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[摘要]
目的 研究槲皮素抗阿霉素诱导心肌毒性的网络多靶标机制。方法 成年ICR小鼠随机分为对照组、阿霉素组和槲皮素组(每组8只)。给药结束后收集血清,用于测量肌酸激酶(CK)和乳酸脱氢酶(LDH)水平。同时快速取心脏组织液氮冷冻,用于蛋白质组学研究,将得到的差异蛋白与槲皮素已知靶标蛋白进行网络分析,筛选其抗阿霉素诱导心肌毒性所靶向的蛋白。结果 槲皮素能显著抑制阿霉素诱导的血清CK和LDH的升高,缓解阿霉素诱导的心肌损伤。蛋白质组学分析结果表明槲皮素通过调节40个差异蛋白的表达来发挥心肌保护作用。基因本体分析和通路富集分析结果表明,槲皮素主要通过调节氧化还原、能量代谢、脂肪酸代谢、高密度脂蛋白和凋亡来发挥心肌保护作用。进一步的网络分析结果筛选出了槲皮素调节以上生物过程和通路靶向的11个靶标蛋白。结论 槲皮素主要通过靶向11个靶标蛋白调节氧化还原、能量代谢、脂肪酸代谢、高密度脂蛋白和凋亡来缓解阿霉素诱导的心肌毒性。
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[Abstract]
Objective To investigate the multi-target action mechanism of quercetin against doxorubicin-induced myocardial toxicity. Methods Adult ICR mice were randomly divided into control group, doxorubicin group, and quercetin treatment group (n=8). After experiments, serum was collected for measurement of creatine kinase and lactate dehydrogenase, and cardiac tissue cryopreservation was rapidly excised for proteomics studies. Finally, a network of differential proteins and known target proteins of quercetin was constructed to identify target proteins of quercetin against doxorubicin-induced myocardial toxicity. Results Quercetin significantly reduced the concentration of doxorubicin-induced elevated serum creatine kinase and lactate dehydrogenase, suggesting that quercetin can alleviate doxorubicin-induced myocardial damage. Proteomic results indicated that quercetin protected doxorubicin-induced cardiotoxicity by regulating differential expression of 40 proteins. Gene ontology analysis and pathway enrichment analysis showed that quercetin mainly exerted myocardial protection by regulating redox, energy metabolism, fatty acid metabolism, high density lipoprotein, and apoptosis. Further network analysis screened out 11 proteins that quercetin targeted to regulate the above biological processes and pathways. Conclusion Quercetin relieves doxorubicin-induced myocardial toxicity by targeting 11 proteins and then regulating redox, energy metabolism, fatty acid metabolism, high-density lipoprotein, and apoptosis.
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[基金项目]
国家自然科学基金资助项目(81773683)