Novel molecular mechanisms of actions of homocysteine, a risk factor of cardiovascular diseases

• Project/Area Number: 16H05107
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Environmental and hygienic pharmacy
• Research Institution: Showa Pharmaceutical University
• Principal Investigator: ISHII Isao 昭和薬科大学, 薬学部, 教授 (90292953)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
• Keywords: ホモシステイン / PPARalpha / オキシトシン / X線結晶構造解析 / 硫化水素 / 活性イオウ分子種 / 心血管病 / 高脂血症 / 結晶構造解析 / 活性イオウ分子 / 絶食応答 / 脳脊髄液 / フィブラート系薬 / 高脂血症薬 / 結晶構造 / 危険因子 / トランススフルレーション / アミノ酸代謝 / PPARalpa / 脂質代謝 / 生体分子 / 生理活性 / プロテオーム / 遺伝子 / 酵素 / PPAR / X線構造解析 / 循環器・高血圧 / リスクファクター

Outline of Final Research Achievements

Elevated plasma levels of homocysteine are considered as a risk factor for cardiovascular diseases and this study aims to reveal yet unknown underlying molecular mechanisms. Here we investigated the structure of PPARa, a candidate of homocysteine target, and found the failure of oxytocin signaling (milk ejection and maternal behavior) in mice lacking cystathionine gamma-lyase that display homocysteinemia.

Academic Significance and Societal Importance of the Research Achievements

高脂血症薬の標的分子であるPPARalphaの構造を解明したことは、同分子を標的とする創薬に貢献できる。また、ホモシステインの作用機序の解明は、心血管病発症進展予防に寄与すると期待される。

Research Products

• [Int'l Joint Research] Rutgers-New Jersey Medical School/Vanderbilt University(米国)
• [Int'l Joint Research] University of Lodz/Poznan University of Life Sciences(ポーランド)
• [Int'l Joint Research] Max Delbruck Center/Charite University Medicine Berlin/German Aerospace Center(ドイツ)
• [Int'l Joint Research] University de Bordeaux(フランス)
• [Int'l Joint Research] Lausanne University Hospital/University of Lausanne(スイス)
• [Int'l Joint Research] Kyungpook National University/Keimyung University/National Ins. of Environmental Research(韓国)
• [Int'l Joint Research] Lausanne University Hospital/University of Lausanne(スイス)
• [Int'l Joint Research] Vanderbilt University(米国)
• [Int'l Joint Research] Friedrich-Alexander University/Charite Campus Virchow/Erlangen University(ドイツ)
• [Int'l Joint Research] University of Exeter(英国)
• [Int'l Joint Research] Universite Paris Descartes(フランス)
• [Int'l Joint Research] Washington State University/University of Michigan, Ann Arbor(米国)
• [Int'l Joint Research] Kyungpook National University/Korea Institute of Radiol and Med Sci(韓国)
• [Int'l Joint Research]
• [Journal Article] Abnormal amino acid profiles of blood and cerebrospinal fluid from cystathionine beta-synthase-deficient mice, an animal model of homocystinuria (2019)
  • Author(s): Akahoshi Noriyuki、Akira Yokoyama、Tomoko Nagata、Asumi Miura、Shotaro Kamata、Isao Ishii
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: -
  • Peer Reviewed
• [Journal Article] Dietary selenium deficiency or selenomethionine excess drastically alters organ selenium contents without altering the expression of most selenoproteins in mice (2019)
  • Author(s): Akahoshi Noriyuki、Anan Yasumi、Hashimoto Yuri、Tokoro Natsumi、Mizuno Ryoka、Hayashi Seiya、Yamamoto Shingo、Shimada Ki-ichi、Kamata Shotaro、Ishii Isao
  • Journal Title: The Journal of Nutritional Biochemistry Volume: 69 Pages: 120-129
  • DOI: 10.1016/j.jnutbio.2019.03.020
  • Peer Reviewed / Open Access
• [Journal Article] Mutations in Homocysteine Metabolism Genes Increase Keratin N-Homocysteinylation and Damage in Mice (2018)
  • Author(s): Borowczyk Kamila、Wroblewski Jacek、Suliburska Joanna、Akahoshi Noriyuki、Ishii Isao、Jakubowski Hieronim
  • Journal Title: International Journal of Genomics Volume: 2018 Pages: 7570850-7570850
  • DOI: 10.1155/2018/7570850
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 2D DIGE proteomic analysis reveals fasting‐induced protein remodeling through organ‐specific transcription factor(s) in mice (2018)
  • Author(s): Kamata S, Yamamoto J, Ohtani H, Tosaka Y, Yoshikawa S, Akahoshi N, Ishii I.
  • Journal Title: FEBS Open Bio Volume: 8 Issue: 9 Pages: 1524-1543
  • DOI: 10.1002/2211-5463.12497
  • Peer Reviewed / Open Access
• [Journal Article] Cystathionine γ-lyase? Produced hydrogen sulfide controls endothelial NO bioavailability and blood pressure (2018)
  • Author(s): Szijarto Istvan Andras、Marko Lajos、Filipovic Milos R.、Miljkovic Jan Lj、Tabeling Christoph、Tsvetkov Dmitry、Wang Ning、Rabelo Luiza A.、Witzenrath Martin、Diedrich Andre、Tank Jens、Akahoshi Noriyuki、Kamata Shotaro、Ishii Isao、Gollasch Maik
  • Journal Title: Hypertension Volume: 71 Issue: 6 Pages: 1210-1217
  • DOI: 10.1161/hypertensionaha.117.10562
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Structural and functional insights into S-thiolation of human serum albumins. (2018)
  • Author(s): Nakashima F, Shibata T, Kamiya K, Yoshitake J, Kikuchi R, Matsushita T, Ishii I, Gimenez-Bastida JA, Schneider C, Uchida K
  • Journal Title: Sci Rep. Volume: 8(1) Issue: 1 Pages: 932-932
  • DOI: 10.1038/s41598-018-19610-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hydrogen sulfide inhibits the NLRP3 inflammasome and reduces cytokine production both in vitro and in a mouse model of inflammation (2018)
  • Author(s): Castelblanco M, Lugrin J, Ehirchiou D, Nasi S, Ishii I, So A, Martinon F, Busso N
  • Journal Title: J Biol Chem Volume: 293 Issue: 7 Pages: 2546-2557
  • DOI: 10.1074/jbc.m117.806869
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Rapid 2D DIGE Proteomic Analysis of Mouse Liver (2017)
  • Author(s): Kamata Shotaro、Ishii Isao
  • Journal Title: Methods Mol Biol Volume: 1664 Pages: 153-166
  • DOI: 10.1007/978-1-4939-7268-5_13
  • ISBN: 9781493972678, 9781493972685
  • Peer Reviewed
• [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] Hydrogen sulfide-producing cystathionine γ-lyase is critical in the progression of kidney fibrosis (2017)
  • Author(s): Han Sang Jun、Noh Mi Ra、Jung Jung-Min、Ishii Isao、Yoo Jeongsoo、Kim Jee In、Park Kwon Moo
  • Journal Title: Free Radic Biol Med Volume: 112 Pages: 423-432
  • DOI: 10.1016/j.freeradbiomed.2017.08.017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion. (2017)
  • Author(s): Takahashi N, Wei FY, Watanabe S, Hirayama M, Ohuchi Y, Fujimura A, Kaitsuka T, Ishii I, Sawa T, Nakayama H, Akaike T, Tomizawa K.
  • Journal Title: Nucleic Acids Res. Volume: 45 Issue: 1 Pages: 435-445
  • DOI: 10.1093/nar/gkw745
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2016)
  • Author(s): Klionsky DJ., Abdelmohsen K., Abe A., Abedin MJ.,Inomata M., et al.
  • Journal Title: Autophagy Volume: 12(1) Issue: 1 Pages: 1-222
  • DOI: 10.1080/15548627.2015.1100356
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation. (2016)
  • Author(s): Wedmann R, Onderka C, Wei S, Szijarto IA, Miljkovic JL, Mitrovic A, Lange M, Savitsky S, Yadav PK, Torregrossa R, Harrer EG, Harrer T, Ishii I, Gollasch M, Wood ME, Galardon E, Xian M, Whiteman M, Banerjee R, Filipovic MR.
  • Journal Title: Chemical Science Volume: 7 Issue: 5 Pages: 3414-3426
  • DOI: 10.1039/c5sc04818d
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Blockade of Sphingosine 1-Phosphate Receptor 2 Signaling Attenuates High-Fat Diet-Induced Adipocyte Hypertrophy and Systemic Glucose Intolerance in Mice (2016)
  • Author(s): Kitada Y, Kajita K, Taguchi K, Mori I, Yamauchi M, Ikeda T, Kawashima M, Asano M, Kajita T, Ishizuka T, Banno Y, Kojima I, Chun J, Kamata S, Ishii I, Morita H.
  • Journal Title: Endocrinology Volume: 印刷中 Issue: 5 Pages: 1839-1851
  • DOI: 10.1210/en.2015-1768
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Role of cystathionine gamma-lyase in immediate renal impairment and inflammatory response in acute ischemic kidney injury. (2016)
  • Author(s): Marko L, Szijarto IA, Filipovic MR, Kassmann M, Balogh A, Park JK, Przybyl L, N'Diaye G, Kramer S, Anders J, Ishii I, Muller DN, Gollasch M.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 27517-27517
  • DOI: 10.1038/srep27517
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immobilization of the gas signaling molecule H2S by radioisotopes: detection, quantification, and in vivo imaging. (2016)
  • Author(s): Sarkar S, Ha YS, Soni N, An GI, Lee W, Kim MH, Huynh PT, Ahn H, Bhatt N, Lee YJ, Kim JY, Park KM, Ishii I, Kang SG, Yoo J.
  • Journal Title: Angewandte Chemie (International ed. in English) Volume: 55 Issue: 32 Pages: 9365-9370
  • DOI: 10.1002/anie.201603813
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cystathionine-gamma-lyase gene deletion protects mice against inflammation and liver sieve injury following polymicrobial sepsis. (2016)
  • Author(s): Gaddam RR, Fraser R, Badiei A, Chambers S, Cogger VC, Le Couteur DG, Ishii I, Bhatia M.
  • Journal Title: PLoS One Volume: 11 Issue: 8 Pages: e0160521-e0160521
  • DOI: 10.1371/journal.pone.0160521
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 適応免疫応答におけるCystathionine gamma-lyase欠損の影響 (2018)
  • Author(s): 竹本麟太郎、宮下雅嗣、吉澤俊紀、赤星軌征、石井功
  • Organizer: 第91回日本生化学会大会
• [Presentation] 食餌性セレノメチオニンの体内蓄積におけるイオウ転移経路（transsulfuration）の役割 (2018)
  • Author(s): 藤波紘平、阿南弥寿美、橋本柚里、赤星軌征、石井功
  • Organizer: 第62回日本薬学会関東支部大会
• [Presentation] 各種リガンド結合核内受容体PPARalphaのCD測定法による熱安定性評価 (2018)
  • Author(s): 本多彰宏、石川諒、山本ゆめ、鎌田祥太郎、石井功
  • Organizer: 第62回日本薬学会関東支部大会
• [Presentation] 食餌性過剰セレノメチオニンのマウス体内分布及び代謝におけるイオウ転移酵素Cystathionine gamma-lyaseの重要な役割 (2018)
  • Author(s): 阿南弥寿美、藤波紘平、橋本柚里、赤星軌征、石井功
  • Organizer: 第29回日本微量元素学会学術集会
• [Presentation] PPARalphaリガンド/PPARalpha-LBD複合体のX線結晶構造解析 (2018)
  • Author(s): 鎌田祥太郎、山本ゆめ、須田圭介、斎藤健太、赤星軌征、大山択次、石井功
  • Organizer: 第17回生命科学研究会
• [Presentation] Selenoprotein profiling in various organs of mice fed with selenium-deficient and high-selenomethionine diets (2018)
  • Author(s): Isao Ishii, Noriyuki Akahoshi, Shotaro Kamata, Yuri Hashimoto, Seiya Hayashi, Natsumi Tokoro, Shingo Yamamoto, Ki-ichi Shimada, Yasumi Anan
  • Organizer: Experimental Biology 2018
  • Int'l Joint Research
• [Presentation] 二系統の高ホモシステイン血症マウスにおける脳脊髄液アミノ酸組成異常 (2018)
  • Author(s): 横山輝，赤星軌征，石井功
  • Organizer: 日本薬学会第138年会
• [Presentation] Cystathionine gamma-lyase欠損母マウスにおける授乳行動異常 (2018)
  • Author(s): 赤星軌征，半田博紀，横山輝，石井功
  • Organizer: 日本薬学会第138年会
• [Presentation] 二系統の高ホモシステイン血症マウスにおける脳脊髄液アミノ酸組成異常 (2018)
  • Author(s): 横山 輝, 赤星 軌征，石井 功
  • Organizer: 日本薬学会年会
• [Presentation] Cystathionine gamma－lyase欠損母マウスにおける授乳行動異常 (2018)
  • Author(s): 赤星 軌征，半田 博紀，横山 輝，石井 功
  • Organizer: 日本薬学会年会
• [Presentation] Cystathionine gamma-lyase欠損マウスにおける妊娠高血圧症候群と育児放棄 (2017)
  • Author(s): 赤星 軌征，半田 博紀，石井 功
  • Organizer: フォーラム2017
• [Presentation] Cystathionine γ-lyase欠損マウスにおける乳清アミノ酸成分の異常 (2017)
  • Author(s): 半田 博紀，横山 輝, 赤星 軌征，石井 功
  • Organizer: フォーラム2017
• [Presentation] Novel targets of homocysteine, a risk factor for cardiovascular disease (2017)
  • Author(s): Isao Ishii
  • Organizer: 韓国薬学会
  • Int'l Joint Research / Invited
• [Presentation] 親電子物質からの生体防御におけるトランススルフレーション酵素(CBS・CTH)の役割 (2016)
  • Author(s): 石井 功
  • 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（東京都 品川区）
  • Invited
• [Presentation] Possible roles of H2S/RSS and homocysteine in the redox signaling via electrophiles. (2016)
  • Author(s): Ishii I
  • Organizer: The 9th International Conference on the Biology, Chemistry, and Therapeutic applications of NO
  • Place of Presentation: 仙台国際センター（宮城県 仙台市）
  • Int'l Joint Research / Invited
• [Presentation] Dietary deprivation of each proteinogenic amino acid induces altered systemic adaptive responses in mice. (2016)
  • Author(s): Kamata S, Yamamoto J, Kamijo K, Ochiai T, Morita T, Yoshitomi Y, Hagiya Y, Kubota M, Ohkubo R, Karube K, Kasahara T, Ishii I.
  • Organizer: The 9th International Conference on the Biology, Chemistry, and Therapeutic applications of NO
  • Place of Presentation: 仙台国際センター（宮城県 仙台市）
  • Int'l Joint Research
• [Presentation] Dietary deprivation of each essential amino acid induces differential systemic adaptive responses in mice. (2016)
  • Author(s): Kamata S, Yamamoto J, Karube K, Ohkubo R, Kasahara T, Ishii I.
  • Organizer: Experimental Biology 2016
  • Place of Presentation: San Diego (USA)
  • Int'l Joint Research
• [Book] 衛生薬学（改訂第2版） (2018)
  • Author(s): 今井浩孝、小椋康光
  • Total Pages: 720
  • Publisher: 南江堂
  • ISBN: 9784524403547
• [Book] 第６版 衛生薬学 健康と環境 (2018)
  • Author(s): 永沼章、姫野誠一郎、平塚明
  • Total Pages: 538
  • Publisher: 丸善出版
  • ISBN: 9784621301784
• [Book] 第６版 衛生薬学 ー健康と環境ー (2018)
  • Author(s): 石井 功
  • Total Pages: 538
  • Publisher: 丸善出版株式会社
  • ISBN: 9784621301784
• [Remarks] 昭和薬科大学衛生化学研究室
  • URL: https://www.shoyaku.ac.jp/research/laboratory/eisei/top