芪参颗粒防治阿霉素所致心肌损伤的作用机制研究及实验验证

Mechanism and Experimental Verification of Qishen Granules in the Treatment of Doxorubicin-induced Myocardial Injury

目的:基于网络药理学及实验研究,验证芪参颗粒(QSG)治疗阿霉素心肌损伤的作用机制。方法:在中药系统药理学数据库与分析平台(TCMSP)筛选QSG的活性成分及作用靶点,借助人类基因数据库(GeneCards)、在线人类孟德尔遗传数据库(OMIM)、遗传药理学与药物基因组学数据库(PharmGKB)等疾病数据库搜索阿霉素心肌损伤靶点,使用蛋白质相互作用分析数据库(STRING)数据库分析蛋白质-蛋白质相互作用(PPI)进行互作分析。利用Cytoscape构建网络,Hiplot数据库进行基因组百科全书(KEGG)富集分析。最后,通过实验对QSG的药效、靶点及通路进行验证。结果:QSG中共检索到174种化学成分,无重复靶点261个,疾病数据库共检索到1 521个无重基因,二者交集靶点为156个。PPI网络提取了排名前十的基因,大多与炎症反应相关。KEGG富集结果显示主要与促分裂原活化的蛋白激酶(MAPK)、磷脂酰肌醇3激酶/蛋白激酶B(PI3K/AKT)、verified by experi及癌症信号通路等相关。体内实验结果表明,QSG可明显提高小鼠的心功能,改善病理组织损伤并降低炎症细胞浸润,同时能显著提高磷酸化蛋白激酶B(p-AKT)并降低磷酸化促分裂原活化的蛋白激酶(p-MAPK)及磷酸化核因子κB(p-NF-κB)的表达。体外结果表明QSG可明显降低炎症介质的含量,且联合使用阿霉素时不会影响阿霉素本身的抗肿瘤效果。结论:QSG显示出良好的抗阿霉素心肌损伤作用,其机制可能与其抗炎作用相关。

Objective:This paper aims to explore the mechanism of Qishen Granules in the treatment of doxorubicin-induced myocardial injury(DIMI) based on network pharmacology and experimental verification.Methods:The active components and targets of Qishen Granules were screened in the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform(TCMSP),and the targets of doxorubicin-induced myocardial injury were searched with the help of disease databases such as The Human Gene Database(Genecards),Online Mendelian Inheritance in Man(OMIM),and Pharmacogenetics and Pharmacogenomics Knowledge Base(PharmGKB).The protein-protein interaction(PPI) was analyzed using the STRING database for interaction analysis.The network was then constructed using Cytoscape,and the Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis was performed using the Hiplot database.Finally,the efficacy,targets,and related pathways of Qishen Granules were verified by experiments.Results:A total of 174 chemical constituents were retrieved in Qishen Granules;261 non-duplicate targets were retrieved,and 1 521 non-duplicate genes were retrieved from the disease database,with 156 intersecting targets.The PPI network extracted the top ten genes,most of which were related to inflammation.KEGG enrichment results showed that mitogen activated-protein kinase(MAPK),phosphoinositide 3-kinase/protein kinase(PI3K/AKT) B,p53,and cancer signaling pathways were the main influencing factors.The results of in vivo experiments showed that Qishen Granules could significantly improve the cardiac function of mice,improve pathological tissue damage,and reduce the infiltration of inflammatory cells,while significantly increasing the expression of p-AKT and reducing the p-MAPK and p-NFκB.The in vitro results showed that Qishen Granules could significantly reduce the content of inflammatory mediators,without affecting the antitumor effect of doxorubicin itself when it was used with doxorubicin.Conclusion:Qishen Granules can protect against DIMI,and the mechanism may be related to its anti-inflammatory effect.