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Reinforcement of colonic epithelial barrier via mAChR

Research Project

Project/Area Number 18K06946
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49010:Pathological biochemistry-related
Research InstitutionAsahikawa Medical College

Principal Investigator

Taniguchi Takanobu  旭川医科大学, 医学部, 教授 (60217130)

Co-Investigator(Kenkyū-buntansha) 矢澤 隆志  旭川医科大学, 医学部, 講師 (00334813)
加藤 剛志  旭川医科大学, 医学部, 准教授 (60194833)
宇和田 淳介  旭川医科大学, 医学部, 助教 (70580314)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
KeywordsTNF / MAP kinase / p38 / ADM17 / STIM1 / SOCE / ADAM17 / 炎症性腸疾患 / ムスカリン受容体 / TNF-α / 腸上皮バリア / TACE
Outline of Final Research Achievements

In intestinal epithelial cells, store-operated calcium entry (SOCE) following muscarinic M3 receptor activation positively regulates p38MAP kinase and activates the protease ADAM17 to cleave/solubilize TNF-α. It was thought that it blocked the pathway and suppressed the spread of inflammation. In the course of this study, we found PNU-120596 as a substance that inhibits p38MAP kinase. Although this substance is widely used as a positive allosteric modulator of α7 nAChR, it binds directly to p38MAP kinase and exerts an inhibitory effect without mediating α7 nAChR.

Academic Significance and Societal Importance of the Research Achievements

腸上皮バリアが破綻すると外来抗原や微生物が侵入し、マクロファージなどの免疫細胞が遊走浸潤して対抗し、TNF-αをはじめとする炎症促進因子を放出して腸上皮バリア機能をさらに低下させるという悪循環が生じ、このことは炎症性腸疾患の病態との関わりが深い。我々の研究成果はムスカリン受容体刺激がTNF-α converting enzyme(TACE)を活性化してTNF-α受容体(TNFR)の密度を低下させると同時に、その可溶化された断片(sTNFR)がTNF-α自体を中和してTNF-α経路を抑制していることを示し、炎症性腸疾患の新しい治療法の可能性を示したものである。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (18 results)

All 2021 2020 2019 2018

All Journal Article (14 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 14 results,  Open Access: 11 results) Presentation (4 results)

  • [Journal Article] Pleiotropic effects of probenecid on three-dimensional cultures of prostate cancer cells2021

    • Author(s)
      Uwada Junsuke、Mukai Shoichiro、Terada Naoki、Nakazawa Hitomi、Islam Mohammad Sayful、Nagai Takahiro、Fujii Masato、Yamasaki Koji、Taniguchi Takanobu、Kamoto Toshiyuki、Yazawa Takashi
    • Journal Title

      Life Sciences

      Volume: 278 Pages: 119554-119554

    • DOI

      10.1016/j.lfs.2021.119554

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Short-chain fatty acid mitigates adenine-induced chronic kidney disease via FFA2 and FFA3 pathways2020

    • Author(s)
      Mikami Daisuke、Kobayashi Mamiko、Uwada Junsuke、Yazawa Takashi、Kamiyama Kazuko、Nishimori Kazuhisa、Nishikawa Yudai、Nishikawa Sho、Yokoi Seiji、Kimura Hideki、Kimura Ikuo、Taniguchi Takanobu、Iwano Masayuki
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

      Volume: 1865 Issue: 6 Pages: 158666-158666

    • DOI

      10.1016/j.bbalip.2020.158666

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evaluation of 17β-hydroxysteroid dehydrogenase activity using androgen receptor-mediated transactivation2020

    • Author(s)
      Yazawa Takashi、Imamichi Yoshitaka、Uwada Junsuke、Sekiguchi Toshio、Mikami Daisuke、Kitano Takeshi、Ida Takanori、Sato Takahiro、Nemoto Takahiro、Nagata Sayaka、Islam Khan Md. Rafiqul、Takahashi Satoru、Ushikubi Fumitaka、Suzuki Nobuo、Umezawa Akihiro、Taniguchi Takanobu
    • Journal Title

      The Journal of Steroid Biochemistry and Molecular Biology

      Volume: 196 Pages: 105493-105493

    • DOI

      10.1016/j.jsbmb.2019.105493

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] AR420626, a selective agonist of GPR41/FFA3, suppresses growth of hepatocellular carcinoma cells by inducing apoptosis via HDAC inhibition2020

    • Author(s)
      Mikami Daisuke、Kobayashi Mamiko、Uwada Junsuke、Yazawa Takashi、Kamiyama Kazuko、Nishimori Kazuhisa、Nishikawa Yudai、Nishikawa Sho、Yokoi Seiji、Taniguchi Takanobu、Iwano Masayuki
    • Journal Title

      Therapeutic Advances in Medical Oncology

      Volume: 12 Pages: 1-13

    • DOI

      10.1177/1758835920913432

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] PNU-120596, a positive allosteric modulator of α7 nicotinic acetylcholine receptor, directly inhibits p38 MAPK2020

    • Author(s)
      Uwada Junsuke、Nakazawa Hitomi、Mikami Daisuke、Islam Mohammad Sayful、Muramatsu Ikunobu、Taniguchi Takanobu、Yazawa Takashi
    • Journal Title

      Biochemical Pharmacology

      Volume: 182 Pages: 114297-114297

    • DOI

      10.1016/j.bcp.2020.114297

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] β-Hydroxybutyrate enhances the cytotoxic effect of cisplatin via the inhibition of HDAC/survivin axis in human hepatocellular carcinoma cell2020

    • Author(s)
      Daisuke Mikami, Mamiko Kobayashi, Junsuke Uwada, Takashi Yazawa, Kazuko Kamiyama, Kazuhisa Nishimori, Yudai Nishikawa, Sho Nishikawa, Seiji Yokoi, Takanobu Taniguchi, and Masayuki Iwano
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 142 Issue: 1 Pages: 1-8

    • DOI

      10.1016/j.jphs.2019.10.007

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Store-operated calcium entry (SOCE) contributes to phosphorylation of p38 MAPK and suppression of TNF-α signalling in the intestinal epithelial cells.2019

    • Author(s)
      Uwada J, Yazawa T, Mikami D, Krug SM, Fromm M, Yoshiki H, Sada K, Muramatsu I, Taniguchi T.
    • Journal Title

      Cell signal.

      Volume: 63 Pages: 109358-109358

    • DOI

      10.1016/j.cellsig.2019.109358

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Nicotinic Acetylcholine Receptor-Mediated Signaling Pathways in Pluripotent Stem Cells2019

    • Author(s)
      Takashi Yazawa, Junsuke Uwada, Yoshitaka Imamichi, Daisuke Mikami, Takahiro Sato, Rafiqul Islam Khan, Mohammad Sayful Islam and Takanobu Taniguchi
    • Journal Title

      American Journal of Biomedical Science & Research

      Volume: 6 Issue: 5 Pages: 361-363

    • DOI

      10.34297/ajbsr.2019.06.001061

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Cyclooxygenase‐2 is acutely induced by CCAAT/enhancer‐binding protein β to produce prostaglandin E 2 and F 2α following gonadotropin stimulation in Leydig cells2019

    • Author(s)
      Yazawa Takashi、Imamichi Yoshitaka、Yuhki Koh‐ichi、Uwada Junsuke、Mikami Daisuke、Shimada Masayuki、Miyamoto Kaoru、Kitano Takeshi、Takahashi Satoru、Sekiguchi Toshio、Suzuki Nobuo、Rafiqul Islam Khan Md.、Ushikubi Fumitaka、Umezawa Akihiro、Taniguchi Takanobu
    • Journal Title

      Molecular Reproduction and Development

      Volume: 86 Issue: 7 Pages: 786-797

    • DOI

      10.1002/mrd.23163

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Augmentation of endogenous acetylcholine uptake and cholinergic facilitation of hippocampal long-term potentiation by acetylcholinesterase inhibition2019

    • Author(s)
      Masuoka T, Uwada J, Kudo M, Yoshiki H, Yamashita Y, Taniguchi T, Nishio M, Ishibashi T, Muramatsu I
    • Journal Title

      Neuroscience

      Volume: 404 Pages: 39-47

    • DOI

      10.1016/j.neuroscience.2019.01.042

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] β-Hydroxybutyrate, a ketone body, reduces the cytotoxic effect of cisplatin via activation of HDAC5 in human renal cortical epithelial cells.2019

    • Author(s)
      Mikami D, Kobayashi M, Uwada J, Yazawa T, Kamiyama K, Nishimori K, Nishikawa Y, Morikawa Y, Yokoi S, Takahashi N, Kasuno K, Taniguchi T, Iwano M.
    • Journal Title

      Life Sci

      Volume: 222 Pages: 125-132

    • DOI

      10.1016/j.lfs.2019.03.008

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transcriptional Regulation of Ovarian Steroidogenic Genes; Recent Findings Obtained from Stem Cell-derived Steroidogenic Cells.2019

    • Author(s)
      Yazawa, T., Imamichi, Y., Sekiguchi, T., Miyamoto, K., Uwada, J., Khan, R., Suzuki, N., Umezawa A. and Taniguchi, T.
    • Journal Title

      BioMed Research International

      Volume: 8973076 Pages: 1-13

    • DOI

      10.1155/2019/8973076

    • Related Report
      2019 Research-status Report 2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Novel regulatory systems for acetylcholine release in rat striatum and anti‐Alzheimer's disease drugs2019

    • Author(s)
      Muramatsu Ikunobu、Uwada Junsuke、Yoshiki Hatsumi、Sada Kiyonao、Lee Kung‐Shing、Yazawa Takashi、Taniguchi Takanobu、Nishio Matomo、Ishibashi Takaharu、Masuoka Takayoshi
    • Journal Title

      Journal of Neurochemistry

      Volume: 印刷中 Issue: 5 Pages: 605-623

    • DOI

      10.1111/jnc.14701

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A short-chain fatty acid, propionate, enhances the cytotoxic effect of cisplatin by modulating GPR41 signaling pathways in HepG2 cells2018

    • Author(s)
      Kobayashi M, Mikami D, Uwada J, Yazawa T, Kamiyama K, Kimura H, Taniguchi T, Iwano M
    • Journal Title

      Oncotarget

      Volume: 9 Issue: 59 Pages: 31342-31354

    • DOI

      10.18632/oncotarget.25809

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Effect of probenecid on 3D-cultured prostate cancer spheroids2020

    • Author(s)
      宇和田 淳介, 矢澤 隆志, 向井 尚一郎, 寺田 直樹, 谷口 隆信
    • Organizer
      第93回日本薬理学会年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Analysis of testicular prostaglandin production and transcriptional regulation of COX-22019

    • Author(s)
      矢澤隆志,今道力敬,宇和田淳介,谷口隆信
    • Organizer
      日本生化学大会
    • Related Report
      2019 Research-status Report
  • [Presentation] Muscarinic acetylcholine receptor regulates p38 MAPK through store-operated calcium entry in intestinal epithelial cells.2018

    • Author(s)
      宇和田淳介,矢澤隆志,谷口隆信
    • Organizer
      日本生化学大会
    • Related Report
      2018 Research-status Report
  • [Presentation] Analysis of steroidogenic pathway using stem cell-derived steroidogenic cells.2018

    • Author(s)
      宇和田淳介,矢澤隆志,谷口隆信
    • Organizer
      日本生化学大会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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