AKT1,EGFR,CASP3,VEGFA and 165 signaling pathways including Apoptosis,PI3K-Akt,FoxO were screened out by network toxicology,.Serum metabolomics analysis identified the serum metabolites affected by artesunate-induced cardiotoxicity included lysophosphatidylcholine,lysophosphatidylethanolamine,indoleacetaldehyde,etc.The results of metabolic pathways enrichment analysis were glycerophosphatidylcholine metabolism and tryptophan metabolism.Conclusion Artesunate 600 mg·kg^(-1) can induce cardiotoxicity in C57BL/6J mice after 1-week administration,and the mechanism is related to glycerophosphatidylcholine metabolism disorder and tryptophan metabolism disorder.This study provides a reference for the early prediction and evaluation of artesunate induced druginduced cardiotoxicity.

关 键 词：青蒿琥酯 代谢组学 心脏毒性 网络毒理学 靶蛋白 

分 类 号：R285.5[医药卫生—中药学]