title: Genipin induces cyclooxygenase-2 expression via NADPH oxidase, MAPKs, AP-1, and NF-κB in RAW 264.7 cells.
abstract: Genipin is a compound found in gardenia fruit extract with diverse pharmacological activities. However, the mechanism underlying genipin-induced cyclooxygenase-2 (COX-2) expression remains unknown. In this study, we investigated the effects of genipin on COX-2 expression and determined that exposure to genipin dose-dependently enhanced the production of prostaglandin E2 (PGE2), a major COX-2 metabolite, in RAW 264.7 cells. These effects were mediated by genipin-induced activation of the COX-2 promoter, as well as AP-1 and NF-κB luciferase constructs. Phosphatidylinositol-3-kinase/Akt and MAPKs were also significantly activated by genipin, and Akt and MAPKs inhibitors (PD98059, SB20358, SP600125, and LY294002) inhibited genipin-induced COX-2 expression. Moreover, genipin increased production of the ROS and the ROS-producing NAPDH-oxidase (NOX) family oxidases, NOX2 and NOX3. Inhibition of NADPH with diphenyleneiodonium attenuated ROS production, COX-2 expression and NF-κB and AP-1 activation. These results suggest that the molecular mechanism mediating ROS-dependent COX-2 up-regulation and PGE2 production by genipin involves activation of Akt, MAPKs and AP-1/NF-κB.
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Tilak
authors.initials: T
authors.lastname: Khanal
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Hyung Gyun
authors.initials: HG
authors.lastname: Kim
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Minh Truong
authors.initials: MT
authors.lastname: Do
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Department of Food and Medicine, International University of Korea, Jinju, Republic of Korea.
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Chung
authors.affiliation: Department of Food Science and Culinary, International University of Korea, Jinju, Republic of Korea.
authors.forename: Hee Suk
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Technology Convergence Support Center, Changwon National University, Changwon, Republic of Korea.
authors.forename: Youn-Joon
authors.initials: YJ
authors.lastname: Park
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea. Electronic address: taecheon@ynu.ac.kr.
authors.forename: Tae Cheon
authors.initials: TC
authors.lastname: Jeong
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea. Electronic address: hgjeong@cnu.ac.kr.
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
mesh_terms: D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D039823:Iridoids / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D039823:Iridoids; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C007834:genipin; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases
keywords: AP-1; COX-2; Genipin; NF-κB; NOX