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2004 Fiscal Year Final Research Report Summary

New therapeutic approach for rheumatoid arthritis by targeting the intracellular molecule.

Research Project

Project/Area Number 14572167
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 応用薬理学・医療系薬学
Research InstitutionToho University School of Medicine (2004)
St. Marianna University School of Medicine (2002-2003)

Principal Investigator

KAWAI Shinichi  Toho University, School of Medicine, Professor, 医学部・内科学講座, 教授 (70129401)

Co-Investigator(Kenkyū-buntansha) KITASATO Hidero  Kitasato University, School of Allied Health Science, Professor, 医療衛生学部, 教授 (90195256)
Project Period (FY) 2002 – 2004
Keywordsapoptosis / PPARgamma / NSAIDs / celecoxib / rheumatoid arthritis / synovial fibroblasts / mPGES-1 / PGDS
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 … More 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

  • Research Products

    (43 results)

All 2005 2004 2003 2002 Other

All Journal Article (42 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Kusunoki N. Recent advances in nonsteroidal anti-inflammatory drugs.2005

    • Author(s)
      Kawai S. et al.
    • Journal Title

      Allergol Int (in press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Prostaglandin E synthase in the pathophysiology of arthritis.2005

    • Author(s)
      Kojima F, et al.
    • Journal Title

      Fundam Clin Pharmacol (in press)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Prostaglandin E2 production in ovarian cancer cell lines is regulated by cyclooxygenase-1,not cyclooxygenase-2.2005

    • Author(s)
      Kino Y, et al.
    • Journal Title

      Prostaglandins Leukot Essent Fatty Acids (in press)

    • Description
      「研究成果報告書概要(和文)」より
  • [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.
    • Journal Title

      J Control Release 102(2)

      Pages: 463-473

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Triptolide, an active compound identified in a traditional Chinese herb, induces apoptosis of rheumatoid synovial fibroblasts.2004

    • Author(s)
      Kusunoki N, et al.
    • Journal Title

      BMC Pharmacol 4(1)

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Optimum formulation for sustained-release insulin.2004

    • Author(s)
      Takenaga M, et al.
    • Journal Title

      Int J Pharm 271(1-2)

      Pages: 85-94

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Membrane-associated prostaglandin E synthase-1 is upregulated by proinflammatory cytokines in chondrocytes from patients with osteoarthritis.2004

    • Author(s)
      Kojima F, et al.
    • Journal Title

      Arthritis Res Ther 6(4)

      Pages: R355-R365

    • Description
      「研究成果報告書概要(和文)」より
  • [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, et al.
    • Journal Title

      Arthritis Rheum 50(6)

      Pages: 1761-1769

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A single treatment with microcapsules containing a CXCR4 antagonist suppresses pulmonary metastasis of murine melanoma.2004

    • Author(s)
      Takenaga M, et al.
    • Journal Title

      Biochem Biophys Res Commun 320(1)

      Pages: 226-232

    • Description
      「研究成果報告書概要(和文)」より
  • [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.2004

    • Author(s)
      Igarashi R, et al.
    • Journal Title

      J Control Release 102(2)

      Pages: 463-473

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Triptolide, an active compound identified in a traditional Chinese herb, induces apoptosis of rheumatoid synovial fibroblasts.2004

    • Author(s)
      Kusunoki N, Yamazaki R, Kitasato H, Beppu M, Aoki H, Kawai S.
    • Journal Title

      BMC Pharmacol (http://www.biomedcentral.com/1471-2210/4/2) 4(1):2

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Optimum formulation for sustained-release insulin.2004

    • Author(s)
      Takenaga M, Yamaguchi Y, Kitagawa A, Ogawa Y, Kawai S, Mizushima Y, Igarashi R.
    • Journal Title

      Int J Pharm 271(1-2)

      Pages: 85-94

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Membrane-associated prostaglandin E synthase-1 is upregulated by proinflammatory cytokines in chondrocytes from patients with osteoarthritis.2004

    • Author(s)
      Kojima F, Naraba H, Miyamoto S, Beppu M, Aoki H, Kawai S.
    • Journal Title

      Arthritis Res Ther 6(4)

      Pages: R355-R365

    • Description
      「研究成果報告書概要(欧文)」より
  • [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.
    • Journal Title

      Arthritis Rheum 50(6)

      Pages: 1761-1769

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] A single treatment with microcapsules containing a CXCR4 antagonist suppresses pulmonary metastasis of murine melanoma.2004

    • Author(s)
      Takenaga M, Tamamura H, Hiramatsu K, Nakamura N, Yamaguchi Y, Kitagawa A, Kawai S, Nakashima H, Fujii N, Igarashi R.
    • Journal Title

      Biochem Biophys Res Commun 320(1)

      Pages: 226-232

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Current drug therapy for rheumatoid arthritis.2003

    • Author(s)
      Kawai S
    • Journal Title

      J Orthop Sci 8(2)

      Pages: 259-263

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Retrovirally introduced prostaglandin D_2 synthase suppresses lung injury induced by bleomycin.2003

    • Author(s)
      Ando M, et al.
    • Journal Title

      Am J Respir Cell Mol Biol 28(5)

      Pages: 582-591

    • Description
      「研究成果報告書概要(和文)」より
  • [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, et al.
    • Journal Title

      Aliment Pharmacol Ther 18(Suppl.1)

      Pages: 146-152

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Plasma leptin levels in patients with burn injury : a preliminary report.2003

    • Author(s)
      Kino Y, et al.
    • Journal Title

      Burns 29(5)

      Pages: 449-453

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Prostaglandin E_2 is an enhancer for interleukin-1β-induced expression of membrane-associated prostaglandin F synthase in rheumatoid synovial fibroblasts.2003

    • Author(s)
      Kojima F, et al.
    • Journal Title

      Arthritis Rheum 48(10)

      Pages: 2819-2828

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Inhibition of monosodium urate monohydrate crystal-induced acute inflammation by retrovirally transfected prostaglandin D synthase.2003

    • Author(s)
      Murakami Y, et al.
    • Journal Title

      Arthritis Rheum 48(10)

      Pages: 2931-2941

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Current drug therapy for rheumatoid arthritis.2003

    • Author(s)
      Kawai S.
    • Journal Title

      J Orthop Sci 8(2)

      Pages: 259-263

    • Description
      「研究成果報告書概要(欧文)」より
  • [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.
    • 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
  • [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.
    • 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
  • [Journal Article] Plasma leptin levels in patients with burn injury : a preliminary report.2003

    • Author(s)
      Kino Y, Kato M, Ikehara Y, Asanuma Y, Akashi K, Kawai S.
    • Journal Title

      Burns 29(5)

      Pages: 449-453

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Prostaglandin E2 is an enhancer for interleukin-16-induced expression of membrane-associated prostaglandin E synthase in rheumatoid synovial fibroblasts.2003

    • Author(s)
      Kojima F, Naraba H, Sasaki Y, Beppu M, Aoki H, Kawai S.
    • Journal Title

      Arthritis Rheum 48(10)

      Pages: 2819-2828

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Inhibition of monosodium urate monohydrate crystal-induced acute inflammation by retrovirally transfected prostaglandin D synthase.2003

    • Author(s)
      Murakami Y, Akahoshi T, Hayashi I, Endo H, Hashimoto A, Kono S, Kondo H, Kawai S, Inoue M, Kitasato H.
    • Journal Title

      Arthritis Rheum 48(10)

      Pages: 2931-2941

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Nonsteroidal anti-inflammatory drugs induce apoptosis in association with activation of peroxisome proliferator-activated receptor γ in rheumatoid synovial cells.2002

    • Author(s)
      Yamazaki R, et al.
    • Journal Title

      J Pharmacol Exp Ther 302(1)

      Pages: 18-25

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Coexpression of microsomal prostaglandin E synthase with cyclooxygenase-2 in human rheumatoid synovial cells.2002

    • Author(s)
      Kojima F, et al.
    • Journal Title

      J Rheumatol 29(9)

      Pages: 1836-1842

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Antiinflammatory effect of retrovirally transfected interleukin-10 on monosodium urate monohydrate crystal-induced acute inflammation in murine air pouches.2002

    • Author(s)
      Murakami Y, et al.
    • Journal Title

      Arthritis Rheum 46(9)

      Pages: 2504-2513

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Selective cyclooxygenase-2 inhibitors show a differential ability to inhibit proliferation and induce apoptosis of colon adenocarcinoma cells.2002

    • Author(s)
      Yamazaki R, et al.
    • Journal Title

      FEBS Lett 531(2)

      Pages: 278-284

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Induction of apoptosis in rheumatoid synovial fibroblasts by celecoxib, but not by other selective cyclooxygenase-2 inhibitors.2002

    • Author(s)
      Kusunoki N, et al.
    • Journal Title

      Arthritis Rheum 46(12)

      Pages: 3159-3167

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Aspirin and sodium salicylate inhibit proliferation and induce apoptosis in rheumatoid synovial cells.2002

    • Author(s)
      Yamazaki R, et al.
    • Journal Title

      J Pharm Pharmacol 54(12)

      Pages: 1675-1679

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Nonsteroidal anti-inflammatory drugs induce apoptosis in association with activation of peroxisome proliferator-activated receptor Y in rheumatoid synovial cells.2002

    • Author(s)
      Yamazaki R, Kusunoki N, Matsuzaki T, Hashimoto S, Kawai S.
    • Journal Title

      J Pharmacol Exp Ther 302(1)

      Pages: 18-25

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Coexpression of microsomal prostaglandin E synthase with cyclooxygenase-2 in human rheumatoid synovial cells.2002

    • Author(s)
      Kojima F, Naraba H, Sasaki Y, Okamoto R, Koshino T, Kawai S.
    • Journal Title

      J Rheumatol 29(9)

      Pages: 1836-1842

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Antiinflammatory effect of retrovirally transfected interleukin-10 on monosodium urate monohydrate crystal-induced acute inflammation in murine air pouches.2002

    • Author(s)
      Murakami Y, Akahoshi T, Kawai S, Inoue M, Kitasato H.
    • Journal Title

      Arthritis Rheum 46(9)

      Pages: 2504-2513

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Selective cyclooxygenase-2 inhibitors show a differential ability to inhibit proliferation and induce apoptosis of colon adenocarcinoma cells.2002

    • Author(s)
      Yamazaki R, Kusunoki N, Matsuzaki T, Hashimoto S, Kawai S.
    • Journal Title

      FEBS Lett 531(2)

      Pages: 278-284

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Induction of apoptosis in rheumatoid synovial fibroblasts by celecoxib, but not by other selective cyclooxygenase-2 inhibitors.2002

    • Author(s)
      Kusunoki N, Yamazaki R, Kawai S.
    • Journal Title

      Arthritis Rheum 46(12)

      Pages: 3159-3167

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Aspirin and sodium salicylate inhibit proliferation and induce apoptosis in rheumatoid synovial cells.2002

    • Author(s)
      Yamazaki R, Kusunoki N, Matsuzaki T, Hashimoto S, Kawai S.
    • Journal Title

      J Pharm Pharmacol 54(12)

      Pages: 1675-1679

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Recent advances in nonsteroidal anti-inflammatory drugs.

    • Author(s)
      Kawai S, Kojima F, Kusunoki N.
    • Journal Title

      Allergol Int (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Prostaglandin E synthase in the pathophysiology of arthritis.

    • Author(s)
      Kojima F, Kato S, Kawai S.
    • Journal Title

      Fundam Clin Pharmacol (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Prostaglandin E2 production in ovarian cancer cell lines is regulated by cyclooxygenase-1, not cyclooxygenase-2.

    • Author(s)
      Kino Y, Kojima F, Kiguchi K, Igarashi R, Ishizuka B, Kawai S.
    • Journal Title

      Prostaglandins Leukot Essent Fatty Acids (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Patent(Industrial Property Rights)] セレコキシブアミノアルキル誘導体2004

    • Inventor(s)
      半田 宏, 川合 眞一, 楠 夏子
    • Industrial Property Rights Holder
      財)理工学振興会
    • Industrial Property Number
      特願2004-044561
    • Filing Date
      2004-02-20
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2006-07-11  

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