The effect of astragaloside IV on doxorubicin-induced cardiotoxicity in young mice: exploring its cardioprotective effect during childhood tumor chemotherapy.
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BACKGROUND: Anthracyclines such as doxorubicin (DOX) are essential treatments in pediatric oncology but are highly associated with severe dose-dependent cardiotoxicity. The developing hearts of young patients are particularly vulnerable to DOX-induced oxidative damage, creating an urgent need for effective and safe cardioprotective strategies. This study aims to explore the protective efficacy of astragaloside IV (AS-IV) against DOX-induced cardiotoxicity in juvenile mice and investigate the underlying molecular mechanisms involving the silent information regulator 1 (Sirt1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling axis and oxidative stress regulation. METHODS: Cell viability, reactive oxygen species (ROS) levels and Sirt1/Nrf2/heme oxygenase-1 gene expression were detected through Cell Counting Kit-8 (CCK-8), dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe and real-time quantitative polymerase chain reaction (RT-qPCR). For in vivo experiments, 3-week-old C57BL/6 young mice were randomly divided into control group, DOX group (3 mg/kg) and AS-IV group (5 mg/kg). Three days after administration, cardiac damage and protective effects were evaluated through weight monitoring, echocardiography, serum creatine kinase muscle/brain (MB) isoenzyme, hematoxylin-eosin staining, and caspase-3 immunofluorescence. RESULTS: In vitro AS-IV significantly increased cell viability (68.5% vs. 56.2%), reduced ROS fluorescence intensity and malondialdehyde content, and up-regulated Sirt1/Nrf2. In vivo studies showed that AS-IV effectively alleviated DOX-induced growth arrest in young mice (body weight growth rate 13.5% vs. -2.3%). Ultrasound showed significant improvement in left ventricular ejection fraction (65.4% vs. 48.2%). Serum creatine kinase isoenzyme MB level decreased from 5.29 to 4.09 ng/mL. In addition, AS-IV significantly reduced myocardial pathological damage, inhibited caspase-3-positive apoptosis rate from 28.5% to 12.4%, and restored tissue superoxide dismutase/glutathione activity. CONCLUSIONS: AS-IV can inhibit oxidative stress and apoptosis by activating the Sirt1/Nrf2, effectively reduce DOX-induced cardiotoxicity in young mice and maintain normal growth and development, and has clinical application potential.