title: Anti-inflammatory effects of 7-hydroxyl-1-methylindole-3-acetonitrile, a synthetic arvelexin derivative, on the macrophages through destabilizing mPGES-1 mRNA and suppressing NF-κB activation.
abstract: We previously demonstrated that 7-hydroxyl-1-methylindole-3-acetonitrile (7-HMIA), a synthesized analog of arvelexin, showed the strong inhibitory effects on LPS-induced NO and PGE2 production in macrophages. In this study, we focused on elucidating the anti-inflammatory properties of 7-HMIA and the mechanisms involved using in vitro and in vivo experimental models. In LPS-induced RAW 264.7 macrophages, 7-HMIA significantly inhibited the release of proinflammatory mediators such as prostaglandin E2 (PGE2), nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). We also found that 7-HMIA suppressed PGE2 production not by inhibiting cyclooxygenase-2 (COX-2) expression or activity, but rather by suppressing the mRNA stability of microsomal prostaglandin E synthase (mPGES-1). Furthermore, 7-HMIA mediated attenuation of inducible NO synthase (iNOS), TNF-α, and IL-6 was closely associated with suppression of transcriptional activities of nuclear factor-kappa B (NF-κB), by decreasing p65 nuclear translocation and Akt phosphorylation. Animal studies revealed that 7-HMIA potently suppressed the carrageenan-induced paw edema and myeloperoxidase (MPO) activity in paw tissues. Taken together, our data indicated that the molecular basis for the anti-inflammatory properties of 7-HMIA involved the inhibition of mRNA stability of mPGES-1 and PI3K/Akt-mediated NF-κB pathways.
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Reactive Oxygen Species Medical Research Center, School of Medicine, Kyung Hee University, Seoul, Republic of Korea; Department of Physiology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Hye-Eun
authors.initials: HE
authors.lastname: Choi
authors.affiliation: Department of Urology, College of Medicine, Dong-A University, Pusan 602-715, Republic of Korea.
authors.forename: Soo-Dong
authors.initials: SD
authors.lastname: Kim
authors.affiliation: Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Laboratory of Medicinal Chemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Yong Sup
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Reactive Oxygen Species Medical Research Center, School of Medicine, Kyung Hee University, Seoul, Republic of Korea; Department of Physiology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Young-Wuk
authors.initials: YW
authors.lastname: Cho
authors.affiliation: Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea. Electronic address: ktlee@khu.ac.kr.
authors.forename: Kyung Tae
authors.initials: KT
authors.lastname: Lee
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002351:Carrageenan; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000378:metabolism; D010766:Phosphorylation; D000071876:Prostaglandin-E Synthases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000067996:RAW 264.7 Cells; D020871:RNA Stability; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep; D000093242:Interleukin-6 Inhibitors; D015850:Interleukin-6
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002351:Carrageenan; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D007211:Indoles; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009569:Nitric Oxide; D009573:Nitrites; D000071876:Prostaglandin-E Synthases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D000093242:Interleukin-6 Inhibitors; C000614155:7-hydroxyl-1-methylindole-3-acetonitrile; C577686:interleukin-6, mouse; D015850:Interleukin-6; C440499:lipopolysaccharide, Escherichia coli O111 B4; C496540:PTGS2 protein, human; C000605865:Ptges protein, mouse
keywords: 7-Hydroxyl-1-methylindole-3-acetonitrile; Inflammatory mediator; Microsomal prostaglandin E synthase; Nuclear factor-kappa B; mRNA stability