Research on detoxification mechanism of environmental electrophiles mediated by reactive sulfur species

• Project/Area Number: 16K18920
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Environmental and hygienic pharmacy
• Research Institution: University of Tsukuba
• Principal Investigator: UNOKI TAKAMITSU 筑波大学, 医学医療系, 特任助教 (00742868)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 活性イオウ分子 / 環境中新電子物質 / 環境中親電子物質 / 親電子物質 / 健康リスク / 環境 / 分析科学

Outline of Final Research Achievements

Environmental electrophiles such as 1,4-napthoquinone (1,4-NQ) and methylmercury easily bind to the protein thiols, thereby inducing cytotoxicity. In this study, we investigated the cytoprotective roles of reactive sulfur species, a highly nucleophilic compounds. We found that exposure of primary mouse hepatocytes to polysulfide and 1,4-NQ markedly decreased 1,4-NQ-mediated cell death and S-arylation of cellular proteins. Activation of cell survival signaling under exposure to 1,4-NQ was suppressed in the presence of polysulfides. These results suggest that reactive sulfur species act as a initial cytoprotective factor by capturing this electrophile.

Research Products

• [Journal Article] The Capture of Cadmium by Reactive Polysulfides Attenuates Cadmium-Induced Adaptive Responses and Hepatotoxicity (2017)
  • Author(s): Akiyama Masahiro、Shinkai Yasuhiro、Unoki Takamitsu、Shim Ilseob、Ishii Isao、Kumagai Yoshito
  • Journal Title: Chem Res Toxicol Volume: 30 Issue: 12 Pages: 2209-2217
  • DOI: 10.1021/acs.chemrestox.7b00278
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Polysulfide Na2S4 regulates the activation of PTEN/Akt/CREB signaling and cytotoxicity mediated by 1,4-naphthoquinone through formation of sulfur adducts (2017)
  • Author(s): Abiko Yumi、Shinkai Yasuhiro、Unoki Takamitsu、Hirose Reiko、Uehara Takashi、Kumagai Yoshito
  • Journal Title: Scientific Report Volume: 7 Issue: 1 Pages: 4814-4814
  • DOI: 10.1038/s41598-017-04590-z
  • NAID: 120007128910
  • Peer Reviewed / Open Access
• [Journal Article] 1,4-Naphthoquinone activates the HSP90/HSF1 pathway through the S-arylation of HSP90 in A431 cells: Negative regulation of the redox signal transduction pathway by persulfides/polysulfides (2017)
  • Author(s): Abiko Y, Sha L, Shinkai Y, Unoki T, Luong NC, Tsuchiya Y, Watanabe Y, Hirose R, Akaike T, Kumagai Y.
  • Journal Title: Free Radic Biol Med Volume: 104 Pages: 118-128
  • DOI: 10.1016/j.freeradbiomed.2016.12.047
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Methylmercury, an environmental electrophile capable of activation and disruption of the Akt/CREB/Bcl-2 signal transduction pathway in SH-SY5Y cells (2016)
  • Author(s): Unoki T, Abiko Y, Toyama T, Uehara T, Tsuboi K, Nishida M, Kaji T, Kumagai Y.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 28944-28944
  • DOI: 10.1038/srep28944
  • NAID: 120007135346
  • Peer Reviewed / Open Access
• [Presentation] ポリスルフィドNa2S4はイオウ付加体形成を通じて1,4-NQによる PTEN/ Akt/CREB シグナルの活性化と細胞毒性を抑制する (2017)
  • Author(s): 鵜木隆光、安孫子ユミ、新開泰弘、広瀬玲子、上原孝、熊谷嘉人
  • Organizer: フォーラム2017：衛生薬学・環境トキシコロジー
• [Presentation] カドミウムによるHSP90の化学修飾を介した転写因子HSF1の活性化と活性イオウ分子によるその制御 (2017)
  • Author(s): 鵜木隆光、新開泰弘、増田章、秋山雅博、Ming XIAN、熊谷嘉人
  • Organizer: 第44回日本毒性学会学術年会
• [Presentation] カドミウムによるHSP90の化学修飾を介する転写因子HSF1の活性化と活性イオウ分子によるその制御 (2017)
  • Author(s): 鵜木隆光、新開泰弘、増田章、秋山雅博、Xian Ming、熊谷嘉人
  • Organizer: 第70回日本酸化ストレス学会
• [Presentation] 1,4-Naphthoquinone-mediated activation of the HSP90/HSF1 signal transduction pathway and its negative regulation by reactive sulfur species in human A431 cells (2016)
  • Author(s): Unoki T, Shinkai Y, Sha L, Hirose R, Kumagai Y
  • Organizer: IUTOX2016 XIV International Congress of Toxicology and X Mexican Congress of Toxicology
  • Place of Presentation: メリダ（メキシコ）
  • Year and Date: 2016-10-02
  • Int'l Joint Research
• [Presentation] 親電子物質による生体影響の二面性：SH-SY5Y 細胞におけるメチル水銀曝露により生じるAkt/CREB/Bcl-2 経路の活性化と破綻 (2016)
  • Author(s): 鵜木隆光、安孫子ユミ、外山喬士、上原孝、坪井康次、西田基宏、鍜冶利幸、熊谷嘉人
  • Organizer: フォーラム2016 衛生薬学・環境トキシコロジー
  • Place of Presentation: 昭和大学旗の台キャンパス（東京都・品川区）
  • Year and Date: 2016-09-10
• [Presentation] 1,4-ナフトキノンによるHSF90/HSF1経路の活性化と活性イオウ分子によるその制御 (2016)
  • Author(s): 鵜木隆光、新開泰弘、沙亮、広瀬玲子、熊谷嘉人
  • Organizer: 第43回日本毒性学会学術年会
  • Place of Presentation: ウインクあいち（愛知県・名古屋市）
  • Year and Date: 2016-06-29
• [Presentation] Sodium tetrasulfide, a reactive sulfur species, protects cells from 1,4-naphthoquinone induced cytotoxicity through sulfur adduct formation (2016)
  • Author(s): Unoki T, Shinkai Y, Abiko Y, Hirose R, Kumagai Y
  • Organizer: The 9th International Conference on the Biology, Chemistry , and Therapeutic Applications of Nitric Oxide. The 16th Annual Scientific Meeting of the Nitric Oxide Society of Japan
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2016-05-20
  • Int'l Joint Research