Molecular pharmacological analysis of anti-inflammatory effects of PAI-1 inhibitor

• Project/Area Number: 25860185
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Kyoto University (2014); Tohoku University (2013)
• Principal Investigator: ATSUHIKO Ichimura 京都大学, 健康長寿社会の総合医療開発ユニット, 特定助教 (10609209)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 分子薬理学 / 創薬 / 炎症 / 薬理学 / 糖尿病 / 肥満 / 代謝

Outline of Final Research Achievements

This research was conducted with the aim to elucidate the molecular pharmacological mechanism of anti-inflammatory effect of PAI-1 inhibitors. The suitable pathological model of inflammation to evaluate efficacy of PAI-1 inhibitors was searched. As a result, we have successfully found anti-inflammatory effect of PAI-1 inhibitors on high fat diet (HFD)-induced obesity model. PAI-1 inhibitors attenuated HFD-induced impaired systemic glucose and energy metabolism. Further analyses of molecular mechanisms of the efficacy of PAI-1 inhibitors demonstrated that PAI-1 inhibitors suppressed accumulation of fat in adipocyte accompanying with the inhibition of infiltration of inflammatory macrophages into adipose tissue and the liver. These results suggest the possibility of PAI-1 inhibitors as novel therapeutic agent of metabolic disorders.

Research Products

• [Journal Article] Inhibition of plasminogen activator inhibitor-1 is a potential therapeutic strategy in ovarian cancer. (2015)
  • Author(s): Mashiko S, Kitatani K, Toyoshima M, Ichimura A, Dan T, Usui T, Ishibashi M, Shigeta S, Nagase S, Miyata T, Yaegashi N
  • Journal Title: Cancer Biology & Therapy Volume: 16 Issue: 2 Pages: 253-260
  • DOI: 10.1080/15384047.2014.1001271
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A Novel Antidiabetic Therapy: free Fatty Acids Receptors as Potential Druggable Targets. (2015)
  • Author(s): Sekiguchi H, Kasubuchi M, Hasegawa S, Pelisch N, Kimura I, Ichimura A.
  • Journal Title: Curr Diabetes Rev. Volume: -
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Plasminogen activator inhibitor-1 (PAI-1) molecule: new physiological roles and clinical applications. (2014)
  • Author(s): Dan T, Ichimura A, Pelisch N, Miyata K, Akahori K, Miyata T.
  • Journal Title: Rinsho Ketsueki. Volume: 55 Pages: 396-404
  • NAID: 130004920665
• [Journal Article] Therapeutic role and ligands of medium- to long-chain Fatty Acid receptors. (2014)
  • Author(s): Hara T, Ichimura A, Hirasawa A.
  • Journal Title: Front Endocrinol Volume: 5 Pages: 83-83
  • DOI: 10.3389/fendo.2014.00083
  • Peer Reviewed / Open Access
• [Journal Article] The role of free fatty acid receptors in the regulation of energy metabolism (2014)
  • Author(s): T. Hara, D. Kashihara, A. Ichimura, I. Kimura, G. Tsujimoto, and A. Hirasawa.
  • Journal Title: Biochem Biophys Acta Volume: 1841 Issue: 9 Pages: 1292-1300
  • DOI: 10.1016/j.bbalip.2014.06.002
  • Peer Reviewed
• [Journal Article] Regulation of Energy Homeostasis via GPR120. (2014)
  • Author(s): Ichimura A, Hara T, Hirasawa A.
  • Journal Title: Front Endocrinol Volume: 11 Pages: 111-111
  • DOI: 10.3389/fendo.2014.00111
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Free fatty acids receptors as therapeutic target for treatment of diabetes. (2014)
  • Author(s): A. Ichimura, S. Hasegawa, M. Kasubuchi, and I. Kimura*
  • Journal Title: Front Pharmacol. Volume: 5 Pages: 236-236
  • DOI: 10.3389/fphar.2014.00236
  • Peer Reviewed / Open Access
• [Journal Article] The PAI-1 antagonist TM5441 attenuates L-NAME-induced hypertension and vascular senescence (2013)
  • Author(s): Boe A, Eren M, Murphy S, Kamide1 C, Ichimura A, Terry D, McAnally D, Smith LH, Miyata T, Vaughan DE
  • Journal Title: Circulation Volume: 128 Issue: 21 Pages: 2318-2324
  • DOI: 10.1161/circulationaha.113.003192
  • Peer Reviewed
• [Journal Article] Free Fatty Acid Receptors and Their Role in Regulation of Energy Metabolism. (2013)
  • Author(s): Hara Takafumi, et al.
  • Journal Title: Reviews of Physiology, Biochemistry and Pharmacology Volume: - Pages: 77-116
  • DOI: 10.1007/112_2013_13
  • ISBN: 9783319009957, 9783319009964
  • Peer Reviewed