参附汤抑制铁死亡缓解化疗药物心脏毒性研究  

Shenfu Decoction Alleviates Cardiotoxicity of Chemotherapy Drugs by Inhibiting Ferroptosis

作　　者：黄海燕[1] 翁嘉灏[2] 陆萍[2] 殷佩浩[3] HUANG Haiyan;WENG Jiahao;LU Ping;YIN Peihao(Department of Cardiovascular Medicine,Shanghai Municipal Hospital of Traditional Chinese Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai 200071,China;Department of Cardiology,Shanghai Municipal Hospital of Traditional Chinese Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai 200071,China;Department of General Surgery,Putuo Hospital,Shanghai University of Traditional Chinese Medicine/Interventional Cancer Institute of Chinese Integrative Medicine,Shanghai University of Traditional Chinese Medicine,Shanghai 200062,China)

机构地区：[1]上海中医药大学附属市中医医院心血管内科,上海200071 [2]上海中医药大学附属市中医医院心病科,上海200071 [3]上海中医药大学附属普陀医院普外科/上海中医药大学中西医结合肿瘤介入研究所,上海200062

出　　处：《世界中医药》2024年第10期1369-1378,1385,共11页World Chinese Medicine

基　　金：国家自然科学基金青年科学基金项目(82104758)——基于mTOR信号通路探讨去甲乌药碱调节血管平滑肌细胞自噬和抗动脉粥样硬化的作用及机制研究;上海中医药大学预算内项目(2021LK065)——基于GAS5-miR-21交互抑制PTEN/AKT信号通路探讨强心方抑制心肌纤维化的作用机制。

摘　　要：目的:本研究拟验证参附汤这一经典名方是否通过铁死亡缓解心力衰竭。方法:网络药理学寻找参附汤、心力衰竭、铁死亡重叠基因。Metascape数据库进行基因本体(GO)富集分析及富集分析和京都基因和基因组百科全书(KEGG)通路预测。用阿霉素对H9C2细胞造心肌细胞损伤模型,测定细胞活力、Fe2+含量、铁死亡marker蛋白、蛋白酪氨酸激酶2(JAK2)-信号转导及转录激活蛋白3(STAT3)信号通路表达。C57小鼠阿霉素注射4周造心力衰竭模型,测定左室心射血分数,观察心肌形态学改变,测定肌肉Fe2+含量,免疫组织化学检测验证心肌相关蛋白表达水平。结果:网络药理学研究证实,共有13个重叠基因。PTGS2蛋白等为参附汤基于铁死亡对心力衰竭调控的核心节点。GO功能分析证实,生物过程相关条目有11个,细胞组分3个;分子功能3个。KEGG预测分信号通路4条。Jak-STAT等通路是心力衰竭主要机制。分子对接证实对接能均小于-5 kcal/mol。参附注射液含药血清汤提高细胞活力,减少铁含量,抑制铁死亡marker蛋白,JAK2-STAT3信号通路。动物实验证实,参附注射液改善了小鼠心肌细胞形态学改变,增加了心功能,佐证了细胞实验中铁死亡及JAK2-STAT3调控机制研究。结论:本研究证实铁死亡是参附汤对心力衰竭调控机制,丰富了参附汤调控心肌死亡途径的科学证据。Objective:To verify whether Shenfu Decoction alleviates heart failure by regulating ferroptosis.Methods:Network pharmacology was employed to identify the common genes shared by Shenfu Decoction,heart failure,and ferroptosis.Metascape was used for Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses.Doxorubicin was used to treat H9C2 cells to establish the cell injury model.The cell viability,Fe 2+content,ferroptosis marker,and expression of the Janus kinase 2(JAK2)-signal transducer and activator of transcription 3(STAT3)signaling pathway were measured.C57 mice were injected with doxorubicin for 4 weeks to establish a model of heart failure.The left ventricular ejection fraction and Fe 2+content in the muscle were measured,and the myocardial morphological changes were observed.Immunohistochemistry was employed to examine the expression level of related proteins in the myocardium.Results:A total of 13 genes shared by Shenfu Decoction,heart failure,and ferroptosis were predicted.Prostaglandin-endoperoxide synthase 2(PTGS2)was the core target of Shenfu Decoction in treating heart failure via ferroptosis.The GO functional analysis revealed 11,3,and 3 terms of biological processes,cellular components,and molecular functions,respectively.The KEGG pathway enrichment analysis predicted 4 signaling pathways.JAK-STAT was the main pathway involved in heart failure.Molecular docking showcased that the docking energy was less than-5 kcal/mol for all the docking combinations.The serum containing Shenfu Decoction improved cell viability,reduced Fe 2+content,inhibited ferroptosis marker,and modulated the JAK2-STAT3 signaling pathway.The animal experiment confirmed that Shenfu Decoction repaired the morphological changes of myocardial cells and improved the cardiac function in mice,which supported the results of the cell experiments on ferroptosis and the modulation mechanism involving the JAK2-STAT3 signaling pathway.Conclusion:This study confirmed that Shenfu Decoction treated heart failure by r

关 键 词：参附汤 心力衰竭 网络药理学 数据挖掘 分子对接 化疗药物 铁死亡 JAK2-STAT3信号通路 

分 类 号：R273[医药卫生—中西医结合]