摘要
艾迪注射液(Aidi Injection,ADI)联合阿霉素(doxorubicin,DOX)是临床肿瘤治疗的常用策略,其在协同抗肿瘤同时,减轻DOX引起的心脏毒性。该研究采用多组学手段,系统阐明ADI降低DOX诱导心脏毒性的作用机制。采用DOX诱导的小鼠心脏毒性模型,通过生化指标和病理检查评价ADI的心脏保护作用。在此基础上,借助转录组学、蛋白组学和代谢组学技术分析不同生理状态下机体内源性物质的变化情况。将各组学中具有显著回调趋势的差异物进行整合分析,筛选出ADI发挥心脏保护作用的关键调控通路,并选取其中的重要靶蛋白进行ELISA试剂盒测定和免疫组化分析。结果表明,ADI能够显著降低模型组小鼠血清心肌肌钙蛋白T(cardiac troponin T,cTnT)和N末端B型脑钠肽前体(N-terminal pro-B-type natriuretic peptide,NT-proBNP)的水平,有效改善心肌组织空泡化和心肌纤维化现象,表明ADI对DOX诱导的心脏毒性具有较好的干预作用。转录组学分析共筛选出400个ADI治疗后显著回调到正常水平的差异基因,富集结果主要涉及心肌纤维化进程、炎症反应和氧化应激反应等作用途径。蛋白组学分析共筛选出70个ADI治疗后显著回调到正常水平的差异蛋白,富集结果主要涉及机体炎症反应、心脏功能以及能量代谢等相关信号通路。代谢组学分析共筛选出51个ADI治疗后显著回调到正常水平的差异代谢物,富集结果主要涉及炎症反应、脂质代谢和能量代谢等多条信号通路。多组学整合分析结果显示亚油酸代谢、花生四烯酸代谢和甘油磷酸脂代谢通路在DOX诱导的机体炎症反应中具有重要作用,而ADI可能通过调控这些通路发挥治疗作用。重要靶蛋白的分析结果显示,ADI会显著调控DOX组中环氧合酶1(cyclooxygenase-1,COX-1)、环氧合酶2(cyclooxygenase-2,COX-2)、前列腺素H2(prostaglandin H2,PGH2)和前列腺素D2(prostaglandin D2,PGD2)的异常表达。综上,ADI可有效改善DOX诱导的心脏毒性,其作用机制可能与调控亚油酸代谢、花生四烯酸代谢和甘油磷酸脂代谢等通路,从而干预机体炎症反应进程有关。
The combination of Aidi Injection(ADI)and doxorubicin(DOX)is a common strategy in the treatment of cancer,which can achieve synergistic anti-tumor effects while attenuating the cardiotoxicity caused by DOX.This study aims to investigate the mechanism of ADI in attenuating DOX-induced cardiotoxicity by multi-omics.DOX was used to induce cardiotoxicity in mice,and the cardioprotective effects of ADI were evaluated based on biochemical indicators and pathological changes.Based on the results,transcriptomics,proteomics,and metabolomics were employed to analyze the changes of endogenous substances in different physiological states.Furthermore,data from multiple omics were integrated to screen key regulatory pathways by which ADI attenuated DOX-induced cardiotoxicity,and important target proteins were selected for measurement by ELISA kits and immunohistochemical analysis.The results showed that ADI significantly reduced the levels of cardiac troponin T(cTnT)and N-terminal pro-B-type natriuretic peptide(NT-proBNP)and effectively ameliorated myocardial fibrosis and intracellular vacuolization,indicating that ADI showed therapeutic effect on DOX-induced cardiotoxicity.The transcriptomics analysis screened out a total of 400 differentially expressed genes(DEGs),which were mainly enriched in inflammatory response,oxidative stress,and myocardial fibrosis.After proteomics analysis,70 differentially expressed proteins were selected,which were mainly enriched in the inflammatory response,cardiac function,and energy metabolism.A total of 51 differentially expressed metabolites were screened by the metabolomics analysis,and they were mainly enriched in multiple signaling pathways,including the inflammatory response,lipid metabolism,and energy metabolism.The integrated data of multiple omics showed that linoleic acid metabolism,arachidonic acid metabolism,and glycerophosphate metabolism pathways played an important role in DOX-induced cardiotoxicity,and ADI may exert therapeutic effects by modulating these pathways.Target validation experiments suggested that ADI significantly regulated abnormal protein levels of cyclooxygenase-1(COX-1),cyclooxygenase-2(COX-2),prostaglandin H2(PGH2),and prostaglandin D2(PGD2)in the model group.In conclusion,ADI may attenuate DOX-induced cardiotoxicity by regulating linoleic acid metabolism,arachidonic acid metabolism,and glycerophosphate metabolism,thus alleviating inflammation of the body.
作者
王艳丽
涂玉洁
朱建华
郑林
黄勇
孙佳
李勇军
潘洁
刘春花
陆苑
WANG Yan-li;TU Yu-jie;ZHU Jian-hua;ZHENG Lin;HUANG Yong;SUN Jia;LI Yong-jun;PAN Jie;LIU Chun-hua;LU Yuan(State Key Laboratory of Functions and Applications of Medicinal Plants/Guizhou Provincial Key Laboratory of Pharmaceutics,Guizhou Medical University,Guiyang 550004,China;Engineering Research Center for the Development and Application of Ethnic Medicine and TCM(Ministry of Education),Guizhou Provincial Engineering Research Center for the Development and Application of Ethnic Medicine and TCM,Guizhou Medical University,Guiyang 550004,China;School of Pharmaceutical Sciences,Guizhou Medical University,Guiyang 550004,China)
出处
《中国中药杂志》
北大核心
2025年第8期2245-2259,共15页
China Journal of Chinese Materia Medica
基金
国家自然科学基金地区基金项目(81860718,82460756)
贵州省科技厅项目(CXTD[2023]019)
贵州省高层次创新型人才项目(GCC[2022]031-1,GCC[2023]036)。
作者简介
王艳丽,硕士研究生,主要从事药理研究,E-mail:1634293312@qq.com;陆苑,副教授,主要从事中药抗肿瘤药理研究,E-mail:luyuan@gmc.edu.cn。
