银杏黄酮苷元减轻多柔比星心脏毒性的作用机制  

Mechanism of ginkgo flavonoid aglycone against doxorubicin-induced cardiotoxicity

作　　者：蔡英 钱丽 王开靓 李琴 刘春花[4] 孙佳[1] 潘洁[4] 李勇军 陆苑[1,3] CAI Ying;QIAN Li;WANG Kaiiang;LI Qin;LIU Chunhua;SUN Jia;PAN Jie;LI Yongjun;LU Yuan(Guizhou Provincial Key Laboratory of Pharmaceutics&State Key Laboratory of Functions and Applications of Medicinal Plants,Guizhou Medical University,Guiyang 550004,China;School of Pharmacy,Guizhou Medical University,Guiyang 550004,China;Key Laboratory of Basic Pharmacology of Ministry of Education,Zunyi Medical University,Guizhou Zunyi 563006,China;Engineering Research Center for the Development and Application of Ethnic Medicine and TCM(Ministry of Education),Guizhou Medical University,Guiyang 550004,China)

机构地区：[1]贵州医科大学贵州省药物制剂重点实验室/省部共建药用植物功效与利用国家重点实验室,贵阳550004 [2]贵州医科大学药学院,贵阳550004 [3]遵义医科大学基础药理教育部重点实验室,贵州遵义563006 [4]贵州医科大学民族药与中药开发应用教育部工程研究中心,贵阳550004

出　　处：《中国药房》2024年第6期659-664,共6页China Pharmacy

基　　金：国家自然科学基金委-贵州喀斯特中心项目(No.U1812403-5);贵州省科技计划项目(No.黔科合基础-ZK〔2022〕一般374,No.黔科合基础〔2020〕1Y381);贵州省基础药理教育部重点实验室开放课题基金资助项目(No.黔教合KY字〔2022〕395号)。

摘　　要：目的探究银杏黄酮苷元(GA)减轻多柔比星(DOX)心脏毒性的潜在作用机制。方法将雄性ICR小鼠随机分为对照组(CON组)、模型组(DOX组)和GA+DOX组(GDOX组),每组12只。DOX组小鼠隔天尾静脉注射DOX药液3mg/kg,GDOX组小鼠每天灌胃GA混悬液100mg/kg+隔天尾静脉注射DOX药液3mg/kg,连续15d。给药结束后,检测各组小鼠血清中天冬氨酸转氨酶(AST)、肌酸激酶(CK)、肌酸激酶同工酶(CK-MB)、乳酸脱氢酶(LDH)水平。基于代谢组学方法,采用超高效液相色谱-四极杆静电场轨道阱串联质谱技术,在主成分分析(PCA)、正交偏最小二乘-判别分析(OPLS-DA)的基础上,以变量重要性投影值≥1、峰面积差异倍数>1且P<0.05为标准筛选差异代谢物(DEMs),并基于HMDB、PubChem等数据库进行生物学分析。结果与CON组比较,DOX组小鼠血清中AST、CK、CK-MB、LDH水平均显著升高(P<0.05);与DOX组比较,GDOX组小鼠血清中上述指标(CK-MB除外)水平均显著降低(P<0.05)。PCA、OPLS-DA结果均显示,CON组、DOX组、GDOX组小鼠心脏组织样品均能完全分离。经数据库匹配后,鉴定出37个共有DEMs,其中DOX组显著上调而GDOX组显著下调的DEMs有17个,DOX组显著下调而GDOX组显著上调的DEMs有8个;涉及通路包括不饱和脂肪酸的生物合成、花生四烯酸代谢、亚油酸代谢、牛磺酸和次牛磺酸代谢,关键代谢物包括二十二碳六烯酸、花生四烯酸、磷脂酰胆碱(16∶0/18∶3)和牛磺酸。结论GA可能通过作用于二十二碳六烯酸、花生四烯酸等关键代谢物来调节不饱和脂肪酸的生物合成、花生四烯酸代谢等代谢途径,进而减轻DOX的心脏毒性。OBJECTIVE To investigate the potential mechanism of the effect of ginkgo flavone aglycone(GA)against doxorubicin(DOX)-induced cardiotoxicity.METHODS The male ICR mice were randomized into control group(CON group),model group(DOX group)and GA+DOX group(GDOX group),with 12 mice in each group.The DOX group was injected with DOX solution at a dose of 3 mg/kg via tail vein every other day,and the GDOX group was given GA suspension intragastrically at a dose of 100 mg/kg every day+DOX solution at a dose of 3 mg/kg via tail vein every other day,for 15 consecutive days.After the end of administration,the serum levels of aspartate aminotransferase(AST),creatine kinase(CK),creatine kinase isoenzyme(CK-MB)and lactate dehydrogenase(LDH)in mice were detected in each group.Based on the metabolomics method,UHPLC-Q-Exactive Orbitrap HRMS method was used;based on principal component analysis(PCA)and orthogonal partial least squares-discriminant analysis(OPLS-DA),the differentially expressed metabolites(DEMs)were screened using the criteria of variable importance in the projection≥1,fold change of peak area>1 and P<0.05;biological analysis was conducted based on databases such as HMDB and PubChem.RESULTS Compared with CON group,serum levels of AST,CK,CK-MB and LDH were increased significantly in DOX group(P<0.05);compared with DOX group,the serum levels of the above indicators(except for CK-MB)were decreased significantly in GDOX group(P<0.05).PCA and OPLS-DA showed that myocardial tissue samples of CON group,DOX group and GDOX group were isolated completely.After database matching,37 common DEMs were identified,among which 17 DEMs were significantly up-regulated in the DOX group and significantly down-regulated in the GDOX group,and 8 DEMs were significantly down-regulated in the DOX group and significantly up-regulated in the GDOX group;pathway enrichment involved the biosynthesis of unsaturated fatty acids,arachidonic acid metabolism,linoleic acid metabolism,taurine and hypotaurine metabolism;the key metabolites in the above

关 键 词：银杏黄酮苷元 多柔比星 心脏毒性 代谢组学 

分 类 号：R965[医药卫生—药理学] R285.5[医药卫生—药学]