title: Schisandrol B protects against acetaminophen-induced acute hepatotoxicity in mice via activation of the NRF2/ARE signaling pathway.
abstract: OBJECTIVE
  The nuclear factor erythroid 2-related factor 2 (NRF2) acts through the antioxidant response element (ARE) to regulate the expression of many detoxifying and antioxidant genes responsible for cytoprotective processes. We previously reported that Schisandrol B (SolB) isolated from Schisandra sphenanthera produced a protective effect against acetaminophen (APAP)-induced liver injury. In this study we investigated whether the NRF2/ARE signaling pathway was involved in this hepato-protective effect.
  
  
  METHODS
  Male C57BL/6 mice were treated with SolB (200 mg · kg(-1) · d(-1), ig) for 3 d before injection of APAP (400 mg/kg, ip). Serum and liver tissue samples were collected 6 h later. The mRNA and protein expression were measured using qRT-PCR and Western blot assay, respectively. The activation of NRF2 was examined in HepG2 cells using luciferase reporter gene assay.
  
  
  RESULTS
  SolB pretreatment significantly alleviated the hepatic injury (large patchy necrosis and hyperemia of the hepatic sinus), the increase of serum AST, ALT levels and hepatic MDA contents, and the decrease of liver and mitochondrial glutathione levels in APAP-treated mice. Furthermore, SolB pretreatment significantly increased nuclear accumulation of NRF2 and increased hepatic expression of NRF2 downstream proteins, including GCLC, GSR, NQO1, GSTs, MRP2, MRP3 and MRP4 in APAP-treated mice. Moreover, treatment with SolB (2.5-20 μmol/L) dose-dependently increased the activity of NRF2 reporter gene in HepG2 cells.
  
  
  CONCLUSIONS
  SolB exhibits a remarkable protective effect against APAP-induced hepatotoxicity, partially via activation of the NRF2/ARE pathway and regulation of NRF2 target genes, which induce detoxification and increase antioxidant capacity.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Yi-ming
authors.initials: YM
authors.lastname: Jiang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.|Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Hua-sen
authors.initials: HS
authors.lastname: Tan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Xiao-mei
authors.initials: XM
authors.lastname: Fan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.|The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Zeng
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Hui-chang
authors.initials: HC
authors.lastname: Bi
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D061745:Antioxidant Response Elements / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D034242:Cyclooctanes / Q000302:isolation & purification / Q000627:therapeutic use*; D004149:Dioxoles / Q000302:isolation & purification / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D017705:Lignans / Q000302:isolation & purification / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D020011:Protective Agents / Q000302:isolation & purification / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D032141:Schisandra / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018712:Analgesics, Non-Narcotic; D034242:Cyclooctanes; D004149:Dioxoles; D017705:Lignans; D051267:NF-E2-Related Factor 2; D020011:Protective Agents; D012333:RNA, Messenger; D000082:Acetaminophen; C033585:schizandrol B