Induction of stress proteins by NSAIDs and its role in their pharmacological activity

• Project/Area Number: 19390023
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Kumamoto University
• Principal Investigator: MIZUSHIMA Tohru Kumamoto University, 大学院・医学薬学研究部, 教授 (00264060)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥19,110,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥4,410,000); Fiscal Year 2008: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000); Fiscal Year 2007: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
• Keywords: NSAIDs / アルツハイマー / ストレス蛋白質 / レポータープラスミド / 炎症性腸疾患 / 炎症性サイトカイン / 熱ショック蛋白質 / 活性酸素種 / HSF1

Research Abstract

細胞、動物レベルで、NSAIDsによる抗アルツハイマー作用へのストレス蛋白質誘導の関与を検討した。その結果、GRP78など種々の小胞体シャペロンの発現を抑制した時、NSAIDsによる抗アルツハイマー作用効果が見られなくなることを見いだした。一方、動物レベルでは、APPの過剰発現マウスを用いて、ストレス蛋白質の過剰発現の効果を調べたところ、アルツハイマー病症状が緩和されることを見いだした。

Research Products

• [Journal Article] Therapeutic effect of lecithinized superoxide dismutase (PC-SOD) against colitis (2009)
  • Author(s): Ishihara, T., Tanaka, K., Tasaka, Y., Namba, T., Suzuki, J., Ishihara, T., Okamoto, S., Hibi, T., Takenaga M., Igarashi, R., Sato, K., Mizushima, Y. and Mizushima, T
  • Journal Title: J. Pharmacol. Exp. Ther 328 Pages: 152-164
  • Peer Reviewed
• [Journal Article] Linkage between phosphorylation of the origin recognition complex and its ATP-binding activity in Saccharomyces cerevisiae. (2009)
  • Author(s): Makise, M.
  • Journal Title: J. Biol. Chem. 284 Pages: 3396-3407
  • Peer Reviewed
• [Journal Article] Up-regulation of S100P expression by non-steroidal anti-inflammatory drugs and its role in their anti-tumorigenic effects. (2009)
  • Author(s): Namba, T.
  • Journal Title: J. Biol. Chem. 284 Pages: 4158-4167
  • Peer Reviewed
• [Journal Article] Analysis of origin recognition complex in Saccharomyces cerevisiae, by use of degron mutants (2008)
  • Author(s): Makise, M., Matsui, N., Yamairi, F., Takahashi, M., Takehara, M., Asano, T. and Mizushima, T
  • Journal Title: J. Biochem. 43 Pages: 455-465
  • NAID: 10024909176
  • Peer Reviewed
• [Journal Article] Development of new type of NSAIDs with lower gastric side effects (2008)
  • Author(s): Mizushima, T
  • Journal Title: Inflammation and Regeneration 28 Pages: 100-104
  • NAID: 10022602322
  • Peer Reviewed
• [Journal Article] a heterodimeric ABC type multidrug efflux pump, in Serratia marcescens (2008)
  • Author(s): Matsuo T, Chen, J., Minato, Y., Ogawa, W., Mizushima, T., Kuroda, T. and Tsuchiya T. SmdAB
  • Journal Title: J. Bacteriol 190 Pages: 648-654
  • Peer Reviewed
• [Journal Article] Analysis of mutant origin recognition complex with reduced ATPase activity in vivo and in vitro (2008)
  • Author(s): Takehara, M., Makise, M., Takenaka, H., Asano, T. and Mizushima, T.
  • Journal Title: Biochem. J. 413 Pages: 535-543
  • Peer Reviewed
• [Journal Article] Prolonging the in vivo residence time of prostaglandin E(1) with biodegradable nanoparticles. (2008)
  • Author(s): Ishihara, T., Takahashi. M., Higaki, M., Takenaga, M., Mizushima, T. and Mizushima Y.
  • Journal Title: Pharm. Res. 25 Pages: 1686-1695
  • Peer Reviewed
• [Journal Article] NSAIDs suppress the expression of claudin-2 to promote invasion activity of cancer cells (2008)
  • Author(s): Mima, S., Takehara, M., Takada, H., Nishimura, T., Hoshino, T., and Mizushima, T.
  • Journal Title: Carcinogenesis 10 Pages: 1994-2000
  • Peer Reviewed
• [Journal Article] Expression and function of TETRAN, a new type of membrane transporter. (2008)
  • Author(s): Ushijima, H., Hiasa, M., Namba, T., Hwang, H-J., Hoshino, T., Mima, S., Tsuchiya, T., Moriyama, Y. and Mizushima, T.
  • Journal Title: Biochem. Biophys. Res. Commun. 374 Pages: 325-330
  • Peer Reviewed
• [Journal Article] Various stress proteins protect gastric mucosal cells against non-steroidal anti-inflammatory drugs. (2007)
  • Author(s): Mizushima, T.
  • Journal Title: Inflammopharmacology 15 Pages: 67-73
  • Peer Reviewed
• [Journal Article] Mechanism for the degradation of origin recognition complex containing Orc5p with a defective walker A motif and its suppression by over-production of Orc4p in yeast cells. (2007)
  • Author(s): Makise, M., Takahashi, N., Matsuda, K., Yamairi, F., Suzuki, K., Tsuchiya, T., and Mizushima, T.
  • Journal Title: Biochem. J. 402 Pages: 397-403
  • Peer Reviewed
• [Journal Article] Endoplasmic reticulum chaperones inhibit the production of amyloid-・peptides. (2007)
  • Author(s): Hoshino, T., Nakaya, T., Araki, W., Suzuki, K., Suzuki, T. and Mizushima, T.
  • Journal Title: Biochem. J. 402 Pages: 81-89
  • Peer Reviewed
• [Journal Article] Up-regulation of 150-kDa oxygen-regulated protein (ORP150) by celecoxib in human gastric carcinoma cells. (2007)
  • Author(s): Namba, T., Hoshino, T., Tanaka, K., Tsutsumi, S., Ishihara, T., Mima S., Suzuki, K., Ogawa, S. and Mizushima, T.
  • Journal Title: Mol. Pharmacol. 71 Pages: 860-870
  • Peer Reviewed
• [Journal Article] Genetic evidence for a protective role of heat shock factor 1 against irritant-induced gastric lesions. (2007)
  • Author(s): Tanaka, K., Tsutsumi, S., Arai, Y., Hoshino, T., Suzuki, K., Takai, E., Itoh, T., Takeuchi, K., Nakai, A. and Mizushima, T.
  • Journal Title: Mol. Pharmacol. 71 Pages: 985-993
  • Peer Reviewed
• [Journal Article] Transcriptional activation of ATF6 by endoplasmic reticulum stressors. (2007)
  • Author(s): Namba, T., Ishihara, T., Tanaka, K., Hoshino, T. and Mizushima, T.
  • Journal Title: Biochem. Biophys. Res. Commun. 355 Pages: 543-548
  • Peer Reviewed
• [Journal Article] Identification of the TPO1 gene in yeast, and its human orthologue TETRAN, which cause resistance to NSAIDs. (2007)
  • Author(s): Mima, S., Ushijima, H., Hwang, H-J., Tsutsumi, S., Makise, M., Yamaguchi, Y., Tsuchiya, T., Mizushima, H. and Mizushima, T.
  • Journal Title: FEBS Lett. 581 Pages: 1457-1463
  • Peer Reviewed
• [Journal Article] Involvement of up-regulation of PUMA in non-steroidal anti-inflammatory drug-induced apoptosis. (2007)
  • Author(s): Ishihara, T., Hoshino, T., Namba, T., Tanaka, K. and Mizushima, T.
  • Journal Title: Biochem. Biophys. Res. Commun. 356 Pages: 711-717
  • Peer Reviewed
• [Journal Article] Simultaneous measurements of K^+ and calcein release from liposomes and the determination of pore size formed in the membrane. (2007)
  • Author(s): Katsu, T., Imamura, T., Komagoe, K., Masuda, K. and Mizushima, T.
  • Journal Title: Anal. Sci. 23 Pages: 517-522
  • NAID: 130004441439
  • Peer Reviewed
• [Journal Article] Molecular cloning and characterization of a multidrug efflux pump, SmfY, from Serratia marcescens. (2007)
  • Author(s): Shahcheraghi, F., Minato, Y., Chen, J., Mizushima, T., Ogawa, W., Kuroda, T. and Tsuchiya T.
  • Journal Title: Biol Pharm Bull 30 Pages: 798-800
  • NAID: 110006271227
  • Peer Reviewed
• [Journal Article] Genetic evidence for a protective role for heat shock factor 1 and heat shock protein 70 against colitis (2007)
  • Author(s): Tanaka, K. Namba, T., Arai, Y., Fujimoto, M., Adachi, H., Sobue, G., Takeuchi, K., Nakai, A. and Mizushima, T.
  • Journal Title: J. Biol. Chem. 282 Pages: 23240-23252
  • Peer Reviewed
• [Journal Article] Interaction between ORC and Cdt1p of Saccharomyces cerevisiae (2007)
  • Author(s): Asano, T., Makise, M., Takehara, M. and Mizushima, T.
  • Journal Title: FEMS Yeast Res 8 Pages: 1256-1262
  • Peer Reviewed
• [Journal Article] Yeast two-hybrid analysis of the origin recognition complex of Saccharomyces cerevisiae : interaction between subunits and identification of binding proteins. (2007)
  • Author(s): Matsuda, K., Makise, M., Sueyasu, Y., Takehara, M., Asano, T. and Mizushima, T.
  • Journal Title: FEMS Yeast Res. 8 Pages: 1263-1269
  • Peer Reviewed
• [Journal Article] Involvement of prostaglandin E_2 in production of amyloid-peptides both in vitro and in vivo. (2007)
  • Author(s): Hoshino, T., Nakaya, T., Houman, T., Sugimoto, Y., Araki, W., Narita, M., Narumiya, S., Suzuki, T. and Mizushima, T.
  • Journal Title: J. Biol. Chem. 282 Pages: 32676-32688
  • Peer Reviewed
• [Journal Article] an RND-type multidrug efflux transporter in Vibrio parahaemolyticus. (2007)
  • Author(s): Matsuo, T., Hayashi, K., Morita, Y., Koterasawa, M., Ogawa, W., Mizushima, T, Tsuchiya, T. and Kuroda, T. VmeAB
  • Journal Title: Microbiology 153 Pages: 4129-4137
  • Peer Reviewed
• [Journal Article] Genetic evidence for a protective role of heat shock factor 1 against irritant-induced gastric lesions. (2007)
  • Author(s): Tanaka, K.
  • Journal Title: Mol.Pharmacol. 71 Pages: 985-993
  • Peer Reviewed
• [Journal Article] Genetic evidence for a protective role for heat shock factor 1 and heat shock protein 70 against colitis. (2007)
  • Author(s): Tanaka, K.
  • Journal Title: J.Biol.Chem. 282 Pages: 23240-23252
  • Peer Reviewed
• [Journal Article] Involvement of prostaglandin E^2 in production of amylold-β peptides both in vitro and in vivo. (2007)
  • Author(s): Hoshino, T.
  • Journal Title: J.Biol.Chem. 282 Pages: 32676-32688
  • Peer Reviewed
• [Journal Article] Inhibition of both COX-1 and COX-2 and resulting decrease in the level of prostaglandins E2 is responsible for NSAID-dependent exacerbation of colitis
  • Author(s): Tanaka, K., Suemasu, S., Ishihara, T., Tasaka, Y., Arai, Y. and Mizushima, T
  • Journal Title: Eur. J. Pharmacol (in press)
  • Peer Reviewed
• [Journal Article] Effect of claudin expression on paracellular permeability, migration and invasion of colonic cancer cells
  • Author(s): Takehara, M., Nishimura, T., Mima, S., Hoshino, T. and Mizushima, T
  • Journal Title: Biol. Pharm. Bull (in press)
  • NAID: 130000117145
  • Peer Reviewed
• [Journal Article] Linkage between phosphorylation of the origin recognition complex and its ATP-binding activity in Saccharomyces cerevisiae.
  • Author(s): Makise, M., Takehara, M., Kuniyasu, A., Matsui, N., Nakayama, H. and Mizushima, T
  • Journal Title: J. Biol. Chem (in press)
  • Peer Reviewed
• [Journal Article] Up-regulation of S100P expression by non-steroidal anti-inflammatory drugs and its role in their anti-tumorigenic effects.
  • Author(s): Namba, T., Houman, T., Nishimura, T., Mima, S., Hoshino, T. and Mizushima, T
  • Journal Title: J. Biol. Chem (in press)
  • Peer Reviewed
• [Journal Article] Positive role of CHOP, a transcription factor involved in the ER stress response in the development of colitis.
  • Author(s): Namba, T., Tanaka, K., Ito, Y., Ishihara, T., Hoshino, T., Gotoh, T., Endo, M., Sato, K. and Mizushima, T
  • Journal Title: Am. J. Pathol (in press)
  • Peer Reviewed
• [Journal Article] Positive role of CHOP, a transcription factor involved in the ER stress response in the development of colitis.
  • Author(s): Namba, T.
  • Journal Title: Am. J. Pathol. (in press)
  • Peer Reviewed
• [Presentation] 医薬品開発の新しい流れ--既存薬の研究から新薬へ-- (2008)
  • Author(s): 水島徹
  • Organizer: 第2回次世代を担う若手医療薬科学シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2008-12-21
• [Presentation] 温故知新創薬研究 (2008)
  • Author(s): 水島徹
  • Organizer: 第二回熊本創薬シンポジウム
  • Place of Presentation: 熊本
  • Year and Date: 2008-12-18
• [Presentation] トランスクリプトソーム解析による医薬品の副作用機構の解明と、その副作用感受性診断、及び創薬への応用 (2008)
  • Author(s): 水島徹
  • Organizer: 創薬バイオマーカー探索研究事業研究発表会
  • Place of Presentation: 東京
  • Year and Date: 2008-11-06
• [Presentation] 私が受け継ぐ医薬品開発研究--リポ剤の次に来るもの-- (2008)
  • Author(s): 水島徹
  • Organizer: 日本DDS学会
  • Place of Presentation: 東京
  • Year and Date: 2008-10-06
• [Presentation] HSF1、及びHSPsの遺伝子改変マウスを用いた、胃潰瘍、及び炎症性腸疾患に対する生体防御機構研究 (2008)
  • Author(s): 水島徹
  • Organizer: 日本薬学会関東支部会
  • Place of Presentation: 千葉
  • Year and Date: 2008-10-04
• [Presentation] NSAIDs潰瘍発症の分子機構 (2008)
  • Author(s): 水島徹
  • Organizer: 日本潰瘍学会
  • Place of Presentation: 札幌
  • Year and Date: 2008-09-23
• [Presentation] 副作用の少ない非ステロイド系抗炎症薬の開発 (2008)
  • Author(s): 水島徹
  • Organizer: 日本薬学会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2008-03-30
• [Presentation] HSF1ノックアウトマウスの、胃潰瘍、炎症性腸疾患感受性 (2008)
  • Author(s): 水島徹
  • Organizer: 日本薬理学会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2008-03-04
• [Presentation] 副作用の少ないNSAIDsの開発物理化学、有機化学、生化学、薬理学など、薬学の総合力を活かした創薬 (2007)
  • Author(s): 水島徹
  • Organizer: 生体膜と薬物の相互作用シンポジウム特別企画
  • Place of Presentation: 仙台
  • Year and Date: 2007-11-10
• [Presentation] 非ステロイド系抗炎症薬による胃潰瘍発症機構とHSP誘導薬による胃粘膜保護 (2007)
  • Author(s): 水島徹
  • Organizer: 九州山口薬学大会
  • Place of Presentation: 熊本
  • Year and Date: 2007-11-02
• [Presentation] 胃潰瘍、炎症性腸疾患に対するHSPの保護効果 (2007)
  • Author(s): 水島徹
  • Organizer: 日本潰瘍学会
  • Place of Presentation: 鳥取
  • Year and Date: 2007-09-21
• [Presentation] 副作用の少ない非ステロイド系抗炎症薬の開発 (2007)
  • Author(s): 水島徹
  • Organizer: 日本炎症・再生学会シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2007-08-04
• [Presentation] 胃潰瘍、炎症性腸疾患に対するHSPの保護効果 (2007)
  • Author(s): 水島徹
  • Organizer: 日本フリーラジカル学会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-05-03