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银杏黄酮苷元减轻多柔比星心脏毒性的作用机制
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蔡 英 1, 2* ,钱 丽 ,王开靓 ,李 琴 ,刘春花 ,孙 佳 ,潘 洁 ,李勇军 ,陆 苑 (1. 贵州医科大学
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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)
中图分类号 R965;R285.5 文献标志码 A 文章编号 1001-0408(2024)06-0659-06
DOI 10.6039/j.issn.1001-0408.2024.06.04
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3 mg/kg,GDOX组小
鼠每天灌胃GA混悬液100 mg/kg+隔天尾静脉注射DOX药液3 mg/kg,连续15 d。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。
关键词 银杏黄酮苷元;多柔比星;心脏毒性;代谢组学
Mechanism of ginkgo flavonoid aglycone against doxorubicin-induced cardiotoxicity
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CAI Ying ,QIAN Li ,WANG Kailiang ,LI Qin ,LIU Chunhua ,SUN Jia ,PAN Jie ,LI Yongjun ,LU Yuan 1, 3
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[1. Guizhou Provincial Key Laboratory of Pharmaceutics & State Key Laboratory of Functions and Applications
of Medicinal Plants, Guizhou Medical University, Guiyang 550004, China; 2. School of Pharmacy, Guizhou
Medical University, Guiyang 550004, China; 3. Key Laboratory of Basic Pharmacology of Ministry of
Education, Zunyi Medical University, Guizhou Zunyi 563006, China; 4. Engineering Research Center for the
Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical
University, Guiyang 550004, China]
ABSTRACT 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
Δ 基金项目 国家自然科学基金委-贵州喀斯特中心项目(No.
component analysis (PCA) and orthogonal partial least squares-
U1812403-5);贵州省科技计划项目(No. 黔科合基础-ZK〔2022〕一般
discriminant analysis (OPLS-DA), the differentially expressed
374,No.黔科合基础〔2020〕1Y381);贵州省基础药理教育部重点实验
metabolites (DEMs) were screened using the criteria of
室开放课题基金资助项目(No.黔教合KY字〔2022〕395号)
*第一作者 硕士研究生。研究方向:中药药效物质基础。E- variable importance in the projection≥1, fold change of peak
mail:3260638059@qq.com area>1 and P<0.05; biological analysis was conducted based
# 通信作者 副教授,硕士生导师,博士。研究方向:中药药效物质 on databases such as HMDB and PubChem. RESULTS
基础。电话:0851-86908648。E-mail:luyuan@gmc.edu.cn Compared with CON group, serum levels of AST, CK, CK-
中国药房 2024年第35卷第6期 China Pharmacy 2024 Vol. 35 No. 6 · 659 ·