| Summary: | Arsenic (As) is a toxic contaminant present in organic and inorganic forms in the environment. Nobiletin (NOB) is a polymethoxy flavone that has recently gained substantial consideration due to its curative impacts. The present experiment was conducted to assess the hepatoprotective efficiency of NOB on As-generated hepatotoxicity. Twenty-four adult rats were equally distributed into four groups and designated as control, As (50 mg/kg)-treated, As + NOB (50 mg/kg and 25 mg/kg, respectively), and NOB (25 mg/kg)-treated groups. After 30 days, experimental animals were decapitated, then blood and tissue samples were collected for further analysis. The group treated with As showed a significant decrease in the activity of antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), peroxidase (POD), glutathione (GSH), glutathione reductase (GSR), and total antioxidant status (TAS), and a substantial increase in the accumulation of As in liver tissues, levels of total oxidant status (TOS), hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), and lipid peroxidation (TBARS). Significant increases in alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) levels were observed in As-treated rats. Moreover, nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, interleukin (IL)-6, and cyclo-oxygenase (COX)-2 activity, as well as the levels of pro-apoptotic markers (Bax, Caspase-3, and Caspase-9) were increased on exposure to As. In contrast, the anti-apoptotic marker (Bcl-2) level was significantly decreased. As administration showed a significant disturbance in hepatic tissue histology. However, cotreatment of NOB with As considerably increased the antioxidant enzyme activity, with a noteworthy reduction in the deposition of As in hepatic tissues, TBARS, and H<sub>2</sub>O<sub>2</sub> levels. NOB-administrated rats showed considerable recovery in terms of inflammation, apoptosis, and histological damage. Hence, NOB can be considered a useful curative compound due to its medicinal properties against As-prompted hepatotoxicity.
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