Liver injury is among the adverse effects of the chemotherapeutic agent cyclophosphamide (CP). This study investigated the protective role of the flavone apigenin (API) against CP-induced liver damage, pointing to the involvement of Nrf2/HO-1 signaling. Rats were treated with API (20 and 40 mg/kg) for 15 days and received CP (150 mg/kg) on day 16. CP caused liver damage manifested by an elevation of transaminases, alkaline phosphatase (ALP), and lactate dehydrogenase (LDH), and histological alterations, including granular vacuolation, mononuclear cell infiltration, and hydropic changes. Hepatic reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO) were increased and glutathione (GSH) and antioxidant enzymes were decreased in CP-administered rats. CP upregulated the inflammatory markers NF-κB p65, TNF-α, IL-6, and iNOS, along with the pro-apoptotic Bax and caspase-3. Pre-treatment with API ameliorated circulating transaminases, ALP, and LDH, and prevented histopathological changes in CP-intoxicated rats. API suppressed ROS, MDA, NO, NF-κB p65, iNOS, inflammatory cytokines, oxidative DNA damage, Bax, and caspase-3 in CP-intoxicated rats. In addition, API enhanced hepatic antioxidants and Bcl-2 and boosted the Nrf2 and HO-1 mRNA abundance and protein. In conclusion, API is effective in preventing CP hepatotoxicity by attenuating oxidative stress, the inflammatory response, and apoptosis. The hepatoprotective efficacy of API was associated with the upregulation of Nrf2/HO-1 signaling.

Chronic hyperglycemia increases the risk of liver damage. Oxidative stress and aberrant inflammatory response are entangled in diabetes-associated liver injury. This study evaluated the protective effect of the flavonoid galangin (Gal) on glucose intolerance, liver injury, oxidative stress, inflammatory response, and Nrf2/HO-1 signaling in diabetic rats. Diabetes was induced by streptozotocin (STZ), and the rats received Gal for six weeks. STZ-induced rats showed glucose intolerance, hypoinsulinemia, elevated glycated hemoglobin (HbA1c), and decreased liver glycogen. Gal ameliorated glucose intolerance, reduced HbA1c%, increased serum insulin and liver glycogen and hexokinase activity, and suppressed glycogen phosphorylase, glucose-6-phosphatase and fructose-1,6-biphosphatase in diabetic rats. Circulating transaminases, ALP and LDH, and liver ROS, MDA, TNF-α, IL-1β, and IL-6 were increased and GSH, SOD, and CAT were diminished in diabetic rats. In addition, diabetic rats exhibited multiple histopathological alterations and marked collagen deposition. Treatment with Gal mitigated liver injury, prevented histopathological alterations, decreased ROS, MDA, pro-inflammatory cytokines, Bax and caspase-3, and enhanced cellular antioxidants and Bcl-2. Gal downregulated hepatic Keap1 in diabetic rats and upregulated Nrf2 and HO-1 mRNA as well as HO-1 activity. Molecular modeling studies revealed the ability of Gal to bind to and inhibit NF-κB and Keap1, and also showed its binding pattern with HO-1. In conclusion, Gal ameliorates hyperglycemia, glucose intolerance, oxidative stress, inflammation, and apoptosis in diabetic rats. Gal improved carbohydrate metabolizing enzymes and upregulated Nrf2/HO-1 signaling.