久保 亜紀子 (クボ アキコ)

Kubo, Akiko

写真a

所属(所属キャンパス)

医学部 医化学教室 (信濃町)

職名

助教(有期)

外部リンク

経歴 【 表示 / 非表示

  • 1996年10月
    -
    2001年09月

    科学技術振興事業団 , ERATO 月田細胞軸プロジェクト, 研究員

  • 2001年10月
    -
    2007年03月

    京都大学医学部, 分子細胞情報学講座, 研究員

  • 2007年02月
    -
    2009年03月

    三菱化学生命科学研究所, 分子加齢医学, 研究員

  • 2009年04月
    -
    継続中

    慶應義塾大学医学部, 医化学教室, 特任講師

学歴 【 表示 / 非表示

  • 1991年04月
    -
    1996年03月

    京都大学, 薬学研究科

    大学院, 単位取得退学, 博士

学位 【 表示 / 非表示

  • 博士(薬学), 京都大学, 課程, 1996年09月

    シソの精油成分の生合成制御機構に関する遺伝生化学的研究

 

研究分野 【 表示 / 非表示

  • 医化学一般

  • 分析化学

研究キーワード 【 表示 / 非表示

  • メタボロミクス

  • 質量分析イメージング

 

論文 【 表示 / 非表示

  • Quantitative imaging mass spectroscopy reveals roles of heme oxygenase-2 for protecting against transhemispheric diaschisis in the brain ischemia

    Goto S., Morikawa T., Kubo A., Takubo K., Fukuda K., Kajimura M., Suematsu M.

    Journal of Clinical Biochemistry and Nutrition (Journal of Clinical Biochemistry and Nutrition)  63 ( 1 ) 70 - 79 2018年07月

    ISSN  0912-0009

     概要を見る

    © 2018 JCBN. Carbon monoxide-generating heme oxygenase-2 is expressed in neurons and plays a crucial role for regulating hypoxic vasodilation through mechanisms unlocking carbon monoxide-dependent inhibition of H2S-generating cystathionine β-synthase expressed in astrocytes. This study aims to examine whether heme oxygenase-2 plays a protective role in mice against stroke. Focal ischemia was induced by middle cerebral artery occlusion. Regional differences in metabolites among ipsilateral and contralateral hemispheres were analysed by quantitative imaging mass spectrometry equipped with an image-processing platform to optimize comparison of local metabolite contents among different animals. Under normoxia, blood flow velocity in precapillary arterioles were significantly elevated in heme oxygenase-2-null mice vs controls, while metabolic intermediates of central carbon metabolism and glutamate synthesis were elevated in the brain of heme oxygenase-2-null mice, suggesting greater metabolic demands to induce hyperemia in these mice. In response to focal ischemia, heme oxygenase-2-null mice exhibited greater regions of ischemic core that coincide with notable decreases in energy metabolism in the contralateral hemisphere as well as in penumbra. In conclusion, these findings suggest that heme oxygenase-2 is involved in mechanisms by which not only protects against compromised energy metabolism of the ipsilateral hemisphere but also ameliorates transhemispheric diaschisis of the contralateral hemisphere in ischemic brain.

  • Gold-nanofève surface-enhanced Raman spectroscopy visualizes hypotaurine as a robust anti-oxidant consumed in cancer survival

    Shiota M., Naya M., Yamamoto T., Hishiki T., Tani T., Takahashi H., Kubo A., Koike D., Itoh M., Ohmura M., Kabe Y., Sugiura Y., Hiraoka N., Morikawa T., Takubo K., Suina K., Nagashima H., Sampetrean O., Nagano O., Saya H., Yamazoe S., Watanabe H., Suematsu M.

    Nature Communications (Nature Communications)  9 ( 1 ) 1561 2018年04月

    ISSN  2041-1723

     概要を見る

    © 2018 The Author(s). Gold deposition with diagonal angle towards boehmite-based nanostructure creates random arrays of horse-bean-shaped nanostructures named gold-nanofève (GNF). GNF generates many electromagnetic hotspots as surface-enhanced Raman spectroscopy (SERS) excitation sources, and enables large-area visualization of molecular vibration fingerprints of metabolites in human cancer xenografts in livers of immunodeficient mice with sufficient sensitivity and uniformity. Differential screening of GNF-SERS signals in tumours and those in parenchyma demarcated tumour boundaries in liver tissues. Furthermore, GNF-SERS combined with quantum chemical calculation identified cysteine-derived glutathione and hypotaurine (HT) as tumour-dominant and parenchyma-dominant metabolites, respectively. CD44 knockdown in cancer diminished glutathione, but not HT in tumours. Mechanisms whereby tumours sustained HT under CD44-knockdown conditions include upregulation of PHGDH, PSAT1 and PSPH that drove glycolysis-dependent activation of serine/glycine-cleavage systems to provide one-methyl group for HT synthesis. HT was rapidly converted into taurine in cancer cells, suggesting that HT is a robust anti-oxidant for their survival under glutathione-suppressed conditions.

  • Targeting Oxygen-Sensing Prolyl Hydroxylase for Metformin-Associated Lactic Acidosis Treatment

    Oyaizu-Toramaru, T., Suhara, T., Hayakawa, N., Nakamura, T., Kubo, A., Minamishima, S., Yamaguchi, K., Hishiki, T., Morisaki, H., Suematsu, M. and Minamishima, Y. A.

    Mol Cell Biol 37 ( 16 )  2017年08月

    ISSN  1098-5549

     概要を見る

    Metformin is one of the most widely used therapeutics for type 2 diabetes mellitus and also has anticancer and antiaging properties. However, it is known to induce metformin-associated lactic acidosis (MALA), a severe medical condition with poor prognosis, especially in individuals with renal dysfunction. Inhibition of prolyl hydroxylase (PHD) is known to activate the transcription factor hypoxia-inducible factor (HIF) that increases lactate efflux as a result of enhanced glycolysis, but it also enhances gluconeogenesis from lactate in the liver that contributes to reducing circulating lactate levels. Here, we investigated the outcome of pharmaceutical inhibition of PHD in mice with MALA induced through the administration of metformin per os and an intraperitoneal injection of lactic acid. We found that the PHD inhibitors significantly increased the expression levels of genes involved in gluconeogenesis in the liver and the kidney and significantly improved the survival of mice with MALA. Furthermore, the PHD inhibitor also improved the rate of survival of MALA induced in mice with chronic kidney disease (CKD). Thus, PHD represents a new therapeutic target for MALA, which is a critical complication of metformin therapy.

  • Inhibition of the oxygen sensor PHD2 in the liver improves survival in lactic acidosis by activating the Cori cycle

    T. Suhara, T. Hishiki, M. Kasahara, N. Hayakawa, T. Oyaizu, T. Nakanishi, A. Kubo, H. Morisaki, W. G. Kaelin, Jr., M. Suematsu and Y. A. Minamishima

    Proceedings of the National Academy of Sciences of the United States of America 112 ( 37 ) 11642 - 7 2015年09月

    ISSN  1091-6490

     概要を見る

    Loss of prolyl hydroxylase 2 (PHD2) activates the hypoxia-inducible factor-dependent hypoxic response, including anaerobic glycolysis, which causes large amounts of lactate to be released from cells into the circulation. We found that Phd2-null mouse embryonic fibroblasts (MEFs) produced more lactate than wild-type MEFs, as expected, whereas systemic inactivation of PHD2 in mice did not cause hyperlacticacidemia. This unexpected observation led us to hypothesize that the hypoxic response activated in the liver enhances the Cori cycle, a lactate-glucose carbon recycling system between muscle and liver, and thereby decreases circulating lactate. Consistent with this hypothesis, blood lactate levels measured after a treadmill or lactate tolerance test were significantly lower in Phd2-liver-specific knockout (Phd2-LKO) mice than in control mice. An in vivo (13)C-labeled lactate incorporation assay revealed that the livers of Phd2-LKO mice produce significantly more glucose derived from (13)C-labeled lactate than control mice, suggesting that blockade of PHD2 in the liver ameliorates lactic acidosis by activating gluconeogenesis from lactate. Phd2-LKO mice were resistant to lactic acidosis induced by injection of a lethal dose of lactate, displaying a significant elongation of survival. Moreover, oral administration of a PHD inhibitor improved survival in an endotoxin shock mice model. These data suggest that PHD2 is a potentially novel drug target for the treatment of lactic acidosis, which is a serious and often fatal complication observed in some critically ill patients.

  • Therapeutic hypothermia achieves neuroprotection via a decrease in acetylcholine with a concurrent increase in carnitine in the neonatal hypoxia-ischemia

    T. Takenouchi, Y. Sugiura, T. Morikawa, T. Nakanishi, Y. Nagahata, T. Sugioka, K. Honda, A. Kubo, T. Hishiki, T. Matsuura, T. Hoshino, T. Takahashi, M. Suematsu and M. Kajimura

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 35 ( 5 ) 794 - 805 2015年05月

    ISSN  1559-7016

     概要を見る

    Although therapeutic hypothermia is known to improve neurologic outcomes after perinatal cerebral hypoxia-ischemia, etiology remains unknown. To decipher the mechanisms whereby hypothermia regulates metabolic dynamics in different brain regions, we used a two-step approach: a metabolomics to target metabolic pathways responding to cooling, and a quantitative imaging mass spectrometry to reveal spatial alterations in targeted metabolites in the brain. Seven-day postnatal rats underwent the permanent ligation of the left common carotid artery followed by exposure to 8% O2 for 2.5 hours. The pups were returned to normoxic conditions at either 38 degrees C or 30 degrees C for 3 hours. The brain metabolic states were rapidly fixed using in situ freezing. The profiling of 107 metabolites showed that hypothermia diminishes the carbon biomass related to acetyl moieties, such as pyruvate and acetyl-CoA; conversely, it increases deacetylated metabolites, such as carnitine and choline. Quantitative imaging mass spectrometry demarcated that hypothermia diminishes the acetylcholine contents specifically in hippocampus and amygdala. Such decreases were associated with an inverse increase in carnitine in the same anatomic regions. These findings imply that hypothermia achieves its neuroprotective effects by mediating the cellular acetylation status through a coordinated suppression of acetyl-CoA, which resides in metabolic junctions of glycolysis, amino-acid catabolism, and ketolysis.

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KOARA(リポジトリ)収録論文等 【 表示 / 非表示

研究発表 【 表示 / 非表示

  • Analyses of minor chemical components of ostrich eggshell by MALDI-Imaging mass spectrometry

    Akiko Kubo, Taku Ito, Suguru Kato, Masaya Nakata, Yoko Saikawa, Makoto Suematsu

    66 th ASMS Conference on Mas Spectrometry and Allied Topics, 2019年06月, ポスター(一般)

  • MALDI質量分析イメージング法によるマウス急性腎虚血におけるアデニル酸代謝解析

    久保 亜紀子・藤井健太郎・宮下和季・菱木貴子・伊藤裕・末松 誠

    第89回日本生化学会年会 (仙台国際センター) , 2016年09月, 口頭(一般), 日本生化学会

  • マウス水晶体における新規抗酸化物質「過硫化グルタチオン」レベル維持には、Cystathionine beta-synthase(CBS)が必要である

    久保 亜紀子善岡尊文,後藤信一,石井 功,菱木貴子, 山本雄広,高野直治,星野岳郎,中村 貴,吉田晃敏,梶村眞弓,末松 誠

    第41回日本医用マススペクトル学会年会 (ウインクあいち) , 2016年09月, ポスター(一般), 日本医用マススペクトル学会

  • Dense accumulation of adenosine in the outer stripes of outer medulla in murine kidney identified by microscopic MALDI-imaging mass spectrometry

    Kubo Akiko,Kentaro Fujii, Kazutoshi Miyashita, Takako Hishiki, Hiroshi Itoh, Makoto Suematsu

    21st International Mass Spectrometry Conference (Toronto convention center) , 2016年08月, ポスター(一般), Canadian Society for Mass Spectrometry

  • 「ヒト大腸がん肝転移病巣のin vivo細胞周期依存的エネルギー代謝を質量分析イメージングで可視化する」

    久保 亜紀子・鮑彦・向井邦晃・菱木貴子・大村光代・南嶋洋司・末松誠

    第38回 日本分子生物学会 第88回 日本生化学会大会 合同大会 (神戸国際会議場) , 2015年12月, シンポジウム・ワークショップ パネル(指名), 日本分子生物学会・日本生化学会

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競争的資金等の研究課題 【 表示 / 非表示

  • 糖尿病性腎症の局所インビボメタボロミクス解析及び代謝変容をターゲットとした治療

    2016年04月
    -
    2019年03月

    久保亜紀子, 補助金,  代表

  • メチオニン代謝の可視化によるがん進展におけるエピゲノム制御機構の解明

    2013年04月
    -
    2016年03月

    科学研究費補助金(文部科学省・日本学術振興会), 久保亜紀子, 補助金,  代表

知的財産権等 【 表示 / 非表示

  • MALDI 用試料調製方法及び試料調製装置

    特願: PCT_JP20114/159946  2014年04月 

    特許: 特許第6153139号  2017年06月

    特許, 共同, PCT国際出願

  • 質量分析を用いたアンモニア測定方法

    特願: 特願2013-209000  2013年10月 

    特開: 特開2015-072237  2015年04月 

    特許: 特許第6115725号  2017年03月

    特許, 共同, 国内出願

 

担当授業科目 【 表示 / 非表示

  • 医化学

    2020年度

  • 医化学

    2019年度

担当経験のある授業科目 【 表示 / 非表示

  • 医化学実習

    慶應義塾, 2015年度, 秋学期, 専門科目, 実習・実験, 112人

 

所属学協会 【 表示 / 非表示

  • 日本医用マススペクトル学会

     
  • 日本細胞生物学会

     
  • The American Society for Cell Biology

     
  • The Society for Neuroscience

     
  • 日本質量分析学会

     

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