Synergistic effect of resveratrol and curcumin against doxorubicin-induced cardiac injury: Network pharmacology, molecular mechanisms and in-vivo evidence
TL;DR
Concomitant therapy with resveratrol and curcumin confers robust cardioprotection against doxorubicin-induced cardiotoxicity in rats, supporting their potential for future investigation as adjunct therapies during anthracycline treatment.
Abstract
To evaluate the cardioprotective effects of resveratrol and curcumin, individually and in combination, against doxorubicin- induced cardiac toxicity and explore the underlying mechanisms via network pharmacology. In silico target prediction, enrichment analyses, and Cytoscape network modeling were performed to investigate shared molecular targets and pathways among resveratrol, curcumin and doxorubicin. Male Wistar rats ( n =6/group) received oral treatments of vehicle, nebivolol (5 mg/kg), resveratrol (20 mg/kg), curcumin (100 mg/kg), resveratrol plus curcumin for 28 d, with cardiotoxicity induced via doxorubicin (2.5 mg/kg, i.p .) on days 7 and 14. Cardioprotection was evaluated using electrocardiographic, hemodynamic, biochemical, RT-PCR, and histopathological assays. Network analysis revealed four common targets (NFE2L2/ Nrf2, TNF, CYP3A4, and MAPT) with significant protein-protein interaction enrichment ( P =0.019 6), implicating modulation of redox balance, inflammation, and xenobiotic metabolism. Concomitant therapy with resveratrol and curcumin significantly mitigated doxorubicin-induced cardiac injury by suppressing relative heart weight, reducing myocardial infarction area, reversing electrocardiographic and conduction abnormalities, attenuating dyslipidemia, and lowering serum CK-MB, LDH, and troponin I leakage ( P < 0.05). Furthermore, combination treatment was more effective in restoring cardiac antioxidants, decreasing lipid peroxidation, downregulating mRNA expressions of TNF-α and NF-κB , upregulating Nrf2 mRNA expression, and improving myocardial architecture compared with individual monotherapies. Concomitant therapy with resveratrol and curcumin confers robust cardioprotection against doxorubicin-induced cardiotoxicity in rats, likely via coordinated activation of Nrf2- mediated antioxidant defenses and suppression of TNF-α/NF- κB-driven inflammation, supporting their potential for future investigation as adjunct therapies during anthracycline treatment.