The protective effect of 7-hydroxycoumarin against cisplatin-induced liver injury is mediated via attenuation of oxidative stress and inflammation and upregulation of Nrf2/HO-1 pathway.

Cisplatin (CIS) is an effective chemotherapy against different solid cancers. However, the adverse effects, including hepatotoxicity, limit its clinical use. 7-hydroxycoumarin (7-HC) possesses antioxidant and hepatoprotective activities, but its protective effect against CIS hepatotoxicity has not been investigated. This study evaluated the effect of 7-HC on liver injury, oxidative stress (OS), and inflammation provoked by CIS. Rats received 7-HC (25, 50, and 100 mg/kg) orally for 2 weeks followed by intraperitoneal injection of CIS (7 mg/kg) at day 15. CIS increased serum transaminases, alkaline phosphatase (ALP), and bilirubin and provoked tissue injury accompanied by elevated reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO). Liver nuclear factor (NF)-κB p65, inducible NO synthase (iNOS), pro-inflammatory cytokines, Bax, and caspase-3 were upregulated, and antioxidant defenses and Bcl-2 were decreased in CIS-treated rats, while 7-HC prevented liver injury and ameliorated OS, inflammatory and apoptosis markers. In addition, 7-HC enhanced nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase (HO)-1 in CIS-administered rats and in silico studies revealed its binding affinity toward HO-1. In conclusion, 7-HC protected against CIS hepatotoxicity by mitigating OS and inflammatory response and modulating Nrf2/HO-1 pathway.

7-hydroxycoumarin modulates Nrf2/HO-1 and microRNA-34a/SIRT1 signaling and prevents cisplatin-induced oxidative stress, inflammation, and kidney injury in rats.

The kidneys are vulnerable to toxicity and acute kidney injury (AKI) is the main adverse effect associated with the clinical use of the chemotherapeutic agent cisplatin (CIS). Oxidative stress and inflammation are implicated in CIS nephrotoxicity. In this study, the effect of the antioxidant 7-hydroxycoumarin (7-HC) against CIS-induced renal intoxication was evaluated. Rats received 7-HC (25, 50, and 100 mg/kg) orally for 14 days and CIS (7 mg/kg) at day 15, and samples were collected 3 days after CIS administration. CIS increased serum urea, creatinine and kidney injury molecule (Kim)-1, caused multiple histopathological changes and increased renal reactive oxygen species (ROS), malondialdehyde (MDA), nitric oxide (NO), NF-κB p65, iNOS, and pro-inflammatory cytokines. 7-HC dose-dependently prevented kidney dysfunction and tissue injury and suppressed ROS and inflammatory mediators. 7-HC boosted renal antioxidants and Bcl-2 while decreased Bax and caspase-3 expression in CIS-administered rats. In addition, 7-HC downregulated Keap-1 and microRNA-34a and upregulated Nrf2, NQO-1, HO-1, and SIRT1. Molecular docking revealed the binding affinity of 7-HC towards NF-κB, Keap-1, and SIRT1. In Conclusion, 7-HC prevented CIS nephrotoxicity by attenuating tissue injury, oxidative stress, inflammation, and apoptotic cell death. The protective efficacy of 7-HC was associated with inhibiting NF-κB and Keap-1, and modulating Nrf2/HO-1 and microRNA34a/Sirt1 signaling.