中药药理与临床2025，Vol.41Issue(9)：2-9,8.
参兰颗粒通过AMPK/PGC-1α/NRF1介导的线粒体保护改善阿霉素性心脏毒性
Shenlan(参兰)Granules Ameliorate Doxorubicin-Induced Cardiotoxicity through AMPK/PGC-1α/NRF1-Mediated Mitochondrial Protection
摘要
Abstract
Objective:To investigate the protective effects and mechanisms of Shenlan(参兰)Granules on doxorubicin(DOX)-induced cardiotox-icity based on the adenosine monophosphate-activated protein kinase(AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α)/nuclear respiratory factor 1(NRF1)signaling pathway.Methods:The mouse model of DOX-induced cardiotoxicity(DIC)was established by intraperitoneal injection of DOX at a dose of 5 mg/kg once a week for 4 consecutive weeks,which resulted in a cu-mulative DOX dose of 20 mg/kg.After successful modeling,mice were randomly allocated into model control,Shenlan Granules(5.2,10.4,and 20.8 g/kg),and pravastatin(0.04 g/kg)groups.In addition,a normal control group was set up.Mice in each group were administrated with corresponding drug or normal saline by gavage once a day for 28 consecutive days.Echocardiography was employed to evaluate cardiac functions in mice.Histological changes in the myocardium were observed via hematoxylin-eosin staining,Masson staining,and wheat germ agglutinin(WGA)staining.Kits were used to measure the levels of creatine kinase-MB(CK-MB),lactate dehydrogenase(LDH),malondi-aldehyde(MDA),superoxide dismutase(SOD),adenosine triphosphate(ATP),mitochondrial membrane potential(JC-1),and mitochondri-al respiratory chain complexes(I-IV)in mice.Transmission electron microscopy was employed to observe the microstructure of mitochondria.The apoptosis of cardiomyocytes was assessed via terminal deoxynucleoitidyl transferase mediated nick end labeling.The expression of P-AMPK in the heart tissue was detected by immunofluorescence.Western blotting was conducted to determine the expression levels of P-AMPK,AMPK,PGC-1α,NRF1,B-cell lymphoma-2(BCL-2),and BCL-2-associated X protein(BAX)in the heart tissue.Results:Com-pared with the normal control group,the model control group exhibited decreases in left ventricular ejection fraction(LVEF),fractional short-ening(FS),and heart index in mice(P<0.01).Pathological changes in the myocardial tissue were observed in the model control group,in-cluding myofiber deformation,inflammatory cell infiltration,and myocardial cell atrophy.In addition,the model control group showcased an in-creased fibrosis area(P<0.01),elevated levels of CK-MB,LDH,and MDA(P<0.01),a lowered level of SOD(P<0.01),reduced cristae and increased vacuoles of mitochondria,a risen cell apoptosis rate(P<0.01),and decreased ATP content,activities of mitochondrial respira-tory chain complexes(I-IV),and mitochondrial membrane potential in the heart tissue(P<0.01).The protein levels of P-AMPK,P-AMPK/AMPK,NRF1,and BCL-2 were down-regulated(P<0.01),while the protein level of BAX was up-regulated(P<0.01)in the model control group.Compared with the model control group,the Shenlan Granules(20.8 g/kg)group showed increases in LVEF,FS,and heart index(P<0.01),alleviated pathological changes in the heart tissue,reduced the myocardial fibrosis area(P<0.01),lowered levels of CK-MB,LDH,and MDA(P<0.01),and an elevated level of SOD(P<0.01).Furthermore,this group showed improved mitochondrial structure and function with reduced vacuoles and increased cristae,a decreased cell apoptosis rate(P<0.01),and increased ATP content,activities of mito-chondrial respiratory chain complexes(I-IV),and mitochondrial membrane potential in the myocardial tissue(P<0.01).The expression lev-els of P-AMPK,NRF1,P-AMPK/AMPK,PGC-1α,and BCL-2 were up-regulated(P<0.01),while that of BAX was down-regulated(P<0.01)in the Shenlan Granules(20.8 g/kg)group.Conclusion:Shenlan Granules can ameliorate DIC via mitochondrial protection mediated by the AMPK/PGC-1α/NRF1 signaling axis.关键词
参兰颗粒/阿霉素/心脏毒性/线粒体/腺苷酸活化蛋白激酶/过氧化物酶体增殖物激活受体γ辅激活因子-1α/核呼吸因子-1Key words
Doxorubicin/Shenlan Granules/Cardiotoxicity/Mitochondria/Adenosine monophosphate-activated protein kinase(AMPK)/Per-oxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC-1α)/Nuclear respiratory factor-1(NRF1)引用本文复制引用
苏东东,靳庆瑞,赵梦,边汝涛,陈晓阳,张理,徐学功..参兰颗粒通过AMPK/PGC-1α/NRF1介导的线粒体保护改善阿霉素性心脏毒性[J].中药药理与临床,2025,41(9):2-9,8.基金项目
河南省科技攻关项目(编号:242102310528) （编号:242102310528）
河南省中医药科学专项课题(编号:2024ZY2164). （编号:2024ZY2164）
