title: Berberine induces heme oxygenase-1 up-regulation through phosphatidylinositol 3-kinase/AKT and NF-E2-related factor-2 signaling pathway in astrocytes.
abstract: Our previous report has shown that berberine effectively inhibits LPS- and IFN-γ-induced neuroinflammation in microglia cells. Recently, we also reported that HO-1 (Heme oxygenase-1) may be a therapeutic target to regulate neuroinflammation in microglia cells. The present study examined the ability of berberine, the major constituents of Chinese herb Rhizoma coptidis, to induce expression of HO-1, and analyzed its signaling mechanism in rat brain astrocytes. HO-1 is known as an antioxidant enzyme which helps to protect against cellular damage and maintains tissue homeostasis. Here, we found that berberine increased HO-1 mRNA and protein expression concentration- and time-dependently. In addition, berberine-induced HO-1 expression was attenuated by PI 3-kinase (phosphatidylinositol 3-kinase) inhibitors LY294002 and wortmannin, and an AKT inhibitor. Treatment of astrocytes with berberine also induced p85 (PI 3-kinase) and AKT phospholation, and increased AKT kinase activity. Berberine also increased NF-E2-related factor-2 (Nrf2) accumulation in the nucleus and increased Nrf2-DNA binding activity as determined by the EMSA (electrophoretic mobility shift assay). Moreover, berberine-induced increase of Nrf2-DNA binding activity was reduced by PI 3-kinase and AKT inhibitors. Berberine-increased HO-1-luciferase activity was also inhibited by co-transfection with dominant-negative (DN) mutants of p85 and AKT. Moreover, berberine-mediated increase of HO-1 transcriptional activity and protein expression were reduced by transfection with siRNA againt Nrf2. These findings suggest that berberine-increased HO-1 expression is mediated by Nrf2 activation through the PI 3-kinase/AKT pathway in astrocytes. Thus, berberine may be useful as a therapeutic agent for the treatment of neuroinflammation-associated disorders.
authors.affiliation: Department of General Surgery, Taichung Tzu Chi General Hospital, Taichung, Taiwan.
authors.forename: Jia-Hong
authors.initials: JH
authors.lastname: Chen
authors.forename: Ssu-Ming
authors.initials: SM
authors.lastname: Huang
authors.forename: Tzu-Wei
authors.initials: TW
authors.lastname: Tan
authors.forename: Hsiao-Yun
authors.initials: HY
authors.lastname: Lin
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chen
authors.forename: Wei-Lan
authors.initials: WL
authors.lastname: Yeh
authors.forename: Shao-Chun
authors.initials: SC
authors.lastname: Chou
authors.forename: Cheng-Fang
authors.initials: CF
authors.lastname: Tsai
authors.forename: I-Hua
authors.initials: IH
authors.lastname: Wei
authors.forename: Dah-Yuu
authors.initials: DY
authors.lastname: Lu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001599:Berberine / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D051267:NF-E2-Related Factor 2; D001599:Berberine; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt