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<p>Citrus fruits are rich in flavonoids, such as diosmin and hesperidin, which exhibit antioxidant properties. The combination of diosmin and hesperidin (DH) has shown potential cardiovascular benefits. Doxorubicin (DOX) is a chemotherapy drug known to cause cardiotoxicity. Hearts pre-treated with DOX show increased susceptibility to ischemia-reperfusion (I/R) damage. This study aimed to investigate the cardioprotective potential of DH against I/R injury in animal models with prior DOX exposure. Rats were divided into five groups: control group (normal saline); DOX group (2.5&#xa0;mg/kg intraperitoneally, six times over two weeks); DOX + low-DH group (50&#xa0;mg/kg/day orally for 14 days); DOX + high-DH group (100&#xa0;mg/kg/day orally for 14 days); and DH group (100&#xa0;mg/kg/day orally for 14 days). Following treatments, isolated hearts underwent global ischemia-reperfusion protocol with hemodynamic measurements recorded at baseline and post-reperfusion. DH pre-treatment significantly reduced DOX-associated cardiac injury, demonstrating protective effects both under baseline conditions and during post-ischemia recovery by improving LVDP and RPP, reducing coronary flow LDH levels, and mitigating histopathological damage (necrosis, degradation, and inflammation). Additionally, DH increased the cardiac GSH to GSSG ratio and enhanced GPx activity, while decreasing GSR activity. Furthermore, DH pretreatment down-regulated the overexpression of AKT, mTORC1, and ULK1 mRNA. Moreover, the molecular docking study demonstrated that Daflon’s active components (diosmin and hesperidin) counteract DOX-induced cardiotoxicity by dually inhibiting both AKT and mTORC1 expression. These findings demonstrated that DH protected against DOX-induced I/R damage via AKT/mTORC1 modulation.</p> Graphical Abstract <p></p>

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Diosmin-Hesperidin Combination Improves Post-Ischemic Cardiac Recovery Via AKT/mTORC1 Modulation in Doxorubicin-Treated Rats

  • 期刊论文

  • 发表日期：

    2026年2月6日

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  • Mahvash Hesari,
  • Dareuosh Shackebaei,
  • Pantea Mohammadi,
  • Seyed Shahram Miraghaee,
  • Kheirollah Yari,
  • Zahra Minoosh Siavosh Haghighi,
  • Mohammad Bagher Majnooni,
  • Fatemeh Yarmohammadi

摘要

Citrus fruits are rich in flavonoids, such as diosmin and hesperidin, which exhibit antioxidant properties. The combination of diosmin and hesperidin (DH) has shown potential cardiovascular benefits. Doxorubicin (DOX) is a chemotherapy drug known to cause cardiotoxicity. Hearts pre-treated with DOX show increased susceptibility to ischemia-reperfusion (I/R) damage. This study aimed to investigate the cardioprotective potential of DH against I/R injury in animal models with prior DOX exposure. Rats were divided into five groups: control group (normal saline); DOX group (2.5 mg/kg intraperitoneally, six times over two weeks); DOX + low-DH group (50 mg/kg/day orally for 14 days); DOX + high-DH group (100 mg/kg/day orally for 14 days); and DH group (100 mg/kg/day orally for 14 days). Following treatments, isolated hearts underwent global ischemia-reperfusion protocol with hemodynamic measurements recorded at baseline and post-reperfusion. DH pre-treatment significantly reduced DOX-associated cardiac injury, demonstrating protective effects both under baseline conditions and during post-ischemia recovery by improving LVDP and RPP, reducing coronary flow LDH levels, and mitigating histopathological damage (necrosis, degradation, and inflammation). Additionally, DH increased the cardiac GSH to GSSG ratio and enhanced GPx activity, while decreasing GSR activity. Furthermore, DH pretreatment down-regulated the overexpression of AKT, mTORC1, and ULK1 mRNA. Moreover, the molecular docking study demonstrated that Daflon’s active components (diosmin and hesperidin) counteract DOX-induced cardiotoxicity by dually inhibiting both AKT and mTORC1 expression. These findings demonstrated that DH protected against DOX-induced I/R damage via AKT/mTORC1 modulation.

Graphical Abstract