DOI: 10.4103/apjtb.apjtb_157_26 ISSN: 2221-1691
Synergistic effect of resveratrol and curcumin against doxorubicin-induced cardiac injury: Network pharmacology, molecular mechanisms and in-vivo evidence
Gaurav Borse, Raosaheb Ghegade, Mahesh Ghaisas, Vaibhav Shinde, Ravindra Kulkarni, Hemant Kamble, Amol Muthal
Objective:
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.
Methods:
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.
Results:
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.
Conclusions:
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.