Investigation on the mechanism of the multiple effects of the inhalation of hydrogen gas for mitigating ischemia reperfusion injury

• Project/Area Number: 16K15599
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: Juntendo University (2017-2018); Nippon Medical School (2016)
• Principal Investigator: Ohta Shigeo 順天堂大学, 医学部, 客員教授 (00125832)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 水素ガス / 分子状水素 / 虚血再灌流障害 / 脂質メディエーター / 転写因子NFAT / 脳梗塞 / 心肺停止後蘇生 / 水素 / 虚血再灌流 / 実験外科学

Outline of Final Research Achievements

We have previously revealed that inhalation of hydrogen gas mitigated oxidative stress injury including ischemia reperfusion by animal model experiments. In this study, we investigated the efficient method for the inhalation of hydrogen gas by using a model animal. Then, we showed the efficacies of the inhalation of hydrogen gas for patients with cerebral infarction and cardiac arrest by clinical studies. Moreover, we revealed the molecular mechanism by which hydrogen exhibits the multiple functions: hydrogen modifies the free radical chain reaction to generate the oxidized phospholipids as a signal mediator. The signal mediator suppressed the calcium signaling, and suppressed the activation of a transcription factor NFAT. Since NFAT transcribes many factors, hydrogen can exert multiple functions for the mitigation of ischemia reperfusion injury.

Academic Significance and Societal Importance of the Research Achievements

水素ガス吸入による虚血再灌流障害を実際の治療に用いられるようにするには、臨床試験によって、患者への有効性を示すことが必要である。本研究によって、水素ガス吸入は、脳梗塞患者と心肺停止後蘇生患者の改善に対して有効であることを示唆した。水素ガス吸入治療は、厚生労働省から先進医療Bとして承認され、研究と同時に治療にも用いられている。薬事承認にあたっては、分子機構を解明することが必要である。本研究では、水素が多機能を発揮する分子機作を明らかにした。また、学術的にも、新たしいシグナル伝達機構の解明に寄与した。

Research Products

• [Journal Article] Acute Supplementation with Molecular Hydrogen Benefits Submaximal Exercise Indices. Randomized, Double-Blinded, Placebo-Controlled Crossover Pilot Study (2019)
  • Author(s): LeBaron TW, Larson AJ, Ohta S, Mikami T, Barlow J, Bulloch J, DeBeliso M
  • Journal Title: J Lifestyle Med. Volume: 9 Issue: 1 Pages: 36-43
  • DOI: 10.15280/jlm.2019.9.1.36
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Taurine supplementation for prevention of stroke-like episodes in MELAS: a multicentre, open-label, 52-week phase III trial. (2019)
  • Author(s): Ohsawa Y, Hagiwara H, Nishimatsu SI, Hirakawa A, Kamimura N, Ohtsubo H, Fukai Y, Murakami T, Koga Y, Goto YI, Ohta S, Sunada Y; KN01 Study Group.
  • Journal Title: J Neurol Neurosurg Psychiatry. Volume: 90 Issue: 5 Pages: 529-536
  • DOI: 10.1136/jnnp-2018-317964
  • Peer Reviewed / Open Access
• [Journal Article] Acute immobilization stress following contextual fear conditioning reduces fear memory: timing is essential (2019)
  • Author(s): Akemi Uwaya, Hyunjin Lee, Jonghyuk Park, Hosung Lee, Junko Muto, Sanae Nakajima, Shigeo Ohta,Toshio Mikami
  • Journal Title: Behavioral and Brain functions Volume: 12 Issue: 1 Pages: 8-8
  • DOI: 10.1186/s12993-016-0092-1
  • Peer Reviewed / Open Access
• [Journal Article] Effects of Molecular Hydrogen Assessed by an Animal Model and Randamized Clinical Study on Mild Cognitive Impairment. (2018)
  • Author(s): Nishimaki K., Asada T.,Ohsawa I.,Nakajima E.,Ikejima C.,Yokota T.,Kamimura N.,Ohta S.
  • Journal Title: Current Alzheimmer Research. Volume: 15 Issue: 5 Pages: 482-492
  • DOI: 10.2174/1567205014666171106145017
  • Peer Reviewed / Open Access
• [Journal Article] Pilot Study on Therapeutic Inhalation of Hydrogen Gas for Improving Patients with Alzheimer’s Disease Assessed by Cognitive Subscale Scores and Magnetic Resonance Diffusion Tensor Imaging (2018)
  • Author(s): Ono H, Nishijima Y, Sakamoto M, Horikosi T, Tamaki M, Oishi W, Naitoh Y, Futaki T, shii S, Suzuki K, Kurihara H and Ohta S
  • Journal Title: International Journal of Alzheimers & Neurological Disorders Volume: 1 Pages: 1-11
  • Peer Reviewed / Open Access
• [Journal Article] Hydrogen Gas Inhalation Treatment in Acute Cerebral Infarction: A Randomized Controlled Clinical Study on Safety and Neuroprotection. (2017)
  • Author(s): Ono H, Nishijima Y, Ohta S, Sakamoto M, Kinone K, Horikosi T, Tamaki M, Takeshita H, Futatuki T, Ohishi W, Ishiguro T, Okamoto S, Ishii S, Takanami H.
  • Journal Title: J Stroke Cerebrovasc Dis. Volume: 26 Issue: 11 Pages: 2587-2594
  • DOI: 10.1016/j.jstrokecerebrovasdis.2017.06.012
  • Peer Reviewed / Open Access
• [Journal Article] Cisplatin selects short forms of the mitochondrial DNA OriB variant (16184-16193 poly-cytosine tract), which confer resistance to cisplatin. (2017)
  • Author(s): Amo T, Kamimura N, Asano H, Asoh S, Ohta S.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 46240-46240
  • DOI: 10.1038/srep46240
  • Peer Reviewed / Open Access
• [Journal Article] Blue light-induced oxidative stress in live skin (2017)
  • Author(s): Nakashima Y, Wolf AM, Ohta S.
  • Journal Title: Free Radic Biol Med Volume: 108 Pages: 300-310
  • DOI: 10.1016/j.freeradbiomed.2017.03.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of Hydrogen Gas Inhalation on Muscular Damage using Mouse Hind Limb Ischemia Reperfusion Injury Model. (2017)
  • Author(s): Watanabe M., Kamimura N., Iuchi K., Nishimaki K., Yokota T., Ogawa R., Ohta S.
  • Journal Title: Plastic and Reconstructive Surgery. Volume: 140 Issue: 6 Pages: 1195-1206
  • DOI: 10.1097/prs.0000000000003878
  • Peer Reviewed
• [Journal Article] The histone 3 lysine 9 methyltransferase inhibitor chaetocin improves prognosis in a rat model of high salt diet-induced heart failure (2017)
  • Author(s): Ono T, Kamimura N, Matsuhashi T, Nagai T, Nishiyama T, Endo J, Hishiki T, Nakanishi T, Shimizu N, Tanaka H, Ohta S, Suematsu M, Ieda M, Sano M, Fukuda K, Kaneda R
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 39752-39752
  • DOI: 10.1038/srep39752
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Effects of Hydrogenized Water on Intracellular Biomarkers for Antioxidants, Glucose Uptake, Insulin Signaling and SIRT 1 and Telomerase Activity (2016)
  • Author(s): 1.Settineri R, Ji J, Luo C, Ellithorpe RR, Mattos GFd, Rosenblatt S, LaValle J, Jinenez A, Ohta S, Nicolson GL
  • Journal Title: American J Food Nutr. Volume: 4 Pages: 161-168
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Feasibility and Safety of Hydrogen Gas Inhalation for Post-Cardiac Arrest Syndrome – First-in-Human Pilot Study – (2016)
  • Author(s): Tamura T, Hayashida K, Sano M, Suzuki M, Shibusawa T, Yoshizawa J, Kobayashi Y, Suzuki T, Ohta S, Morisaki H, Fukuda K, Hori S.
  • Journal Title: Circulation Journal Volume: 80 Issue: 8 Pages: 1870-1873
  • DOI: 10.1253/circj.CJ-16-0127
  • NAID: 130005166118
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Presentation] Moleculeh hydrogen improves cognitive abilityin mild cognitive impairment and modest Alzheimer's disease. (2019)
  • Author(s): Shigeo Ohta
  • Organizer: Alzheimers and Parkinsons Diseases Program
  • Int'l Joint Research / Invited
• [Presentation] Hydrogen Medicine: from basic science to clinical applications (2018)
  • Author(s): Shigeo Ohta
  • Organizer: 第5回国際循環器科学アカデミー（IACS-AS） Second Announcement_Smolenice
  • Int'l Joint Research / Invited
• [Presentation] 水素医学のこの一年の発展2017-2018 (2018)
  • Author(s): 太田成男
  • Organizer: 第8回日本分子状水素医学生物学会
  • Invited
• [Presentation] タウリン大量療法による MELAS 脳卒中様発作の再発抑制 (2018)
  • Author(s): 太田成男
  • Organizer: 第18回日本ミトコンドリア学会
• [Presentation] 水素水の飲用によってApoE4遺伝子保因者の経度認知障害が改善する。 (2017)
  • Author(s): 太田成男
  • Organizer: 第7回日本分子状水素医学生物学会
• [Presentation] ミトコンドリアからみた認知症予防 (2017)
  • Author(s): 太田 成男
  • Organizer: 睡眠・認知症予防シンポジウム3
  • Place of Presentation: 中部大学（愛知）
  • Invited
• [Presentation] 分子水素の可能性 (2017)
  • Author(s): 太田 成男
  • Organizer: 第33回スパズム・シンポジウム
  • Place of Presentation: 大阪国際会議場（大阪）
  • Invited
• [Presentation] The molecular mechanism by which H2 regulates gene expression.What is the primary target of H2? (2016)
  • Author(s): Shigeo Ohta
  • Organizer: 3rd Symposium of Chinese Hydrogen Biomedical Association
  • Place of Presentation: Taian City (China)
  • Year and Date: 2016-09-25
  • Int'l Joint Research / Invited
• [Presentation] 分子状水素による酸化ストレス軽減と遺伝子発現制御：基礎医学から臨床応用へ (2016)
  • Author(s): 太田 成男
  • Organizer: 日本臨床検査自動化学会第48回大会
  • Place of Presentation: パシフィコ横浜（神奈川）
  • Year and Date: 2016-09-22
  • Invited
• [Presentation] 細胞死を抑制する分子状水素 (2016)
  • Author(s): 太田 成男
  • Organizer: 第25回日本Cell Death学会学術集会
  • Place of Presentation: 品川区立総合区民会館（東京）
  • Year and Date: 2016-09-09
  • Invited
• [Presentation] 水素研究のup-to-date (2016)
  • Author(s): 太田 成男
  • Organizer: 第16回日本抗加齢医学会総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-06-10
  • Invited
• [Presentation] 分子状水素による遺伝子発現制御 (2016)
  • Author(s): 太田 成男
  • Organizer: 日本分子状水素医学生物学会設立記念大会（第6回年会）
  • Place of Presentation: ワークピア横浜（神奈川）
  • Year and Date: 2016-05-28
  • Invited
• [Presentation] Introduction of Japanese Society of Hydrogen and current situation of hydrogen in Japan (2016)
  • Author(s): Shigeo Ohta
  • Organizer: 2016 KOREA International Symposium on Hydrogen
  • Place of Presentation: Seoul(KOREA)
  • Int'l Joint Research / Invited
• [Presentation] 水素医学の創始、展開、応用とメカニズム (2016)
  • Author(s): 太田 成男
  • Organizer: NPO法人国際医科学研究会第12回フォーラム
  • Place of Presentation: フクラシア品川（東京）
  • Invited
• [Book] ここまでわかった 水素水最新Q&A: 続・水素水とサビない身体 (2017)
  • Author(s): 太田 成男
  • Total Pages: 187
  • Publisher: 小学館
• [Book] 老化制御と疾患－エイジング研究の進歩－ (2016)
  • Author(s): 太田 成男
  • Total Pages: 5
  • Publisher: 日本臨床
• [Remarks] 順天堂大学研究者情報データベース
  • URL: https://www.juntendo.ac.jp/graduate/kenkyudb/search/researcher.php?MID=5478
• [Remarks] 日本医科大学先端医学研究所細胞生物学
  • URL: https://www.nms.ac.jp/ig/saiboseibutsu/