title: Nobiletin attenuates lipopolysaccharide/D‑galactosamine‑induced liver injury in mice by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF‑κB‑mediated cytokine production.
abstract: Inflammation and oxidative stress serve an important role in the development of lipopolysaccharide/D-galactosamine (LPS/GalN)‑induced acute liver injury. Nobiletin, which is found in high quantities in the peel of citrus fruits, is able to modulate immune responses, including inflammatory response and oxidative stress. The present study aimed to evaluate the protective effects of nobiletin on LPS/GalN‑induced acute liver injury. Male C57BL/6 mice were intraperitoneally treated with nobiletin (50, 100 and 200 mg/kg) 2 h prior to LPS/GalN injection. Liver injury was observed in the LPS/GalN group, as demonstrated by increased levels of serum hepatic enzymes and hepatic inflammatory mediators, as well as by histopathological alterations. Treatment with nobiletin reduced serum alanine aminotransferase and aspartate aminotransferase levels, improved hepatic structure, and suppressed hepatic interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α production 24 h after LPS/GalN exposure. Western blot analysis revealed that nobiletin treatment inhibited inducible nitric oxide synthase and cyclooxygenase‑2 liver expression. In addition, nobiletin suppressed LPS/GalN‑induced phosphorylation and degradation of inhibitor of nuclear factor (NF)‑κB (IκB)α, as well as NF‑κB p65 translocation into the nucleus. Nobiletin also upregulated the expression of nuclear NF‑E2‑related factor 2 (Nrf2) and cytoplasmic heme oxygenase‑1. In conclusion, these results indicate that nobiletin serves a protective role in LPS/GalN‑induced acute liver injury via activation of the Nrf2 antioxidant pathway and subsequent inhibition of NF‑κB‑mediated cytokine production. These findings support the potential for nobiletin as a therapeutic agent for the treatment of acute liver injury.
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China.
authors.forename: Zhenxing
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China.
authors.forename: Xuanfei
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China.
authors.forename: Kun
authors.initials: K
authors.lastname: He
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China.
authors.forename: Junhua
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Gong
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D047309:Flavones / Q000494:pharmacology*; D005688:Galactosamine / Q000009:adverse effects; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D016207:Cytokines; D047309:Flavones; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D005688:Galactosamine; C008661:nobiletin; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2