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Sestrin2 protects against acetaminophen-induced liver injury.
Chem Biol Interact. 2017 May 01; 269:50-58.CB

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+Show Affiliations

College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.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.College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.MRC-GHF, College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38584, Republic of Korea.MRC-GHF, College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38584, Republic of Korea.College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea. Electronic address: shki@chosun.ac.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28209544

Citation

Kim, Seung Jung, et al. "Sestrin2 Protects Against Acetaminophen-induced Liver Injury." Chemico-biological Interactions, vol. 269, 2017, pp. 50-58.
Kim SJ, Kim KM, Yang JH, et al. Sestrin2 protects against acetaminophen-induced liver injury. Chem Biol Interact. 2017;269:50-58.
Kim, S. J., Kim, K. M., Yang, J. H., Cho, S. S., Kim, J. Y., Park, S. J., Lee, S. K., Ku, S. K., Cho, I. J., & Ki, S. H. (2017). Sestrin2 protects against acetaminophen-induced liver injury. Chemico-biological Interactions, 269, 50-58. https://doi.org/10.1016/j.cbi.2017.02.002
Kim SJ, et al. Sestrin2 Protects Against Acetaminophen-induced Liver Injury. Chem Biol Interact. 2017 May 1;269:50-58. PubMed PMID: 28209544.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sestrin2 protects against acetaminophen-induced liver injury. AU - Kim,Seung Jung, AU - Kim,Kyu Min, AU - Yang,Ji Hye, AU - Cho,Sam Seok, AU - Kim,Ji Young, AU - Park,Su Jung, AU - Lee,Sang Kyu, AU - Ku,Sae Kwang, AU - Cho,Il Je, AU - Ki,Sung Hwan, Y1 - 2017/02/13/ PY - 2016/09/28/received PY - 2016/12/29/revised PY - 2017/02/03/accepted PY - 2017/2/18/pubmed PY - 2017/5/10/medline PY - 2017/2/18/entrez KW - Acetaminophen KW - JNK KW - Oxidative stress KW - Sestrin2 SP - 50 EP - 58 JF - Chemico-biological interactions JO - Chem. Biol. Interact. VL - 269 N2 - 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. SN - 1872-7786 UR - https://www.unboundmedicine.com/medline/citation/28209544/Sestrin2_protects_against_acetaminophen_induced_liver_injury_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0009-2797(16)30410-0 DB - PRIME DP - Unbound Medicine ER -