Tangeretin protects against nodularin-R-induced hepatotoxicity by modulating oxidative stress, inflammation, and apoptosis.

Nodularin (NOD) is a cyanobacterial toxin that induces severe biochemical and structural alterations in the liver. This study aimed to investigate the protective effects of tangeretin (TAN) against NOD-R-induced hepatotoxicity by evaluating biochemical, oxidative stress, histopathological, and immunohistochemical alterations in a murine model. Fifty-six male mice were randomly allocated to four experimental groups (n = 14/group): Control, TAN, NOD-R, and TAN + NOD-R. The control, TAN, and NOD-R groups received intraperitoneal (i.p.) injections of 0.9% saline containing 0.1% dimethyl sulfoxide (DMSO), TAN (100 mg/kg b.w., 0.9% saline 0.1% DMSO), and NOD-R (15 µg/kg b.w., 0.9% saline), respectively, for 7 consecutive days. The TAN + NOD-R group was administered TAN (100 mg/kg b.w.) for 10 consecutive days and concurrently challenged with NOD-R (15 µg/kg b.w.) from days 4 to 10. At the end of the experimental period, blood samples were collected for the determination of serum aminotransferase activities and oxidative stress parameters, while liver tissues were examined for oxidative stress biomarkers, histopathological alterations, and immunohistochemical expression of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), caspase - 3, and proliferating cell nuclear antigen (PCNA). NOD-R exposure significantly increased serum aminotransferase activities and malondialdehyde (MDA) levels and significantly decreased glutathione (GSH) levels and superoxide dismutase (SOD) concentrations, as well as catalase (CAT) and glutathione peroxidase (GSH-Px) activities. Moreover, NOD-R administration induced marked histopathological alterations and significantly increased hepatic expression of TNF-α, iNOS, caspase - 3, and PCNA. On the other hand, TAN pretreatment significantly alleviated NOD-R-induced hepatotoxicity by decreasing aminotransferase activities and MDA levels, restoring antioxidant defenses, attenuating histopathological changes, and downregulating the expression of TNF-α, iNOS, caspase - 3, and PCNA. The findings of this study indicated that TAN can be considered a protective agent against oxidative stress and NOD-R-induced hepatotoxicity.