Kubo, Akiko



School of Medicine, Department of Biochemistry (Shinanomachi)



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Career 【 Display / hide

  • 1996.10

    JST, ERATO Tsukita Cell Axis Project, Researcher

  • 2001.10

    Kyoto University, School of Medicine, Department of Cell Biology, 研究員

  • 2007.02

    Mitsubishi Institute for Life Sciences, 分子加齢医学, 研究員

  • 2009.04

    Keio University, School of Medicine, Department of Biochemistry., Project assistant professor

Academic Background 【 Display / hide

  • 1991.04

    Kyoto University, 薬学研究科

    Graduate School, Withdrawal after completion of doctoral course requirements, Doctoral course

Academic Degrees 【 Display / hide

  • 博士(薬学), Kyoto University, Coursework, 1996.09



Research Areas 【 Display / hide

  • General medical chemistry

  • Analytical chemistry

Research Keywords 【 Display / hide

  • Metabolomics

  • Imaging Mass Spectrometry


Papers 【 Display / hide

  • 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. and Suematsu, M.

    J Clin Biochem Nutr (Journal of Clinical Biochemistry and Nutrition)  63 ( 1 ) 70 - 79 2018.07

    ISSN  0912-0009

     View Summary

    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 beta-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-nanofeve 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. and Suematsu, M.

    Nat Commun (Nature Communications)  9 ( 1 ) 1561 2018.04

    ISSN  2041-1723

     View Summary

    Gold deposition with diagonal angle towards boehmite-based nanostructure creates random arrays of horse-bean-shaped nanostructures named gold-nanofeve (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 )  2017.08

    ISSN  1098-5549

     View Summary

    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 2015.09

    ISSN  1091-6490

     View Summary

    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 2015.05

    ISSN  1559-7016

     View Summary

    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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Papers, etc., Registered in KOARA 【 Display / hide

Presentations 【 Display / hide

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • 高血糖時の分枝鎖アミノ酸代謝に着目した糖尿病性腎症発症機構の解明と予防法の開発


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 久保 亜紀子, Grant-in-Aid for Scientific Research (C), Principal Investigator

  • 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


    久保亜紀子, Principal Investigator

  • 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


    Grant-in-Aid for Scientific Research, 久保亜紀子, Principal Investigator

Intellectual Property Rights, etc. 【 Display / hide

  • MALDI 用試料調製方法及び試料調製装置

    Application No.: PCT_JP20114/159946  2014.04 

    Registration No.: 特許第6153139号  2017.06

    Patent, Joint, PCT international application

  • 質量分析を用いたアンモニア測定方法

    Application No.: 特願2013-209000  2013.10 

    Announcement No.: 特開2015-072237  2015.04 

    Registration No.: 特許第6115725号  2017.03

    Patent, Joint, National application


Courses Taught 【 Display / hide







Courses Previously Taught 【 Display / hide

  • 医化学実習

    Keio University, 2015, Autumn Semester, Major subject, Laboratory work/practical work/exercise, 112people


Memberships in Academic Societies 【 Display / hide

  • 日本質量分析学会

  • 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


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