Doxorubicin (DOX) is an available chemotherapeutic drug for treating various tumors. However, its effectiveness is limited by cardiotoxicity. Amentoflavone (AMF), a natural biflavonoid separated from Cycas thouarsii ethyl acetate fraction, displays promising anticancer, anti-inflammatory, and antioxidant effects. Thus, our research aims to explore whether AMF could boost cardioprotective effects against DOX cardiotoxicity and reveal the potential underlying mechanisms of cardioprotection. Mice were classified into four groups; Normal control, Untreated DOX group, and DOX groups treated with AMF (40 and 80 mg/kg, respectively) intraperitoneal injection daily for four days before doxorubicin administration and for additional three days following DOX administration to assess cardiotoxicity. Echocardiography showed that AMF 80 treated group was protected from DOX cardiotoxicity. Additionally, it alleviated histopathological structural alterations and effectively restored heart weight and body weight ratio. These effects were confirmed biochemically by a substantially reduced serum creatine kinase-MB (CK-MB) and aspartate aminotransferase (AST) levels. AMF effectively restored nuclear respiratory factor-1(NRF-1), mitochondrial transcription factor A (TFAM), and normalized heat shock protein − 27(HSP-27) expression levels compared to the DOX group. Moreover, AMF mitigated oxidative stress conditions and significantly suppressed NADPH oxidase (NOX) expression levels. It also showed significant anti-inflammatory effects via suppressing interleukin-6 (IL-6) expression and decreasing nuclear factor Kabba B (NF-κb) immune-staining. In addition, AMF markedly reduced FAS ligand (FASL) expression and p53 immune staining in cardiac tissue.

This study is the first for the in vivo potential beneficial effects of AMF against acute DOX cardiotoxicity, possibly via exerting antioxidant, anti-inflammatory, and anti-apoptotic effects and restoring mitochondrial function.Doxorubicin-induced cardiotoxicity by several mechanisms including NOX up regulation resulting in oxidative stress, suppression of HSP-27 leading to apoptosis and oxidative stress, activation of NFĸB, FASL, P53 inducing myocardial apoptosis, and down-regulation of mitochondrial genes NRF-1, TFAM leading to mitochondrial dysfunction. All these events eventually induced myocardial damage. AMF prior treatment safeguards against DOX cardiotoxicity by modulation of all these pathways and preserving mitochondrial function. Amentoflavone (AMF), FAS ligand (FASL), Heat shock protein-27 (HSP-27), NADPH oxidase (NOX), Nuclear factor Kabba B (NFĸB), Nuclear respiratory factor-1(NRF-1) and Mitochondrial transcription factor A(TFAM).

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Mishita
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Journal of Heart and Cardiovascular Research