title: The antioxidative potential of farrerol occurs via the activation of Nrf2 mediated HO-1 signaling in RAW 264.7 cells.
abstract: Farrerol, (S)-2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-6,8-dimethyl-4-benzopyrone, isolated from rhododendron, has been shown to have antioxidative potential, but the molecular mechanism underlying this activity remains unclear. The inducible expression of heme oxygenase-1 (HO-1), a potent antioxidative and cytoprotective enzyme, is known to play an important role in cytoprotection in a variety of pathological models. In this study, we evaluated the antioxidative potential of farrerol against oxidative damage and investigated its antioxidative mechanism in RAW 264.7 cells. The molecular mechanism underlying the cytoprotective function of farrerol was determined by analyzing intracellular signaling pathways, transcriptional activation and the inhibitory effect of HO-1 on ROS production. Farrerol induced antioxidant enzymes mRNA expression, HO-1 protein expression and nuclear translocation of NF-E2-related factor 2 in RAW 264.7 macrophage cells. Farrerol down-regulated the expression of the Keap1 protein and the thiol reducing agents attenuated farrerol-induced HO-1 expression. Further investigation utilizing Western blotting and specific inhibitors of Akt, p38, JNK and ERK demonstrated that Akt, p38, and ERK axis of signaling pathway mediates HO-1 expression. Moreover, tert-butyl hydroperoxide (t-BHP)-induced oxidative damage was ameliorated by farrerol treatment in a dose-dependent manner, which was abolished by Akt, p38, ERK and HO-1 inhibitors (Snpp). It is hence likely that farrerol inactivated KEAP-1 or activated the Akt, p38 and ERK to facilitate the release of Nrf2 from Keap1 and subsequent reduced the intracellular production of reactive oxygen species via the induction of HO-1 expression. These results support the central role of HO-1 in the cytoprotective effect of farrerol.
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ci
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China; Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130061, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Lv
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China.
authors.forename: Lidong
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Translational Medicine, The First Hospital, Jilin University, Changchun 130001, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Peng
authors.affiliation: 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; Suzhou Institute of Systems Medicine, Suzhou 215123, China; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: fxfqin1@gmail.com.
authors.forename: F Xiao-Feng
authors.initials: FX
authors.lastname: Qin
authors.affiliation: 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; Suzhou Institute of Systems Medicine, Suzhou 215123, China; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095, USA. Electronic address: gcheng@mednet.ucla.edu.
authors.forename: Genhong
authors.initials: G
authors.lastname: Cheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020122:tert-Butylhydroperoxide / Q000633:toxicity
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D002867:Chromones; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; C015881:farrerol; D020122:tert-Butylhydroperoxide; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Farrerol; Heme oxygenase-1; Mitogen-activated protein kinase; Nuclear translocation of NF-E2-related factor 2; Phosphatidylinositol 3-kinase