Noguchi, Saki

写真a

Affiliation

Faculty of Pharmacy, Department of Pharmacy 薬剤学講座 (Shiba-Kyoritsu)

Position

Research Associate/Assistant Professor/Instructor

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Academic Background 【 Display / hide 】

  • 2006.04
    -
    2012.03

    Keio University, Faculty of Pharmacy, 薬学科

  • 2013.04
    -
    2017.03

    Keio University, Graduate School of Pharmacy, 薬学専攻

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Academic Degrees 【 Display / hide 】

  • Ph.D.(Pharmacy), Keio University, Coursework, 2017.03

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Licenses and Qualifications 【 Display / hide 】

  • Pharmacist, 2012.04

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Research Areas 【 Display / hide 】

  • Life Science / Clinical pharmacy (Pharmaceutics, Pharmacokinetics, Transporter)

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Papers 【 Display / hide 】

  • Fetal ezrin expression affects macrophages and regulatory T cells in mouse placental decidua

    Tomohiro Nishimura, Ryo Mizokami, Mayuko Yamanaka, Masaya Takahashi, Yuko Yoshida, Yuya Ogawa, Saki Noguchi, Masatoshi Tomi

    Biochemical and Biophysical Research Communications 735 2024.11

    Accepted,  ISSN  0006291X

    　View Summary

    Ezrin is a cross-linker protein between membrane proteins and cytosolic actin, abundantly expressed in the placenta among the ERM protein family. Ezrin gene knockout mice exhibit fetal growth restriction after gestational day (GD) 15.5. This study aimed to clarify the effect of ezrin on immune cells that influence fetal growth and immune tolerance. Ezrin heterozygous knockout (Ez+/−) mice were interbred, and the gene expressions and immune cell distributions in the placentas of wild-type (Ez+/+) and ezrin knockout (Ez−/−) fetuses were analyzed. IL-6 expression in the placenta of Ez−/− fetuses was significantly higher than in Ez+/+ fetuses at GD 15.5. The mRNA expression of IL-6 in the uterine decidua attached to Ez−/− fetuses was higher compared to that attached to Ez+/+ fetuses but not in the junctional zone and labyrinth. Classical M1 and M2 macrophages in the decidua were analyzed by flow cytometry using CD86 and CD206 as markers. M1 macrophages increased in the decidua attached to Ez−/− mice compared to Ez+/+ mice, while M2 macrophages did not increase. CD4-positive T cells showed a reduction in the decidua attached to Ez−/− fetuses. Further analysis involved the subcutaneous administration of tacrolimus in pregnant Ez+/− mice from GD 8.5 to GD 15.5, which prevented the decrease in fetal body weight and decidual CD4-positive T cells in Ez−/− mice at GD 15.5. These results suggest that impaired expression of fetoplacental-derived ezrin induces inflammatory conditions in the uterine decidua through M1 polarization of macrophages, increased IL-6, and decreased CD4-positive T cells, including Treg cells.

  • Conversion of Olmesartan to Olmesartan Medoxomil, A Prodrug that Improves Intestinal Absorption, Confers Substrate Recognition by OATP2B1.

    Naomi Fukazawa, Tomohiro Nishimura, Keisuke Orii, Saki Noguchi, Masatoshi Tomi

    Pharmaceutical research 41 ( 5 ) 849 - 861 2024.05

    ISSN  07248741

    　View Summary

    PURPOSE: Olmesartan medoxomil (olmesartan-MX), an ester-type prodrug of the angiotensin II receptor blocker (ARB) olmesartan, is predominantly anionic at intestinal pH. Human organic anion transporting polypeptide 2B1 (OATP2B1) is expressed in the small intestine and is involved in the absorption of various acidic drugs. This study was designed to test the hypothesis that OATP2B1-mediated uptake contributes to the enhanced intestinal absorption of olmesartan-MX, even though olmesartan itself is not a substrate of OATP2B1. METHODS: Tetracycline-inducible human OATP2B1- and rat Oatp2b1-overexpressing HEK 293 cell lines (hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293, respectively) were established to characterize OATP2B1-mediated uptake. Rat jejunal permeability was measured using Ussing chambers. ARBs were quantified by liquid chromatography-tandem mass spectrometry. RESULTS: Significant olmesartan-MX uptake was observed in hOATP2B1/T-REx-293 and rOatp2b1/T-REx-293 cells, whereas olmesartan uptake was undetectable or much lower than olmesartan-MX uptake, respectively. Furthermore, olmesartan-MX exhibited several-fold higher uptake in Caco-2 cells and greater permeability in rat jejunum compared to olmesartan. Olmesartan-MX uptake in hOATP2B1/T-REx-293 cells and in Caco-2 cells was significantly decreased by OATP2B1 substrates/inhibitors such as 1 mM estrone-3-sulfate, 100 µM rifamycin SV, and 100 µM fluvastatin. Rat Oatp2b1-mediated uptake and rat jejunal permeability of olmesartan-MX were significantly decreased by 50 µM naringin, an OATP2B1 inhibitor. Oral administration of olmesartan-MX with 50 µM naringin to rats significantly reduced the area under the plasma concentration-time curve of olmesartan to 76.9%. CONCLUSION: Olmesartan-MX is a substrate for OATP2B1, and the naringin-sensitive transport system contributes to the improved intestinal absorption of olmesartan-MX compared with its parent drug, olmesartan.

  • Involvement of GAT2/Slc6a13 in hypotaurine uptake at fetal-facing plasma membrane of syncytiotrophoblasts at mid-to-late gestation in rats and mice.

    Tomohiro Nishimura, Hikari Araki, Kei Higuchi, Saki Noguchi, Kei Saito, Kanako Hara, Haruya Yagishita, Risa Akashi, Sakiko Obata, Masatoshi Tomi

    Placenta 147   59 - 67 2024.03

    ISSN  01434004

    　View Summary

    INTRODUCTION: Hypotaurine, a precursor to taurine, is known for its antioxidant properties and is prominently present in fetal plasma and the placenta. Our previous research revealed that ezrin-knockout mice experience fetal growth retardation, coinciding with reduced hypotaurine levels in fetal plasma. This study aims to elucidate the expression and role of hypotaurine transporters within the placenta. METHODS: We employed quantitative RT-PCR to measure mRNA expression of GAT transporter family members in the placenta during mid-to-late gestation. LC/MS/MS was used to analyze the distribution of hypotaurine in different placental subregions. Immunohistochemistry was utilized to examine the localization of GAT2 in mice. Placental hypotaurine uptake from fetal circulation was studied via umbilical perfusion in rats. RESULTS: Among hypotaurine transporters, GAT2 exhibited increased mRNA and protein expression in murine placenta during mid-to-late gestation. Notably, GAT2/Slc6a13 mRNA and hypotaurine were most concentrated in the labyrinth of murine placenta. In contrast, enzymes responsible for hypotaurine synthesis, such as cysteine dioxygenase, cysteine sulfinic acid decarboxylase, and 2-aminoethanethiol dioxygenase, showed minimal expression in the labyrinth. These findings suggest that GAT2 is a key determinant of hypotaurine levels in the placental labyrinth. Immunohistochemical examination unveiled that GAT2 was predominantly localized on the fetal-facing plasma membrane within syncytiotrophoblasts, which co-localized with ezrin. In rat umbilical perfusion experiments, the GAT2/3 and TauT inhibitor, SNAP-5114, significantly reduced hypotaurine extraction from fetal circulation to the placenta. DISCUSSION: The results suggest that GAT2 plays a pivotal role in the concentrative uptake of hypotaurine from fetal plasma within syncytiotrophoblasts of the placenta.

  • Breast Cancer Resistance Protein Limits Fetal Transfer of Tadalafil in Mice

    Nishimura T., Ishii M., Tanaka H., Noguchi S., Ikeda T., Tomi M.

    Journal of Pharmaceutical Sciences (Journal of Pharmaceutical Sciences)   2023.11

    Research paper (scientific journal), Accepted,  ISSN  00223549

    　View Summary

    Tadalafil, a phosphodiesterase 5 (PDE5) inhibitor, is a candidate therapeutic agent for fetal growth restriction and hypertensive disorders of pregnancy. In this study, we elucidated the fetal transfer of tadalafil in comparison with that of sildenafil, the first PDE5 inhibitor to be approved. We also examined the contributions of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP) to fetal transfer. Tadalafil or sildenafil was administered to wild-type, Mdr1a/b-double-knockout or Bcrp-knockout pregnant mice by continuous infusion from gestational day (GD) 14.5 to 17.5, and the fetal-to-maternal plasma concentration ratio of unbound drug (unbound F/M ratio) was evaluated at GD 17.5. The values of unbound F/M ratio of tadalafil and sildenafil in wild-type mice were 0.80 and 1.6, respectively. The unbound F/M ratio of tadalafil was increased to 1.1 and 1.7 in Mdr1a/b-knockout and Bcrp-knockout mice, respectively, while the corresponding values for sildenafil were equal to or less than that in wild-type mice, respectively. A transcellular transport study revealed that basal-to-apical transport of both tadalafil and sildenafil was significantly higher than transport in the opposite direction in MDCKII-BCRP cells. Our research reveals that tadalafil is a newly identified substrate of human and mouse BCRP, and it appears that the fetal transfer of tadalafil is, at least in part, attributed to the involvement of BCRP within the placental processes in mice. The transfer of sildenafil to the fetus was not significantly constrained by BCRP, even though sildenafil was indeed a substantial substrate for BCRP.

  • L-type Amino Acid Transporter 1 (SLC7A5)-Mediated Transport of Pregabalin at the Rat Blood-Spinal Cord Barrier and its Sensitivity to Plasma Branched-Chain Amino Acids

    Tomoya Akashi, Saki Noguchi, Yu Takahashi, Tomohiro Nishimura, Masatoshi Tomi

    Journal of Pharmaceutical Sciences (Elsevier)  112 ( 4 ) 1137 - 1144 2023.01

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  00223549

    　View Summary

    Pregabalin is an anti-neuropathic pain drug inhibiting the α2δ subunit of the voltage-dependent calcium channel in the spinal cord. The aim of this study is to characterize the transport mechanism of pregabalin at the blood-spinal cord barrier (BSCB) by means of in vivo experiments in rats and in vitro studies using primary-cultured rat spinal cord endothelial cells. We isolated endothelial cells by culturing rat spinal cord tissue in the presence of puromycin, and confirmed the expression of BSCB markers such as Cd31, Mdr1a, and Claudin-5. The uptake of pregabalin by primary-cultured rat spinal cord endothelial cells was sodium-independent and was significantly inhibited by L-leucine, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, and JPH203. These results suggest the involvement of L-type amino acid transporter (LAT) 1. LAT1 mRNA and protein was expressed in primary-cultured rat spinal cord endothelial cells, which is consistent with LAT1 expression at the BSCB. In the in vivo study, the transfer of pregabalin to rat spinal cord and brain was significantly decreased by the pre-administration of branched chain amino acids (BCAAs), which are endogenous substrates of LAT1. Our results indicate that pregabalin transport across the BSCB is mediated at least in part by LAT1 and is inhibited by plasma BCAAs.

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

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Reviews, Commentaries, etc. 【 Display / hide 】

  • 【「今さら聞けない」をスッキリ解消する 妊娠・授乳と薬】[妊娠と薬]妊娠による生理学的変化と薬物動態

    西村 友宏, 野口 幸希

    薬事 ((株)じほう)  62 ( 4 ) 717 - 727 2020.03

    Other, Joint Work,  ISSN  0016-5980

    　View Summary

    ＜Points＞▼妊娠による生理学的変動は薬物血中濃度に影響を与えるため、投与量や投与頻度の調節が必要な場合がある。▼血漿容積の増加により血漿タンパク濃度が減少するため、血漿タンパク結合率が減少し、薬物の分布容積や消失速度の増大につながる。▼肝薬物代謝酵素の発現変動が起こるが、その変動は代謝酵素の分子種により異なる。▼糸球体濾過量の上昇により、腎排泄型薬物の消失が促進される。▼治療薬物モニタリング(TDM)対象薬物にはTDMを行うことが推奨され、また血中濃度の解釈は血漿タンパク結合率が変動していることを考慮する必要がある。(著者抄録)

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Presentations 【 Display / hide 】

  • 自然流産モデルマウス胎盤におけるpregnancy-specific glycoproteinファミリーのタンパク質定量

    橋本 理梨佳, 佐伯 愛子, 菅沼 名津季, 西村 友宏, 野口 幸希, 登美 斉俊

    第39回日本生殖免疫学会学術集会 (富山) , 

    2024.12
    , 

    Oral presentation (general)

  • ヒト胎盤灌流からの胎児薬物暴露量予測精度の向上

    野口 幸希, 黒沢 健, 西村 友宏, 千葉 康司, 登美 斉俊

    第4回妊娠と薬情報研究会学術集会 (東京) , 

    2024.10
    , 

    Symposium, workshop panel (nominated)

  • ヒト栄養膜幹細胞から分化させた合胞体栄養膜細胞におけるpropionic acid輸送機構

    緑川 凜, 堀 武志, 野口 幸希, 西村 友宏, 梶 弘和, 登美 斉俊

    第32回日本胎盤学会学術集会 (岡山) , 

    2024.10
    , 

    Oral presentation (general)

  • 胎盤関門におけるMATE1の発現量種差と薬物の胎児移行性

    鈴木 あしゅかん, 坂本 瞭, 山内 青依, 橋本 理梨佳, 野口 幸希, 西村 友宏, 登美 斉俊

    第45回生体膜と薬物の相互作用シンポジウム (徳島) , 

    2024.10
    , 

    Oral presentation (general)

  • 胎仔胎盤系のOCTN1がエルゴチオネインの胎仔移行と胎仔成長に与える影響

    西本 隼翔, 西村 友宏, 中村 綾音, 石本 尚大, 野口 幸希, 加藤 将夫, 登美 斉俊

    第44回日本妊娠高血圧学会学術集会 (宇都宮) , 

    2024.09
    , 

    Oral presentation (general)

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

  • Analysis of the regulation of placental barrier factors for prediction of placental endocrine disruption

    2023.04
    -
    2026.03

    野口 幸希, 基盤研究(C), Principal investigator

  • 有機酸取り込みトランスポーターを標的とした腎不全予防法の提案

    2022.08
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 野口 幸希, 研究活動スタート支援, Principal investigator

  • 尿細管の両面動態にアプローチする先天性代謝疾患治療法の開拓

    2020.04
    -
    2022.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 野口 幸希, Grant-in-Aid for Early-Career Scientists , Principal investigator

  • トリプトファンバランスに着目した食事による胎児成長支援戦略の構築

    2018.04
    -
    2021.03

    日本学術振興会, 科学研究費助成事業 基盤研究(B), 基盤研究(B), No Setting

    　View Summary

    胎盤関門においてトリプトファン(Trp)輸送を担う可能性が高いLAT輸送体のタンパク発現分子数を定量した結果、ヒトおよびラット胎盤関門において、LAT1およびLAT2タンパクの発現分子数定量に成功した。ヒトではLAT1およびLAT2の発現分子数が共に高かったのに対し、ラットにおいてはLAT1の発現量がLAT2に比べて数倍高いことが示された。げっ歯類胎盤における免疫染色においても、LAT1は胎盤関門の母体側細胞膜において高く発現していたのに対し、LAT2の発現は明確には示されなかった。さらに、LAT1が同様に高く発現している血液脳関門においては、血中アミノ酸濃度の変動がLAT1を介した脳への輸送速度を制御していることを、実験的に明らかにした。これらの結果は、LAT基質アミノ酸の総量に対するTrp存在比率(%)で定義されるTrpインデックスが、胎児など組織関門で制御されている領域へのTrp供給量、そしてキヌレインおよびセロトニン濃度を規定するとの仮説をサポートする成果として、重要である。
    日本食品標準成分表に基づきTrpインデックスを算出したところ、食品の種類によってTrpインデックスは5倍以上異なっていた。得られたTrpインデックスに基づくと、Trp欠乏を補う食品としては通常、タンパク質に富み、Trpのアミノ酸スコアが100%を満たす魚・肉・大豆などが同列に推奨されるが、Trpインデックスがより低い魚類や肉類と比較して、高い大豆が望ましいといったより適切な指導が可能となる。

  • 降圧薬同効薬間の有害事象報告頻度比較分析に基づく妊娠高血圧症治療薬開拓

    2018.04
    -
    2021.03

    日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), No Setting

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    妊婦においては治療方法が限定的であり、有効な薬物治療法が確立されていない妊娠高血圧症候群に対して、現在は使用が禁忌とされている降圧薬の有効性、安全性を検証し、妊婦においても安全な降圧薬を見出すことを目的としている。これまでに臨床における副作用データベース検索によって、禁忌とされている降圧薬としてアンジオテンシンII受容体拮抗薬（ARB）のうちIrbesartanが比較的胎児に対して毒性を示す頻度が低い可能性を見出している。今年度は、ARB同効薬間で胎児移行性や副作用が異なる可能性を非臨床において検討した。ARBの胎児移行性は、ARB同効薬間で差が生じることを示すため、妊娠高血圧症を呈するモデルラットにおいてOlmesartanとIrbesartanを投与して血圧、母体血中濃度、胎児血中濃度等を評価した。OlmesartanおよびIrbesartanはいずれも母体の高血圧を改善した。胎児移行性はOlmesartanが高く、Irbesartanが低いことを見出し、胎児における血清アルブミンへの結合を考慮した非結合型血漿中濃度においてもIrbesartanは胎児移行性が低いことを見出した。また、Olmesartan投与時には当該妊娠高血圧症モデルラットが呈する胎児発育不全が改善されなかったのに対し、Irbesartan投与においては改善されたため、IrbesartanはARB同効薬の中でも比較的選択的に妊娠高血圧症の改善効果と低胎児毒性を表すことが示された。

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Courses Taught 【 Display / hide 】

  • STUDY OF MAJOR FIELD: (PHARMACEUTICS)

    2024

  • SPECIAL PRACTICE IN TISSUE CULTURE AND GENE TECHNOLOGY

    2024

  • SEMINAR: (PHARMACEUTICS)

    2024

  • RESEARCH FOR BACHELOR'S THESIS 1

    2024

  • PHARMACEUTICS LABORATORY COURSE

    2024

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Courses Previously Taught 【 Display / hide 】

  • ENGLISH EXERCISES FOR PHARMACEUTICAL SCIENCES

    Keio University

    2023.04
    -
    2024.03

  • PHARMACEUTICS LABORATORY COURSE

    Keio University

    2023.04
    -
    2024.03

  • BIOPHARMACEUTICS

    Keio University

    2023.04
    -
    2024.03

  • STUDY OF MAJOR FIELD: (PHARMACEUTICS)

    Keio University

    2023.04
    -
    2024.03

  • PHARMACEUTICAL-ENGLISH SEMINAR

    Keio University

    2023.04
    -
    2024.03

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