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Journal of Zhejiang University SCIENCE B
ISSN 1673-1581(Print), 1862-1783(Online), Monthly
2024 Vol.25 No.9 P.756-772
Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis
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.
Key words: Cynaroside; Doxorubicin; Pyroptosis; Cardiotoxicity; Oxidative stress
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。
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DOI:
10.1631/jzus.B2300691
CLC number:
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On-line Access:
2024-08-27
Received:
2023-10-17
Revision Accepted:
2024-05-08
Crosschecked:
2024-09-23