title: 8β-hydroxy-3-oxopimar-15-ene exerts anti-inflammatory effects by inhibiting ROS-mediated activation of the TRAF6-ASK1-p38 signaling pathway.
abstract: The flying squirrel's droppings (Pteropus pselaphon) have been used for improving the blood circulation, arresting bleeding to treat hematological disorders, and reducing pain. Here, 8β-hydroxy-3-oxopimar-15-ene (OXO), one of main constituents of P. pselaphon, was examined for its anti-inflammatory activity in murine macrophages. We found that OXO significantly suppressed LPS-induced nitric oxide (NO) without exerting cytotoxic effects on RAW 264.7 cells. OXO inhibited the expression of LPS-induced iNOS and COX-2 protein and their mRNA in a dose-dependent manner. Also, TNF-α, IL-6, and PGE2 secretion was decreased by OXO in LPS-stimulated macrophages. These inflammatory biomarkers were attributed to the suppression of LPS-induced activation of p38 MAPK and subsequent activation of two components of AP-1 (c-Jun and c-Fos), but not of ERK, JNK, NF-κB. Moreover, OXO inhibited LPS-induced intracellular reactive oxygen species (ROS) production and co-incubation of OXO and hydrogen peroxide (H2O2) suppressed the phosphorylation of p38 in a concentration-dependent manner. In addition, OXO completely disrupted the formation of TRAF6-ASK complex in the cells. Therefore, we demonstrate here that OXO can potentially inhibit several biomarkers related to inflammation through inhibition of ROS-mediated activation of TRAF6-ASK1-p38 pathway.
authors.affiliation: College of Korean Medicine, Kyung Hee University , Seoul , Republic of Korea and.
authors.forename: Jae-Heung
authors.initials: JH
authors.lastname: Cho
authors.forename: Jong Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Lee
authors.forename: Dongwoo
authors.initials: D
authors.lastname: Nam
authors.forename: Bum Sang
authors.initials: BS
authors.lastname: Shim
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Song
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Jung
authors.forename: Won-Seok
authors.initials: WS
authors.lastname: Chung
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000276:immunology / Q000378:metabolism; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D048848:MAP Kinase Kinase Kinase 5 / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages; D051379:Mice; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology* / Q000378:metabolism; D012589:Sciuridae; D048029:TNF Receptor-Associated Factor 6 / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology* / Q000378:metabolism
chemical_list: C587782:8-hydroxy-3-oxopimar-15-ene; D000893:Anti-Inflammatory Agents; D004224:Diterpenes; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D015232:Dinoprostone