Elucidation of mechanisms for metabolic disorder and chronic inflammation by S-nitrosylation, a novel protein modification after translation.

• Project/Area Number: 16K19048
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: SHINOZAKI Shohei 東京医科歯科大学, 大学院医歯学総合研究科, 非常勤講師 (40622626)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 糖尿病 / インスリン抵抗性 / メタボリックシンドローム / S-ニトロソ化 / iNOS / 一酸化窒素 / インスリン抵抗 / 老化 / β細胞 / 動脈硬化 / 慢性炎症

Outline of Final Research Achievements

In this study, we focused on the development of age-related diseases, including metabolic syndrome, diabetes and arteriosclerosis. To clarify relationships between metabolic reprogramming and protein S-nitrosylation, we studied about 1) DNA and histone methylation / demethylation enzymes; 2) GSNOR-KO mice; 3) natural compounds which inhibit protein S-nitrosylation and/or iNOS.
Within this study period, 1) we identified novel S-nitrosylated DNA and histone methylation / demethylation enzymes. 2) In GSNOR-KO mice, it was revealed that S-nitrosylation affects diabetes and obesity. 3) Natural compounds, derived from food, inhibit S-nitrosylation are identified and confirmed beneficial effects of diabetes.

Research Products

• [Int'l Joint Research] Harvard Medical School(米国)
• [Journal Article] Beneficial effects of xanthohumol on obesity and insulin resistance in obese, diabetic (ob/ob) mice. (2018)
  • Author(s): Mabuchi, S., Shinozaki, S., Soejima, Y., Tsuzuki, T., Naito, H., Sawabe, M., Kaneki, M., Shimokado, K.
  • Journal Title: Open Access Journal of Foood and Nutrition Volume: 1 Pages: 1-10
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Burn-induced muscle metabolic derangements and mitochondrial dysfunction are associated with activation of HIF-1α and mTORC1: Role of protein farnesylation (2017)
  • Author(s): Nakazawa Harumasa、Ikeda Kazuhiro、Shinozaki Shohei、Kobayashi Masayuki、Ikegami Yuichi、Fu Ming、Nakamura Tomoyuki、Yasuhara Shingo、Yu Yong-Ming、Martyn J. A. Jeevendra、Tompkins Ronald G.、Shimokado Kentaro、Yorozu Tomoko、Ito Hideki、Inoue Satoshi、Kaneki Masao
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 6618-6618
  • DOI: 10.1038/s41598-017-07011-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] iNOS as a Driver of Inflammation and Apoptosis in Mouse Skeletal Muscle after Burn Injury: Possible Involvement of Sirt1 S-Nitrosylation-Mediated Acetylation of p65 NF-κB and p53. (2017)
  • Author(s): Nakazawa H, Chang K, Shinozaki S, Yasukawa T, Ishimaru K, Yasuhara S, Yu YM, Martyn JA, Tompkins RG, Shimokado K, Kaneki M
  • Journal Title: PLoS One Volume: 12(1) Issue: 1 Pages: e0170391-e0170391
  • DOI: 10.1371/journal.pone.0170391
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 糖尿病と慢性炎症 (2016)
  • Author(s): 篠崎昇平
  • Organizer: 第58回日本老年医学会学術集会
  • Place of Presentation: 石川県金沢市 石川県立音楽堂
  • Year and Date: 2016-06-09
  • Invited
• [Presentation] S-nitrosylation of SIRT1 as a hub of and inflammatory spiral. (2016)
  • Author(s): Shohei Shinozaki
  • Organizer: The 9th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide.
  • Place of Presentation: 宮城県仙台市 仙台国際センター
  • Year and Date: 2016-05-20
  • Int'l Joint Research / Invited