齋藤 義正 (サイトウ ヨシマサ)

Saito, Yoshimasa

写真a

所属(所属キャンパス)

薬学部 薬学科 薬物治療学講座 (芝共立)

職名

准教授

 
 

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  • 遺伝子診断と個別化医療.「ゲノム創薬科学」

    齋藤 義正, 裳華房, 2017年10月

    担当範囲: pp269-287

  • エピジェネティクスとアンチエイジング医学.「アンチエイジング医学の基礎と臨床」第3版.

    齋藤 義正, メジカルビュー社, 東京, 2015年09月

    担当範囲: pp42-44

  • Advanced Glycation End-products (AGEs)阻害薬がOLEFTラットの肝および脂肪組織に及ぼす影響. 「酸化ストレスと肝疾患 8巻」.

    木村真規、南雲まい、飯田陽子、山田華名、齋藤義正、齋藤英胤., 株式会社嵯峨野, 東京, 2012年09月

    担当範囲: pp67-72

  • 加齢と消化器系の変化.「高齢者用食品の開発と展望」.

    齋藤義正、齋藤英胤., シーエムシー出版, 東京, 2012年07月

    担当範囲: pp7-12

論文 【 表示 / 非表示

  • Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging

    Uchida R., Saito Y., Nogami K., Kajiyama Y., Suzuki Y., Kawase Y., Nakaoka T., Muramatsu T., Kimura M., Saito H.

    npj Aging and Mechanisms of Disease (npj Aging and Mechanisms of Disease)  5 ( 1 )  2019年12月

     概要を見る

    © 2018, The Author(s). To understand the molecular features underlying stem cell aging, we established intestinal epithelial organoids derived from both young and aged mice and investigated alterations in their senescence and epigenetic status. Senescence-related changes including accumulation of senescence-associated β-galactosidase and up-regulation of Cdkn1a (p21) by DNA demethylation were observed in intestinal epithelial organoids derived from aged mice. We also demonstrated that the important stem cell marker Lgr5 was epigenetically silenced by trimethylation of histone H3 lysine 27, inducing suppression of Wnt signaling and a decrease of cell proliferation in organoids from aged mice. We further treated intestinal epithelial organoids from aged mice with nicotinamide mononucleotide (NMN), a key NAD + intermediate. As a result, the organoids showed a higher NAD + level, increased cell proliferative ability, activation of Lgr5 and suppression of senescence-associated genes, indicating that treatment with NMN could ameliorate senescence-related changes in intestinal epithelia. These findings suggest that organoids derived from aged animals could be a powerful research tool for investigating the molecular mechanisms underlying stem cell aging and for development of some form of anti-aging intervention, thus contributing to prolongation of healthy life expectancy.

  • Circulating microRNA-1246 as a possible biomarker for early tumor recurrence of hepatocellular carcinoma

    Chuma M., Toyoda H., Matsuzaki J., Saito Y., Kumada T., Tada T., Kaneoka Y., Maeda A., Yokoo H., Ogawa K., Kamiyama T., Taketomi A., Matsuno Y., Yazawa K., Takeda K., Kunisaki C., Ogushi K., Moriya S., Hara K., Nozaki A., Kondo M., Fukuda H., Numata K., Tanaka K., Maeda S., Sakamoto N.

    Hepatology Research (Hepatology Research)  49 ( 7 ) 810 - 822 2019年07月

    ISSN  13866346

     概要を見る

    © 2019 The Japan Society of Hepatology Aims: Early tumor recurrence (ETR) after hepatic resection is a crucial predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify clinically significant serum microRNAs (miRNAs) involved in the ETR of HCC. Methods: We compared expression profiles of circulating miRNAs from serum samples between five HCC patients with ETR (recurrence within 12 months after hepatectomy) and five HCC patients without recurrence using microarray analysis of miRNA. The identified miRNA associated with ETR was further verified in 121 HCC patients, 73 liver disease patients, and 15 health controls by real-time quantitative reverse transcription–polymerase chain reaction (PCR). Results: Of the approximately 2000 miRNAs analyzed, we identified 15 miRNAs for which expression levels correlated significantly with ETR. Of these miRNAs, we further investigated expression of miRNA-1246 (miR-1246). Quantitative PCR confirmed that miR-1246 was upregulated in HCC with ETR, compared to the level in HCC without ETR (P < 0.001). Serum miR-1246 showed a receiver operating characteristic curve area of 0.762, with 77.4% specificity and 54.1% sensitivity in discriminating HCC patients with ETR from HCC patients without ETR. Altered expression of miR-1246 was associated with aggressive tumor characteristics, including tumor–node–metastasis classification (P = 0.0413), tumor differentiation (P = 0.0419), and portal vein invasion (P = 0.0394). Moreover, multivariate Cox regression analysis identified serum miR-1246 level as an independent risk factor for overall survival (hazard ratio, 2.784; 95% confidence interval, 1.528–5.071; P = 0.0008). Conclusion: Circulating miR-1246 in serum has strong potential as a novel ETR and prognostic biomarker for HCC.

  • Establishment of Patient-Derived Organoids and Drug Screening for Biliary Tract Carcinoma

    Saito Y., Muramatsu T., Kanai Y., Ojima H., Sukeda A., Hiraoka N., Arai E., Sugiyama Y., Matsuzaki J., Uchida R., Yoshikawa N., Furukawa R., Saito H.

    Cell Reports (Cell Reports)  27 ( 4 ) 1265 - 1276.e4 2019年04月

     概要を見る

    © 2019 The Author(s) Biliary tract carcinomas (BTCs) are among the most aggressive malignancies and have a poor prognosis. Here, we successfully established organoid lines derived from intrahepatic cholangiocarcinoma, gallbladder cancer, and neuroendocrine carcinoma of the ampulla of Vater. These organoids derived from BTCs were cultured stably for >1 year and closely recapitulated the histopathology, gene expression, and genetic alterations evident in the primary tumors. Gene expression profiling of the organoids revealed that SOX2 could be a potential prognostic biomarker for patients with BTC. We screened a compound library consisting of drugs used clinically for their ability to suppress organoids derived from BTCs and found that the antifungal drugs amorolfine and fenticonazole significantly suppressed the growth of organoids derived from BTCs with minimal toxicity to normal biliary epithelial cells. Patient-derived organoids may be a powerful research tool for the clarification of molecular pathogenesis and the discovery of biomarkers and therapeutic drugs for refractory cancers.

  • CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy

    Tsugawa H., Mori H., Matsuzaki J., Sato A., Saito Y., Imoto M., Suematsu M., Suzuki H.

    Autophagy (Autophagy)  15 ( 2 ) 242 - 258 2019年02月

    ISSN  15548627

     概要を見る

    © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. Helicobacter pylori-derived CagA, a type IV secretion system effector, plays a role as an oncogenic driver in gastric epithelial cells. However, upon delivery into gastric epithelial cells, CagA is usually degraded by macroautophagy/autophagy. Hence, the induction of autophagy in H. pylori-infected epithelial cells is an important host-protective ability against gastric carcinogenesis. However, the mechanisms by which autophagosome-lysosome fusion is regulated, are unknown. Here, we report that enhancement of LAMP1 (lysosomal associated membrane protein 1) expression is necessary for autolysosome formation. LAMP1 expression is induced by nuclear translocated LRP1 (LDL receptor related protein 1) intracellular domain (LRP1-ICD) binding to the proximal LAMP1 promoter region. Nuclear translocation of LRP1-ICD is enhanced by H. pylori infection. In contrast, CAPZA1 (capping actin protein of muscle Z-line alpha subunit 1) inhibits LAMP1 expression via binding to LRP1-ICD in the nuclei. The binding of CAPZA1 to LRP1-ICD prevents LRP1-ICD binding to the LAMP1 proximal promoter. Thus, in CAPZA1-overexpressing gastric epithelial cells infected with H. pylori, autolysosome formation is inhibited and CagA escapes autophagic degradation. These findings identify CAPZA1 as a novel negative regulator of autolysosome formation and suggest that deregulation of CAPZA1 expression leads to increased risk of gastric carcinogenesis. Abbreviations: CagA: cytotoxin-associated gene A; CAPZA1: capping actin protein of muscle Z-line alpha subunit 1; ChIP: chromatin immunoprecipitation; GTF2I: general transcription factor IIi; HDAC: histone deacetylase; LAMP1: lysosomal associated membrane protein 1; LRP1: LDL receptor related protein 1; LRP1-ICD: CagA intracellular domain; qPCR: quantitative polymerase chain reaction; VacA: vacuolating cytotoxin.

  • Vonoprazan-based third-line therapy has a higher eradication rate against sitafloxacin-resistant Helicobacter pylori

    Saito Y., Konno K., Sato M., Nakano M., Kato Y., Saito H., Serizawa H.

    Cancers (Cancers)  11 ( 1 )  2019年01月

     概要を見る

    © 2019 by the authors. Licensee MDPI, Basel, Switzerland. Eradication of Helicobacter pylori (H. pylori) is an effective strategy for preventing various gastrointestinal diseases such as gastric cancer and mucosa-associated lymphoid tissue (MALT) lymphoma. However, the eradication success rate is decreasing because of a recent increase in drug-resistant strains of H. pylori. Here, we evaluated the success rate of eradication therapy with vonoprazan (VPZ), a new potassium-competitive acid blocker, against drug-resistant H. pylori. In total, 793 patients who received H. pylori eradication therapy were investigated retrospectively. All underwent esomeprazole (EPZ)-based triple therapy (n = 386) or VPZ-based triple therapy (n = 407) for first-, second- and third-line H. pylori eradication for 7 days. The overall success rates of first- and third-line H. pylori eradication were significantly higher for VPZ-based triple therapy (88.4% and 93.0%, respectively, per protocol (PP)) than for EPZ-based triple therapy (69.5% and 56.5%, respectively, PP). Moreover, the success rates of first- and third-line eradication of clarithromycin (CLR)- and sitafloxacin (STFX)-resistant H. pylori were significantly higher for VPZ-based triple therapy (72.0% and 91.7%, PP) than for EPZ-based triple therapy (38.5% and 20.0%, PP). In addition, patient age did not affect the eradication rate of VPZ-based first-line therapy, whereas the success rate of EPZ-based therapy was lower in patients under 65 years of age. Our results clearly demonstrated that VPZ-based therapy achieved a higher eradication rate even against CLR- and STFX-resistant H. pylori, and that patient age did not affect the eradication rate of VPZ-based therapy. These findings suggest that dual therapy using VPZ and amoxicillin may be sufficient for standard H. pylori eradication, and may thus also be beneficial for avoiding antibiotic misuse.

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総説・解説等 【 表示 / 非表示

研究発表 【 表示 / 非表示

  • 慢性胃炎・胃がんとピロリ菌

    齋藤 義正

    第102回日本消化器病学会関東支部市民公開講座, 2018年09月, 公開講演,セミナー,チュートリアル,講習,講義等

  • Helicobacter pyloriに対する3次および4次除菌治療におけるボノプラザンの効果に関する検討

    佐藤萌香、齋藤義正、中野 雅、加藤裕佳子、齋藤英胤、芹澤 宏

    第24回日本ヘリコバクター学会学術集会, 2018年06月, ポスター(一般)

  • 企業におけるヘリコバクターピロリ感染に関する意識調査

    芹澤 宏、有木 寿史、齋藤 義正

    第24回日本ヘリコバクター学会学術集会, 2018年06月, ポスター(一般)

  • 常在細菌の代謝産物butyrateはH. pylori感染胃粘膜において発がんリスクを増強する

    津川 仁、加藤 智尋、齋藤 義正、杉浦 悠毅、松井 英則、加部 泰明、末松 誠、鈴木 秀和

    第24回日本ヘリコバクター学会学術集会, 2018年06月, シンポジウム・ワークショップ パネル(公募)

  • 胆道系悪性腫瘍由来オルガノイドの長期培養と創薬研究への応用

    齋藤 義正, 齋藤 英胤

    第54回日本肝臓学会総会, 2018年06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

  • NAD+およびエピゲノムの制御による老化メカニズムの解明と新たな抗加齢介入の開発

    2019年06月
    -
    2021年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 齋藤 義正, 挑戦的研究(萌芽), 補助金,  代表

  • オルガノイド培養による胆道・膵臓腫瘍細胞バンクの構築と個別化治療への応用

    2017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, 齋藤 義正, 基盤研究(B), 補助金,  代表

  • 腸管上皮幹細胞における加齢に伴うエピゲノム変化に着目した老化の分子機構の解明

    2016年04月
    -
    2018年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 齋藤 義正, 挑戦的萌芽研究, 補助金,  代表

  • 胆道・膵臓がん幹細胞のマイクロRNAとエピゲノム異常を標的とした診断・治療戦略

    2014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, 齋藤 義正, 基盤研究(B), 補助金,  代表

     研究概要を見る

    がん幹細胞は現行の抗腫瘍薬に抵抗性を示し、がんの増殖・浸潤・転移の主な原因となっている。本研究の目的は難治がんの代表である胆道・膵臓がんに対し、がん幹細胞を標的とした革新的な治療法を開発することである。この目的を達成するために、幹細胞の新たな3次元培養法であるオルガノイド培養技術により、胆道・膵臓がん患者由来のがん組織を用いてオルガノイドを樹立した。樹立した胆道・膵臓がんオルガノイドを用いて遺伝子変異・遺伝子発現解析や薬剤感受性試験などを行うことで、既存の低分子化合物やmiR-34aをはじめとするがん抑制マイクロRNAが胆道・膵臓がんに対する安全かつ効果的な治療薬の候補となることが示された。

知的財産権等 【 表示 / 非表示

  • がん幹細胞集団の調製方法、異種移植片の調製方法、スクリーニング方法、miR-34aの発現量を低下させる方法及びがん幹細胞増殖抑制剤

    特願: 特願2015-142164  2015年07月 

    特許, 共同, 国内出願

受賞 【 表示 / 非表示

  • 第18回日本抗加齢医学会総会 最優秀演題賞

    齋藤義正, 2018年05月, 腸管上皮オルガノイドを用いたステムセルエイジングの検討

    受賞区分: 国内学会・会議・シンポジウム等の賞,  受賞国: 日本

  • 日本抗加齢医学会優秀演題賞 

    木村真規、井手晴香、白井栄里奈、内田諒英、齋藤義正、齋藤英胤. , 2016年06月, 第16回 日本抗加齢医学会総会, 高脂肪食摂取時の脂肪組織における老化マーカー遺伝子の発現変化とDNAメチル化阻害薬の効果. 

    受賞区分: 国内学会・会議・シンポジウム等の賞

     説明を見る

    プログラム・抄録集: 170, 2016/6/10/12.

  • 日本抗加齢医学会優秀演題賞 

    内田諒英、齋藤義正、中岡哉彰、村松俊英、木村真規、齋藤英胤. , 2016年06月, 第16回 日本抗加齢医学会総会 プログラム・抄録集: 174, 2016/6/10/12., オルガノイド培養法により樹立した腸管上上皮幹細胞における stem cell aging の検討. 

     説明を見る

    プログラム・抄録集: 174, 2016/6/10/12.

  • 慶應義塾大学薬学部学部長賞

    2015年

    受賞区分: 塾内表彰等

  • Best poster award

    Saito Y., 2012年01月, "The 2nd Asian Pacific Topic Conference, Asian Pacific Helicobacter Pylori Meeting 2012", Dysfunctional gastric emptying with downregulation of muscle-specific microRNAs in Helicobacter pylori-infected mice.

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担当授業科目 【 表示 / 非表示

  • 疾患分子生物学特論

    2019年度

  • 卒業研究(薬科学科)

    2019年度

  • 生命・研究倫理

    2019年度

  • 症例検討B

    2019年度

  • 薬物治療学3

    2019年度

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