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Journal of Zhejiang University SCIENCE B 2024 Vol.25 No.9 P.756-772

http://doi.org/10.1631/jzus.B2300691


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


Author(s):  Hai ZOU, Mengyu ZHANG, Xue YANG, Huafeng SHOU, Zhenglin CHEN, Quanfeng ZHU, Ting LUO, Xiaozhou MOU, Xiaoyi CHEN

Affiliation(s):  Department of Critical Care Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China; more

Corresponding email(s):   mouxz@zju.edu.cn, joicecxy@hotmail.com

Key Words:  Cynaroside, Doxorubicin, Pyroptosis, Cardiotoxicity, Oxidative stress


Hai ZOU, Mengyu ZHANG, Xue YANG, Huafeng SHOU, Zhenglin CHEN, Quanfeng ZHU, Ting LUO, Xiaozhou MOU, Xiaoyi CHEN. Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis[J]. Journal of Zhejiang University Science B, 2024, 25(9): 756-772.

@article{title="Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis",
author="Hai ZOU, Mengyu ZHANG, Xue YANG, Huafeng SHOU, Zhenglin CHEN, Quanfeng ZHU, Ting LUO, Xiaozhou MOU, Xiaoyi CHEN",
journal="Journal of Zhejiang University Science B",
volume="25",
number="9",
pages="756-772",
year="2024",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2300691"
}

%0 Journal Article
%T Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis
%A Hai ZOU
%A Mengyu ZHANG
%A Xue YANG
%A Huafeng SHOU
%A Zhenglin CHEN
%A Quanfeng ZHU
%A Ting LUO
%A Xiaozhou MOU
%A Xiaoyi CHEN
%J Journal of Zhejiang University SCIENCE B
%V 25
%N 9
%P 756-772
%@ 1673-1581
%D 2024
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2300691

TY - JOUR
T1 - Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis
A1 - Hai ZOU
A1 - Mengyu ZHANG
A1 - Xue YANG
A1 - Huafeng SHOU
A1 - Zhenglin CHEN
A1 - Quanfeng ZHU
A1 - Ting LUO
A1 - Xiaozhou MOU
A1 - Xiaoyi CHEN
J0 - Journal of Zhejiang University Science B
VL - 25
IS - 9
SP - 756
EP - 772
%@ 1673-1581
Y1 - 2024
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2300691


Abstract: 
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 receptor γ coactivator-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.

木犀草苷通过调节AMPK/SIRT3/Nrf2通路抑制阿霉素诱导的心肌细胞焦亡

邹海1,2,张梦宇3,杨雪4,寿华锋5,陈正琳6,竺泉峰6,罗婷7,牟晓洲4,8,陈晓怡4,8
1复旦大学附属肿瘤医院重症医学科,中国上海市,200032
2复旦大学上海医学院肿瘤学系,中国上海市,200032
3湘湖实验室,中国杭州市,311231
4浙江省人民医院(杭州医学院附属人民医院)临床医学研究所,浙江省肿瘤分子诊断与个体化治疗研究重点实验室,中国杭州市,310014
5浙江省人民医院(杭州医学院附属人民医院)妇科,生殖医学中心,中国杭州市,310014
6浙江中医药大学研究生院,中国杭州市,310053
7农产品质量安全危害因子与风险防控国家重点实验室,农业农村部农产品质量安全风险评估实验室(杭州),浙江省农业科学院农产品质量安全与营养研究所,中国杭州市,310021
8浙江省人民医院(杭州医学院附属人民医院)普外科,肿瘤中心,肝胆胰外科及微创外科,中国杭州市,310014
摘要:阿霉素(DOX)是一种可用于治疗血液系统恶性肿瘤及实体瘤的常用化疗药物,但其临床应用受到明显的心脏毒性的限制。木犀草苷(Cyn)是一种存在于金银花中的类黄酮苷类化合物,具有调节炎症、细胞焦亡和氧化应激等潜在的生物学功能。本研究通过每周一次腹腔注射DOX(5 mg/kg)并连续注射三周以构建DOX诱导的心脏毒性(DIC)小鼠模型,用于评估Cyn的作用。治疗组小鼠每两天给予右唑嗪、MCC950和Cyn处理。通过血液生化、组织病理学、免疫组织化学、定量反转录聚合酶链反应(RT-qPCR)和蛋白质印迹(western blotting)等方法探讨Cyn治疗对心脏的保护作用及其可能机制。研究结果显示,Cyn治疗在缓解DIC方面具有显著的效果,能在一定程度上有效缓解氧化应激,维持细胞凋亡平衡并增强小鼠心脏功能。上述这些作用主要通过调节核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)、半胱氨酸天冬氨酸蛋白酶-1(caspase-1)和GSDMD等与焦亡相关基因的转录水平来实现。此外,机制研究表明,Cyn可以显著调节DOX诱导心肌损伤小鼠组织中关键基因5’-磷酸腺苷活化蛋白激酶(AMPK)、过氧化物酶体增殖物激活受体γ共激活剂-1α(PGC-1α)、去乙酰化酶Sirtuin3(SIRT3)和核因子-E2相关因子2(Nrf2)的表达,因此我们推测AMPK/SIRT3/Nrf2通路在对抗DOX诱导的心肌细胞损伤中起着核心作用。综上所述,本研究证实了Cyn通过调节AMPK/SIRT3/Nrf2通路在治疗DIC方面的潜力。

关键词:木犀草苷;阿霉素;焦亡;心脏毒性;氧化应激

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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