Mechanism of ginkgo flavonoid aglycone against doxorubicin-induced cardiotoxicity

CAI Ying; QIAN Li; WANG Kailiang; LI Qin; LIU Chunhua; SUN Jia; PAN Jie; LI Yongjun; LU Yuan

doi:10.6039/j.issn.1001-0408.2024.06.04

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Mechanism of ginkgo flavonoid aglycone against doxorubicin-induced cardiotoxicity

更新时间：2024-04-09

- Mechanism of ginkgo flavonoid aglycone against doxorubicin-induced cardiotoxicity
- ZHONGGUO YAOFANG Vol. 35, Issue 6, Pages: 659-664(2024)
- 作者机构：
  
  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
- 作者简介：
- 基金信息：
- DOI：10.6039/j.issn.1001-0408.2024.06.04
  CLC： R965;R285.5
- Published：30 March 2024，
  
  Received：18 September 2023，
  
  Revised：03 January 2024，
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蔡英,钱丽,王开靓等.银杏黄酮苷元减轻多柔比星心脏毒性的作用机制 ^Δ[J].中国药房,2024,35(06):659-664.

CAI Ying,QIAN Li,WANG Kailiang,et al.Mechanism of ginkgo flavonoid aglycone against doxorubicin-induced cardiotoxicity[J].ZHONGGUO YAOFANG,2024,35(06):659-664.
蔡英,钱丽,王开靓等.银杏黄酮苷元减轻多柔比星心脏毒性的作用机制 ^Δ[J].中国药房,2024,35(06):659-664. DOI： 10.6039/j.issn.1001-0408.2024.06.04.

CAI Ying,QIAN Li,WANG Kailiang,et al.Mechanism of ginkgo flavonoid aglycone against doxorubicin-induced cardiotoxicity[J].ZHONGGUO YAOFANG,2024,35(06):659-664. 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

＜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（

＜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（

＜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。

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 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

＜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 （

＜0.05）； compared with DOX group， the serum levels of the above indicators （except for CK-MB） were decreased significantly in GDOX group （

＜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 pathways included docosahexaenoic acid， arachidonic acid， phosphatidylcholine （16∶0/18∶3） and taurine.

CONCLUSIONS

GA may regulate the biosynthesis of unsaturated fatty acids， arachidonic acid metabolism and other metabolic pathways by acting on the core metabolites such as docosahexaenoic acid and arachidonic acid， thus alleviating the cardiotoxic effects of DOX.

关键词

银杏黄酮苷元多柔比星心脏毒性代谢组学

Keywords

doxorubicincardiotoxicitymetabolomics

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