Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis  

作　　者：Hai ZOU Mengyu ZHANG Xue YANG Huafeng SHOU Zhenglin CHEN Quanfeng ZHU Ting LUO Xiaozhou MOU Xiaoyi CHEN 

机构地区：[1]Department of Critical Care Medicine,Fudan University Shanghai Cancer Center,Shanghai,200032,China [2]Department of Oncology,Shanghai Medical College,Fudan University,Shanghai,200032,China [3]Xianghu Laboratory,Hangzhou,311231,China [4]Clinical Research Institute,Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province,Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital),Hangzhou Medical College,Hangzhou,310014,China [5]Center for Reproductive Medicine,Department of Gynecology,Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital),Hangzhou Medical College,Hangzhou,310014,China [6]Graduate School of Zhejiang Chinese Medical University,Hangzhou,310053,China [7]State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products,Laboratory(Hangzhou)for Risk Assessment of Agricultural Products of Ministry of Agriculture,Institute of Agro-product Safety and Nutrition,Zhejiang Academy of Agricultural Sciences,Hangzhou,310021,China [8]General Surgery,Cancer Center,Department of Hepatobiliary&Pancreatic Surgery and Minimally Invasive Surgery,Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital),Hangzhou Medical College,Hangzhou,310014,China

出　　处：《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》2024年第9期756-772,共17页浙江大学学报（英文版）B辑（生物医学与生物技术）

基　　金：Zhejiang Traditional Chinese Medicine Science and Technology Project(Nos.2022ZZ004 and GZY-ZJ-KJ-Z24062),China.

摘　　要：Doxorubicin(DOX)is a commonly administered chemotherapy drug for treating hematological malignancies and solid tumors;however,its clinical application is limited by significant cardiotoxicity.Cynaroside(Cyn)is a flavonoid glycoside distributed in honeysuckle,with confirmed potential biological functions in regulating inflammation,pyroptosis,and oxidative stress.Herein,the effects of Cyn were evaluated in a DOX-induced cardiotoxicity(DIC)mouse model,which was established by intraperitoneal injections of DOX(5 mg/kg)once a week for three weeks.The mice in the treatment group received dexrazoxane,MCC950,and Cyn every two days.Blood biochemistry,histopathology,immunohistochemistry,reverse transcription-quantitative polymerase chain reaction(RT-qPCR),and western blotting were conducted to investigate the cardioprotective effects and potential mechanisms of Cyn treatment.The results demonstrated the significant benefits of Cyn treatment in mitigating DIC;it could effectively alleviate oxidative stress to a certain extent,maintain the equilibrium of cell apoptosis,and enhance the cardiac function of mice.These effects were realized via regulating the transcription levels of pyroptosis-related genes,such as nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3),caspase-1,and gasdermin D(GSDMD).Mechanistically,for DOX-induced myocardial injury,Cyn could significantly modulate the expression of pivotal genes,including adenosine monophosphate-activated protein kinase(AMPK),peroxisome proliferator-activated receptorγcoactivator-1α(PGC-1α),sirtuin 3(SIRT3),and nuclear factor erythroid 2-related factor 2(Nrf2).We attribute it to the mediation of AMPK/SIRT3/Nrf2 pathway,which plays a central role in preventing DOX-induced cardiomyocyte injury.In conclusion,the present study confirms the therapeutic potential of Cyn in DIC by regulating the AMPK/SIRT3/Nrf2 pathway.

关 键 词：Cynaroside DOXORUBICIN PYROPTOSIS CARDIOTOXICITY Oxidative stress 

分 类 号：R285.5[医药卫生—中药学]