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Physiological role of polyamines and search for a detoxifying medicine against its toxic metabolite acrolein

Research Project

Project/Area Number 21K06714
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47060:Clinical pharmacy-related
Research InstitutionChiba Institute of Science

Principal Investigator

Kashiwagi Keiko  千葉科学大学, 薬学部, 教授 (80169424)

Co-Investigator(Kenkyū-buntansha) 五十嵐 一衛  株式会社アミンファーマ研究所, その他部局等, 代表取締役 (60089597)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsポリアミン / アクロレイン / 翻訳 / ヒストン修飾 / ヒストン脱メチル化酵素 / アクロレイン除去剤 / 高度好熱菌 / Thermus thermophilus / 遺伝子発現制御 / 老化防止薬
Outline of Research at the Start

細胞増殖因子であるポリアミン(スペルミジン、スペルミン)は、細胞増殖・生存率維持に重要な蛋白質の合成を、翻訳レベルで促進する。エピジェネティックコントロールの一つであるヒストンアセチル化酵素中にポリアミンにより翻訳レベルで発現調節される蛋白質を見出した。本研究ではヒストンメチル化に注目し、ポリアミンは翻訳を促進することにより遺伝子発現を制御することを確立する。
アクロレインは、スペルミンの酸化分解により生じ、脳梗塞、アルツハイマー病等の疾患の増悪因子で、老化物質と考えられる。本研究では、副作用が少ないアクロレイン除去物質を老化防止薬として探索し、超高齢化社会を迎える日本の将来に役立てる。

Outline of Final Research Achievements

Polyamines (putrescine, spermidine, and spermine) are cationic aliphatic amines present in almost all living organisms. Polyamines are essential for cell growth and viability, interact with mainly RNA and stimulate protein synthesis which is important for cell growth and viability at the translational level. We have proposed that a set of genes whose expression is enhanced by polyamines at the level of translation can be classified as a “polyamine modulon”. Since histone methylation, one of the epigenetic controls, is reduced by polyamines, we identified three histone demethylases as members of polyamine modulon.
Acrolein is produced by the oxidative decomposition of spermine and is an aggravating factor for tissue-damaging diseases in old age such as cerebral infarction and Alzheimer's disease. It was discovered that lysine and taurine, which are food ingredients inside, reduce the toxicity of acrolein.

Academic Significance and Societal Importance of the Research Achievements

ヒストン修飾などのエピジェネティックな遺伝子発現制御に異常が起こると、発がんや、免疫制御異常が起こることが知られているが、その制御機構は不明な点が多い。本研究では、細胞増殖必須因子ポリアミンがヒストン脱メチル化酵素の翻訳レベルにおける発現調節因子であることを明らかにし、ヒストン修飾異常解明や新薬開発に繋がる端緒となる成果が得られた。また、ポリアミン代謝により生じる不飽和アルデヒドであるアクロレインは脳梗塞、アルツハイマー病等の老齢時の組織障害性疾患の増悪因子であるが、この毒性を軽減する物質を同定できた。超老齢化社会を迎える日本に大いに役立つと考えられる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (21 results)

All 2024 2023 2022 2021 Other

All Journal Article (10 results) (of which Int'l Joint Research: 10 results,  Peer Reviewed: 10 results,  Open Access: 5 results) Presentation (10 results) (of which Int'l Joint Research: 2 results,  Invited: 2 results) Remarks (1 results)

  • [Journal Article] Caldomycin, a new guanidopolyamine produced by a novel agmatine homocoupling enzyme involved in homospermidine biosynthesis2024

    • Author(s)
      Kobayashi Teruyuki、Sakamoto Akihiko、Hisano Tamao、Kashiwagi Keiko、Igarashi Kazuei、Takao Koichi、Uemura Takeshi、Furuchi Takemitsu、Sugita Yoshiaki、Moriya Toshiyuki、Oshima Tairo、Terui Yusuke
    • Journal Title

      Scientific Reports

      Volume: 14 Issue: 1 Pages: 7566-7566

    • DOI

      10.1038/s41598-024-58296-0

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Putrescine Biosynthesis from Agmatine by Arginase (TtARG) in <i>Thermus thermophilus</i>2023

    • Author(s)
      Kobayashi Teruyuki、Sakamoto Akihiko、Kashiwagi Keiko、Igarashi Kazuei、Takao Koichi、Uemura Takeshi、Moriya Toshiyuki、Oshima Tairo、Terui Yusuke
    • Journal Title

      The Journal of Biochemistry

      Volume: 174 Issue: 1 Pages: 81-88

    • DOI

      10.1093/jb/mvad026

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Transient Receptor Potential Ankyrin 1 (TRPA1) Channel Mediates Acrolein Cytotoxicity in Human Lung Cancer Cells2023

    • Author(s)
      Sakamoto Akihiko、Terui Yusuke、Igarashi Kazuei、Kashiwagi Keiko
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 14 Pages: 11847-11847

    • DOI

      10.3390/ijms241411847

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Urinary Amino Acid-Conjugated Acrolein and Taurine as New Biomarkers for Detection of Dementia2023

    • Author(s)
      Yoshida Madoka、Uemura Takeshi、Mizoi Mutsumi、Waragai Masaaki、Sakamoto Akihiko、Terui Yusuke、Kashiwagi Keiko、Igarashi Kazuei
    • Journal Title

      Journal of Alzheimer's Disease

      Volume: 92 Issue: 1 Pages: 361-369

    • DOI

      10.3233/jad-220912

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] A search for acrolein scavengers among food components2023

    • Author(s)
      Uemura Takeshi、Uchida Masashi、Nakamura Mizuho、Shimekake Momo、Sakamoto Akihiko、Terui Yusuke、Higashi Kyohei、Ishii Itsuko、Kashiwagi Keiko、Igarashi Kazuei
    • Journal Title

      Amino Acids

      Volume: - Issue: 4 Pages: 509-518

    • DOI

      10.1007/s00726-023-03248-7

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Molecular Characteristics of Toxicity of Acrolein Produced from Spermine2023

    • Author(s)
      Kashiwagi Keiko、Igarashi Kazuei
    • Journal Title

      Biomolecules

      Volume: 13 Issue: 2 Pages: 298-298

    • DOI

      10.3390/biom13020298

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Polyamines produced by an extreme thermophile are essential for cell growth at high temperature2022

    • Author(s)
      Sakamoto Akihiko、Tamakoshi Masatada、Moriya Toshiyuki、Oshima Tairo、Takao Koichi、Sugita Yoshiaki、Furuchi Takemitsu、Niitsu Masaru、Uemura Takeshi、Igarashi Kazuei、Kashiwagi Keiko、Terui Yusuke
    • Journal Title

      The Journal of Biochemistry

      Volume: 172 Issue: 2 Pages: 109-115

    • DOI

      10.1093/jb/mvac048

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Alkaline Stress Causes Changes in Polyamine Biosynthesis in Thermus thermophilus2022

    • Author(s)
      Kobayashi Teruyuki、Sakamoto Akihiko、Kashiwagi Keiko、Igarashi Kazuei、Moriya Toshiyuki、Oshima Tairo、Terui Yusuke
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 21 Pages: 13523-13523

    • DOI

      10.3390/ijms232113523

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Translational Regulation of Clock Genes BMAL1 and REV-ERBα by Polyamines2021

    • Author(s)
      Sakamoto A, Terui Y, Uemura T, Igarashi K, Kashiwagi K.
    • Journal Title

      Int J Mol Sci.

      Volume: 22(3) Issue: 3 Pages: 1307-1307

    • DOI

      10.3390/ijms22031307

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Functional roles of polyamines and their metabolite acrolein in eukaryotic cells2021

    • Author(s)
      Igarashi Kazuei、Kashiwagi Keiko
    • Journal Title

      Amino Acids

      Volume: 53 Issue: 10 Pages: 1473-1492

    • DOI

      10.1007/s00726-021-03073-w

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] TRPA1チャネルを介したアクロレインの細胞毒性機構2023

    • Author(s)
      坂本明彦,照井祐介,五十嵐一衛,柏木敬子
    • Organizer
      第96回日本生化学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Thermus thermophilusにおけるアルギナーゼによるプトレッシンの生合成2023

    • Author(s)
      小林照幸,坂本明彦,柏木敬子,五十嵐一衛,高尾浩一,植村武史,森屋利幸,大島泰郎,照井祐介
    • Organizer
      第96回日本生化学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] eIF5A2はミトコンドリアを活性化することで細胞増殖を促進する2023

    • Author(s)
      鈴木雅斗,米野雅大,鈴木健裕,真中瞳,多森翔馬,佐藤聡,秋本和憲,堂前直,松本健,吉田稔,柏木敬子,五十嵐一衛,東恭平
    • Organizer
      日本ポリアミン学会第14回年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Thermus thermophilusのホモスペルミジン生合成に関与する新規アグマチンホモカップリング酵素の同定2023

    • Author(s)
      小林照幸,坂本明彦,久野玉雄,柏木敬子,五十嵐一衛,高尾浩一,植村武史,古地壯光,杉田義昭,森屋利幸,大島泰郎,照井祐介
    • Organizer
      日本ポリアミン学会第14回年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Thermus thermophilus の プトレッシン生合成経路2023

    • Author(s)
      小林照幸, 坂本明彦, 柏木敬子, 五十嵐一衛, 高尾浩一, 植村武史, 森屋利幸,大島泰郎, 照井祐介
    • Organizer
      日本ポリアミン学会第13回年会
    • Related Report
      2022 Research-status Report
  • [Presentation] ポリアミンによるヒストン脱メチル化酵素の合成促進2023

    • Author(s)
      坂本明彦, 照井祐介, 五十嵐一衛, 柏木敬子
    • Organizer
      日本ポリアミン学会第13回年会
    • Related Report
      2022 Research-status Report
  • [Presentation] 認知症疾患における尿中アミノ酸抱合アクロレインとタウリン量の低下2023

    • Author(s)
      吉田円,植村武史,溝井睦美,藁谷正明,坂本明彦,照井祐介,柏木敬子,五十嵐一衛
    • Organizer
      日本ポリアミン学会第13回年会
    • Related Report
      2022 Research-status Report
  • [Presentation] Molecular mechanisms of cell and tissue toxicity caused by acrolein.2022

    • Author(s)
      K. Igarashi, T. Uemura, A. Sakamoto, Y. Terui, K. Kashiwagi
    • Organizer
      6th International Conference on Polyamines: Biochemical, Physiological and Clinical Perspectives. Italy, 2022
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Regulation of gene expression through translational stimulation of histone modifying enzymes by polyamines.2022

    • Author(s)
      K. Kashiwagi, A. Sakamoto, Y. Terui, K. Igarashi
    • Organizer
      6th International Conference on Polyamines: Biochemical, Physiological and Clinical Perspectives. Italy, 2022
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] ポリアミンによる翻訳促進に基づく遺伝子発現調節2021

    • Author(s)
      柏木 敬子、坂本 明彦、照井 祐介、植村 武史、五十嵐 一衛
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Research-status Report
  • [Remarks] 千葉科学大学 薬学部 病態生化学研究室

    • Related Report
      2021 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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