Obtusifolin improves cisplatin-induced hepatonephrotoxicity via the Nrf2/HO-1 signaling pathway

Abstract

Cisplatin (CIS) is a highly effective chemotherapeutic drug, but one of its most serious side effects is hepatonephrotoxicity, which varies based on its dosage and duration of use. Previous studies have reported that obtusifolin (OBS) exhibits several pharmacological effects, including antioxidant and antidiabetic activities. In this study, we investigated the protective effects of OBS against CIS-induced hepatonephrotoxicity. OBS (0.5 and 1 mg/kg, i.p.) was administered to male mice for 10 days, while CIS (20 mg/kg, i.p.) was administered on day 7 to induce hepatonephrotoxicity. The results showed that OBS reduced the CIS-induced elevations in AST, ALT, ALP, BUN, and creatinine levels by approximately 14%, 11%, 9%, 18%, and 14%, respectively. OBS also decreased liver and kidney MDA levels by approximately 31% and 25%, while enhancing liver and kidney GSH, SOD, and CAT levels by 50-36%, 80-70%, and 95-55%, respectively. In association with oxidative stress and the apoptotic process, OBS reduced liver and kidney mRNA expression levels of Nrf2 (by approximately 1.7- and 1.6-fold, respectively), HO-1 (by 1.6- and 1.4-fold, respectively), and Bcl-2 (by 1.6- and 1.4-fold, respectively). Additionally, OBS suppressed the mRNA expression levels of NF-kappa B (by 0.7- and 0.7-fold), TNF-alpha (by 0.6- and 0.6-fold), Bax (by 0.8- and 0.7-fold), and Cas-3 (by 0.7- and 0.7-fold). Protein expression analysis revealed that OBS increased Nrf2 (showing a 1.7- to 1.2-fold) and Bcl-2 levels (by 1.3- to 1.8-fold), and reduced Bax (by 0.7- to 0.8-fold) and caspase-3 (by 0.7- and 0.7-fold) levels altered by CIS treatment. Histopathological examinations confirmed that OBS reduced liver and kidney damage caused by CIS. In conclusion, OBS significantly improved CIS-induced hepatonephrotoxicity by reducing oxidative stress, inflammation, and apoptosis via modulation of the Nrf2/HO-1 pathway. These findings suggest that OBS could be a potential therapeutic agent for mitigating the side effects of chemotherapeutics.