oxadin and Disease-Models--Animal

Acetaminophen (APAP) overdose is a major cause of drug-induced liver injury worldwide. Our current study was performed to assess the potential protective effects of γ-oryzanol (ORY) on APAP-induced liver injury in mice and explore the underlying molecular mechanisms. We unveiled that ORY alleviated the APAP-induced death of HL-7702 hepatocytes in vitro and liver injury in mice. Moreover, ORY promoted the nuclear translocation of Nrf2, increased the expressions of Nrf2-downstream antioxidative enzymes, including HO-1, NQO1, GCLC, and GCLM, and thereby restrained APAP-induced oxidative stress in hepatocytes. Moreover, ORY modulated the AMPK/GSK3β axis that acts upstream of Nrf2 in hepatocytes. Compound C, an inhibitor of AMPK, prevented the ORY-mediated activation of Nrf2 and protection against APAP toxicity in HL-7702 hepatocytes. Additionally, in the liver of mice receiving APAP, ORY suppressed the nuclear translocation of the NF-κB p65 subunit, downregulated the expressions of iNOS and COX-2, and reduced the levels of pro-inflammatory factors including TNF-α, IL-1β, IL-6, and NO. Taken together, our findings revealed that ORY is capable of ameliorating APAP-induced liver injury. The modulation of AMPK/GSK3β/Nrf2 and NF-κB signaling pathways is implicated in the hepatoprotective activity of ORY.

Topics: Acetaminophen; AMP-Activated Protein Kinases; Animals; Antioxidants; Cell Survival; Chemical and Drug Induced Liver Injury, Chronic; Disease Models, Animal; Glutamate-Cysteine Ligase; Glycogen Synthase Kinase 3 beta; Heme Oxygenase-1; Hepatocytes; Interleukin-1beta; Interleukin-6; Liver; Male; Membrane Proteins; Mice; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; NF-kappa B; Nitric Oxide Synthase Type II; Oxazines; Oxidative Stress; Phenylpropionates; Signal Transduction; Tumor Necrosis Factor-alpha