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The exploration of pathophysiology of chronic stress and its therapeutic targets

Research Project

Project/Area Number 16K15411
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field General internal medicine(including psychosomatic medicine)
Research InstitutionSaitama Medical University (2018-2019)
Nagoya University (2016-2017)

Principal Investigator

Takeshita Kyosuke  埼玉医科大学, 医学部, 教授 (70444403)

Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsストレス / 情動ストレス / ACE2 / レニン-アンギオテンシン系 / キサンチン酸化酵素 / DPP-4 / 慢性炎症 / 酸化ストレス / 耐糖能異常 / Dipeptidyl Peptidase-4 / 内科
Outline of Final Research Achievements

Chronic stress is closely linked to the metabolic syndrome, diabetes, hyperuricemia and thromboembolism, but the mechanisms remain elusive. We reported that stress targets visceral adipose tissue (VAT), inducing lipolysis, low-grade inflammation with production of inflammatory adipokines, metabolic derangements such as insulin resistance, and prothrombotic state. We recently showed that DPP-4 and xanthine oxidoreductase (XOR) are involved in the VAT inflammation.
Furthermore, two-week daily restraint stress activated the classical renin-angiotensin system (RAS) to evoke intestinal inflammation in mice, and perturbate microbiota and serotonin metabolism.
The treatments with DPP-4 inhibitor, XOR inhibitor, and angiotensin II receptor blocker respectively improved the stress-induced pathology.

Academic Significance and Societal Importance of the Research Achievements

慢性ストレスはメタボリック症候群、糖尿病、高尿酸血症、血栓症の原因となりうるが、機序は不明であったが、これを明らかにした。特に高血圧、糖尿病、高尿酸血症治療薬でこれらの病態を抑えることができたのはdrug repositioning、成人病、メタボリック症候群の治療の動機付けになると考える。
これらの結果についてプレスリリースを行ったところ、マスコミ各社より取材、SNSで話題になるなど社会的な関心の高さがうかがえた。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (7 results)

All 2020 2019 2018 2017 2016

All Journal Article (6 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 6 results,  Open Access: 3 results,  Acknowledgement Compliant: 3 results) Presentation (1 results)

  • [Journal Article] Sharpening the Focus: Acupuncture Interrupts the Brain?Gut Vicious Cycle Underlying Functional Dyspepsia2020

    • Author(s)
      Takeshita Kyosuke
    • Journal Title

      Digestive Diseases and Sciences

      Volume: 65 Issue: 6 Pages: 1578-1580

    • DOI

      10.1007/s10620-020-06080-1

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chronic stress augments esophageal inflammation, and alters the expression of transient receptor potential vanilloid?1 and protease?activated receptor 2 in a murine model2019

    • Author(s)
      Wulamu Wubulikasimu、Yisireyili Maimaiti、Aili Aikebaier、Takeshita Kyosuke、Alimujiang Aziguli、Aipire Aliyeguli、Li Yiliang、Jiang Yuan、Aizezi Maimaitiaili、Li Zanlin、Abudureyimu Kelimu
    • Journal Title

      Molecular Medicine Reports

      Volume: 2019 Pages: 5386-5396

    • DOI

      10.3892/mmr.2019.10192

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Xanthine oxidase inhibition by febuxostat attenuates stress-induced hyperuricemia, glucose dysmetabolism, and prothrombotic state in mice.2017

    • Author(s)
      Maimaiti Yisireyili
    • Journal Title

      Scientific Reports

      Volume: 7(1) Issue: 1 Pages: 1266-1266

    • DOI

      10.1038/s41598-017-01366-3

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Sokolow-Lyon voltage is suitable for monitoring improvement in cardiac function and prognosis of patients with idiopathic dilated cardiomyopathy.2017

    • Author(s)
      Fukaya K, Takeshita K, Okumura T, Hiraiwa H, Aoki S, Ichii T, Sugiura Y, Kitagawa K, Kondo T, Watanabe N, Kano N, Furusawa K, Sawamura A, Morimoto R, Bando Y, Murohara T.
    • Journal Title

      Ann Noninvasive Electrocardiol.

      Volume: 22 Issue: 5

    • DOI

      10.1111/anec.12431

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] O-GlcNAc on NOTCH1 EGF repeats regulates ligand-induced Notch signaling and vascular development in mammals2017

    • Author(s)
      *Shogo Sawaguchi, *Shweta Varshney, *Mitsutaka Ogawa, Yuta Sakaidani, Hirokazu Yagi, Kyosuke Takeshita, Toyoaki Murohara, Koichi Kato, Subha Sundaram , Pamela Stanley and Tetsuya Okajima. (*equal contribution)
    • Journal Title

      eLife

      Volume: 6

    • DOI

      10.7554/elife.24419

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Dipeptidyl peptidase- IV inhibitor alogliptin improves stress-induced insulin resistance and prothrombotic state in a murine model.2016

    • Author(s)
      Maimaiti Yisireyili
    • Journal Title

      Psychoneuroendocrinology

      Volume: 73 Pages: 186-195

    • DOI

      10.1016/j.psyneuen.2016.08.004

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Xanthine oxidase inhibitor attenuates stress-induced hyperuricemia and prothrombotic state2018

    • Author(s)
      竹下享典
    • Organizer
      第40回 日本血栓止血学会学術集会
    • Related Report
      2018 Research-status Report

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Published: 2016-04-21   Modified: 2021-02-19  

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