KEIO RESEARCHERS INFORMATION SYSTEM

Career 【 Display / hide 】

Career 【 Display / hide 】

• 2002.04

  -

  2004.03

  慶應義塾大学病院, 内科学, 研修医

• 2008.04

  -

  2010.03

  慶應義塾大学医学部, 解剖学, 特別研究助教

• 2010.04

  -

  2016.03

  慶應義塾大学医学部, 解剖学, 助教

• 2013.10

  -

  2015.08

  Brigham and Women's Hospital / Harvard Medical School / HHMI, Microbiology and Immunology, Postdoctoral fellow / Research fellow

• 2016.04

  -

  2017.12

  慶應義塾大学医学部, 解剖学, 専任講師

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Academic Background 【 Display / hide 】

Academic Background 【 Display / hide 】

• 1996.04

  -

  2002.03

  Keio University, 医学部

  Graduated

• 2004.04

  -

  2008.03

  慶應義塾大学, 医学部医学研究科博士過程, 医学研究科・生理系専攻

  Graduate School, Completed, Doctoral course

Academic Degrees 【 Display / hide 】

Academic Degrees 【 Display / hide 】

• 博士号（医学）, 慶應義塾大学

Licenses and Qualifications 【 Display / hide 】

Licenses and Qualifications 【 Display / hide 】

• 医師免許

Research Areas 【 Display / hide 】

Research Areas 【 Display / hide 】

• Life Science / Functional biochemistry

• Life Science / Neuroscience-general

• Life Science / Pharmacology

• Life Science / Medical biochemistry

• Life Science / Immunology

Research Keywords 【 Display / hide 】

Research Keywords 【 Display / hide 】

• D-アミノ酸

• キラル生物学

• 宿主-微生物相互作用

• 微生物・免疫学

• 生化学

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Papers 【 Display / hide 】

Papers 【 Display / hide 】

• Plasma d-asparagine and the d/l-serine ratio reflect chronic kidney diseases in children regardless of physique

  Morishita T., Nishizaki N., Taniguchi S., Sakai S., Kimura T., Mita M., Nakagawa M., Endo A., Ohtomo Y., Yasui M., Shimizu T., Sasabe J.

  Amino Acids 56 ( 1 )  2024.12

  ISSN  09394451

  　View Summary

  Biomarkers that accurately reflect renal function are essential in management of chronic kidney diseases (CKD). However, in children, age/physique and medication often alter established renal biomarkers. We studied whether amino acid enantiomers in body fluids correlate with renal function and whether they are influenced by physique or steroid medication during development. We conducted a prospective study of children 2 to 18 years old with and without CKD. We analyzed associations of serine/asparagine enantiomers in body fluids with major biochemical parameters as well as physique. To study consequences of kidney dysfunction and steroids on serine/asparagine enantiomers, we generated juvenile mice with uninephrectomy, ischemic reperfusion injury, or dexamethasone treatment. We obtained samples from 27 children, of which 12 had CKD due to congenital (n = 7) and perinatal (n = 5) causes. Plasma d-asparagine and the d/l-serine ratio had robust, positive linear associations with serum creatinine and cystatin C, and detected CKD with high sensitivity and specificity, uninfluenced by body size or biochemical parameters. In the animal study, kidney dysfunction increased plasma d-asparagine and the d/l-serine ratio, but dexamethasone treatment did not. Thus, plasma d-asparagine and the d/l-serine ratio can be useful markers for renal function in children.

  • Access to Document (DOI)

• Sodium benzoate attenuates 2,8-dihydroxyadenine nephropathy by inhibiting monocyte/macrophage TNF-α expression

  Oshima Y., Wakino S., Kanda T., Tajima T., Itoh T., Uchiyama K., Yoshimoto K., Sasabe J., Yasui M., Itoh H.

  Scientific Reports 13 ( 1 )  2023.12

  　View Summary

  Sodium benzoate (SB), a known D-amino acid oxidase (DAO) enzyme inhibitor, has an anti-inflammatory effect, although its role in renal damage has not been explored. 2,8-dihydroxyadenine crystal induced chronic kidney disease, in which TNF-α is involved in the pathogenesis, was established by oral adenine administration in C57BL/6JJcl mice (AdCKD) with or without SB to investigate its renal protective effects. SB significantly attenuated AdCKD by decreasing serum creatinine and urea nitrogen levels, and kidney interstitial fibrosis and tubular atrophy scores. The survival of AdCKD mice improved 2.6-fold by SB administration. SB significantly decreased the number of infiltrating macrophages observed in the positive F4/80 immunohistochemistry area and reduced the expression of macrophage markers and inflammatory genes, including TNF-α, in the kidneys of AdCKD. Human THP-1 cells stimulated with either lipopolysaccharide or TNF-α showed increased expression of inflammatory genes, although this was significantly reduced by SB, confirming the anti-inflammatory effects of SB. SB exhibited renal protective effects in AdCKD in DAO enzyme deficient mice, suggesting that anti-inflammatory effect of SB was independent of DAO enzyme activity. Moreover, binding to motif DNA sequence, protein level, and mRNA level of NF-κB RelB were significantly inhibited by SB in AdCKD kidneys and lipopolysaccharide treated THP-1 cells, respectively. We report that anti-inflammatory property of SB is independent of DAO enzymatic activity and is associated with down regulated NF-κB RelB as well as its downstream inflammatory genes such as TNF-α in AdCKD.

  • Access to Document (DOI)

• Homeostasis of serine enantiomers is disrupted in the post-mortem caudate putamen and cerebrospinal fluid of living Parkinson's disease patients

  Di Maio A., Nuzzo T., Gilio L., Serra M., Buttari F., Errico F., De Rosa A., Bassi M.S., Morelli M., Sasabe J., Sulzer D., Carta M., Centonze D., Usiello A.

  Neurobiology of Disease 184 2023.08

  ISSN  09699961

  　View Summary

  L-serine generated in astrocytes plays a pivotal role in modulating essential neurometabolic processes, while its enantiomer, D-serine, specifically regulates NMDA receptor (NMDAR) signalling. Despite their physiological relevance in modulating cerebral activity, serine enantiomers metabolism in Parkinson's disease (PD) remains elusive. Using High-Performance Liquid Chromatography (HPLC), we measured D- and L-serine levels along with other amino acids known to modulate NMDAR function, such as L-glutamate, L-aspartate, D-aspartate, and glycine, in the post-mortem caudate putamen (CPu) and superior frontal gyrus (SFG) of PD patients. Moreover, we examined these amino acids in the cerebrospinal fluid (CSF) of de novo living PD, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS) patients versus subjects with other neurological disorders (OND), used as control. We found higher D-serine and L-serine levels in the CPu of PD patients but not in the SFG, a cerebral region that, in contrast to the CPu, is not innervated by nigral dopaminergic terminals. We also highlighted a significant elevation of both serine enantiomers in the CSF samples from PD but not in those of AD and ALS patients, compared with control subjects. By contrast, none or only minor changes were found in the amount of other NMDAR modulating amino acids. Our findings identify D-serine and L-serine level upregulation as a biochemical signature associated with nigrostriatal dopaminergic degeneration in PD.

  • Access to Document (DOI)

• Mammals sustain amino acid homochirality against chiral conversion by symbiotic microbes

  Gonda Y., Matsuda A., Adachi K., Ishii C., Suzuki M., Osaki A., Mita M., Nishizaki N., Ohtomo Y., Shimizu T., Yasui M., Hamase K., Sasabe J.

  Proceedings of the National Academy of Sciences of the United States of America 120 ( 15 )  2023.04

  ISSN  00278424

  　View Summary

  Mammals exhibit systemic homochirality of amino acids in L-configurations. While ribosomal protein synthesis requires rigorous chiral selection for L-amino acids, both endogenous and microbial enzymes convert diverse L-amino acids to D-configurations in mammals. However, it is not clear how mammals manage such diverse D-enantiomers. Here, we show that mammals sustain systemic stereo dominance of L-amino acids through both enzymatic degradation and excretion of D-amino acids. Multidimensional high performance liquidchromatography analyses revealed that in blood, humans and mice maintain D-amino acids at less than several percent of the corresponding L-enantiomers, while D-amino acids comprise ten to fifty percent of the L-enantiomers in urine and feces. Germ-free experiments showed that vast majority of D-amino acids, except for D-serine, detected in mice are of microbial origin. Experiments involving mice that lack enzymatic activity to catabolize D-amino acids showed that catabolism is central to the elimination of diverse microbial D-amino acids, whereas excretion into urine is of minor importance under physiological conditions. Such active regulation of amino acid homochirality depends on maternal catabolism during the prenatal period, which switches developmentally to juvenile catabolism along with the growth of symbiotic microbes after birth. Thus, microbial symbiosis largely disturbs homochirality of amino acids in mice, whereas active host catabolism of microbial D-amino acids maintains systemic predominance of L-amino acids. Our findings provide fundamental insight into how the chiral balance of amino acids is governed in mammals and further expand the understanding of interdomain molecular homeostasis in host-microbial symbiosis.

  • Access to Document (DOI)

• Endogenous D-serine exists in the mammalian brain independent of synthesis by serine racemase

  Osaki A., Aoyama M., Mita M., Hamase K., Yasui M., Sasabe J.

  Biochemical and Biophysical Research Communications 641   186 - 191 2023.01

  ISSN  0006291X

  　View Summary

  Activation of N-methyl-D-aspartate receptors (NMDARs) requires binding of a co-agonist in addition to L-glutamate. D-serine binds to the co-agonist site on GluN1 subunits of NMDARs and modulates glutamatergic neurotransmission. While loss of GluN1 subunits in mice results in neonatal death due to respiratory failure, animals that lack a D-serine synthetic enzyme, serine racemase (SR), show grossly normal growth. However, SR-independent origins of D-serine in the brain remain unclarified. In the present study, we investigated the origin of brain D-serine in mice. Loss of SR significantly reduced D-serine in the cerebral cortex, but a portion of D-serine remained in both neonates and adults. Although D-serine was also produced by intestinal bacteria, germ-free experiments did not influence D-serine levels in the cerebral cortex. In addition, treatment of SR-knockout mice with antibiotics showed a significant reduction of intestinal D-serine, but no reduction in the brain. On the other hand, restriction of dietary intake reduced systemic circulation of D-serine and resulted in a slight decrease of D-serine in the cerebral cortex, but did not account for brain D-serine found in the SR-knockout mice. Therefore, our findings show that endogenous D-serine of non-SR origin exists in the brain. Such previously unrecognized, SR-independent, endogenous D-serine may contribute baseline activity of NMDARs, especially in developing brain, which has minimal SR expression.

  • Access to Document (DOI)

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

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

• D-amino acids and cell proliferation

  Sasabe, Jumpei

  科学研究費補助金研究成果報告書 2023

• Chirality of serine in the cellular proliferation and tumor therapy

  Sasabe, Jumpei

  福澤諭吉記念慶應義塾学事振興基金事業報告集 (福澤基金運営委員会)  2023

• Roles of serine enantiomers in cell proliferation and cancer

  Sasabe, Jumpei

  福澤諭吉記念慶應義塾学事振興基金事業報告集 (福澤基金運営委員会)  2022

• Host-microbe interaction through innate immune factor DAO

  Sasabe, Jumpei

  科学研究費補助金研究成果報告書 2018

• Cellular stress by proteins contaminated with D-serine as a novel therapeutic target of amyotrophic lateral sclerosis

  Sasabe, Jumpei

  科学研究費補助金研究成果報告書 2011

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Reviews, Commentaries, etc. 【 Display / hide 】

Reviews, Commentaries, etc. 【 Display / hide 】

• Astrocytic d-amino acid oxidase degrades d-serine in the hindbrain

  Gonda Y., Ishii C., Mita M., Nishizaki N., Ohtomo Y., Hamase K., Shimizu T., Sasabe J.

  FEBS Letters (FEBS Letters)   2022

  ISSN  00145793

  　View Summary

  d-Serine modulates excitatory neurotransmission by binding to N-methyl-d-aspartate glutamate receptors. d-Amino acid oxidase (DAO) degrades d-amino acids, such as d-serine, in the central nervous system, and is associated with neurological and psychiatric disorders. However, cell types that express brain DAO remain controversial, and whether brain DAO influences systemic d-amino acids in addition to brain d-serine remains unclear. Here, we created astrocyte-specific DAO-conditional knockout mice. Knockout in glial fibrillary acidic protein-positive cells eliminated DAO expression in the hindbrain and increased d-serine levels significantly in the cerebellum. Brain DAO did not influence levels of d-amino acids in the forebrain or periphery. These results show that astrocytic DAO regulates d-serine specifically in the hindbrain.

  • Access to Document (DOI)

• Editorial: Bioscience of D-amino acid oxidase from biochemistry to pathophysiology

  Pollegioni L., Sasabe J.

  Frontiers in Molecular Biosciences (Frontiers in Molecular Biosciences)  5 ( NOV )  2018.11

  • Access to Document (DOI)

• Emerging role of D-Amino acid metabolism in the innate defense

  Sasabe J., Suzuki M.

  Frontiers in Microbiology (Frontiers in Microbiology)  9 ( MAY )  2018.05

  　View Summary

  © 2018 Sasabe and Suzuki. Mammalian innate and adaptive immune systems use the pattern recognition receptors, such as toll-like receptors, to detect conserved bacterial and viral components. Bacteria synthesize diverse D-amino acids while eukaryotes and archaea generally produce two D-amino acids, raising the possibility that many of bacterial D-amino acids are bacteria-specific metabolites. Although D-amino acids have not been identified to bind to any known pattern recognition receptors, D-amino acids are enantioselectively recognized by some other receptors and enzymes including a flavoenzyme D-amino acid oxidase (DAO) in mammals. At host-microbe interfaces in the neutrophils and intestinal mucosa, DAO catalyzes oxidation of bacterial D-amino acids, such as D-alanine, and generates H2O2, which is linked to antimicrobial activity. Intestinal DAO also modifies the composition of microbiota through modulation of growth for some bacteria that are dependent on host nutrition. Furthermore, regulation and recognition of D-amino acids in mammals have additional meanings at various host-microbe interfaces; D-phenylalanine and D-tryptophan regulate chemotaxis of neutrophils through a G-coupled protein receptor, D-serine has a bacteriostatic role in the urinary tract, D-phenylalanine and D-leucine inhibit innate immunity through the sweet taste receptor in the upper airway, and D-tryptophan modulates immune tolerance in the lower airway. This mini-review highlights recent evidence supporting the hypothesis that D-amino acids are utilized as inter-kingdom communication at host-microbe interface to modulate bacterial colonization and host defense.

  • Access to Document (DOI)

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

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

• Serine chirality in the development of neuroinflammation

  2024.06

  -

  2026.03

  挑戦的研究（萌芽）, Principal investigator

• D-アミノ酸による細胞内代謝調節機構と細胞増殖制御

  2022.06

  -

  2024.03

  MEXT,JSPS, Grant-in-Aid for Scientific Research, 挑戦的研究（萌芽）, Principal investigator

• 共生細菌が調節するアミノ酸キラリティによる宿主エネルギー代謝機構の解明

  2021.04

  -

  2026.03

  MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), Principal investigator

• 小腸粘膜防御因子DAOの腸内細菌と宿主による制御機構の解明

  2016.04

  -

  2019.03

  MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

Awards 【 Display / hide 】

Awards 【 Display / hide 】

• 慶應医学賞研究奨励賞

  2017

• Best Presentation Award Boston Bacterial Meeting 2015

  2015, Harvard Medical School

• D-アミノ酸学会奨励賞

  2012

• 慶應義塾大学三四会奨励賞

  2012

• 慶應義塾大学塾長賞

  2008

Courses Taught 【 Display / hide 】

Courses Taught 【 Display / hide 】

• PHYSIOLOGY OF HUMAN BODY

  2025

• PHARMACOLOGY

  2025

• PHARMACOLOGY

  2024

• PHARMACOLOGY

  2023

• PHARMACOLOGY

  2022

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Courses Previously Taught 【 Display / hide 】

Courses Previously Taught 【 Display / hide 】

• 薬理学

  Keio University

  2018.04

  -

  Present

  , 

  Autumn Semester, Lecture, Within own ｆaculty

• 基礎分子細胞生物学

  Keio University

  2018.04

  -

  2022.03

  , 

  Autumn Semester, Lecture

• 生化学

  Keio University

  2018.04

  -

  2019.03

  , 

  Autumn Semester, Lecture

• 組織学

  Keio University

  2010.04

  -

  2017.03

  , 

  Spring Semester, Lecture

• 解剖学

  慶應義塾大学

  2010.04

  -

  2017.03

  , 

  Undergraduate (specialized), Laboratory work/practical work/exercise, Within own ｆaculty

Memberships in Academic Societies 【 Display / hide 】

Memberships in Academic Societies 【 Display / hide 】

• 日本薬理学会

  　

• 日本生化学会

  　

• D-アミノ酸学会

  　

Committee Experiences 【 Display / hide 】

Committee Experiences 【 Display / hide 】

• 2017.04

  -

  Present

  運営委員, D-アミノ酸学会