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Vinpocetine (Vin), a synthetic-derivative of the Vinca alkaloid- Vincamine, has been reported to possess a variety of health benefits. We herein investigated the critical role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant response in the protection of Vin against H2O2 and paracetamol (APAP)-induced liver toxicity. For this purpose, a normal human hepatic cell line (L02 cells) was incubated with cytotoxic concentrations of H2O2 or APAP in the presence or absence of Vin. To evaluate the responses, MTS Cell Viability assay, immunoblotting, biochemical assays, and molecular docking approach were used. Viability analysis showed that treatment of L02 cells with Vin prevented the cytotoxicity induced by H2O2 and APAP. It was evidenced by the fact that Vin dumped H2O2 and APAP cytotoxicity and reactive oxygen species (ROS) generation. The immunoblotting analysis shows that Vin increased Nrf2 expression along with the expression of target protein, heme oxygenase-1 (HO-1), and increased intracellular glutathione (GSH) level. Interestingly, we found that Vin could enhance the thermal stability of Keap1, which indicated the potential interaction between Vin and Keap1. Furthermore, molecular docking revealed that Vin possibly competed with Nrf2 for Keap1-binding site, with hydrogen and stearic interactions. Collectively, Vin effectively protects against H2O2 and APAP -induced hepatotoxicity via executing Nrf2-mediated antioxidative signaling pathway. Meanwhile, Vin interrupts protein-protein interaction between Keap1 and Nrf2 which might also contribute to decrease Nrf2 degradation and stabilize protein expression. Thus, Vin-based adjuvant therapy may represent a smart drug regimen to mitigate drug-induced oxidative stress and liver injuries.
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