title: In vitro and in vivo hepatoprotective effect of ganodermanontriol against t-BHP-induced oxidative stress.
abstract: BACKGROUND
  Ganoderma lucidum (Fr.) Karst. (Ganodermataceae) is a mushroom which is used as a traditional remedy in the treatment of human diseases such as hepatitis, liver disorders, hypercholesterolemia, arthritis, bronchitis and tumorigenic diseases. This study targets the evaluation of hepatoprotective activity of ganodermanontriol, a sterol isolated from Ganoderma lucidum, and the investigation of its mechanism of action in Hepa1c1c7 and murine liver cells upon tert-butyl hydroperoxide (t-BHP)-induced inflammation. t-BHP was utilized to stimulate an anti-inflammatory reaction in the hepatic cell lines and murine hepatic tissue examined. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-PCR) were used to estimate the expression of ganodermanontriol (GDT)-induced proteins, including heme oxidase-1 (HO-1) and mitogen-activated protein kinases (MAPKs) as well as the corresponding mRNA. Luciferase assays were conducted to evaluate the interaction between NF-E2-related factor-2 (Nrf-2), the antioxidant response element (ARE), and the promoter region of the HO-1 gene and subsequent gene expression. Biochemical markers for hepatotoxicity were monitored to assess whether GDT protected the cells from the t-BHP-mediated oxidative stimuli.
  
  
  RESULTS
  GDT induced HO-1 expression via the activation of Nrf-2 nuclear translocation and the subsequent transcription of the HO-1 gene in vitro and in vivo, which seemed to be regulated by phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and p38 signaling pathways. GDT exhibited in vitro and in vivo hepatoprotective activity as determined by the lowered levels of hepatic enzymes and malondialdehydes and the elevated glutathione levels.
  
  
  CONCLUSIONS
  This study validates the ethnopharmacological application of Ganoderma lucidum as a treatment for hepatic disorders. GDT induced in vitro and in vivo anti-inflammatory activity in t-BHP-damaged hepatic cells through the expression of HO-1, and in which PI3K/Akt and p38 kinases are involved. Our study motivates further research in the exploration of potent hepatoprotective agents from Ganoderma lucidum.
authors.affiliation: National Institute of Medicinal Materials (NIMM), 3B Quangtrung, Hoankiem, Hanoi, Vietnam; College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Do Thi
authors.initials: do T
authors.lastname: Ha
authors.forename: Joonseok
authors.initials: J
authors.lastname: Oh
authors.forename: Nguyen Minh
authors.initials: NM
authors.lastname: Khoi
authors.forename: Trong Tuan
authors.initials: TT
authors.lastname: Dao
authors.forename: Le Viet
authors.initials: le V
authors.lastname: Dung
authors.forename: Thi Nguyet Que
authors.initials: TN
authors.lastname: Do
authors.forename: Sang Myung
authors.initials: SM
authors.lastname: Lee
authors.forename: Tae Su
authors.initials: TS
authors.lastname: Jang
authors.forename: Gil-Saeng
authors.initials: GS
authors.lastname: Jeong
authors.forename: MinKyun
authors.initials: M
authors.lastname: Na
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000378:metabolism; D005638:Fruit; D032902:Ganoderma; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D007810:Lanosterol / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010936:Plant Extracts; D020011:Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020122:tert-Butylhydroperoxide
chemical_list: D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D005978:Glutathione; D051547:Heme Oxygenase-1; D007810:Lanosterol; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D051267:NF-E2-Related Factor 2; D019869:Phosphatidylinositol 3-Kinases; D010936:Plant Extracts; D020011:Protective Agents; D051057:Proto-Oncogene Proteins c-akt; D020122:tert-Butylhydroperoxide; C495636:Nfe2l2 protein, mouse; C558586:ganodermanontriol; C496542:Hmox1 protein, mouse
keywords: Ganoderma lucidum; Ganodermanontriol; Heme oxygenase-1; Hepatoprotective activity; Oxidative stress