Mechanism of <italic style="font-style: italic">Ginkgo</italic> flavone aglycone in alleviating doxorubicin-induced cardiotoxicity based on transcriptomics and proteomics

TU Yujie; CAI Ying; CHENG Xueyi; SUN Jia; PAN Jie; LIU Chunhua; LI Yongjun; HUANG Yong; ZHENG Lin; LU Yuan

doi:10.6039/j.issn.1001-0408.2024.21.04

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Mechanism of Ginkgo flavone aglycone in alleviating doxorubicin-induced cardiotoxicity based on transcriptomics and proteomics

更新时间：2025-09-25

- Mechanism of Ginkgo flavone aglycone in alleviating doxorubicin-induced cardiotoxicity based on transcriptomics and proteomics
- ZHONGGUO YAOFANG Vol. 35, Issue 21, Pages: 2596-2602(2024)
- 作者机构：
  
  1.贵州医科大学省部共建药用植物功效与利用国家重点实验室/贵州省药物制剂重点实验室，贵阳　550004
  2.贵州医科大学药学院，贵阳　550004
  3.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.1001-0408.2024.21.04
  CLC： R965
- Received：25 June 2024，
  
  Revised：2024-10-12，
  
  Accepted：12 October 2024，
  
  Published：15 November 2024
- 稿件说明：
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涂玉洁,蔡英,程雪怡,等.基于转录组学和蛋白质组学研究银杏黄酮苷元减轻多柔比星心脏毒性的作用机制[J].中国药房,2024,35(21):2596-2602.

TU Yujie,CAI Ying,CHENG Xueyi,et al.Mechanism of Ginkgo flavone aglycone in alleviating doxorubicin-induced cardiotoxicity based on transcriptomics and proteomics[J].ZHONGGUO YAOFANG,2024,35(21):2596-2602.
涂玉洁,蔡英,程雪怡,等.基于转录组学和蛋白质组学研究银杏黄酮苷元减轻多柔比星心脏毒性的作用机制[J].中国药房,2024,35(21):2596-2602. DOI： 10.6039/j.issn.1001-0408.2024.21.04.

TU Yujie,CAI Ying,CHENG Xueyi,et al.Mechanism of Ginkgo flavone aglycone in alleviating doxorubicin-induced cardiotoxicity based on transcriptomics and proteomics[J].ZHONGGUO YAOFANG,2024,35(21):2596-2602. DOI： 10.6039/j.issn.1001-0408.2024.21.04.

摘要

目的

基于转录组学和蛋白质组学研究银杏黄酮苷元（GA）降低多柔比星（DOX）心脏毒性的作用机制。

方法

将36只小鼠随机分为对照组（CON组，隔天尾静脉注射等体积生理盐水+每天灌胃等体积生理盐水）、DOX组（隔天尾静脉注射3 mg/kg DOX）和GDOX组（每天灌胃100 mg/kg GA+隔天尾静脉注射3 mg/kg DOX），每组12只，连续给药/生理盐水15 d。收集小鼠心脏组织进行RNA-Seq转录组学测序和4D-Label-free定量蛋白质组学分析，筛选差异表达基因和蛋白并对其进行京都基因与基因组百科全书（KEGG）富集分析。测定小鼠心脏组织中爱帕琳肽（Apelin）、磷脂酰肌醇3-激酶（PI3K）和蛋白激酶B（Akt）的mRNA和蛋白表达水平及PI3K、Akt蛋白的磷酸化水平进行验证。将H9c2心肌细胞分为对照组（CON组）、DOX组（2 μmol/L）和GDOX组（2 μg/mL GA+2 μmol/L DOX），测定细胞存活率及细胞中糖酵解关键物质水平。

结果

筛选得到6条转录组学与蛋白质组学的共同通路，包括Apelin信号通路、PI3K-Akt信号通路、胰岛素抵抗等；其中以Apelin、PI3K-Akt信号通路中富集到的基因数目最多。靶点验证实验结果显示，与CON组比较，DOX组小鼠心脏组织中Apelin、PI3K和Akt的mRNA相对表达量和蛋白表达水平，以及PI3K、Akt蛋白的磷酸化水平均显著降低（

＜0.05或

＜0.01）；与DOX组比较，GDOX组小鼠心脏组织中Apelin、PI3K和Akt的mRNA相对表达量及PI3K、Akt蛋白的磷酸化水平均显著升高（

＜0.05或

＜0.01）。细胞实验表明，与CON组比较，DOX组细胞存活率显著降低（

＜0.05），细胞中葡萄糖相对摄取量以及丙酮酸、乳酸的相对生成量均显著增加（

＜0.05），ATP相对生成量显著减少（

＜0.05）；与DOX组比较，GDOX组细胞存活率显著升高（

＜0.05），细胞中丙酮酸、乳酸的相对生成量均显著减少（

＜0.05）。

结论

GA可能是通过上调心脏组织中Apelin、PI3K和Akt的mRNA及其蛋白表达，调控糖酵解过程，进而改善DOX引起的心脏毒性作用。

Abstract

OBJECTIVE

To investigate the mechanism by which

Ginkgo

flavone aglycone （GA） reduces the cardiotoxicity of doxorubicin （DOX） based on transcriptomics and proteomics.

METHODS

Thirty-six mice were randomly assigned to control group （CON group， tail vein injection of equal volume of physiological saline every other day+daily intragastric administration of an equal volume of physiological saline）， DOX group （tail vein injection of 3 mg/kg DOX every other day）， and GDOX group （daily intragastric administration of 100 mg/kg GA+tail vein injection of 3 mg/kg DOX every other day）， with 12 mice in each group. The administration of drugs/physiological saline was continued for 15 days. Mouse heart tissues were collected for RNA-Seq transcriptomic sequencing and 4D-Label-free quantitative proteomic analysis to screen differentially expressed genes and proteins， which were then subjected to Kyoto encyclopedia of genes and genomes （KEGG） enrichment analysis. The expression levels of Apelin peptide （Apelin）， phosphatidylinositol 3-kinase （PI3K）， and protein kinase B （Akt） mRNA and protein in mouse heart tissues， as well as the phosphorylation levels of PI3K and Akt proteins， were verified. H9c2 cardiomyocytes were divided into control group （CON group）， DOX group （2 μmol/L）， and GDOX group （2 μg/mL GA+2 μmol/L DOX） to determine cell viability and the levels of key glycolytic substances in the cells.

RESULTS

Six common pathways were identified from transcriptomics and proteomics， including the Apelin signaling pathway， the PI3K-Akt signaling pathway， and insulin resistance. Among them， the Apelin and PI3K-Akt signaling pathways were the most enriched in terms of gene numbers. Target validation experiments showed that compared to the CON group， the relative expression of Apelin， PI3K and Akt mRNA and protein levels， as well as the phosphorylation levels of PI3K and Akt proteins， were significantly decreased in the DOX group （

＜0.05 or

＜0.01）. The relative expression of Apelin， PI3K and Akt mRNA and the phosphorylation levels of PI3K and Akt proteins were significantly increased in the GDOX group as compared with the DOX group （

＜0.05 or

＜0.01）. Cellular experiments indicated that compared to the CON group， cell viability in the DOX group was significantly decreased （

＜0.05）， the relative uptake of glucose and the relative production of pyruvate and lactate were significantly increased （

＜0.05）， and the relative production of ATP was significantly reduced （

＜0.05）. Compared to the DOX group， cell viability in the GDOX group was significantly increased （

＜0.05）， and the relative production of pyruvate and lactate was significantly reduced （

＜0.05）.

CONCLUSIONS

GA may alleviate DOX-induced cardiotoxicity by upregulating the mRNA and protein expression of Apelin， PI3K， and Akt in heart tissues， and regulating glycolytic processes.

关键词

Keywords

references

RAWAT P S ， JAISWAL A ， KHURANA A ， et al . Doxorubicin-induced cardiotoxicity：an update on the molecular mechanism and novel therapeutic strategies for effective management [J ] . Biomedicine Pharmacother ， 2021 ， 139 ： 111708 .

宋浩静，杜亚斌，于泽芳，等 . UPLC-MS/MS法多组分测定研究银杏叶提取物注射液的质量一致性 [J ] . 中国临床药理学杂志， 2019 ， 35 （ 19 ）： 2407 - 2411 .

SONG H J ， DU Y B ， YU Z F ， et al . De termination of the mass consistency of extract of Ginkgo biloba leaves injection of different manufacturers by UPLC-MS/MS method [J ] . Chin J Clin Pharmacol ， 2019 ， 35 （ 19 ）： 2407 - 2411 .

宋忠军，朱晓青，何艳，等 . 银杏黄酮苷元对多柔比星治疗肝癌的增效减毒作用 [J ] . 中国药房， 2022 ， 33 （ 16 ）： 1937 - 1942，1949 .

SONG Z J ， ZHU X Q ， HE Y ， et al . Effects of increasing efficacy and decreasing toxicity of Ginkgo flavone aglycone on doxorubicin in the treatment of liver cancer [J ] . China Pharm ， 2022 ， 33 （ 16 ）： 1937 - 1942，1949 .

LEE S Y ， LEE H ， YUN S H ， et al . Application of multiomics technology for the elucidation of anti-pneumococcal activity of 3-acyl-2-phenylamino-1，4-dihydroquinolin-4-one（APDQ） derivative against Streptococcus pneumoniae [J ] . Sci Rep ， 2020 ， 10 （ 1 ）： 20685 .

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 [J ] . 中国药房， 2024 ， 35 （ 6 ）： 659 - 664 .

CAI Y ， QIAN L ， WANG K L ， et al . Mechanism of Ginkgo flavonoid aglycone against doxorubicin-induced cardiotoxicity [J ] . China Pharm ， 2024 ， 35 （ 6 ）： 659 - 664 .

DAVALIEVA K ， KIPRIJANOVSKA S ， DIMOVSKI A ，　 et al . Comparative evaluation of two methods for LC-MS/MS proteomic analysis of formalin fixed and paraffin embedded tissues [J ] . J Proteomics ， 2021 ， 235 ： 104117 .

KINJO T ， HIGASHI H ， UNO K ， et al . Apelin/apelin receptor system：molecular characteristics，physiological roles，and prospects as a target for disease prevention and pharmacotherapy [J ] . Curr Mol Pharmacol ， 2021 ， 14 （ 2 ）： 210 - 219 .

KUBA K ， SATO T ， IMAI Y ， et al . Apelin and Elabela/Toddler； double ligands for APJ/Apelin receptor in heart development，physiology，and pathology [J ] . Peptides ， 2019 ， 111 ： 62 - 70 .

杨嘉豪，崔瑞琴，周波，等 . 温阳消饮方对慢性心力衰竭大鼠PI3K-Akt信号通路表达及相关凋亡蛋白的影响 [J ] . 中华中医药杂志， 2020 ， 35 （ 1 ）： 145 - 149 .

YANG J H ， CUI R Q ， ZHOU B ， et al . Effects of Wenyang xiaoyin formula on the expression of PI3K-Akt signal pathway and related apoptotic proteins in chronic heart failure rats [J ] . China J Tradit Chin Med Pharm ， 2020 ， 35 （ 1 ）： 145 - 149 .

YUE T T ， CAO Y J ， CAO Y X ， et al . Shuxuening injection inhibits apoptosis and reduces myocardial ischemia-reperfusion injury in rats through PI3K/Akt pathway [J ] . Chin J Integr Med ， 2024 ， 30 （ 5 ）： 421 - 432 .

庞夏云，周瑞，宋若彤，等 . 珠子参总皂苷对人宫颈癌细胞系HeLa增殖、凋亡及自噬的影响 [J ] . 中国中药杂志， 2024 ， 49 （ 14 ）： 3848 - 3856 .

PANG X Y ， ZHOU R ， SONG R T ， et al . Effect of total saponins from Panacis Majoris Rhizoma on proliferation，apoptosis and autophagy of human cervical carcinoma HeLa cells [J ] . China J Chin Mater Med ， 2024 ， 49 （ 14 ）： 3848 - 3856 .

FENG J H ， ZHAO H ， DU M Z ， et al . The effect of apelin-13 on pancreatic islet beta cell mass and myocardial fatty acid and glucose metabolism of experimental type 2 diabetic rats [J ] . Peptides ， 2019 ， 114 ： 1 - 7 .

ZHAO L G ， LI P L ， DAI Y ， et al . Mibefradil alleviates high-glucose-induced cardiac hypertrophy by inhibiting PI3K/Akt/mTOR-mediated autophagy [J ] . J Cardiovasc Pharmacol ， 2020 ， 76 （ 2 ）： 246 - 254 .

DE JONG K A ， LOPASCHUK G D . Complex energy metabolic changes in heart failure with preserved ejection fraction and heart failure with reduced ejection fraction [J ] . Can J Cardiol ， 2017 ， 33 （ 7 ）： 860 - 871 .

YUAN Y ， FAN S M ， SHU L X ， et al . Exploration the mechanism of doxorubicin-induced heart failure in rats by integration of proteomics and metabolomics data [J ] . Front Pharmacol ， 2020 ， 11 ： 600561 .

LING G J ， WANG X P ， TAN N N ， et al . Mechanisms and drug intervention for doxorubicin-induced cardiotoxicity based on mitochondrial bioenergetics [J ] . Oxid Med Cell Longev ， 2022 ， 2022 ： 7176282 .

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Mechanism of ginkgo flavonoid aglycone against doxorubicin-induced cardiotoxicity

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Related Institution

Guizhou Provincial Key Laboratory of Pharmaceutics & State Key Laboratory of Functions and Applications of Medicinal Plants， Guizhou Medical University

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Mechanism of Ginkgo flavone aglycone in alleviating doxorubicin-induced cardiotoxicity based on transcriptomics and proteomics

DOI：10.6039/j.issn.1001-0408.2024.21.04

摘要

Abstract

关键词

Keywords

references