The role of PKC for unsaturated carbonyl compounds-induced cell injury and disease onset

• Project/Area Number: 18K11654
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 63030:Chemical substance influence on environment-related
• Research Institution: Hokkaido University
• Principal Investigator: HIGASHI Tsunehito 北海道大学, 医学研究院, 助教 (90453018)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 不飽和カルボニル化合物 / 細胞死 / プロテインキナーゼC / 細胞傷害

Outline of Final Research Achievements

Various chemical compounds exist in human environment, and affect human health. Unsaturated carbonyl compounds are generally generated by combustion of organic chemicals. Although unsaturated carbonyl compounds are highly toxic, the molecular mechanism for their cytotoxicity has been unclear. I have reported that the unsaturated carbonyl compounds induce cell death by activation of specific signaling pathway in cells. I also have revealed that cysteine and several cysteine derivatives directly react with unsaturated carbonyl compounds and detoxify them.

Academic Significance and Societal Importance of the Research Achievements

不飽和カルボニル化合物は、有機化合物の燃焼によって発生する毒性化合物であり、生体内で細胞死を引き起こすと考えられている。不飽和カルボニル化合物に暴露されやすい肺や心血管系の細胞死は、それぞれ慢性閉塞性肺疾患や動脈硬化症といった疾患の発症・進展の原因となると考えられる。本研究の成果は、環境中の化学物質に起因するこれらの疾患の発症の予防や進展の抑制方法の開発につながるものと期待される。

Research Products

• [Journal Article] Decreased Proteasomal Function Induces Neuronal Loss and Memory Impairment (2021)
  • Author(s): Tomaru Utano、Ito Tomoki、Ohmura Yu、Higashikawa Kei、Miyajima Syota、Tomatsu Ruka、Higashi Tsunehito、Ishizu Akihiro、Kuge Yuji、Yoshioka Mitsuhiro、Kasahara Masanori
  • Journal Title: The American Journal of Pathology Volume: 191 Issue: 1 Pages: 144-156
  • DOI: 10.1016/j.ajpath.2020.10.004
  • Peer Reviewed
• [Journal Article] Cigarette smoke extract induces ferroptosis in vascular smooth muscle cells (2020)
  • Author(s): Sampilvanjil Ariunaa、Karasawa Tadayoshi、Yamada Naoya、Komada Takanori、Higashi Tsunehito、Baatarjav Chintogtokh、Watanabe Sachiko、Kamata Ryo、Ohno Nobuhiko、Takahashi Masafumi
  • Journal Title: American Journal of Physiology-Heart and Circulatory Physiology Volume: 318 Issue: 3 Pages: H508-H518
  • DOI: 10.1152/ajpheart.00559.2019
  • Peer Reviewed / Open Access
• [Journal Article] Mitofusin 2 is involved in chemotaxis of neutrophil-like differentiated HL-60 cells (2019)
  • Author(s): Mazaki Yuichi、Takada Shingo、Nio-Kobayashi Junko、Maekawa Satoshi、Higashi Tsunehito、Onodera Yasuhito、Sabe Hisataka
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 513 Issue: 3 Pages: 708-713
  • DOI: 10.1016/j.bbrc.2019.04.037
  • Peer Reviewed / Open Access
• [Journal Article] Pyrenocine A induces monopolar spindle formation and suppresses proliferation of cancer cells (2019)
  • Author(s): Myobatake Yusuke、Kamisuki Shinji、Tsukuda Senko、Higashi Tsunehito、Chinen Takumi、Takemoto Kenji、Hachisuka Masami、Suzuki Yuka、Takei Maya、Tsurukawa Yukine、Maekawa Hiroaki、Takeuchi Toshifumi、Matsunaga Tomoko M.、Sahara Hiroeki、Usui Takeo、Matsunaga Sachihiro、Sugawara Fumio
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 27 Issue: 23 Pages: 115149-115149
  • DOI: 10.1016/j.bmc.2019.115149
  • Peer Reviewed / Open Access
• [Journal Article] Autoantibodies undetectable by chemiluminescent enzyme immunoassay require extended antigen-antibody reaction time for detection (2019)
  • Author(s): Mai Y, Ujiie H, Higashi T, Yamagami J, Iwata H, Shimizu H
  • Journal Title: Br J Dermatol Volume: 180 Issue: 1 Pages: 215-216
  • DOI: 10.1111/bjd.17121
  • Peer Reviewed
• [Journal Article] Glutathione and cysteines suppress cytotoxicity of gas phase of cigarette smoke by direct reacting with unsaturated carbonyl compounds in the gas phase (2019)
  • Author(s): Higashi Tsunehito、Elmeligy Enas、Mai Yosuke、Noya Yoichi、Terada Koji、Mazaki Yuichi、Kuge Yuji、Miwa Soichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 509 Issue: 4 Pages: 988-993
  • DOI: 10.1016/j.bbrc.2019.01.040
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Annexin A2 is involved in activation of extracellular signal-regulated kinase upon endothelin-1 stimulation (2019)
  • Author(s): Mazaki Yuichi、Higashi Tsunehito、Horinouchi Takahiro、Miwa Soichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 511 Issue: 1 Pages: 69-72
  • DOI: 10.1016/j.bbrc.2019.02.040
  • Peer Reviewed
• [Journal Article] Endothelin type B receptor interacts with the 78-kDa glucose-regulated protein. (2019)
  • Author(s): Mazaki, Y., Higashi, T., Onodera, Y., Nam, JM., Hashimoto, A., Hashimoto, S., Horinouchi, T., and Miwa, S.
  • Journal Title: FEBS Lett Volume: 593(6) Issue: 6 Pages: 644-651
  • DOI: 10.1002/1873-3468.13347
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protein kinase C-dependent cell damage by unsaturated carbonyl compounds in vascular cells (2018)
  • Author(s): Higashi T, Mai Y, Mazaki Y
  • Journal Title: J Biosci Bioeng Volume: 126 Issue: 4 Pages: 527-532
  • DOI: 10.1016/j.jbiosc.2018.04.020
  • NAID: 40021697445
  • Peer Reviewed
• [Presentation] Protein kinase C b is involved in unsaturated carbonyl compounds-induced cell death in macrophages (2020)
  • Author(s): Tsunehito HIgashi, Yuichi Mazaki
  • Organizer: JAACT2020 Fuchu
  • Int'l Joint Research
• [Presentation] 不飽和カルボニル化合物による細胞死に関与するPKCアイソフォームの同定 (2020)
  • Author(s): 東恒仁、真崎雄一
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] タバコ煙タール相による細胞死誘導メカニズム (2020)
  • Author(s): 東恒仁、真崎雄一
  • Organizer: 第93回日本薬理学会年会
• [Presentation] システイン誘導体による煙中の不飽和カルボニル化合物の解毒メカニズムの解明 (2019)
  • Author(s): 東恒仁、Enas Elmeligy、眞井洋輔、野矢洋一、真崎雄一、久下裕司、三輪聡一
  • Organizer: 第71回日本生物工学会大会
• [Presentation] 抗酸化物質によるタバコ煙ガス相の分子メカニズムの解明 (2019)
  • Author(s): 東恒仁、Enas Elmeligy、眞井洋輔、野矢洋一、久下裕司、真崎雄一、三輪聡一
  • Organizer: 第92回日本薬理学会年会
• [Presentation] 不飽和カルボニル化合物が血管構成細胞に及ぼす影響の解明 (2018)
  • Author(s): 東恒仁、眞井洋輔、真崎雄一
  • Organizer: 第70回日本生物工学会大会
• [Presentation] 不飽和カルボニル化合物はプロテインキナーゼC依存的に心血管系細胞の細胞死を誘導する (2018)
  • Author(s): 東恒仁、眞井洋輔、真崎雄一
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] Molecular mechanism for unsaturated carbonyl compounds-induced vascular cell death (2018)
  • Author(s): Tsunehito Higashi, Yosuke Mai, Yuichi Mazaki
  • Organizer: ASCB/EMBO 2018 Meeting
  • Int'l Joint Research
• [Remarks] 北海道大学大学院医学研究院細胞薬理学教室ホームページ
  • URL: https://plaza.umin.ac.jp/cellular_pharm/
• [Remarks] 北海道大学大学院医学研究院・薬理学分野・細胞薬理学教室
  • URL: http://plaza.umin.ac.jp/cellular_pharm/?p=12
• [Remarks] 北海道大学大学院医学研究院細胞薬理学教室
  • URL: http://plaza.umin.ac.jp/cellular_pharm/?p=12