甘草查耳酮 A 可通过 PI3K/AKT/MDM2/p53 通路减轻多柔比星诱导的心脏毒性中的铁变态反应

Ganxiao Chen, Shunxiang Luo, Hongdou Guo, Jiayi Lin, Shanghua Xu
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摘要

甘草中的黄酮类化合物甘草查尔酮 A(Lico A)具有多种药理活性,可调节氧化应激、血糖、炎症和脂质代谢。本研究旨在探索 Lico A 在减轻与多柔比星诱导的心脏毒性(DIC)相关的铁变态反应方面的潜在机制。首先,应用网络药理学分析确定了甘草中的活性成分及其与 DIC 相关的靶基因。随后,为了评估甘草 A 在 DIC 小鼠模型中的作用,测量了心电图、心肌损伤标志物和心肌组织病理学变化。此外,还测量了细胞模型中的细胞活力、活性氧(ROS)、亚铁、谷胱甘肽/二硫化谷胱甘肽(GSH/GSSG)和丙二醛(MDA)等铁中毒标志物。最后,在体外和体内测量了 PI3K/AKT/MDM2/p53 信号通路和铁变态相关蛋白。生物信息学结果显示,包括Lico A在内的8种主要甘草化合物主要调控DIC中的p53和PI3K/AKT信号通路等靶标。在 DIC 小鼠模型中,Lico A 能明显改善血清生物标志物、组织病理学和心电图异常。用 Lico A 预处理可提高用多柔比星处理的 H9C2 细胞的存活率。此外,服用 Lico A 还降低了 ROS、亚铁和 MDA 的水平,提高了 GSH/GSSG 的水平。在蛋白质水平上,Lico A 增加了 PI3K/AKT/MDM2 的磷酸化,减少了 p53 的积累,并诱导了 SLC7A11 和 GPX4 表达的上调。总之,Lico A 可通过激活 PI3K/AKT/MDM2 信号抑制 p53 介导的铁变态反应,从而减轻 DIC。
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Licochalcone A alleviates ferroptosis in doxorubicin-induced cardiotoxicity via the PI3K/AKT/MDM2/p53 pathway

Licochalcone A (Lico A), a flavonoid found in licorice, possesses multiple pharmacological activities in modulating oxidative stress, glycemia, inflammation, and lipid metabolism. This study aimed to explore the potential mechanism of Lico A in mitigating ferroptosis associated with doxorubicin-induced cardiotoxicity (DIC). Initially, network pharmacology analysis was applied to identify the active components present in licorice and their targeted genes associated with DIC. Subsequently, to assess the role of Lico A in a DIC mouse model, electrocardiograms, myocardial injury markers, and myocardial histopathological changes were measured. Additionally, cell viability, reactive oxygen species (ROS), ferrous iron, glutathione/glutathione disulfide (GSH/GSSG), and malondialdehyde (MDA) were measured in the cell model as hallmarks of ferroptosis. Finally, the PI3K/AKT/MDM2/p53 signaling pathway and ferroptosis-related proteins were measured in vitro and in vivo. Bioinformatics results revealed that 8 major compounds of licorice, including Lico A, primarily regulated targets such as p53 and the PI3K/AKT signaling pathways in DIC. In the mouse model of DIC, Lico A significantly ameliorated serum biomarkers, histopathology, and electrocardiogram abnormalities. Pretreatment with Lico A enhanced the viability of H9C2 cells treated with doxorubicin. Furthermore, Lico A administration resulted in decreased levels of ROS, ferrous iron, and MDA and increased levels of GSH/GSSG. At the protein level, Lico A increased the phosphorylation of PI3K/AKT/MDM2, reduced p53 accumulation, and induced the upregulation of SLC7A11 and GPX4 expression. However, selective inhibition of PI3K/AKT and plasmid-based overexpression of p53 significantly abolished the anti-ferroptosis functions of Lico A. In conclusion, Lico A attenuates DIC by suppressing p53-mediated ferroptosis through activating PI3K/AKT/MDM2 signaling.

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