2004 Fiscal Year Final Research Report Summary
New therapeutic approach for rheumatoid arthritis by targeting the intracellular molecule.
| Project/Area Number |
14572167
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Toho University School of Medicine (2004)
St. Marianna University School of Medicine (2002-2003) |
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Principal Investigator |
KAWAI Shinichi Toho University, School of Medicine, Professor, 医学部・内科学講座, 教授 (70129401)
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| Co-Investigator(Kenkyū-buntansha) |
KITASATO Hidero Kitasato University, School of Allied Health Science, Professor, 医療衛生学部, 教授 (90195256)
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| Project Period (FY) |
2002 – 2004
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| Keywords | apoptosis / PPARgamma / NSAIDs / celecoxib / rheumatoid arthritis / synovial fibroblasts / mPGES-1 / PGDS |
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| Research Abstract |
We found that some conventional nonsteroidal anti-inflammatory drugs(NSAIDs) such as indometacin and diclofenac induced apoptosis in rheumatoid synovial fibroblasts (J Pharmacol Exp Ther 2002;302:18). We also found that celecoxib, a selective cyclooxygenase (COX)-2 inhibitor, exert pro-apoptotic effect on rheumatoid synovial fibroblasts (Arthritis Rheum 2002;46:3159) and colon cancer cell lines (FEBS Lett 2002;531:278) by COX-independent mechanisms. In addition, high concentration of aspirin and salicylate (J Pharm Pharmacol 2002;54:1675), and triptolide, an active compound identified in a traditional Chinese herb (BMC Pharmacol 2002;4:2), induce apoptosis in rheumatoid synovial cells. From these finding, we hypothesized that some intracellular molecules play an important role in inducing apoptosis by these anti-inflammatory agents. During the research procedure, we invented a novel potent pro-apoptotic agent derived from celecoxib. We are now trying to find the targeting molecule to i
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nduce apoptosis. Concerning arachidonic acid cascade, recent studies revealed that not only COX but also terminal enzymes such as prostaglandin E synthase(PGES) are important in the understanding of the pathogenesis of inflammation and mechanisms of action of NSAIDs. PGES is a recently identified terminal enzyme that acts downstream of COX and catalyzes the conversion of prostaglandin(PG) H2 to PGE2. At least three isozymes have been cloned so far, which are called membrane-associated PGES(mPGES)-1,mPGES-2,and cytosolic PGES. Induction of mPGES-1 in the component of articular tissues of patients with rheumatoid arthritis and osteoarthritis has been demonstrated in vitro by us (J Rheumatol 2002;29:1836 & Arthritis Res Ther 2004;6:R355). We then showed that PGE2 is an enhancer for interleukin-16-induced expression of mPGES-1 in rheumatoid synovial fibroblasts (Arthritis Rheum 2003;48:2819). These findings suggest that mPGES-1 may be a novel therapeutic target for arthritis. PGD synthase(PGDS) is an enzyme to produce an intrinsic pro-apoptotic PG (15-deoxy-Δ^<12,14>-PGJ2). We also found the anti-inflammatory effects of the retrovirally transfected PGDS-expressing fibroblasts in bleomycin-induced lung injury (Am J Respir Cell Mol Biol 2003;28:582) and monosodium urate monohydrate crystal-induced acute inflammation (Arthritis Rheum 2003;48:2931) in animal models. PGDS or 15-deoxy-Δ^<12,14>-PGJ2 will possibly be another target molecule for the novel therapy for rheumatoid arthritis and other rheumatic diseases. Less
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Research Products
(43 results)
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[Journal Article] Brain-derived neurotrophic factor bound with lecithin derivative showed a markedly enhanced pharmacological potency due to its potent cell membrane affinity followed by prolonged MAPK activation.2005
Author(s)
Igarashi R, Nakayama T, Takenaga M, Ichinohe M, Yamaguchi Y, Matsumoto K, Kitagawa A, Nakamura N, Kawai S, Nakagawa T, Taiji M, Nakayama C, Mizushima Y.
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Journal Title
J Control Release 102(2)
Pages: 463-473
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody : A multicenter, double-blind, placebo-controlled trial.2004
Author(s)
Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Hashimoto J, Azuma J, Kishimoto T.
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Journal Title
Arthritis Rheum 50(6)
Pages: 1761-1769
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Retrovirally introduced prostaglandin D2 synthase suppresses lung injury induced by bleomycin.2003
Author(s)
Ando M, Murakami Y, Kojima F, Endo H, Kitasato H, Hashimoto A, Kobayashi H, Majima M, Inoue M, Kondo H, Kawai S, Hayashi I.
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Journal Title
Am J Respir Cell Mol Biol 28(5)
Pages: 582-591
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Effects of rebamipide, a gastro-protective drug on the Helicobacter pylori status and inflammation in the gastric mucosa of patients with gastric ulcer : a randomized double-blind placebo-controlled multicentre trial.2003
Author(s)
Fujioka T, Arakawa T, Shimoyama T, Yoshikawa T, Itoh M, Asaka M, Ishii H, Kuwayama H, Sato R, Kawai S, Takemoto T, Kobayashi K.
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Journal Title
Aliment Pharmacol Ther 18(Suppl.1)
Pages: 146-152
Description
「研究成果報告書概要(欧文)」より
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