Protodioscin alleviates cyclophosphamide-mediated liver damage in mice by targeting Nrf2/HO-1, NF-κB/NLRP3 inflammasome, and mitochondrial apoptosis pathways.

Abstract

Cyclophosphamide is a currently used antineoplastic drug to manage a number of malignant tumors. Hepatotoxicity is one of the most significant complications of cyclophosphamide therapy, which restricts its clinical application. Protodioscin, as a natural saponin, possesses multiple striking biological properties. This preclinical research was conducted to assess the ameliorative influences of protodioscin against cyclophosphamide-triggered hepatotoxicity. Forty male mice were apportioned into five distinct groups: control (normal saline) group, cyclophosphamide (200 mg/kg, i.p.) group, protodioscin (12.5, 25, and 50 mg/kg, i.p.) + cyclophosphamide groups. The mice received protodioscin for 10 days and cyclophosphamide was administrated on day 5. The results exhibited that protodioscin significantly attenuated the activities of ALT, AST, and ALP as well as the serum level of total bilirubin. Protodioscin remarkably inhibited ROS generation and upregulated the protein expression of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) to suppress hepatic oxidative stress as documented by an increase in SOD level and a reduction in MDA level. Furthermore, protodioscin remarkably diminished the protein expression of nuclear factor κB (NF-κB) and NLRP3 as well as the mRNA expression of tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) to inhibit hepatic inflammation. Protodioscin markedly downregulated the mRNA expression of Bax and caspase-3 and upregulated the mRNA expression of Bcl-2 to block hepatic apoptosis. Notably, protodioscin treatment effectively improved the cyclophosphamide-induced pathological alterations in liver tissue. These data accentuate that protodioscin can serve as a promising hepatoprotective compound to considerably prevent liver damage caused by cyclophosphamide.