Mechanism of Ginkgo flavone aglycone in alleviating doxorubicin-induced cardiotoxicity based on transcriptomics and proteomics
- VernacularTitle: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
- Author:
Yujie TU
1
,
2
;
Ying CAI
1
,
2
;
Xueyi CHENG
1
,
2
;
Jia SUN
1
;
Jie PAN
3
;
Chunhua LIU
3
;
Yongjun LI
2
,
3
;
Yong HUANG
3
;
Lin ZHENG
1
;
Yuan LU
1
Author Information
1. State Key Laboratory of Functions and Applications of Medicinal Plants/Guizhou Provincial Key Laboratory of Pharmaceutics，Guizhou Medical University，Guiyang 550004，China
2. School of Pharmacy，Guizhou Medical University，Guiyang 550004，China
3. Engineering Research Center for the Development and Application of Ethnic Medicine and TCM（Ministry of Education），Guizhou Medical University，Guiyang 550004，China
- Publication Type:Journal Article
- Keywords:
Ginkgo flavone aglycone;
doxorubicin;
cardiotoxicity;
transcriptomics;
proteomics;
toxicity reduction mechanism
- From:
China Pharmacy
2024;35(21):2596-2602
- CountryChina
- Language:Chinese
-
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 （P＜0.05 or P＜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 （P＜0.05 or P＜0.01）. Cellular experiments indicated that compared to the CON group， cell viability in the DOX group was significantly decreased （P＜0.05）， the relative uptake of glucose and the relative production of pyruvate and lactate were significantly increased （P＜0.05）， and the relative production of ATP was significantly reduced （P＜0.05）. Compared to the DOX group， cell viability in the GDOX group was significantly increased （P＜ 0.05）， and the relative production of pyruvate and lactate was significantly reduced （P＜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.
