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Regulation of redox signaling by reactive sulfur species in nervous system

Research Project

Project/Area Number 16H04674
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurochemistry/Neuropharmacology
Research InstitutionOsaka Prefecture University

Principal Investigator

Ihara Hideshi  大阪府立大学, 理学(系)研究科(研究院), 教授 (60254447)

Co-Investigator(Kenkyū-buntansha) 澤 智裕  熊本大学, 大学院生命科学研究部(医), 教授 (30284756)
中嶋 秀満  大阪府立大学, 生命環境科学研究科, 准教授 (30405360)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2018: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2017: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2016: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Keywords活性イオウ分子 / レドックスシグナル / 神経変性 / 活性イオウ分子種 / 細胞内情報伝達 / レドックッスシグナル
Outline of Final Research Achievements

It had become obvious that ROS/redox signaling is pathophysiologically important in the nervus system. However, little was known about the role of reactive sulfur species, which is endogenous regulator of ROS/redox signaling. We used MeHg as an environmental electrophile and found that exposure of cells to the exogenous electrophile elevated intracellular concentrations of 8-nitro-cGMP, accompanied by depletion of reactive persulfide species and 8-SH-cGMP which is a metabolite of 8-nitro-cGMP. Exposure to MeHg also induced S-guanylation and activation of H-Ras followed by activation of MAPK and injury to cerebellar granule neurons. The electrophile-induced activation of redox signaling and the consequent cell damage were attenuated by pretreatment with a reactive persulfide species donor. Our results suggest that reactive persulfide species may be potential therapeutic targets for attenuating neurodegeneration.

Academic Significance and Societal Importance of the Research Achievements

メチル水銀を用いた酸化ストレスを介する神経変性疾患モデルで、神経毒性の発現にレドックスシグナルの亢進と細胞内の活性イオウ分子種の枯渇が一因であることを明らかにした。また、外因的活性イオウ分子ドナーによる細胞内活性イオウ分子の補充が、神経毒性を緩和することを明らかにしている。これらの結果は、活性イオウ分子が神経変性疾患の治療ターゲットになることを示唆している。また、新規の活性イオウ分子ドナーの開発、活性イオウ分子の生合成酵素の同定も行っているので、今後これらの知見をベースにした神経変性疾患に対する新たな治療戦略が展開されることが期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (47 results)

All 2019 2018 2017 2016

All Journal Article (16 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 16 results,  Open Access: 11 results,  Acknowledgement Compliant: 2 results) Presentation (30 results) (of which Int'l Joint Research: 5 results,  Invited: 5 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Enhanced Cellular Polysulfides Negatively Regulate TLR4 Signaling and Mitigate Lethal Endotoxin Shock2019

    • Author(s)
      Zhang Tianli、Ono Katsuhiko、Tsutsuki Hiroyasu、Ihara Hideshi、Islam Waliul、Akaike Takaaki、Sawa Tomohiro
    • Journal Title

      Cell Chemical Biology

      Volume: in press Issue: 5 Pages: 686-698.e4

    • DOI

      10.1016/j.chembiol.2019.02.003

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Redox regulation of Ca2+/calmodulin-dependent protein kinase IV via oxidation of its active-site cysteine residue2019

    • Author(s)
      Takata Tsuyoshi、Kimura Jun、Ihara Hideshi、Hatano Naoya、Tsuchiya Yukihiro、Watanabe Yasuo
    • Journal Title

      Free Radical Biology and Medicine

      Volume: 130 Pages: 99-106

    • DOI

      10.1016/j.freeradbiomed.2018.10.440

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 8-Nitro-cGMP attenuates context-dependent fear memory in mice.2019

    • Author(s)
      Kishimoto Y, Kasamatsu S, Yanai S, Endo S, Akaike T, Ihara H.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 511 Issue: 1 Pages: 141-147

    • DOI

      10.1016/j.bbrc.2019.01.138

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] SNAP-25 S-Guanylation and SNARE Complex Formation.2019

    • Author(s)
      Kishimoto Y, Akaike T, Ihara H.
    • Journal Title

      Methods Mol Biol

      Volume: 1860 Pages: 163-173

    • DOI

      10.1007/978-1-4939-8760-3_9

    • ISBN
      9781493987597, 9781493987603
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Polysulfide stabilization by tyrosine and hydroxyphenyl-containing derivatives that is important for a reactive sulfur metabolomics analysis.2019

    • Author(s)
      Hamid HA, Tanaka A, Ida T, Nishimura A, Matsunaga T, Fujii S, Morita M, Sawa T, Fukuto JM, Nagy P, Tsutsumi R, Motohashi H, Ihara H, Akaike T.
    • Journal Title

      Redox Biol

      Volume: 21 Pages: 101096-101096

    • DOI

      10.1016/j.redox.2019.101096

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 2-Oxo-histidine-containing dipeptides are functional oxidation products2018

    • Author(s)
      Ihara Hideshi、Kakihana Yuki、Yamakage Akane、Kai Kenji、Shibata Takahiro、Nishida Motohiro、Yamada Ken-ichi、Uchida Koji
    • Journal Title

      Journal of Biological Chemistry

      Volume: 294 Issue: 4 Pages: 1279-1289

    • DOI

      10.1074/jbc.ra118.006111

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Involvement of nitric oxide/reactive oxygen species signaling via 8-nitro-cGMP formation in 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in PC12 cells and rat cerebellar granule neurons2018

    • Author(s)
      Masuda Kumiko、Tsutsuki Hiroyasu、Kasamatsu Shingo、Ida Tomoaki、Takata Tsuyoshi、Sugiura Kikuya、Nishida Motohiro、Watanabe Yasuo、Sawa Tomohiro、Akaike Takaaki、Ihara Hideshi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 495 Issue: 3 Pages: 2165-2170

    • DOI

      10.1016/j.bbrc.2017.12.088

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 8-Nitro-cGMP attenuates the interaction between SNARE complex and complexin through S-guanylation of SNAP-252018

    • Author(s)
      Kishimoto Y, Kunieda K, Kitamura A, Kakihana Y, Akaike T, Ihara H.
    • Journal Title

      ACS Chem Neurosci

      Volume: 9 Issue: 2 Pages: 217-223

    • DOI

      10.1021/acschemneuro.7b00363

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics2017

    • Author(s)
      Akaike Takaaki、、、Nishida Motohiro(4)、、、、、、Fujii Shigemoto(20)、、、Motohashi Hozumi(26)
    • Journal Title

      Nature Communications

      Volume: 8 Issue: 1 Pages: 1177-1177

    • DOI

      10.1038/s41467-017-01311-y

    • NAID

      120007134656

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Exposure to Electrophiles Impairs Reactive Persulfide-Dependent Redox Signaling in Neuronal Cells2017

    • Author(s)
      Ihara Hideshi、Kasamatsu Shingo、Kitamura Atsushi、Nishimura Akira、Tsutsuki Hiroyasu、Ida Tomoaki、Ishizaki Kento、Toyama Takashi、Yoshida Eiko、Abdul Hamid Hisyam、Jung Minkyung、Matsunaga Tetsuro、Fujii Shigemoto、Sawa Tomohiro、Nishida Motohiro、Kumagai Yoshito、Akaike Takaaki
    • Journal Title

      Chem. Res. Toxicol

      Volume: 30 Issue: 9 Pages: 1673-1684

    • DOI

      10.1021/acs.chemrestox.7b00120

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Reactive sulfur species inactivate Ca2+/calmodulin-dependent protein kinase IV via S-polysulfidation of its active-site cysteine residue2017

    • Author(s)
      Takata T, Ihara H, Hatano N, Tsuchiya Y, Akaike T, Watanabe Y.
    • Journal Title

      Biochem J

      Volume: 474 Issue: 15 Pages: 2547-2562

    • DOI

      10.1042/bcj20170092

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ferulic acid and its water-soluble derivatives inhibit nitric oxide production and inducible nitric oxide synthase expression in rat primary astrocytes2017

    • Author(s)
      Kikugawa M, Ida T, Ihara H, Sakamoto T
    • Journal Title

      Bioscience, biotechnology, and biochemistry

      Volume: 81 Issue: 8 Pages: 1607-1611

    • DOI

      10.1080/09168451.2017.1336925

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 8-Nitro-cGMP promotes bone growth through expansion of growth plate cartilage2017

    • Author(s)
      Hoshino Marie、Kaneko Kotaro、Miyamoto Yoichi、Yoshimura Kentaro、Suzuki Dai、Akaike Takaaki、Sawa Tomohiro、Ida Tomoaki、Fujii Shigemoto、Ihara Hideshi、Tanaka Junichi、Tsukuura Risa、Chikazu Daichi、Mishima Kenji、Baba Kazuyoshi、Kamijo Ryutaro
    • Journal Title

      Free Radic Biol Med

      Volume: 110 Pages: 63-71

    • DOI

      10.1016/j.freeradbiomed.2017.05.022

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Synthesis of L-cysteine derivatives containing stable sulfur isotopes and application of this synthesis to reactive sulfur metabolome2017

    • Author(s)
      Ono K, Jung M, Zhang T, Tsutsuki H, Sezaki H, Ihara H, Wei FY, Tomizawa K, Akaike T, Sawa T.
    • Journal Title

      Free Radic Biol Med

      Volume: 106 Pages: 69-79

    • DOI

      10.1016/j.freeradbiomed.2017.02.023

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Superoxide generation from nNOS splice variants and its potential involvement in redox signal regulation2017

    • Author(s)
      Ihara H, Kitamura A, Kasamatsu S, Ida T, Kakihana Y, Tsutsuki H, Sawa T, Watanabe Y, Akaike T.
    • Journal Title

      Biochem J

      Volume: 474 Issue: 7 Pages: 1149-1162

    • DOI

      10.1042/bcj20160999

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Quantitative determination of polysulfide in albumins, plasma proteins and biological fluid samples using a novel combined assays approach2017

    • Author(s)
      keda, M. Ishima, Y. Shibata, A. Chuang, V. T. G. Sawa, T. Ihara, H. Watanabe, H. Xian, M. Ouchi, Y. Shimizu, T. Ando, H. Ukawa, M. Ishida, T. Akaike, T. Otagiri, M. Maruyama, T.
    • Journal Title

      Analytica Chimica Acta

      Volume: 969 Pages: 18-25

    • DOI

      10.1016/j.aca.2017.03.027

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 酸化イミダゾールジペプチドの検出2018

    • Author(s)
      垣花優希,山陰茜,柴田貴広,内田浩二,居原秀
    • Organizer
      レドックス研究会2018
    • Related Report
      2018 Annual Research Report
  • [Presentation] 酸化イミダゾールジペプチド産生の分子メカニズムの解明2018

    • Author(s)
      垣花優希,内田浩二,居原秀
    • Organizer
      第18 回日本NO学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 生体内における2-cysteinyl carnosine の検出2018

    • Author(s)
      田中アキラ,居原秀
    • Organizer
      第18 回日本NO学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 活性イオウ分子解析システムの開発と応用2018

    • Author(s)
      居原秀
    • Organizer
      第18 回日本NO学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] メチル水銀による活性イオウ分子種依存的レドックスシグナルの破綻2018

    • Author(s)
      居原秀, 北村篤志, 笠松真吾, 井田智章, 西田基宏, 澤智裕, 熊谷嘉人, 赤池 孝章
    • Organizer
      第45回日本毒性学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] メチル水銀の新規毒性発現機構―活性イオウ分子/レドクスシグナル制御系の破綻―2018

    • Author(s)
      居原秀
    • Organizer
      第72回日本細菌学会東北支部総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] イミダゾールジペプチドによる抗酸化メカニズムの解明2018

    • Author(s)
      居原秀
    • Organizer
      第16回レドックス・ライフイノベーションシンポジウム
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] A NOVEL MECHANISM FOR ELECTROPHILIC CYTOTOXICITY VIA IMPAIRMENT OF REACTIVE PERSULFIDE SPECIES-REGULATED REDOX SIGNALING2018

    • Author(s)
      H Ihara, S Kasamatsu, M Nishida, T Sawa, Y Kumagai, T Akaike
    • Organizer
      第10 回国際NO学会
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] TRANSLATION-COUPLED PROTEIN POLYSULFIDATION, A UNIQUE BIOSYNTHESIS PATHWAY OF CYSTEINE PERSULFIDE2018

    • Author(s)
      T Ida, A Nishimura, M Morita, H Ihara, T Sawa, S Fujii, H Motohashi, T Akaike
    • Organizer
      第10 回国際NO学会
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] NEURONAL NOS EXPRESSION PROMOTES ACETYLCHOLINE RECEPTOR SIGNALING ENHANCEMENT2018

    • Author(s)
      Y Tsuchiya, T Takata, H Ihara, Y Watanabe
    • Organizer
      第10 回国際NO学会
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Exposure to Electrophiles Impairs Reactive Persulfide-dependent Redox Signaling in Neuronal Cells2018

    • Author(s)
      H Ihara
    • Organizer
      第91回日本生化学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 銅イオン特異的な酸化イミダゾールジペプチド産生2018

    • Author(s)
      垣花優希,内田浩二,居原秀
    • Organizer
      メタルバイオサイエンス研究会2018
    • Related Report
      2018 Annual Research Report
  • [Presentation] 安定同位体イオウで標識されたシステイン誘導体の合成と活性イオウメタボロームの構築2017

    • Author(s)
      小野勝彦、ジョンミンキョン、張田力、津々木博康、居原秀、瀬崎浩史、赤池孝章、澤智裕
    • Organizer
      第17回日本NO学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] ニコチン性アセチルコリン受容体を介した細胞内信号系におけるNO合成酵素とそのSer847リン酸化修飾の意義2017

    • Author(s)
      土屋幸弘 、丹澤夏実、高田剛、居原秀、渡邊泰男
    • Organizer
      第17回日本NO学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 酸化ストレスに対する細胞内カルノシンの神経保護効果2017

    • Author(s)
      山陰茜、垣花優希、柴田貴広、内田浩二、居原秀
    • Organizer
      第17回日本NO学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 活性硫黄分子種によるアミロイドβ毒性の制御機構2017

    • Author(s)
      松原実咲、赤池孝章、居原秀
    • Organizer
      第17回日本NO学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 活性イオウ分子によるカルモデュリンキナーゼIVのポリスルフィド化とその意義2017

    • Author(s)
      高田剛、居原秀、土屋幸弘 、赤池孝章、渡邊泰男
    • Organizer
      第17回日本NO学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] アルコールデヒドロゲナーゼ5の酵素活性制御におけるタンパク質ポリサルファ化機能2017

    • Author(s)
      井田智章、笠松真吾、Morshedul Alam、守田匡伸、居原秀、西村明 、松永哲郎 、藤井重元、本橋ほづみ、赤池孝章
    • Organizer
      第17回日本NO学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 酸化ストレスに依存して酸化イミダゾールジペプチドが産生される2017

    • Author(s)
      垣花優希 、山陰茜、柴田貴広、内田浩二、居原秀
    • Organizer
      第70回日本酸化ストレス学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 硫化水素/活性イオウ分子種を簡易検出するための抗体の作製2017

    • Author(s)
      居原秀、笠松真吾、赤池 孝章
    • Organizer
      第70回日本酸化ストレス学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 内因性親電子シグナル経路と活性イオウ分子のクロストークと環境毒性学2017

    • Author(s)
      居原秀
    • Organizer
      第44回日本毒性学会学
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] The effect of 8-nitro-cGMP on SNARE complex2017

    • Author(s)
      岸本祐典、柳井修一、遠藤昌吾、赤池孝章、居原 秀
    • Organizer
      第60回日本神経化学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] S-guanylation of SNAP-25 by 8-nitro-cGMP attenuates the interaction of SNARE complex with complexin2017

    • Author(s)
      Kishimoto Y, Kunieda K, Akaike T, Ihara H
    • Organizer
      2017 ISN-ESN Meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Detection and quantification of 2-oxo-histidine-containing dipeptides2017

    • Author(s)
      Hideshi Ihara, Yuki Kakihana, Akane Yamakage, Takahiro Shibata, Koji Uchida
    • Organizer
      SFRBM 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 酸化イミダゾールジペプチドの発見と生成メカニズムの解明2017

    • Author(s)
      垣花優希、居原秀、山陰茜、柴田貴広、内田浩二
    • Organizer
      ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] 親電子性物質による活性イオウ分子種依存性レドックスシグナルの破綻2017

    • Author(s)
      北村篤志、笠松真吾 、西村明、井田智章 、西田基宏、熊谷嘉人、赤池孝章、居原秀
    • Organizer
      ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] アセチルコリン受容体信号系におけるNOSによるレドックス制御の意義2017

    • Author(s)
      土屋幸弘、井出亜弓、内藤恵、丹澤夏実、高田剛、居原秀、渡邊泰男
    • Organizer
      ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] ニトロソグルタチオン還元酵素(GSNOR)選択的欠損マウスの開発2017

    • Author(s)
      松永哲郎、西村明、笠松真吾、Morshedul Alam、井田智章、守田匡伸、居原秀、藤井重元、下田 翔、西田基宏、本橋ほづみ、赤池孝章
    • Organizer
      ConBio2017
    • Related Report
      2017 Annual Research Report
  • [Presentation] メチル水銀の新たな毒性メカニズム2017

    • Author(s)
      西村 明、西村 明幸、笠松真吾、居原 秀、松永哲郎、井田智章、守田匡伸、 藤井重元、熊谷嘉人、西田基宏、赤池孝章
    • Organizer
      第66回東北公衆衛生学会
    • Related Report
      2017 Annual Research Report
  • [Presentation] 活性イオウ分子種によるメチル水銀毒性制御機構2016

    • Author(s)
      北村篤志 笠松真吾 津々木博康 井田智章 藤井重元 澤智裕 赤池孝章 居原秀
    • Organizer
      第39回日本分子生物学会
    • Place of Presentation
      横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Annual Research Report
  • [Patent(Industrial Property Rights)] 特定のサルファイド化合物に結合する抗体及びその使用2017

    • Inventor(s)
      居原 秀
    • Industrial Property Rights Holder
      大阪府立大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-031238
    • Filing Date
      2017-02-22
    • Related Report
      2016 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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