title: Sestrin2 protects against acetaminophen-induced liver injury.
abstract: Acetaminophen (APAP) overdose accounts for half of the cases of acute liver failure worldwide. We previously reported that Sestrin2 (Sesn2) protects against d-galactosamine/lipopolysaccharide-induced acute fulminant liver failure. In this study, we demonstrated that Sesn2 protects APAP-induced liver injury in mice, using a recombinant adenovirus encoding Sesn2 (Ad-Sesn2). First, we found that treatment of mice with toxic levels of APAP significantly reduced Sesn2 expression. Tail-vein injection with Ad-Sesn2 inhibited APAP-induced serum alanine aminotransferase and aspartate aminotransferase levels and markedly reduced hepatocyte degeneration and inflammatory cell infiltration. Additionally, APAP-induced glutathione depletion and reactive oxygen species generation were inhibited by Ad-Sesn2 treatment. Consistently, hepatic inflammatory gene expression and proinflammatory cytokine levels were also inhibited in Sesn2-infected mice, and we observed reduced APAP-mediated apoptotic signaling by terminal transferase-mediated dUTP nick-end labeling staining of the hepatic tissue. At a high dose of APAP, the mortality rate of Ad-Sesn2-infected mice was significantly lower than that of control mice. Furthermore, Sesn2 prevented APAP-induced damage through suppression of downstream mitogen-activated protein kinase pathway activation. Therefore, Sesn2 exerted a protective effect against APAP-induced acute liver damage by inhibiting oxidative stress and proinflammatory signaling.
authors.affiliation: College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.
authors.forename: Seung Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea; College of Pharmacy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Kyu Min
authors.initials: KM
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Yang
authors.affiliation: College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.
authors.forename: Sam Seok
authors.initials: SS
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.
authors.forename: Su Jung
authors.initials: SJ
authors.lastname: Park
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
authors.forename: Sang Kyu
authors.initials: SK
authors.lastname: Lee
authors.affiliation: MRC-GHF, College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38584, Republic of Korea.
authors.forename: Sae Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: MRC-GHF, College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38584, Republic of Korea.
authors.forename: Il Je
authors.initials: IJ
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea. Electronic address: shki@chosun.ac.kr.
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Ki
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000256:Adenoviridae / Q000235:genetics; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010544:Peroxidases; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D000084622:Sestrins
chemical_list: D000082:Acetaminophen; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D005978:Glutathione; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D010544:Peroxidases; D017382:Reactive Oxygen Species; C529380:Sesn2 protein, mouse; D000084622:Sestrins
keywords: Acetaminophen; JNK; Oxidative stress; Sestrin2