Studies on the physiological role of ascorbic acid in SOD1/Akr1a double knockout mice with increased oxidative stress

• Project/Area Number: 16K16592
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied health science
• Research Institution: Yamagata University
• Principal Investigator: Homma Takujiro 山形大学, 大学院医学系研究科, 助教 (70743566)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 酸化ストレス / スーパーオキシド / ビタミンC / 小胞体ストレス / オートファジー

Outline of Final Research Achievements

To elucidate the physiological role of superoxide and ascorbic acid in vivo, we have established the SOD1/Akr1a double knockout (DKO) mice.The DKO mice had serious phenotype with heightened oxidative stress. After AsA withdrawal, all DKO mice died within two weeks. The AsA withdrawal for a week significantly increased plasma ALT levels but had no effect on cardiac function in the DKO mice.

Research Products

• [Journal Article] The viability of primary hepatocytes in maintained under a low cysteine-glutathione redox state with a marked elevation in ophthalmic acid production. (2017)
  • Author(s): Lee, J., Kang, E. S., Kobayashi, S., Homma, T., Sato, H., Seo, H. G., and Fujii, J.
  • Journal Title: Exp. Cell Res. Volume: 361 Issue: 1 Pages: 178-191
  • DOI: 10.1016/j.yexcr.2017.10.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Decreased reproductive performance in xCT-knockout male mice. (2017)
  • Author(s): Hamashima, S., Homma, T., Kobayashi, S., Ishii, N., Kurahashi, T., Watanabe, R., Kimura, N., Sato, H., and Fujii, J.
  • Journal Title: Free Radic. Res. Volume: 51 Issue: 9-10 Pages: 851-860
  • DOI: 10.1080/10715762.2017.1388504
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mice in the early stage of liver steatosis caused by a high fat diet are resistant to thioacetamide-induced hepatotoxicity and oxidative stress (2017)
  • Author(s): Lee Jaeyong、Homma Takujiro、Fujii Junichi
  • Journal Title: Toxicol Lett Volume: 277 Pages: 92-103
  • DOI: 10.1016/j.toxlet.2017.06.005
  • Peer Reviewed
• [Journal Article] xCT deficiency aggravates acetaminophen-induced hepatotoxicity under inhibition of the transsulfuration pathway (2017)
  • Author(s): Eun Sil Kang, Jaeyong Lee, Takujiro Homma, Toshihiro Kurahashi, Sho Kobayashi, Atsunori Nabeshima, Sohsuke Yamada, Han GeuK Seo, Satoshi Miyata, Hideyo Sato, Junichi Fujii
  • Journal Title: Free Radic Res Volume: 51 Issue: 1 Pages: 80-90
  • DOI: 10.1080/10715762.2017.1282157
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oxidative stress caused by a SOD1 deficiency ameliorates thioacetamide-triggered cell death via CYP2E1 inhibition but stimulates liver steatosis. (2017)
  • Author(s): Takaya Shirato, Takujiro Homma, Jaeyong Lee, Toshihiro Kurahashi, Junichi Fujii
  • Journal Title: Archives of Toxicology Volume: 91 Issue: 3 Pages: 1319-1333
  • DOI: 10.1007/s00204-016-1785-9
  • Peer Reviewed
• [Journal Article] Heightened aggressive behavior in mice deficient in aldo-keto reductase 1a (Akr1a). (2017)
  • Author(s): Takujiro Homma, Ryusuke Akihara, Satoshi Okano, Mototada Shichiri, Yasukazu Yoshida, Ken-ichi Yamada, Satoshi Miyata, Osamu Nakajima, Junichi Fujii
  • Journal Title: Behavioural Brain Research Volume: 319 Pages: 219-224
  • DOI: 10.1016/j.bbr.2016.11.038
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A high fat diet temporarily renders Sod1-deficient mice resistant to an oxidative insult (2017)
  • Author(s): Junitsu Ito, Naoki Ishii, Ryusuke Akihara, Jaeyong Lee, Toshihiro Kurahashi, Takujiro Homma, Ryo Kawasaki, Junichi Fujii
  • Journal Title: J Nutr Biochem Volume: 40 Pages: 44-52
  • DOI: 10.1016/j.jnutbio.2016.10.018
  • Peer Reviewed
• [Journal Article] Heat stress promotes the down-regulation of IRE1α in cells: An atypical modulation of the UPR pathway (2016)
  • Author(s): Takujiro Homma, Junichi Fujii
  • Journal Title: Exp Cell Res Volume: 349 Issue: 1 Pages: 128-138
  • DOI: 10.1016/j.yexcr.2016.10.006
  • Peer Reviewed
• [Journal Article] Ablation of aldehyde reductase aggravates carbon tetrachloride-induced acute hepatic injury involving oxidative stress and endoplasmic reticulum stress (2016)
  • Author(s): Ryusuke Akihara, Takujiro Homma, Jaeyong Lee, Ken-ichi Yamada, Satoshi Miyata, Junichi Fujii
  • Journal Title: Biochem Biophys Res Commun Volume: 478 Issue: 2 Pages: 765-771
  • DOI: 10.1016/j.bbrc.2016.08.022
  • Peer Reviewed
• [Journal Article] Ascorbic acid prevents acetaminophen-induced hepatotoxicity in mice by ameliorating glutathione recovery and autophagy. (2016)
  • Author(s): Kurahashi T, Lee J, Nabeshima A, Homma T, Kang ES, Saito Y, Yamada S, Nakayama T, Yamada K, Miyata S, Fujii J.
  • Journal Title: Arch Biochem Biophys Volume: 604 Pages: 36-46
  • DOI: 10.1016/j.abb.2016.06.004
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Trichloroethylene exposure aggravates behavioral abnormalities in mice that are deficient in superoxide dismutase. (2016)
  • Author(s): Otsuki N, Homma T, Fujiwara H, Kaneko K, Hozumi Y, Shichiri M, Takashima M, Ito J, Konno T, Kurahashi T, Yoshida Y, Goto K, Fujii S, Fujii J.
  • Journal Title: Regul Toxicol Pharmacol Volume: 79 Pages: 83-90
  • DOI: 10.1016/j.yrtph.2016.05.007
  • Peer Reviewed
• [Journal Article] The SOD1 transgene expressed in erythroid cells alleviates fatal phenotype in congenic NZB/NZW-F1 mice. (2016)
  • Author(s): Otsuki N, Konno T, Kurahashi T, Suzuki S, Lee J, Okada F, Iuchi Y, Homma T, Fujii J.
  • Journal Title: Free Radic Res Volume: 50 Issue: 7 Pages: 793-800
  • DOI: 10.1080/10715762.2016.1178388
  • Peer Reviewed
• [Presentation] Heterozygous SOD1 deficiency causes male infertility by triggering autoimmune response in mice with the NZW background. (2017)
  • Author(s): Takujiro Homma, Naoki Ishii, Sho Kobayashi, and Junichi Fujii.
  • Organizer: 8th Joint Meeting of Society for Free Radical Research Australasia and Japan with International Symposium on Coenzyme Q10
  • Int'l Joint Research
• [Presentation] シスチントランスポーター・xCT欠損マウスは雄性生殖能が低下する (2017)
  • Author(s): 本間拓二郎、浜島真司、小林翔、倉橋敏裕、渡辺連、木村直子、佐藤英世、藤井順逸
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Presentation] シスチントランスポーター・xCTの男性生殖能における役割の検討 (2017)
  • Author(s): 本間拓二郎、浜島真司、小林翔、倉橋敏裕、渡辺連、木村直子、佐藤英世、藤井順逸
  • Organizer: 第70回日本酸化ストレス学会学術集会
• [Presentation] SOD1-knockout mice are resistant to lethal effects of thioacetamide-induced hepatotoxicity. (2016)
  • Author(s): Takujiro Homma, Takaya Shirato, Jaeyong Lee, Toshihiro Kurahashi, Junichi Fujii.
  • Organizer: The 23rd Annual Meeting, a joint meeting with the Society for Free Radical Research International (SfRBM/SFRRI 2016)
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2016-11-16
  • Int'l Joint Research
• [Presentation] 熱ストレス障害に対する小胞体ストレス応答の解析；熱ストレスはIRE1発現を減少させる (2016)
  • Author(s): 本間拓二郎、藤井順逸
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター会議棟（仙台市）
  • Year and Date: 2016-09-25
• [Presentation] SOD1欠損による酸化ストレスはシトクロムP450活性を抑制することで薬剤誘発性肝障害を軽減する (2016)
  • Author(s): 本間拓二郎、白土貴也、李在勇、倉橋敏裕、藤井順逸
  • Organizer: 第69回日本酸化ストレス学会学術集会
  • Place of Presentation: 仙台国際センター会議棟（仙台市）
  • Year and Date: 2016-08-30
• [Presentation] SOD1欠損による酸化ストレスはシトクロムP450活性を抑制することで薬剤誘発性肝障害を軽減する (2016)
  • Author(s): 本間拓二郎、白土貴也、李在勇、倉橋敏裕、藤井順逸
  • Organizer: 日本生化学会 東北支部 第82回例会・シンポジウム
  • Place of Presentation: 弘前大学医学部（弘前市）
  • Year and Date: 2016-05-21
• [Book] Superoxide Dismutase (SOD): Sources, Therapeutic Uses and Health Benefits. (2016)
  • Author(s): Takujiro Homma, Junichi Fujii
  • Total Pages: 197
  • Publisher: Nova Science Publishers, Inc
• [Book] Ascorbic Acid: Properties, Synthesis and Applications. (2016)
  • Author(s): Junichi Fujii, Takujiro Homma, Sho Kobayashi
  • Total Pages: 285
  • Publisher: Nova Science Publishers, Inc