野口　幸希 (ノグチ　サキ)

Noguchi, Saki

写真a

所属（所属キャンパス）

薬学部 薬学科 薬剤学講座 （芝共立）

職名

助教
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学位 【 表示 ／ 非表示 】

  • 博士（薬学）, 慶應義塾大学大学院, 課程, 2017年03月

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論文 【 表示 ／ 非表示 】

  • MicroRNA-126 suppresses the invasion of trophoblast-model JEG-3 cells by targeting LIN28A

    Pan X., Noguchi S., Ando M., Nishimura T., Tomi M.

    Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications)  545   132 - 137 2021年03月

    研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0006291X

    　概要を見る

    © 2021 Elsevier Inc. Inadequate trophoblast invasion and impaired trophoblast-induced vascular remodeling are features of preeclampsia. In this context, an angiogenesis-related microRNA, miR-126, is abnormally expressed in preeclampsia placentas, but its role in trophoblast development remains unclear. The purpose of this study was to investigate the roles of miR-126 in the proliferation, migration, and invasion processes of trophoblast cells using the human choriocarcinoma-derived JEG-3 cell line as a model. The mRNA expression profiling of JEG-3 cells with and without miR-126 overexpression, in combination with bioinformatics analysis, identified LIN28A as a putative target of miR-126. The results of real-time RT-PCR and luciferase assay were consistent with this idea. Overexpression of miR-126 in JEG-3 cells decreased the invasive ability of the cells without affecting proliferation or migration. The invasiveness of JEG-3 cells was significantly reduced to a similar extent by knockdown of LIN28A with siRNA and by miR-126-overexpression-induced downregulation of LIN28A, although the level of LIN28A protein was much lower in the siLIN28A-transfected cells. These results indicate that miR-126 suppresses JEG-3 cell invasion by targeting LIN28A, and suggest that miR-126-mediated downregulation of LIN28A might contribute to the onset/deterioration of preeclampsia.

  • Fluorouracil uptake in triple-negative breast cancer cells: Negligible contribution of equilibrative nucleoside transporters 1 and 2

    Noguchi S., Takagi A., Tanaka T., Takahashi Y., Pan X., Kibayashi Y., Mizokami R., Nishimura T., Tomi M.

    Biopharmaceutics and Drug Disposition （Biopharmaceutics and Drug Disposition)  2021年01月

    研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1099-081X

    　概要を見る

    © 2021 John Wiley & Sons Ltd. Equilibrative nucleoside transporters (ENTs) 1 and 2 reportedly accept fluorouracil as a substrate. Here, we evaluated ENT1/2 expression at the messenger RNA (mRNA), protein, and functional levels in a panel of four triple-negative breast cancer (TNBC) cell lines, BT-549, Hs578T, MDA-MB-231, and MDA-MB-435, and we examined the relationship of the observed profiles to fluorouracil sensitivity. Nitrobenzylthioinosine (NBMPR) at 0.1 μM inhibits only ENT1, while dipyridamole at 10 μM or NBMPR at 100 μM inhibits both ENT1 and ENT2. We found that the uptake of [3H]uridine, a typical substrate of ENT1 and ENT2, was decreased to approximately 40% by 0.1 μM NBMPR. At 100 μM, NBMPR almost completely blocked the saturable uptake of [3H]uridine, but this does not imply a functional role of ENT2, because 10 μM dipyridamole showed similar inhibition to 0.1 μM NBMPR. Expression of ENT1 mRNA was almost 1 order of magnitude higher than that of ENT2 in all TNBC cell lines. Liquid chromatography-tandem mass spectrometry(LC-MS/MS) LC-MS/MS-based targeted protein quantification showed that ENT1 protein levels were in the range of 9.3–30 fmol/μg protein in plasma membrane fraction of TNBC cell lines, whereas ENT2 protein was below the detection limit. [3H]Fluorouracil uptake was insensitive to 0.1 μM NBMPR and 10 μM dipyridamole, suggesting a negligible contribution of ENT1 and ENT2 to fluorouracil uptake. The levels of ENT1 mRNA, ENT1 protein, ENT2 mRNA, and ENT1-mediated [3H]uridine uptake in the four TNBC cell lines showed no correlation with fluorouracil sensitivity. These results indicate that neither ENT1 nor ENT2 contributes significantly to the fluorouracil sensitivity of TNBC cell lines.

  • Development of a pharmacokinetic model of transplacental transfer of metformin to predict in vivo fetal exposure

    Kurosawa K., Chiba K., Noguchi S., Nishimura T., Tomi M.

    Drug Metabolism and Disposition （Drug Metabolism and Disposition)  48 （ 12 ） 1293 - 1302 2020年12月

    研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00909556

    　概要を見る

    Copyright © 2020 The Author(s). Two types of systems are used in ex vivo human placental perfusion studies to predict fetal drug exposures, that is, closed systems with recirculation of the maternal and fetal buffer and open systems using a single-pass mode without recirculation. The in vivo fetal/maternal (F:M) ratio of metformin, a cationic drug that crosses the placenta, is consistent with that reported in an open system ex vivo but not with that in a closed system. In the present study, we aimed to develop a pharmacokinetic (PK) model of transplacental transfer of metformin to predict in vivo fetal exposure to metformin and to resolve the apparent inconsistency between open and closed ex vivo systems. The developed model shows that the difference between open and closed systems is due to the difference in the time required to achieve the steady state. The model-predicted F:M ratio (approx. 0.88) is consistent with reported in vivo values [mean (95% confidence interval): 1.10 (0.69–1.51)]. The model incorporates bidirectional transport via organic cation transporter 3 (OCT3) at the basal plasma membrane, and simulations indicate that the use of trimethoprim (an OCT3 inhibitor) to prevent microbial growth in the placenta ex vivo has a negligible effect on the overall maternal-to-fetal and fetal-to-maternal clearances. The model could successfully predict in vivo fetal exposure using ex vivo human placental perfusion data from both closed and open systems. This transplacental PK modeling approach is expected to be useful for evaluating human fetal exposures to other poorly permeable compounds, besides metformin. SIGNIFICANCE STATEMENT We developed a pharmacokinetic model of transplacental transfer of metformin, used to treat gestational diabetes mellitus, in order to predict in vivo fetal exposure and resolve the discrepancy between reported findings in open and closed ex vivo perfusion systems. The discrepancy is due to a difference in the time required to reach the steady state. The model can predict in vivo fetal exposure using data from both closed and open systems.

  • Substrate recognition of renally eliminated angiotensin II receptor blockers by organic anion transporter 4

    Noguchi S., Okochi M., Atsuta H., Kimura R., Fukumoto A., Takahashi K., Nishimura T., Tomi M.

    Drug Metabolism and Pharmacokinetics （Drug Metabolism and Pharmacokinetics)  36   100363 2020年10月

    研究論文（学術雑誌）, 共著, 査読有り,  ISSN  13474367

    　概要を見る

    © 2020 The Japanese Society for the Study of Xenobiotics Organic anion transporter (OAT) 4, which is localized at the apical membrane of human renal proximal tubules, transports olmesartan, an angiotensin II receptor blocker (ARB). Many ARBs, including olmesartan, undergo partial tubular secretion as active forms, and inhibit OAT4-mediated uptake activity. Here, we examined the substrate recognition of various ARBs by OAT4 in order to assess whether OAT4 might be involved in the renal handling of ARBs. Concentration-dependent OAT4-mediated uptake of azilsartan, candesartan, carboxylosartan, losartan, and valsartan was observed with Km values of 6.6, 31, 7.2, 13, and 1.7 μM, respectively, in the absence of extracellular Cl−. In the presence of extracellular Cl−, OAT4-mediated uptake of dianionic ARBs (azilsartan, candesartan, carboxylosartan, and valsartan) was lower and reached a steady state faster than in the absence of extracellular Cl−. Thus, OAT4 is proposed to use extracellular Cl− as a counterpart for anion efflux. Our results suggest that OAT4 may play a role in the excretion of azilsartan, candesartan, carboxylosartan, and valsartan, as well as olmesartan. In contrast, OAT4-mediated uptake of losartan, a monoanionic ARB, was little affected by extracellular Cl−, suggesting that only OAT4-mediated dianion transport is Cl−-sensitive.

  • Contribution of Prostaglandin Transporter OATP2A1/SLCO2A1 to Placenta-to-Maternal Hormone Signaling and Labor Induction

    Inagaki M., Nishimura T., Nakanishi T., Shimada H., Noguchi S., Akanuma S.i., Tachikawa M., Hosoya K.i., Tamai I., Nakashima E., Tomi M.

    iScience （iScience)  23 （ 5 ） 101098 - 101098 2020年05月

    研究論文（学術雑誌）, 共著, 査読有り

    　概要を見る

    © 2020 The Author(s) Molecular Biology; Endocrinology

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KOARA（リポジトリ）収録論文等 【 表示 ／ 非表示 】

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総説・解説等 【 表示 ／ 非表示 】

  • 【「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年03月

    その他記事, 共著,  ISSN  0016-5980

    　概要を見る

    ＜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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研究発表 【 表示 ／ 非表示 】

  • miR-126によるLIN28A制御を介した、胎盤栄養膜モデルJEG-3細胞の浸潤抑制

    野口 幸希、潘 暁楽、西村 友宏、登美 斉俊

    日本薬学会第141年会 (オンライン) , 2021年03月, 口頭（一般）, 日本薬学会

  • 胎盤におけるOCTN1の発現とメトホルミン輸送への関与の検討

    中口佳美、西村友宏、市田智久、高橋優、野口幸希、丸山哲夫、石本尚大、加藤将夫、登美斉俊

    第35 回⽇本薬物動態学会年会 (オンライン) , 2020年12月, 口頭（一般）, ⽇本薬物動態学会

  • エステル修飾型酸性プロドラッグに対するOATP2B1の輸送能

    深澤 尚美, 野口 幸希, 西村 友宏, 登美 斉俊

    第5回トランスポーター研究会関東部会 (Web) , 2020年11月, ポスター（一般）

  • OAT1及びOAT3を介したアンジオテンシンⅡ受容体拮抗薬輸送の評価

    三輪 晴香, 野口 幸希, 加島 里菜, 西村 友宏 登美斉俊

    第5回トランスポーター研究会関東部会 (Web) , 2020年11月, ポスター（一般）

  • プレガバリンのラット脳移行における血漿中LAT1基質アミノ酸の影響

    野口 幸希, 高橋 優 西村 友宏, 登美 斉俊

    第15回トランスポーター研究会年会 (Web) , 2020年10月, 口頭（一般）

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競争的資金等の研究課題 【 表示 ／ 非表示 】

  • 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年04月
    -
    2022年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 野口 幸希, 若手研究, 補助金,  代表

  • 胎盤合胞体化と内分泌機能の成熟制御機構を標的とした妊娠合併症治療戦略

    2018年04月
    -
    2020年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 野口　幸希, 若手研究, 補助金,  代表

  • ヒト胎盤特異的輸送体による胎児環境制御機構の解明と病態時変動マーカーの探索

    2016年04月
    -
    2017年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 野口 幸希, 特別研究員奨励費, 補助金,  代表

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担当授業科目 【 表示 ／ 非表示 】

  • 課題研究（薬剤学）

    2021年度

  • 細胞培養・遺伝子実験特別演習

    2021年度

  • 演習（薬剤学）

    2021年度

  • 卒業研究１（薬学科）

    2021年度

  • 実務実習事前学習（実習）

    2021年度

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