ABSTRACT
Cisplatin (CIS) is a chemotherapeutic medication for the treatment of cancer. However, hepatotoxicity is among the adverse effects limiting its use. Caroxylon salicornicum is traditionally used for treating inflammatory diseases. In this investigation, three flavonoids, four coumarins, and three sterols were detected in the petroleum ether fraction of C. salicornicum (PEFCS). The isolated phytochemicals exhibited binding affinity toward Keap1, NF-κB, and SIRT1 in silico. The hepatoprotective role of PEFCS (100, 200 and 400 mg/kg) was investigated in vivo. Rats received PEFCS for 14 days and CIS on day 15. CIS increased ALT, AST and ALP and caused tissue injury along with increased ROS, MDA, and NO. Hepatic NF-κB p65, pro-inflammatory mediators, Bax and caspase-3 were increased in CIS-treated animals while antioxidants and Bcl-2 were decreased. PEFCS mitigated hepatocyte injury, and ameliorated transaminases, ALP, oxidative stress (OS) and inflammatory markers. PEFCS downregulated pro-apoptosis markers and boosted Bcl-2 and antioxidants. In addition, PEFCS upregulated Nrf2, HO-1, and SIRT1 in CIS-administered rats. In conclusion, PEFCS is rich in beneficial phytoconstituents and conferred protection against liver injury by attenuating OS and inflammation and upregulating Nrf2 and SIRT1.
ABSTRACT
Cisplatin (CIS) is an effective chemotherapeutic drug used for the treatment of many types of cancers, but its use is associated with adverse effects. Nephrotoxicity is a serious side effect of CIS and limits its therapeutic utility. Haloxylon salicornicum is a desert shrub used traditionally in the treatment of inflammatory disorders, but neither its flavonoid content nor its protective efficacy against CIS nephrotoxicity has been investigated. In this study, seven flavonoids were isolated from H. salicornicum methanolic extract (HSE) and showed in silico binding affinity with NF-κB, Keap1, and SIRT1. The protective effect of HSE against CIS nephrotoxicity was investigated. Rats received HSE (100, 200, and 400 mg/kg) for 14 days followed by a single injection of CIS. The drug increased Kim-1, BUN, and creatinine and caused multiple histopathological changes. CIS-administered rats showed an increase in renal ROS, MDA, NO, TNF-α, IL-1ß, and NF-κB p65. HSE prevented tissue injury, and diminished ROS, NF-κB, and inflammatory mediators. HSE enhanced antioxidants and Bcl-2 and downregulated pro-apoptosis markers. These effects were associated with downregulation of Keap1 and microRNA-34a, and upregulation of SIRT1 and Nrf2/HO-1 signaling. In conclusion, H. salicornicum is rich in flavonoids, and its extract prevented oxidative stress, inflammation, and kidney injury, and modulated Nrf2/HO-1 and SIRT1 signaling in CIS-treated rats.
