Nrf2-mediated liver protection by esculentoside A against acetaminophen toxicity through the AMPK/Akt/GSK3β pathway.
Acetaminophen (APAP) overdose accounts for the majority of acute liver failure cases, and oxidative stress plays a key role in its toxic effects. Esculentoside A (EsA) has anti-oxidant activities, but its therapeutic potential for APAP hepatotoxicity remains unknown. This study aimed to assess the protective effects and mechanism of EsA against APAP-induced hepatotoxicity in vitro and in vivo. In vitro, EsA treatment inhibited APAP- or H2O2-induced cytotoxicity, H2O2and O2-production, glutathione (GSH) depletion and apoptosis dependent on nuclear factor erythroid-2-related factor 2 (Nrf2) activation in HepG2 cells. Moreover, EsA significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and serine/threonine kinase (Akt), as well as glycogen synthase kinase 3 beta (GSK-3β) inhibitory phosphorylation at Ser9. Furthermore, an AMPK inhibitor (compound c) abolished the effects of EsA on AKT phosphorylation, GSK-3β inactivation, Nrf2 nuclear translocation and cytoprotection. With regard to APAP-induced acute liver injury, EsA attenuated the APAP-stimulated increases in the serum ALT and AST levels, as well as centrilobular necrosis and GSH depletion in the mice. In addition, it decreased the GSSG level, GSSG-to-GSH ratio, and the phosphorylation and mitochondrial translocation of c-Jun N-terminal kinase (JNK). Further, the protective potential of EsA against mitochondrial dysfunction was exhibited not only by inhibiting Bax mitochondrial translocation and the release of mitochondrial inter-membrane proteins, such as apoptosis-inducing factor (AIF), but also by activating Nrf2/HO-1. Collectively, our findings suggest that EsA has protective potential against APAP toxicity by potentiating the Nrf2-regulated survival mechanism through the AMPK/Akt/GSK3β pathway.
Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China.
Lidong
L
Wang
Department of Obstetrics and Gynecology, the First Hospital of Jilin University, Changchun 130021, China.
Songling
S
Zhang
Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China.
Hang
H
Cheng
Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China.
Hongming
H
Lv
Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China; Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA.
Genhong
G
Cheng
Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China. Electronic address: cixinxin@jlu.edu.cn.
Xinxin
X
Ci
D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism; D064113:CRISPR-Cas Systems; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics* / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics*; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology*; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D051033:Apoptosis Inducing Factor; C494827:Bax protein, mouse; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C494830:AIFM1 protein, mouse; D012503:Saponins; D051028:bcl-2-Associated X Protein; D013481:Superoxides; D000082:Acetaminophen; C076297:esculentoside A; D009828:Oleanolic Acid; D006861:Hydrogen Peroxide; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases