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Expression, functions, and synthesis regulation of reactive sulfur species in vascular endothelial cells

Research Project

Project/Area Number 19K07089
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
Research InstitutionTokyo University of Science

Principal Investigator

Kaji Toshiyuki  東京理科大学, 薬学部薬学科, 教授 (90204388)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords血管内皮細胞 / 活性イオウ分子 / TGF-β / FGF-2 / バイオオルガノメタリクス / 細胞内シグナル経路 / 動脈硬化 / 活性イオウ分子産生酵素 / 重金属 / 鉛 / 小胞体ストレス / 有機-無機ハイブリッド分子 / 銅錯体 / 細胞増殖因子
Outline of Research at the Start

血管病変防御に重要な役割を果たしている血管内皮細胞における低分子量型活性イオウ分子の機能とその発現調節を担う細胞内シグナル経路を解明する。そのために,培養血管内皮細胞を用い,亜鉛イオンの毒性軽減や生体防御タンパク質メタロチオネインの誘導への役割や,内皮細胞機能調節因子,有害重金属および有機-無機ハイブリッド分子による活性イオウ分子産生酵素群の発現制御とそれを担う細胞内シグナル経路を解析する。

Outline of Final Research Achievements

Vascular endothelial cells are the only cell type in direct contact with blood, covering the lumen of blood vessels with a monolayer. The reactive sulfur species is a molecule with an excess of sulfur atoms added to the thiol group of L-cysteine, but its function and regulation of expression in vascular endothelial cells are still unknown. This study suggest that reactive sulfur species are produced in vascular endothelial cells in response to exogenous chemicals as well as cytokines/growth factors, and that endothelial cell functions are regulated by the reactive sulfur species. The reactive sulfur species-producing enzymes involved in this response varied depending on the stimuli, and the intracellular signaling pathways mediating the induction of these enzymes were also found to be diverse.

Academic Significance and Societal Importance of the Research Achievements

血管内皮細胞の機能障害は動脈硬化病変,高血圧,血栓症などの血管病変の要因となる。本研究は,血管内皮細胞における活性イオウ分子の機能と合成調節が活性イオウ分子産生酵素の特定とその酵素の誘導を介在する細胞内シグナル経路のレベルで明らかにしたものであり,血管内皮細胞の機能調節の解明を確実に一歩進めたものであり,動脈硬化などの血管病変の予防と治療に新しい視点と展開をもたらす知見を提供するものである。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (28 results)

All 2021 2020 2019 Other

All Journal Article (12 results) (of which Peer Reviewed: 12 results,  Open Access: 12 results) Presentation (14 results) (of which Invited: 3 results) Remarks (2 results)

  • [Journal Article] Sodium trisulfide, a sulfane sulfur donor, stimulates bovine aortic endothelial cell proliferation in culture2021

    • Author(s)
      Takahashi, M., Iwai, R., Takasawa, R., Nakano, T., Fujie, T., Hara, T., Hara, Y., Yamamoto, C.* and Kaji, T.*
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 46 Issue: 7 Pages: 341-344

    • DOI

      10.2131/jts.46.341

    • NAID

      130008060478

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Synthesis of reactive sulfur species in cultured vascular endothelial cells after exposure to TGF-β1: Induction of cystathionine γ-lyase and cystathionine β-synthase expression mediated by the ALK5-Smad2/3/4 and ALK5-Smad2/3-ATF4 pathways2021

    • Author(s)
      37.Takahashi, M., Fujie, T., Nakano, T., Hara, T., Shinkai, Y., Takasawa, R., Hara, Y., Kumagai, Y., Yamamoto, C.* and Kaji, T.*
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 21 Pages: 11762-11762

    • DOI

      10.3390/ijms222111762

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fibroblast Growth Factor-2 Upregulates Reactive Sulfur Species Production <i>via</i> ERK1/2 Signal-Mediated Cystathionine γ-Lyase Induction in Cultured Bovine Aortic Endothelial Cells2021

    • Author(s)
      Takahashi, M., Kubota, T., Fujie, T., Shinkai, Y., Kumagai, Y., Nakano, T., Hara, T., Yamamoto, C.* and Kaji, T.*
    • Journal Title

      BPB Reports

      Volume: 4 Issue: 6 Pages: 175-181

    • DOI

      10.1248/bpbreports.4.6_175

    • NAID

      130008115933

    • ISSN
      2434-432X
    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Arsenite inhibits tissue-type plasminogen activator synthesis through NRF2 activation in cultured human vascular endothelial EA.hy926 cells2021

    • Author(s)
      Tsuyoshi Nakano, Tsutomu Takahashi, Chika Yamamoto, Eiko Yoshida, Toshiyuki Kaji, and Yasuyuki Fujiwara
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 22 Issue: 2 Pages: 739-739

    • DOI

      10.3390/ijms22020739

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transcriptional induction of cystathionine γ-lyase, a reactive sulfur-producing enzyme, by copper diethyldithiocarbamate in cultured vascular endothelial cells2020

    • Author(s)
      Tomoya Fujie, Akane Takahashi, Musubu Takahashi, Takato Hara, Asuka Soyama, Kosho Makino, Hideyo Takahashi, Chika Yamamoto, Yoshito Kumagai, Hiroshi Naka and Toshiyuki Kaji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 17 Pages: 6053-6053

    • DOI

      10.3390/ijms21176053

    • NAID

      120007163377

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cell density-dependent fibroblast growth factor-2 signaling regulates syndecan-4 expression in cultured vascular endothelial cells2020

    • Author(s)
      Takato Hara, Shiori Yabushita, Chika Yamamoto and Toshiyuki Kaji
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 21 Issue: 10 Pages: 3698-3698

    • DOI

      10.3390/ijms21103698

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Zn(II)2,9-dimethyl-1,10-phenanthroline stimulates cultured bovine aortic endothelial cell proliferation2020

    • Author(s)
      Takehiro Nakamura, Eiko Yoshida, Takato Hara, Tomoya Fujie, Chika Yamamoto, Yasuyuki Fujiwara, Fumihiko Ogata, Naohito Kawasaki, Ryo Takita, Masanobu Uchiyama and Toshiyuki Kaji
    • Journal Title

      RSC Advances

      Volume: 10 Issue: 69 Pages: 42327-42337

    • DOI

      10.1039/d0ra06731h

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cell density-dependent accumulation of low polarity gold nanocluster in cultured vascular endothelial cells2020

    • Author(s)
      Takato Hara, Misato Saeki, Yuichi Negishi, Toshiyuki Kaji, and Chika Yamamoto
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 45 Issue: 12 Pages: 795-800

    • DOI

      10.2131/jts.45.795

    • NAID

      130007948829

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Induction of metallothionein isoforms in cultured bovine aortic endothelial cells exposed to cadmium2020

    • Author(s)
      Tomoya Fujie, Yusuke Ozaki, Fukuta Takenaka, Misaki Nishio, Takato Hara, Yasuyuki Fujiwara, Chika Yamamoto, and Toshiyuki Kaji
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 45 Issue: 12 Pages: 801-806

    • DOI

      10.2131/jts.45.801

    • NAID

      130007948808

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cell density-dependent modulation of perlecan synthesis by dichloro(2,9-dimethyl-1,10-phenanthroline)zinc(II) in vascular endothelial cells2020

    • Author(s)
      Takato Hara, Sayaka Sakamaki, Atsuya Ikeda, Takehiro Nakamura, Chika Yamamoto, Toshiyuki Kaji
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 45 Issue: 2 Pages: 109-115

    • DOI

      10.2131/jts.45.109

    • NAID

      130007798450

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Intracellular accumulation-independent cytotoxicity of pentavalent organoantimony compounds in cultured vascular endothelial cells2019

    • Author(s)
      Takato Hara, Shihoko Nakano, Yuki Kitamura, Chika Yamamoto, Shuji Yasuike, Toshiyuki Kaji
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 44 Issue: 12 Pages: 845-848

    • DOI

      10.2131/jts.44.845

    • NAID

      130007759779

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Possible mechanisms underlying transcriptional induction of metallothionein isoforms by tris(pentafluorophenyl)stibane, tris(pentafluorophenyl)arsane, and tris(pentafluorophenyl)phosphane in cultured bovine aortic endothelial cells2019

    • Author(s)
      Tomoya Fujie, Fukuta Takenaka, Eiko Yoshida, Shuji Yasuike, Yasuyuki Fujiwara, Yasuhiro Shinkai, Yoshito Kumagai, Chika Yamamoto, Toshiyuki Kaji
    • Journal Title

      The Journal of Toxicological Sciences

      Volume: 44 Issue: 5 Pages: 327-333

    • DOI

      10.2131/jts.44.327

    • NAID

      130007642916

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] FGF-2の血管内皮細胞増殖の促進への活性イオウ分子の関与2021

    • Author(s)
      高橋 結,藤江 智也,久保田 采佳,岩井 瑠里,山本 千夏,鍜冶 利幸
    • Organizer
      第48回日本毒性学会学術年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 鉛はPERK-ATF4経路の活性化によって血管内皮細胞の活性イオウ分子産生を促進させる2021

    • Author(s)
      高橋 結,藤江智也,宇多川直利,中野 剛,新開泰弘,熊谷嘉人,山本千夏,鍜冶利幸
    • Organizer
      メタルバイオサイエンス研究会2021
    • Related Report
      2021 Annual Research Report
  • [Presentation] TGF-β1-ALK5-Smad2/3/4-ATF4経路を介した活性イオウ分子の増加はTGF-β1の血管内皮細胞増殖抑制作用をmodulateする2021

    • Author(s)
      高橋 結,藤江智也,中野 毅,新開泰弘,熊谷嘉人,山本千夏,鍜冶利幸
    • Organizer
      フォーラム2021:衛生薬学・環境トキシコロジー
    • Related Report
      2021 Annual Research Report
  • [Presentation] 鉛による血管内皮細胞の活性イオウ分子合成の誘導とその機構2021

    • Author(s)
      高橋 結、藤江 智也、宇田川 直利、新開 泰弘、熊谷 嘉人、山本 千夏、鍜冶 利幸
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Research-status Report
  • [Presentation] 重金属のシグナルトキシコロジー2020

    • Author(s)
      鍜冶 利幸
    • Organizer
      第47回日本毒性学会学術年会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] メチル水銀毒性発現機序の解明に向けた挑戦2020

    • Author(s)
      鍜冶 利幸
    • Organizer
      第47回日本毒性学会学術年会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] TGF-β1による培養血管内皮細胞の活性イオウ分子産生酵素の発現調節を担う細胞内 シグナル経路2020

    • Author(s)
      髙橋 結,藤江 智也,髙橋 茜,山本 千夏,鍜冶 利幸
    • Organizer
      第47回日本毒性学会学術年会
    • Related Report
      2020 Research-status Report
  • [Presentation] TGF-β1による血管内皮細胞の活性イオウ分子産生酵素発現調節2020

    • Author(s)
      髙橋 結,藤江 智也,髙橋 茜,山本 千夏,鍜冶 利幸
    • Organizer
      フォーラム2020:衛生薬学・環境トキシコロジー
    • Related Report
      2020 Research-status Report
  • [Presentation] FGF-2 による血管内皮細胞の活性イオウ分子産生酵素 CSE の発現誘導2020

    • Author(s)
      久保田 采佳,髙橋 結,藤江 智也,山本 千夏,鍜冶 利幸
    • Organizer
      フォーラム2020:衛生薬学・環境トキシコロジー
    • Related Report
      2020 Research-status Report
  • [Presentation] TGF-β1による培養血管内皮細胞の活性イオウ分子産生酵素群の発現調節2020

    • Author(s)
      高橋 結,高橋 茜,藤江 智也,山本 千夏,鍜冶 利幸
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Research-status Report
  • [Presentation] TGF-β1による培養血管内皮細胞の活性イオウ分子産生酵素の発現調節を担う細胞内シグナル経路2020

    • Author(s)
      高橋 結,藤江 智也,高橋 茜,山本 千夏,鍜冶 利幸
    • Organizer
      第47回日本毒性学会学術年会
    • Related Report
      2019 Research-status Report
  • [Presentation] 血管内皮細胞において銅錯体 Cu10 は ERK/p38 MAPK 経路を介して活性イオウ分子産生酵素 CSE の転写を誘導する2019

    • Author(s)
      高橋 茜 ,高橋 結 ,藤江 智也 ,原 崇人 ,山本 千夏 ,中 寛史 ,鍜冶 利幸
    • Organizer
      メタルバイオサイエンス研究会2019
    • Related Report
      2019 Research-status Report
  • [Presentation] 金属のシグナルトキシコロジー2019

    • Author(s)
      鍜冶利幸
    • Organizer
      メタルバイオサイエンス研究会2019
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 血管内皮細胞のメタロチオネイン誘導における活性イオウ産生酵素の役割2019

    • Author(s)
      遠藤 広貴, 藤江 智也, 山本 千夏, 鍜冶 利幸
    • Organizer
      第46回日本毒性学会学術年会
    • Related Report
      2019 Research-status Report
  • [Remarks] RIDAI

    • URL

      https://www.tus.ac.jp/ridai/doc/ji/RIJIA01Detail.php?act=nam&kin=ken&diu=6347

    • Related Report
      2020 Research-status Report 2019 Research-status Report
  • [Remarks] Pure

    • URL

      https://tus.elsevierpure.com/ja/persons/toshiyuki-kaji

    • Related Report
      2020 Research-status Report 2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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