title: Schisandra chinensis α-iso-cubebenol induces heme oxygenase-1 expression through PI3K/Akt and Nrf2 signaling and has anti-inflammatory activity in Porphyromonas gingivalis lipopolysaccharide-stimulated macrophages.
abstract: Heme oxygenase-1 (HO-1) is a potent anti-inflammatory molecule that regulates pro-inflammatory mediators. Several studies have indicated that HO-1 expression is induced by a variety of stimuli such as lipopolysaccharide (LPS), cytokines, oxidative stress, and antioxidant phytochemicals. In this study, we assessed the anti-inflammatory effects of a novel α-iso-cubebenol isolated from dried fruits of Schisandra chinensis in human macrophage THP-1 cells and investigated the involvement of HO-1 signaling. We first observed that α-iso-cubebenol induced HO-1 mRNA and protein expression in a dose- and time-dependent manner via activation of erythroid-specific nuclear factor-regulated factor 2 (Nrf2). We also found that α-iso-cubebenol induced phosphorylation of phosphoinositide 3-kinase (PI3K)/Akt and extracellular-regulated kinase (ERK) in a time-dependent manner. Furthermore, treatment of THP-1 cells with inhibitors and siRNA specific for PI3K/Akt and ERK decreased the expression of HO-1. These results suggested that α-iso-cubebenol induced HO-1 expression through the activation of PI3K/Akt, ERK, and Nrf2 signaling. Next, α-iso-cubebenol strongly inhibited Porphyromonas gingivalis LPS-stimulated pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-12). Moreover, we observed that α-iso-cubebenol treatment inhibited nuclear levels and activity of NF-κB in a dose-dependent manner. Additionally, treatment with tin-protoporphyrin (SnPP), a selective inhibitor of HO-1, reversed the α-iso-cubebenol-mediated inhibition of P. gingivalis LPS-induced pro-inflammatory cytokines. Hence, α-iso-cubebenol might induce anti-inflammatory effects on P. gingivalis LPS-stimulated human THP-1 macrophages by mediating the activation of PI3k/Akt and ERK that leads to over-expression of HO-1 and Nrf-2. These findings suggest that α-iso-cubebenol may be considered as a novel therapeutic agent to ameliorate periodontitis.
authors.affiliation: Bio-IT Fusion Technology Research Institute, Pusan National University, Busan, Republic of Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Park
authors.forename: Da Jung
authors.initials: DJ
authors.lastname: Park
authors.forename: Young Hun
authors.initials: YH
authors.lastname: Kim
authors.forename: YoungHee
authors.initials: Y
authors.lastname: Kim
authors.forename: Young-Whan
authors.initials: YW
authors.lastname: Choi
authors.forename: Sang-Joon
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000302:isolation & purification / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004224:Diterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D005638:Fruit / Q000737:chemistry; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D015394:Molecular Structure; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016966:Porphyromonas gingivalis / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D032141:Schisandra / Q000737:chemistry*; D012717:Sesquiterpenes; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004224:Diterpenes; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012717:Sesquiterpenes; C571662:alpha-iso-cubebenol; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt