2025/08/22 更新

写真a

オガワ トシフミ
小川 俊史
所属
医学部 生理学講座細胞生理学分野 助教
職名
助教
外部リンク

研究キーワード

  • 糖尿病性心筋症

  • 代謝

  • 糖尿病

  • サルコペニア

研究分野

  • ライフサイエンス / 循環器内科学

  • ライフサイエンス / 生理学

  • ライフサイエンス / 代謝、内分泌学

学歴

  • 札幌医科大学   大学院医学研究科   地域医療人間総合医学専攻 発生分化・加齢制御医学領域 心血管細胞代謝病態学

    2018年4月 - 2023年3月

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  • 札幌医科大学   医学部   医学科

    2008年4月 - 2014年3月

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経歴

  • 札幌医科大学   医学部 細胞生理学講座 兼 循環器・腎臓・代謝内分泌内科学講座   助教

    2023年4月 - 現在

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  • JR札幌病院   循環器内科/腎臓内科/糖尿病内科   医長

    2020年4月 - 2023年3月

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  • 札幌循環器病院   内科・循環器内科

    2019年4月 - 2020年3月

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  • 札幌医科大学   循環器・腎臓・代謝内分泌内科学講座

    2018年12月 - 2019年3月

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  • 北海道立江差病院   循環器内科

    2018年8月 - 2018年11月

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  • 札幌医科大学   循環器・腎臓・代謝内分泌内科学講座

    2018年4月 - 2018年7月

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  • 帯広厚生病院   循環器内科

    2017年4月 - 2018年3月

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  • 札幌医科大学   循環器・腎臓・代謝内分泌内科学講座

    2016年4月 - 2017年3月

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  • 札幌医科大学   附属病院   初期臨床研修医

    2015年4月 - 2016年3月

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  • 市立釧路総合病院   初期臨床研修医

    2014年3月 - 2015年4月

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▼全件表示

所属学協会

  • 日本肥満学会

    2024年2月 - 現在

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  • 日本生理学会

    2024年1月 - 現在

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  • 日本内分泌学会

    2022年4月 - 現在

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  • 日本心不全学会

    2021年5月 - 現在

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  • 日本糖尿病学会

    2019年12月 - 現在

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  • 日本心臓リハビリテーション学会

    2018年4月 - 現在

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  • 日本内科学会

    2016年2月 - 現在

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  • 日本循環器学会

    2015年4月 - 現在

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論文

  • Machine learning-based analyses of contributing factors for the development of hypertension: a comparative study. 国際誌

    Marenao Tanaka, Yukinori Akiyama, Kazuma Mori, Itaru Hosaka, Keisuke Endo, Toshifumi Ogawa, Tatsuya Sato, Toru Suzuki, Toshiyuki Yano, Hirofumi Ohnishi, Nagisa Hanawa, Masato Furuhashi

    Clinical and experimental hypertension (New York, N.Y. : 1993)   47 ( 1 )   2449613 - 2449613   2025年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: Sufficient attention has not been given to machine learning (ML) models using longitudinal data for investigating important predictors of new onset of hypertension. We investigated the predictive ability of several ML models for the development of hypertension. METHODS: A total of 15 965 Japanese participants (men/women: 9,466/6,499, mean age: 45 years) who received annual health examinations were randomly divided into a training group (70%, n = 11,175) and a test group (30%, n = 4,790). The predictive abilities of 58 candidates including fatty liver index (FLI), which is calculated by using body mass index, waist circumference and levels of γ-glutamyl transferase and triglycerides, were investigated by statistics analogous to the area under the curve (AUC) in receiver operating characteristic curve analyses using ML models including logistic regression, random forest, naïve Bayes, extreme gradient boosting and artificial neural network. RESULTS: During a 10-year period (mean period: 6.1 years), 2,132 subjects (19.1%) in the training group and 917 subjects (19.1%) in the test group had new onset of hypertension. Among the 58 parameters, systolic blood pressure, age and FLI were identified as important candidates by random forest feature selection with 10-fold cross-validation. The AUCs of ML models were 0.765-0.825, and discriminatory capacity was significantly improved in the artificial neural network model compared to that in the logistic regression model. CONCLUSIONS: The development of hypertension can be simply and accurately predicted by each ML model using systolic blood pressure, age and FLI as selected features. By building multiple ML models, more practical prediction might be possible.

    DOI: 10.1080/10641963.2025.2449613

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  • Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Is an Independent Risk Factor for the Development of Ischemic Heart Disease ― A 10-Year Cohort Study ―

    Toshifumi Ogawa, Tatsuya Sato, Marenao Tanaka, Yukinori Akiyama, Kei Nakata, Hidemichi Kouzu, Kazuma Mori, Hiroki Aida, Wataru Kawaharata, Itaru Hosaka, Toru Suzuki, Nagisa Hanawa, Masato Furuhashi

    Circulation Reports   2025年4月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Circulation Society  

    DOI: 10.1253/circrep.cr-25-0019

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  • Unraveling Novel Subsets of Lymphocytes Involved in Sac Expansion in the Tertiary Lymphoid Structure Within an Abdominal Aortic Aneurysm. 国際誌

    Itaru Hosaka, Ippei Ikegami, Takuma Mikami, Tatsuya Sato, Toshifumi Ogawa, Kei Mukawa, Marenao Tanaka, Keisuke Endo, Yukinori Akiyama, Akihito Ohkawa, Junji Nakazawa, Tsuyoshi Shibata, Tomohiro Nakajima, Yutaka Iba, Chikara Shiiku, Satoshi Sumino, Ryuji Koshima, Kenichi Takano, Shingo Ichimiya, Nobuyoshi Kawaharada, Masato Furuhashi

    Journal of the American Heart Association   14 ( 6 )   e040279   2025年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Chronic inflammation is involved in the development of abdominal aortic aneurysm (AAA). A tertiary lymphoid structure (TLS) within vascular lesions has recently been focused on for its role in modulation of inflammation in local tissues. We aimed to elucidate the relationships between TLS and pathophysiology of AAA. METHODS: Abdominal aortic samples obtained from 37 patients with AAA (men/women: 34/3, age: 72.8±9.9 years) and 15 autopsied patients who died from non-aortic events (men/women: 11/4, age: 65.5±9.8 years) were investigated. RESULTS: TLSs in AAA lesions were confirmed by focal infiltration of CD3-positive cells surrounding germinal center-like structures containing CD20-positive cells between the tunica adventitia and tunica media layers. The formation of a TLS was significantly more prevalent in AAA patients than in autopsied patients. The number of TLSs in AAA lesions was positively correlated with sac diameter (r=0.357, P=0.035) and the amount of intraluminal thrombosis (r=0.466, P=0.005). T cells and B cells were predominant cellular populations among CD45+ cells in AAA lesions. There was a significantly positive correlation between the proportions of interfollicular T follicular helper (CD3+CD4+CD45RA-CXCR5+PD-1+) cells and double negative B (CD3-CD19+IgD-CD27-) cells, and they were positively correlated with sac diameter, intraluminal thrombosis, and serum lipids. Deposited single-cell RNA-sequencing data for AAA showed that T follicular helper cells and double negative B cells were associated with lipid metabolism, T cell activation/proliferation and inflammation. CONCLUSIONS: The formation of a TLS in AAA lesions is associated with sac diameter and intraluminal thrombosis in connection with interfollicular T follicular helper cells and double negative B cells, which may contribute to the pathophysiology of AAA and might be novel therapeutic targets for the development of AAA.

    DOI: 10.1161/JAHA.124.040279

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  • The Combination of PPARα Agonist GW7647 and Imeglimin Has Potent Effects on High-Glucose-Induced Cellular Biological Responses in Human Retinal Pigment Epithelium Cells. 国際誌

    Nami Nishikiori, Megumi Watanabe, Megumi Higashide, Araya Umetsu, Toshifumi Ogawa, Masato Furuhashi, Hiroshi Ohguro, Tatsuya Sato

    Bioengineering (Basel, Switzerland)   12 ( 3 )   2025年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Hyperglycemic changes in the cellular biological properties of retinal pigment epithelium cells are involved in the pathophysiology of diabetic retinopathy (DR). To assess the effects of the new anti-diabetic agent imeglimin (Ime) on DR, the pharmacological effects of Ime and those of metformin (Met) in combination with the PPARα agonist GW7646 (GW) on adult retinal pigment epithelium (ARPE19) cells cultured in high-glucose conditions were compared. METHODS: Cell viability, levels of reactive oxygen species (ROS), monolayer barrier function measured by transepit very much helial electrical resistance (TEER), and metabolic functions determined by an extracellular flux analyzer were evaluated. RESULTS: While glucose concentrations did not alter cell viability regardless of the presence of Met or Ime, levels of ROS were significantly increased by the high-glucose conditions, and increased levels of ROS were significantly alleviated by the combination of Ime and GW but not by Met alone. Similarly, TEER values were increased by high-glucose conditions, but the effects of high-glucose conditions were dramatically enhanced by the combination of Ime and GW. Furthermore, a metabolic assay showed that an energetic shift was induced by the combination of Ime and GW, whereas energy status became quiescent with Met or Ime alone. CONCLUSIONS: The collective results suggest that Ime in combination with GW has synergetic effects on high-glucose-induced cellular biological changes in ARPE19 cells.

    DOI: 10.3390/bioengineering12030265

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  • LINC02154 promotes cell cycle and mitochondrial function in oral squamous cell carcinoma. 国際誌

    Takeshi Niinuma, Hiroshi Kitajima, Tatsuya Sato, Toshifumi Ogawa, Kazuya Ishiguro, Masahiro Kai, Eiichiro Yamamoto, Yui Hatanaka, Iyori Nojima, Mutsumi Toyota, Akira Yorozu, Shohei Sekiguchi, Noritsugu Tohse, Masato Furuhashi, Hiroshi Ohguro, Akihiro Miyazaki, Hiromu Suzuki

    Cancer science   116 ( 2 )   393 - 405   2025年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Long noncoding RNAs (lncRNAs) play pivotal roles in the development of human malignancies, though their involvement in oral squamous cell carcinoma (OSCC) remains incompletely understood. Using The Cancer Genome Atlas (TCGA) dataset, we analyzed expression of 7840 lncRNAs in primary head and neck squamous cell carcinoma (HNSCC) and found that upregulation of LINC02154 is associated with a poorer prognosis. LINC02154 knockdown in OSCC cell lines induced cell cycle arrest and apoptosis, and significantly attenuated tumor growth in vitro and in vivo. Notably, depletion of LINC02154 downregulated FOXM1, a master regulator of cell cycle-related genes. RNA pulldown and mass spectrometry analyses identified a series of proteins that could potentially interact with LINC02154, including HNRNPK and LRPPRC. HNRNPK stabilizes FOXM1 expression by interacting with the 3'-UTR of FOXM1 mRNA, which suggests LINC02154 and HNRNPK promote cell cycling by regulating FOXM1 expression. Additionally, LINC02154 positively regulates HNRNPK expression by inhibiting microRNAs targeting HNRPNK. Moreover, LINC02154 affects mitochondrial function by interacting with LRPPRC. Depletion of LINC02154 suppressed expression of mitochondrial genes, including MTCO1 and MTCO2, and inhibited mitochondrial respiratory function in OSCC cells. These results suggest that LINC02154 exerts its oncogenic effects by modulating the cell cycle and oxidative phosphorylation in OSCC, highlighting LINC02154 as a potential therapeutic target.

    DOI: 10.1111/cas.16379

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  • High-Glucose-Induced Metabolic and Redox Alterations Are Distinctly Modulated by Various Antidiabetic Agents and Interventions Against FABP5/7, MITF and ANGPTL4 in Melanoma A375 Cells 国際誌

    Nami Nishikiori, Hiroshi Ohguro, Megumi Watanabe, Megumi Higashide, Toshifumi Ogawa, Masato Furuhashi, Tatsuya Sato

    International Journal of Molecular Sciences   26 ( 3 )   1014 - 1014   2025年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI AG  

    Hyperglycemia-induced effects on cellular metabolic properties and reactive oxygen species (ROS) generation play pivotal roles in the pathogenesis of malignant melanoma (MM). This study assessed how metabolic states, ROS production, and related gene expression are modulated by antidiabetic agents. The anti-diabetic agents metformin (Met) and imeglimin (Ime), inhibitors of fatty acid-binding proteins 5/7 (MF6) and microphthalmia-associated transcription factor (MITF) (ML329), and siRNA-mediated knockdown of angiopoietin-like protein 4 (ANGPTL4), which affect mitochondrial respiration, ROS production, and related gene expression, were tested in A375 (MM cell line) cells cultured in low (5.5 mM) and high glucose (50 mM) conditions. Cellular metabolic functions were significantly and differently modulated by Met, Ime, MF6, or ML329 and knockdown of ANGPTL4. High glucose significantly enhanced ROS production, which was alleviated by Ime but not by Met. Both MF6 and ML329 reduced ROS levels under both low and high glucose conditions. Knockdown of ANGPTL4 enhanced the change in glucose-dependent ROS production. Gene expression related to mitochondrial respiration and the pathogenesis of MM was significantly modulated by different glucose conditions, antidiabetic agents, MF6, and ML329. These findings suggest that glucose-dependent changes in cellular metabolism and redox status are differently modulated by antidiabetic agents, inhibition of fatty acid-binding proteins or MITF, and ANGPTL4 knockdown in A375 cells.

    DOI: 10.3390/ijms26031014

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  • Effects of linsitinib on M22 and IGF:1-treated 3D spheroids of human orbital fibroblasts. 国際誌

    Fumihito Hikage, Megumi Suzuki, Tatsuya Sato, Araya Umetsu, Toshifumi Ogawa, Nami Nishikiori, Masato Furuhashi, Hiroshi Ohguro, Megumi Watanabe

    Scientific reports   15 ( 1 )   384 - 384   2025年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To elucidate the role of IGF1R inhibition in the pathogenesis of Graves' orbitopathy (GO), the effects of linsitinib (Lins) on a recombinant human TSHR antibody (M22) and IGF1 to activate TSHR and IGF1R of human orbital fibroblasts (HOFs) obtained from patients without GO (HOFs) and patients with GO (GHOFs) were studied using in vitro three-dimensional (3D) spheroid models in addition to their 2D planar cell culture. For this purpose, we evaluated 1) cellular metabolic functions by using a seahorse bioanalyzer (2D), 2) physical properties including size and stiffness of 3D spheroids, and mRNA expression of several extracellular matrix (ECM) proteins, their modulators (CCL2 LOX, CTGF, MMPs), ACTA2 and inflammatory cytokines (IL1β, IL6). Administration of IGF1 and M22 induced increases of cellular metabolic functions with the effect on HOFs being much more potent than the effect on GHOFs, suggesting that IGF1R and TSHR of GHOFs may already be stimulated. Lins had effects similar to those of IGF1/M22 on cellular biological functions of HOFs but not on those of GHOFs. As for physical properties of 3D GHOFs spheroids, stiffness but not size was significantly increased by IGF1 and/or M22. In contrast, Lins significantly inhibited the M22-induced increase in stiffness despite the fact that Lins alone had no effect. The mRNA expression levels of several genes of ECM proteins and most of the other genes also fluctuated similarly to the changes in stiffness of 3D spheroids despite the fact that Lins induced up-regulation of inflammatory cytokines and MMP3. The findings presented herein indicate that IGF1R inhibition by Lins may beneficially affect GO-related fibrogenesis.

    DOI: 10.1038/s41598-024-83193-x

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  • mTOR Inhibitors Modulate the Biological Nature of TGF-β2-Treated or -Untreated Human Trabecular Meshwork Cells in Different Manners. 国際誌

    Megumi Watanabe, Tatsuya Sato, Toshiyuki Yano, Megumi Higashide, Toshifumi Ogawa, Nami Nishikiori, Masato Furuhashi, Hiroshi Ohguro

    Biomedicines   12 ( 11 )   2024年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background/Objectives: Mammalian target of rapamycin (mTOR) inhibition may have been suggested to have a beneficial effect on the glaucomatous human trabecular meshwork (HTM). To study the effects of the mTOR inhibitors rapamycin (Rapa) and Torin1 on the glaucomatous HTM, transforming growth factor-β2 (TGF-β2)-treated two-dimensionally (2D) and three-dimensionally (3D) cultured HTM cells were used. Methods: We evaluated (1) the levels of autophagy via Western blot analysis using a specific antibody against microtubule-associated protein 1 light chain 3 (LC3), (2) barrier capacity based on transepithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC) permeability (2D), (3) cellular metabolic functions (2D), (4) the size and stiffness of spheroids, and (5) the mRNA expression of ECM proteins. Results: TGF-β2-induced inhibition of autophagy was significantly inhibited by Rapa and Torin1. Rapa and Torin1 substantially decreased barrier capacity in both TGF-β2-untreated and TGF-β2-treated HTM cells. Cellular metabolic analysis indicated that Rapa, but not Torin1, substantially enhanced both mitochondrial and glycolytic functions of TGF-β2-untreated HTM cells. In the physical properties of spheroids, TGF-β2 resulted in the formation of down-sized and stiffened spheroids. mTOR inhibitors decreased the size but not the stiffness of TGF-β2-untreated spheroids and significantly reduced the TGF-β2-related increase in the stiffness but not the size of spheroids. The diverse effects of mTOR inhibitors on TGF-β2-untreated and TGF-β2-treated spheroids were also observed in the mRNA expression of extracellular matrix proteins. Conclusions: The results taken together suggest that mTOR inhibitors significantly influence the biological aspects of both a single layer and multiple layers of the TGF-β2-treated HTM and untreated HTM.

    DOI: 10.3390/biomedicines12112604

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  • Unexpected and Synergistical Effects of All-Trans Retinoic Acid and TGF-β2 on Biological Aspects of 2D and 3D Cultured ARPE19 Cells. 国際誌

    Megumi Higashide, Megumi Watanabe, Tatsuya Sato, Toshifumi Ogawa, Araya Umetsu, Soma Suzuki, Masato Furuhashi, Hiroshi Ohguro, Nami Nishikiori

    Biomedicines   12 ( 10 )   2024年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objectives: To study the effects of all-trans retinoic acid (ATRA) on TGF-β2-induced effects of human retinal pigment epithelium cells under normoxia and hypoxia conditions. Methods: Two-dimensionally (2D) and three-dimensionally (3D) cultured ARPE19 cells were subjected to cellular functional analyses by transepithelial electrical resistance (TEER) and an extracellular flux assay (2D), measurement of levels of reactive oxygen species (ROS), gene expression analyses of COL1, αSMA, Zo-1, HIF1α, and PGC1α (2D), and physical property analyses (3D). Results: Under a normoxia condition, treatment with 100 nM ATRA substantially decreased barrier function regardless of the presence of 5 ng/mL TGF-β2 in 2D ARPE19 monolayer cells. Under a hypoxia condition, treatment with ATRA conversely increased barrier function, but the effect was masked by a marked increase in effects induced by TGF-β2. Although ATRA alone did not affect cellular metabolism and ROS levels in 2D ARPE cells, treatment with ATRA under a hypoxia condition did not affect ROS levels but shifted cellular metabolism from mitochondrial respiration to glycolysis. The changes of cellular metabolism and ROS levels were more pronounced with treatment of both ATRA and TGF-β2 independently of oxygen conditions. Changes in mRNA expressions of some of the above genes suggested the involvement of synergistical regulation of cellular functions by TGF-β2 and hypoxia. In 3D ARPE spheroids, the size was decreased and the stiffness was increased by either treatment with TGF-β2 or ATRA, but these changes were unexpectedly modulated by both ATRA and TGF-β2 treatment regardless of oxygen conditions. Conclusions: The findings reported herein indicate that TGF-β2 and hypoxia synergistically and differentially induce effects in 2D and 3D cultured ARPE19 cells and that their cellular properties are significantly altered by the presence of ATRA.

    DOI: 10.3390/biomedicines12102228

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  • Contribution of MLKL to the development of doxorubicin-induced cardiomyopathy and its amelioration by rapamycin.

    Masaki Shimizu, Wataru Ohwada, Toshiyuki Yano, Hidemichi Kouzu, Tatsuya Sato, Toshifumi Ogawa, Arata Osanami, Yuki Toda, Hiroshi Nagahama, Masaya Tanno, Tetsuji Miura, Atsushi Kuno, Masato Furuhashi

    Journal of pharmacological sciences   156 ( 1 )   9 - 18   2024年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Necroptosis, necrosis characterized by RIPK3-MLKL activation, has been proposed as a mechanism of doxorubicin (DOX)-induced cardiomyopathy. We showed that rapamycin, an mTORC1 inhibitor, attenuates cardiomyocyte necroptosis. Here we examined role of MLKL in DOX-induced myocardial damage and protective effects of rapamycin. Cardiomyopathy was induced in mice by intraperitoneal injections of DOX (10 mg/kg, every other day) and followed for 7 days. DOX-treated mice showed a significant decline in LVEF assessed by cardiac MRI (45.5 ± 5.1% vs. 65.4 ± 4.2%), reduction in overall survival rates, and increases in myocardial RIPK3 and MLKL expression compared with those in vehicle-treated mice, and those changes were prevented by administration of rapamycin (0.25 mg/kg) before DOX injection. In immunohistochemical analyses, p-MLKL signals were detected in the cardiomyocytes of DOX-treated mice, and the signals were reduced by rapamycin. Mlkl+/- and Mlkl-/- mice were similarly resistant to DOX-induced cardiac dysfunction, indicating that a modest reduction in MLKL level is sufficient to prevent the development of DOX-induced cardiomyopathy. However, evidence of cardiomyocyte necrosis assessed by C9 immunostaining, presence of replacement fibrosis, and electron microscopic analyses was negligible in the myocardium of DOX-treated mice. Thus, MLKL-mediated signaling contributes to DOX-induced cardiac dysfunction primarily by a necrosis-independent mechanism, which is inhibitable by rapamycin.

    DOI: 10.1016/j.jphs.2024.06.005

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  • FABP5 Is a Possible Factor for the Maintenance of Functions of Human Non-Pigmented Ciliary Epithelium Cells. 国際誌

    Megumi Higashide, Megumi Watanabe, Tatsuya Sato, Araya Umetsu, Nami Nishikiori, Toshifumi Ogawa, Masato Furuhashi, Hiroshi Ohguro

    International journal of molecular sciences   25 ( 17 )   2024年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To elucidate the possible biological roles of fatty acid-binding protein 5 (FABP5) in the intraocular environment, the cells from which FABP5 originates were determined by using four different intraocular tissue-derived cell types including human non-pigmented ciliary epithelium (HNPCE) cells, retinoblastoma (RB) cells, adult retinal pigment epithelial19 (ARPE19) cells and human ocular choroidal fibroblast (HOCF) cell lines, and the effects of FABP ligand 6, a specific inhibitor for FABP5 and FABP7 were analyzed by RNA sequencing and seahorse cellular metabolic measurements. Among these four different cell types, qPCR analysis showed that FABP5 was most prominently expressed in HNPCE cells, in which no mRNA expression of FABP7 was detected. In RNA sequencing analysis, 166 markedly up-regulated and 198 markedly down-regulated differentially expressed genes (DEGs) were detected between non-treated cells and cells treated with FABP ligand 6. IPA analysis of these DEGs suggested that FABP5 may be involved in essential roles required for cell development, cell survival and cell homeostasis. In support of this possibility, both mitochondrial and glycolytic functions of HNPCE cells, in which mRNA expression of FABP5, but not that of FABP7, was detected, were shown by using a Seahorse XFe96 Bioanalyzer to be dramatically suppressed by FABP ligand 6-induced inhibition of the activity of FABP5. Furthermore, in IPA upstream analysis, various unfolded protein response (UPR)-related factors were identified as upstream and causal network master regulators. Analysis by qPCR analysis showed significant upregulation of the mRNA expression of most of UPR-related factors and aquaporin1 (AQP1). The findings in this study suggest that HNPCE is one of intraocular cells producing FABP5 and may be involved in the maintenance of UPR and AQP1-related functions of HNPCE.

    DOI: 10.3390/ijms25179285

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  • Metabolic dysfunction-associated steatotic liver disease (SLD) and alcohol-associated liver disease, but not SLD without metabolic dysfunction, are independently associated with new onset of chronic kidney disease during a 10-year follow-up period. 国際誌

    Kazuma Mori, Marenao Tanaka, Tatsuya Sato, Yukinori Akiyama, Keisuke Endo, Toshifumi Ogawa, Toru Suzuki, Hiroki Aida, Wataru Kawaharata, Kei Nakata, Itaru Hosaka, Araya Umetsu, Nagisa Hanawa, Masato Furuhashi

    Hepatology research : the official journal of the Japan Society of Hepatology   2024年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIMS: The new nomenclature of steatotic liver disease (SLD) including metabolic dysfunction-associated SLD (MASLD), MASLD and increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD) has recently been proposed. We aimed to elucidate the relationship between each category of SLD and chronic kidney disease (CKD). METHODS: We investigated the effects of various SLDs on the development of CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or positive for urinary protein, during a 10-year period in 12 138 Japanese subjects (men / women, 7984/4154; mean age, 48 years) who received annual health examinations including abdominal ultrasonography. RESULTS: The prevalences of SLD without metabolic dysfunction (SLD-MD[-]), MASLD, MetALD, and ALD were 1.7%, 26.3%, 4.9%, and 1.9%, respectively. During the follow-up period, 1963 subjects (16.2%) (men / women, 1374 [17.2%]/589 [14.2%]) had new onset of CKD. Multivariable Cox proportional hazard model analyses after adjustment of age, sex, eGFR, current smoking habit, diabetes mellitus, hypertension, and dyslipidemia showed that the hazard ratios (HR [95% confidence interval]) for the development of CKD in subjects with MASLD (1.20 [1.08-1.33], p = 0.001) and those with ALD (1.41 [1.05-1.88], p = 0.022), but not those with MetALD (1.11 [0.90-1.36], p = 0.332), were significantly higher than the HR in subjects with non-SLD. Interestingly, subjects with SLD-MD[-] had a significantly lower HR (0.61 [0.39-0.96], p = 0.034) than that in subjects with non-SLD. The addition of the novel classification of SLDs into traditional risk factors for the development of CKD significantly improved the discriminatory capacity. CONCLUSIONS: MASLD and ALD, but not SLD-MD[-], are independently associated with the development of CKD.

    DOI: 10.1111/hepr.14097

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  • Fatty Acid-Binding Protein 4-Mediated Regulation Is Pivotally Involved in Retinal Pathophysiology: A Review. 国際誌

    Hiroshi Ohguro, Megumi Watanabe, Fumihito Hikage, Tatsuya Sato, Nami Nishikiori, Araya Umetsu, Megumi Higashide, Toshifumi Ogawa, Masato Furuhashi

    International journal of molecular sciences   25 ( 14 )   2024年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Fatty acid-binding proteins (FABPs), a family of lipid chaperone molecules that are involved in intracellular lipid transportation to specific cellular compartments, stimulate lipid-associated responses such as biological signaling, membrane synthesis, transcriptional regulation, and lipid synthesis. Previous studies have shown that FABP4, a member of this family of proteins that are expressed in adipocytes and macrophages, plays pivotal roles in the pathogenesis of various cardiovascular and metabolic diseases, including diabetes mellitus (DM) and hypertension (HT). Since significant increases in the serum levels of FABP4 were detected in those patients, FABP4 has been identified as a crucial biomarker for these systemic diseases. In addition, in the field of ophthalmology, our group found that intraocular levels of FABP4 (ioFABP4) and free fatty acids (ioFFA) were substantially elevated in patients with retinal vascular diseases (RVDs) including proliferative diabetic retinopathy (PDR) and retinal vein occlusion (RVO), for which DM and HT are also recognized as significant risk factors. Recent studies have also revealed that ioFABP4 plays important roles in both retinal physiology and pathogenesis, and the results of these studies have suggested potential molecular targets for retinal diseases that might lead to future new therapeutic strategies.

    DOI: 10.3390/ijms25147717

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  • Tirzepatide ameliorates eating behaviors regardless of prior exposure to glucagon-like peptide receptor agonists in Japanese patients with type 2 diabetes mellitus. 国際誌

    Toru Suzuki, Tatsuya Sato, Marenao Tanaka, Keisuke Endo, Kei Nakata, Toshifumi Ogawa, Itaru Hosaka, Yukinori Akiyama, Araya Umetsu, Masato Furuhashi

    Journal of diabetes and its complications   38 ( 7 )   108779 - 108779   2024年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIMS: To investigate effects of tirzepatide, a dual receptor agonist for glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1), on eating behaviors. METHODS: Eating behaviors were evaluated by using a validated questionnaire survey in 33 Japanese patients with type 2 diabetes mellitus (T2DM) (mean age: 51.8 years) who were treated with tirzepatide (2.5 mg/week for 4 weeks and then 5.0 mg/week) for 6 months (M). RESULTS: Treatment with tirzepatide significantly decreased median hemoglobin A1c (HbA1c) (baseline/3 M/6 M: 7.3 %/6.0 %/5.8 %), mean body weight (BW) (baseline/3 M/6 M: 87.7 kg/82.0 kg/79.6 kg) and mean relative score of eating behaviors (baseline/3 M/6 M: 57.0/50.7/45.9). In the GLP-1 receptor agonist (GLP-1RA) naïve group (n = 20, men/women: 13/7), HbA1c and BW were continuously decreased up to 6 M. Changes in eating behaviors were mainly observed in the first 3 M. In the GLP-1RA non-naïve group (n = 13, men/women: 8/5), reductions in HbA1c and BW were predominant in the first 3 M, and changes in eating behaviors were observed up to 6 M. There were no significant correlations of changes in scores of eating behaviors with changes in glycemic control or those in BW. CONCLUSIONS: Tirzepatide ameliorates eating behaviors as well as glycemic management and obesity in Japanese patients with T2DM, and the patterns of improvement are partially dependent on prior exposure to GLP-1RAs.

    DOI: 10.1016/j.jdiacomp.2024.108779

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  • Lysophosphatidic Acid Modulates TGF-β2-Induced Biological Phenotype in Human Conjunctival Fibroblasts. 国際誌

    Megumi Watanabe, Yuri Tsugeno, Tatsuya Sato, Megumi Higashide, Nami Nishikiori, Araya Umetsu, Toshifumi Ogawa, Masato Furuhashi, Hiroshi Ohguro

    Life (Basel, Switzerland)   14 ( 6 )   2024年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Although lysophosphatidic acid (LPA) is known to have multiple pathophysiological roles, its contributions to ocular tissues, especially conjunctival fibrogenesis, remain to be elucidated. METHODS: To study this issue, the effects of LPA on transforming growth factor-β2 (TGF-β2)-induced fibrogenesis of two-dimensional (2D) and three-dimensional (3D) cultures of human conjunctival fibroblasts (HconF) were examined by the following analyses: (1) planar proliferation determined by transepithelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC)-dextran permeability measurements, (2) real-time metabolic analyses, (3) measurements of the size and stiffness of 3D spheroids, and (4) mRNA expression of extracellular matrix (ECM) molecules and their modulators. RESULTS: LPA had no effect on TGF-β2-induced increase in the planar proliferation of HconF cells. LPA induced a more quiescent metabolic state in 2D HconF cells, but this metabolic suppression by LPA was partially blunted in the presence of TGF-β2. In contrast, LPA caused a substantial decrease in the hardness of 3D HconF spheroids independently of TGF-β2. In agreement with these different LPA-induced effects between 2D and 3D cultured HconF cells, mRNA expressions of ECM and their modulators were differently modulated. CONCLUSION: The findings that LPA induced the inhibition of both TGF-β2-related and -unrelated subepithelial proliferation of HconF cells may be clinically applicable.

    DOI: 10.3390/life14060770

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  • FABP4 Is an Indispensable Factor for Regulating Cellular Metabolic Functions of the Human Retinal Choroid. 国際誌

    Hiroshi Ohguro, Megumi Watanabe, Tatsuya Sato, Nami Nishikiori, Araya Umetsu, Megumi Higashide, Toshifumi Ogawa, Masato Furuhashi

    Bioengineering (Basel, Switzerland)   11 ( 6 )   2024年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The purpose of the current study was to elucidate the physiological roles of intraocularly present fatty acid-binding protein 4 (FABP4). Using four representative intraocular tissue-derived cell types, including human non-pigmented ciliary epithelium (HNPCE) cells, retinoblastoma (RB) cells, adult retinal pigment epithelial19 (ARPE19) cells and human ocular choroidal fibroblast (HOCF) cells, the intraocular origins of FABP4 were determined by qPCR analysis, and the intracellular functions of FABP4 were investigated by seahorse cellular metabolic measurements and RNA sequencing analysis using a specific inhibitor for FABP4, BMS309403. Among these four different cell types, FABP4 was exclusively expressed in HOCF cells. In HOCF cells, both mitochondrial and glycolytic functions were significantly decreased to trace levels by BMS309403 in a dose-dependent manner. In the RNA sequencing analysis, 67 substantially up-regulated and 94 significantly down-regulated differentially expressed genes (DEGs) were identified in HOCF cells treated with BMS309403 and those not treated with BMS309403. The results of Gene Ontology enrichment analysis and ingenuity pathway analysis (IPA) revealed that the DEGs were most likely involved in G-alpha (i) signaling, cAMP-response element-binding protein (CREB) signaling in neurons, the S100 family signaling pathway, visual phototransduction and adrenergic receptor signaling. Furthermore, upstream analysis using IPA suggested that NKX2-1 (thyroid transcription factor1), HOXA10 (homeobox A10), GATA2 (gata2 protein), and CCAAT enhancer-binding protein A (CEBPA) were upstream regulators and that NKX homeobox-1 (NKX2-1), SFRP1 (Secreted frizzled-related protein 1) and TREM2 (triggering receptor expressed on myeloid cells 2) were causal network master regulators. The findings in this study suggest that intraocularly present FABP4 originates from the ocular choroid and may be a critical regulator for the cellular homeostasis of non-adipocyte HOCF cells.

    DOI: 10.3390/bioengineering11060584

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  • TGF-β Isoforms and Local Environments Greatly Modulate Biological Nature of Human Retinal Pigment Epithelium Cells. 国際誌

    Nami Nishikiori, Tatsuya Sato, Toshifumi Ogawa, Megumi Higashide, Araya Umetsu, Soma Suzuki, Masato Furuhashi, Hiroshi Ohguro, Megumi Watanabe

    Bioengineering (Basel, Switzerland)   11 ( 6 )   2024年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To characterize transforming growth factor-β (TGF-β) isoform (TGF-β1~3)-b's biological effects on the human retinal pigment epithelium (RPE) under normoxia and hypoxia conditions, ARPE19 cells cultured by 2D (two-dimensional) and 3D (three-dimensional) conditions were subjected to various analyses, including (1) an analysis of barrier function by trans-epithelial electrical resistance (TEER) measurements; (2) qPCR analysis of major ECM molecules including collagen 1 (COL1), COL4, and COL6; α-smooth muscle actin (αSMA); hypoxia-inducible factor 1α (HIF1α); and peroxisome proliferator-activated receptor-gamma coactivator (PGC1α), a master regulator for mitochondrial respiration;, tight junction-related molecules, Zonula occludens-1 (ZO1) and E-cadherin; and vascular endothelial growth factor (VEGF); (3) physical property measurements of 3D spheroids; and (4) cellular metabolic analysis. Diverse effects among TGF-β isoforms were observed, and those effects were also different between normoxia and hypoxia conditions: (1) TGF-β1 and TGF-β3 caused a marked increase in TEER values, and TGF-β2 caused a substantial increase in TEER values under normoxia conditions and hypoxia conditions, respectively; (2) the results of qPCR analysis supported data obtained by TEER; (3) 3D spheroid sizes were decreased by TGF-β isoforms, among which TGF-β1 had the most potent effect under both oxygen conditions; (4) 3D spheroid stiffness was increased by TGF-β2 and TGF-β3 or by TGF-β1 and TGF-β3 under normoxia conditions and hypoxia conditions, respectively; and (5) the TGF-β isoform altered mitochondrial and glycolytic functions differently under oxygen conditions and/or culture conditions. These collective findings indicate that the TGF-β-induced biological effects of 2D and 3D cultures of ARPE19 cells were substantially diverse depending on the three TGF-β isoforms and oxygen levels, suggesting that pathological conditions including epithelial-mesenchymal transition (EMT) of the RPE may be exclusively modulated by both factors.

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  • The Specific ROCK2 Inhibitor KD025 Alleviates Glycolysis through Modulating STAT3-, CSTA- and S1PR3-Linked Signaling in Human Trabecular Meshwork Cells. 国際誌

    Megumi Watanabe, Tatsuya Sato, Araya Umetsu, Toshifumi Ogawa, Nami Nishikiori, Megumi Suzuki, Masato Furuhashi, Hiroshi Ohguro

    Biomedicines   12 ( 6 )   2024年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    To investigate the biological significance of Rho-associated coiled-coil-containing protein kinase (ROCK) 2 in the human trabecular meshwork (HTM), changes in both metabolic phenotype and gene expression patterns against a specific ROCK2 inhibitor KD025 were assessed in planar-cultured HTM cells. A seahorse real-time ATP rate assay revealed that administration of KD025 significantly suppressed glycolytic ATP production rate and increased mitochondrial ATP production rate in HTM cells. RNA sequencing analysis revealed that 380 down-regulated and 602 up-regulated differentially expressed genes (DEGs) were identified in HTM cells treated with KD025 compared with those that were untreated. Gene ontology analysis revealed that DEGs were more frequently related to the plasma membrane, extracellular components and integral cellular components among cellular components, and related to signaling receptor binding and activity and protein heterodimerization activity among molecular functions. Ingenuity Pathway Analysis (IPA) revealed that the detected DEGs were associated with basic cellular biological and physiological properties, including cellular movement, development, growth, proliferation, signaling and interaction, all of which are associated with cellular metabolism. Furthermore, the upstream regulator analysis and causal network analysis estimated IL-6, STAT3, CSTA and S1PR3 as possible regulators. Current findings herein indicate that ROCK2 mediates the IL-6/STAT3-, CSTA- and S1PR3-linked signaling related to basic biological activities such as glycolysis in HTM cells.

    DOI: 10.3390/biomedicines12061165

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  • Downregulation of Mitochondrial Fusion Protein Expression Affords Protection from Canonical Necroptosis in H9c2 Cardiomyoblasts. 国際誌

    Yuki Toda, Sang-Bing Ong, Toshiyuki Yano, Atsushi Kuno, Hidemichi Kouzu, Tatsuya Sato, Wataru Ohwada, Yuki Tatekoshi, Toshifumi Ogawa, Masaki Shimizu, Masaya Tanno, Masato Furuhashi

    International journal of molecular sciences   25 ( 5 )   2024年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Necroptosis, a form of necrosis, and alterations in mitochondrial dynamics, a coordinated process of mitochondrial fission and fusion, have been implicated in the pathogenesis of cardiovascular diseases. This study aimed to determine the role of mitochondrial morphology in canonical necroptosis induced by a combination of TNFα and zVAD (TNF/zVAD) in H9c2 cells, rat cardiomyoblasts. Time-course analyses of mitochondrial morphology showed that mitochondria were initially shortened after the addition of TNF/zVAD and then their length was restored, and the proportion of cells with elongated mitochondria at 12 h was larger in TNF/zVAD-treated cells than in non-treated cells (16.3 ± 0.9% vs. 8.0 ± 1.2%). The knockdown of dynamin-related protein 1 (Drp1) and fission 1, fission promoters, and treatment with Mdivi-1, a Drp-1 inhibitor, had no effect on TNF/zVAD-induced necroptosis. In contrast, TNF/zVAD-induced necroptosis was attenuated by the knockdown of mitofusin 1/2 (Mfn1/2) and optic atrophy-1 (Opa1), proteins that are indispensable for mitochondrial fusion, and the attenuation of necroptosis was not canceled by treatment with Mdivi-1. The expression of TGFβ-activated kinase (TAK1), a negative regulator of RIP1 activity, was upregulated and the TNF/zVAD-induced RIP1-Ser166 phosphorylation, an index of RIP1 activity, was mitigated by the knockdown of Mfn1/2 or Opa1. Pharmacological TAK1 inhibition attenuated the protection afforded by Mfn1/2 and Opa1 knockdown. In conclusion, the inhibition of mitochondrial fusion increases TAK1 expression, leading to the attenuation of canonical necroptosis through the suppression of RIP1 activity.

    DOI: 10.3390/ijms25052905

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  • ドキソルビシン誘発性心筋症の発症におけるMLKLの寄与(Contribution of MLKL to the Development of Doxorubicin-induced Cardiomyopathy)

    清水 将輝, 大和田 渉, 矢野 俊之, 神津 英至, 佐藤 達也, 長南 新太, 小川 俊史, 戸田 悠貴, 久野 篤史, 丹野 雅也, 古橋 眞人

    日本循環器学会学術集会抄録集   88回   PJ073 - 1   2024年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • 心筋細胞のネクロプトーシスにおけるミトコンドリア動態の影響(Impact of Mitochondrial Dynamics on Necroptosis in Cardiomyocytes)

    戸田 悠貴, 矢野 俊之, 久野 篤史, 丹野 雅也, 神津 英至, 佐藤 達也, 大和田 渉, 舘越 勇輝, 小川 俊史, 清水 将輝, 古橋 眞人

    日本循環器学会学術集会抄録集   88回   PJ080 - 3   2024年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

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  • High-intensity interval training using electrical stimulation ameliorates muscle fatigue in chronic kidney disease-related cachexia by restoring mitochondrial respiratory dysfunction. 国際誌

    Hiroyori Fusagawa, Tatsuya Sato, Takashi Yamada, Azuma Naito, Nao Tokuda, Nao Yamauchi, Nobutoshi Ichise, Toshifumi Ogawa, Takuro Karaushi, Atsushi Teramoto, Noritsugu Tohse

    Frontiers in physiology   15   1423504 - 1423504   2024年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Exercise, especially high-intensity interval training (HIIT), can increase mitochondrial respiratory capacity and enhance muscular endurance, but its systemic burden makes it difficult to safely and continuously prescribe for patients with chronic kidney disease (CKD)-related cachexia who are in poor general condition. In this study, we examined whether HIIT using electrical stimulation (ES), which does not require whole-body exercise, improves muscle endurance in the skeletal muscle of 5/6 nephrectomized rats, a widely used animal model for CKD-related cachexia. METHODS: Male Wistar rats (10 weeks old) were randomly assigned to a group of sham-operated (Sham) rats and a group of 5/6 nephrectomy (Nx) rats. HIIT was performed on plantar flexor muscles in vivo with supramaximal ES every other day for 4 weeks to assess muscle endurance, myosin heavy-chain isoforms, and mitochondrial respiratory function in Nx rats. A single session was also performed to identify upstream signaling pathways altered by HIIT using ES. RESULTS: In the non-trained plantar flexor muscles from Nx rats, the muscle endurance was significantly lower than that in plantar flexor muscles from Sham rats. The proportion of myosin heavy chain IIa/x, mitochondrial content, mitochondrial respiratory capacity, and formation of mitochondrial respiratory supercomplexes in the plantaris muscle were also significantly decreased in the non-trained plantar flexor muscles from Nx rats than compared to those in plantar flexor muscles from Sham rats. Treatment with HIIT using ES for Nx rats significantly improved these molecular and functional changes to the same degrees as those in Sham rats. Furthermore, a single session of HIIT with ES significantly increased the phosphorylation levels of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK), pathways that are essential for mitochondrial activation signaling by exercise, in the plantar muscles of both Nx and Sham rats. CONCLUSION: The findings suggest that HIIT using ES ameliorates muscle fatigue in Nx rats via restoration of mitochondrial respiratory dysfunction with activation of AMPK and p38 MAPK signaling. Our ES-based HIIT protocol can be performed without placing a burden on the whole body and be a promising intervention that is implemented even in conditions of reduced general performance status such as CKD-related cachexia.

    DOI: 10.3389/fphys.2024.1423504

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  • Predictive modeling for the development of diabetes mellitus using key factors in various machine learning approaches

    Marenao Tanaka, Yukinori Akiyama, Kazuma Mori, Itaru Hosaka, Kenichi Kato, Keisuke Endo, Toshifumi Ogawa, Tatsuya Sato, Toru Suzuki, Toshiyuki Yano, Hirofumi Ohnishi, Nagisa Hanawa, Masato Furuhashi

    Diabetes Epidemiology and Management   100191 - 100191   2023年12月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.deman.2023.100191

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  • Adenosine monophosphate deaminase in the endoplasmic reticulum-mitochondria interface promotes mitochondrial Ca2+ overload in type 2 diabetes rat hearts.

    Arata Osanami, Tatsuya Sato, Yuki Toda, Masaki Shimizu, Atsushi Kuno, Hidemichi Kouzu, Toshiyuki Yano, Wataru Ohwada, Toshifumi Ogawa, Tetsuji Miura, Masaya Tanno

    Journal of diabetes investigation   14 ( 4 )   560 - 569   2023年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    AIMS/INTRODUCTION: We previously showed that upregulation of myocardial adenosine monophosphate deaminase (AMPD) is associated with pressure overload-induced diastolic dysfunction in type 2 diabetes hearts. Here, we examined involvement of AMPD localized in the endoplasmic reticulum-mitochondria interface in mitochondrial Ca2+ overload and its pathological significance. MATERIALS AND METHODS: We used type 2 diabetes Otsuka Long-Evans Tokushima Fatty rats (OLETF) and non-diabetes Long-Evans Tokushima Otsuka Fatty rats (LETO) as well as AMPD3-overexpressing H9c2 cells and human embryonic kidney 293 cells. RESULTS: OLETF, but not LETO, showed diastolic dysfunction under the condition of phenylephrine-induced pressure overload. The levels of 90-kDa AMPD3 in outer mitochondrial membranes/endoplasmic reticulum and mitochondria-associated endoplasmic reticulum membrane (MAM) fractions were significantly higher in OLETF than in LETO. The area of the MAM quantified by electron microscopic analysis was 57% larger, mitochondrial Ca2+ level under the condition of pressure overload was 47% higher and Ca2+ retention capacity in MAM-containing crude mitochondria isolated before the pressure overloading was 21% lower in OLETF than in LETO (all P-values <0.05). Transfection of FLAG-AMPD3 in cells resulted in significant enlargement of the MAM area, and impairment in pyruvate/malate-driven adenosine triphosphate-stimulated and uncoupler-stimulated mitochondrial respiration compared with those in control cells. CONCLUSIONS: The findings suggest that 90-kDa AMPD3 localized in the endoplasmic reticulum-mitochondria interface promotes formation of the MAM, inducing mitochondrial Ca2+ overload and dysfunction in type 2 diabetes hearts.

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  • Nuclear translocation of MLKL enhances necroptosis by a RIP1/RIP3-independent mechanism in H9c2 cardiomyoblasts.

    Shoya Ino, Toshiyuki Yano, Atsushi Kuno, Masaya Tanno, Hidemichi Kouzu, Tatsuya Sato, Tomohisa Yamashita, Wataru Ohwada, Arata Osanami, Toshifumi Ogawa, Yuki Toda, Masaki Shimizu, Tetsuji Miura

    Journal of pharmacological sciences   151 ( 2 )   134 - 143   2023年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Accumulating evidence suggests that necroptosis of cardiomyocytes contributes to cardiovascular diseases. Lethal disruption of the plasma membrane in necroptosis is induced by oligomers of mixed lineage kinase domain-like (MLKL) that is translocated to the membrane from the cytosol. However, the role played by cytoplasmic-nuclear shuttling of MLKL is unclear. Here, we tested the hypothesis that translocation of MLKL to the nucleus promotes the necroptosis of cardiomyocytes. Activation of the canonical necroptotic signaling pathway by a combination of TNF-α and zVAD (TNF/zVAD) increased nuclear MLKL levels in a RIP1-activity-dependent manner in H9c2 cells, a rat cardiomyoblast cell line. By use of site-directed mutagenesis, we found a nuclear export signal sequence in MLKL and prepared its mutant (MLKL-L280/283/284A), though a search for a nuclear import signal was unsuccessful. MLKL-L280/283/284A localized to both the cytosol and the nucleus. Expression of MLKL-L280/283/284A induced necroptotic cell death, which was attenuated by GppNHp, an inhibitor of Ran-mediated nuclear import, but not by inhibition of RIP1 activity or knockdown of RIP3 expression. GppNHp partly suppressed H9c2 cell death induced by TNF/zVAD treatment. These results suggest that MLKL that is translocated to the nucleus via RIP1-mediated necroptotic signaling enhances the necroptosis of cardiomyocytes through a RIP1-/RIP3-independent mechanism.

    DOI: 10.1016/j.jphs.2022.12.009

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  • Downregulation of extramitochondrial BCKDH and its uncoupling from AMP deaminase in type 2 diabetic OLETF rat hearts. 国際誌

    Toshifumi Ogawa, Hidemichi Kouzu, Arata Osanami, Yuki Tatekoshi, Tatsuya Sato, Atsushi Kuno, Yugo Fujita, Shoya Ino, Masaki Shimizu, Yuki Toda, Wataru Ohwada, Toshiyuki Yano, Masaya Tanno, Takayuki Miki, Tetsuji Miura

    Physiological reports   11 ( 4 )   e15608   2023年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Systemic branched-chain amino acid (BCAA) metabolism is dysregulated in cardiometabolic diseases. We previously demonstrated that upregulated AMP deaminase 3 (AMPD3) impairs cardiac energetics in a rat model of obese type 2 diabetes, Otsuka Long-Evans-Tokushima fatty (OLETF). Here, we hypothesized that the cardiac BCAA levels and the activity of branched-chain α-keto acid dehydrogenase (BCKDH), a rate-limiting enzyme in BCAA metabolism, are altered by type 2 diabetes (T2DM), and that upregulated AMPD3 expression is involved in the alteration. Performing proteomic analysis combined with immunoblotting, we discovered that BCKDH localizes not only to mitochondria but also to the endoplasmic reticulum (ER), where it interacts with AMPD3. Knocking down AMPD3 in neonatal rat cardiomyocytes (NRCMs) increased BCKDH activity, suggesting that AMPD3 negatively regulates BCKDH. Compared with control rats (Long-Evans Tokushima Otsuka [LETO] rats), OLETF rats exhibited 49% higher cardiac BCAA levels and 49% lower BCKDH activity. In the cardiac ER of the OLETF rats, BCKDH-E1α subunit expression was downregulated, while AMPD3 expression was upregulated, resulting in an 80% lower AMPD3-E1α interaction compared to LETO rats. Knocking down E1α expression in NRCMs upregulated AMPD3 expression and recapitulated the imbalanced AMPD3-BCKDH expressions observed in OLETF rat hearts. E1α knockdown in NRCMs inhibited glucose oxidation in response to insulin, palmitate oxidation, and lipid droplet biogenesis under oleate loading. Collectively, these data revealed previously unrecognized extramitochondrial localization of BCKDH in the heart and its reciprocal regulation with AMPD3 and imbalanced AMPD3-BCKDH interactions in OLETF. Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy.

    DOI: 10.14814/phy2.15608

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  • Abrupt Onset of Cardiac Tamponade in Sarcoidosis.

    Toshiyuki Yano, Shin Hisahara, Nobutaka Nagano, Takahiro Noto, Toshifumi Ogawa, Ryo Nishikawa, Masayuki Koyama, Hidemichi Kouzu, Atsuko Muranaka, Akiyoshi Hashimoto, Shun Shimohama, Tetsuji Miura

    International heart journal   62 ( 5 )   1176 - 1181   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sarcoidosis is a systemic inflammatory disease characterized by the formation of noncaseating epithelioid granulomas. Multiple organs, including the lung, eyes, and skin, are involved in this disorder, and cardiac involvement is a major cause of morbidity and mortality in patients with this disorder. We present the case history of a 22-year-old man with neurosarcoidosis complicated by abrupt onset of cardiac tamponade. Cardiac tamponade is a rare but potentially fatal manifestation of sarcoidosis, which is treatable with glucocorticoid therapy. Including the present case, previously reported cases of sarcoidosis with cardiac tamponade are reviewed to delineate its clinical characteristics.

    DOI: 10.1536/ihj.21-167

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  • Xanthine oxidoreductase-mediated injury is amplified by upregulated AMP deaminase in type 2 diabetic rat hearts under the condition of pressure overload. 国際誌

    Yusuke Igaki, Masaya Tanno, Tatsuya Sato, Hidemichi Kouzu, Toshifumi Ogawa, Arata Osanami, Toshiyuki Yano, Atsushi Kuno, Takayuki Miki, Takashi Nakamura, Tetsuji Miura

    Journal of molecular and cellular cardiology   154   21 - 31   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: We previously reported that upregulated AMP deaminase (AMPD) contributes to diastolic ventricular dysfunction via depletion of the adenine nucleotide pool in a rat model of type 2 diabetes (T2DM), Otsuka Long-Evans-Tokushima Fatty rats (OLETF). Meanwhile, AMPD promotes the formation of substrates of xanthine oxidoreductase (XOR), which produces ROS as a byproduct. Here, we tested the hypothesis that a functional link between upregulated AMPD and XOR is involved in ventricular dysfunction in T2DM rats. METHODS AND RESULTS: Pressure-volume loop analysis revealed that pressure overloading by phenylephrine infusion induced severer left ventricular diastolic dysfunction (tau: 14.7 ± 0.8 vs 12.5 ± 0.7 msec, left ventricular end-diastolic pressure: 18.3 ± 1.5 vs 12.2 ± 1.3 mmHg, p < 0.05) and ventricular-arterial uncoupling in OLETF than in LETO, non-diabetic rats, though the baseline parameters were comparable in the two groups. While the pressure overload did not affect AMPD activity, it increased XOR activity both in OLETF and LETO, with OLETF showing significantly higher XOR activity than that in LETO (347.2 ± 17.9 vs 243.2 ± 6.1 μg/min/mg). Under the condition of pressure overload, myocardial ATP level was lower, and levels of xanthine and uric acid were higher in OLETF than in LETO. Addition of exogenous inosine, a product of AMP deamination, to the heart homogenates augmented XOR activity. OLETF showed 68% higher tissue ROS levels and 47% reduction in mitochondrial state 3 respiration compared with those in LETO. Overexpression of AMPD3 in H9c2 cells elevated levels of hypoxanthine and ROS and reduced the level of ATP. Inhibition of XOR suppressed the production of tissue ROS and mitochondrial dysfunction and improved ventricular function under the condition of pressure overload in OLETF. CONCLUSIONS: The results suggest that increases in the activity of XOR and the formation of XOR substrates by upregulated AMPD contribute to ROS-mediated diastolic ventricular dysfunction at the time of increased cardiac workload in diabetic hearts.

    DOI: 10.1016/j.yjmcc.2021.01.002

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  • Postpartum Heart Failure Complicated With Thyroiditis: A Concealed Aggravator of Peripartum Cardiomyopathy? 国際誌

    Hidemichi Kouzu, Toshiyuki Yano, Nobutaka Nagano, Masayuki Koyama, Toshifumi Ogawa, Yugo Fujita, Atsuko Muranaka, Tetsuji Miura

    The Canadian journal of cardiology   35 ( 6 )   796.e1-796.e3   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The etiology of peripartum cardiomyopathy (PPCM) remains unestablished, but the involvement of abnormal autoimmunity has been suggested. We report a case of PPCM that was triggered by postpartum thyroiditis. Despite the presence of myocardial damage indicated by cardiac magnetic resonance imaging, the patient's cardiac function completely recovered with the addition of bromocriptine to standard therapies. We discuss the role of thyroid hormones in the development of PPCM through aggravation of a prolactin-dependent antiangiogenic effect, and we argue that more attention should be paid to postpartum thyroiditis as a novel risk factor for PPCM.

    DOI: 10.1016/j.cjca.2019.03.013

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  • Successful Transcatheter Diagnosis and Medical Treatment of Right Atrial Involvement in IgG4-related Disease.

    Toshiyuki Yano, Motohisa Yamamoto, Atsushi Mochizuki, Toshifumi Ogawa, Nobutaka Nagano, Takefumi Fujito, Junichi Nishida, Daigo Nagahara, Koki Abe, Takayuki Miki, Chisako Suzuki, Hiroki Takahashi, Hatsue Ishibashi-Ueda, Tetsuji Miura

    International heart journal   59 ( 5 )   1155 - 1160   2018年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    IgG4-related disease (IgG4-RD) is a fibro-inflammatory disorder characterized by lymphoplasmacytic infiltration of numerous IgG4-positive plasma cells, leading to fibrous thickening in the affected tissue. Typical cardiovascular manifestations of IgG4-RD are periaortitis, coronary arteritis, and pericarditis. Rare cases of myocardial involvement in IgG4-RD have been reported, but surgical resection or open biopsy was required for the diagnosis in those cases. Here, we report a case in which percutaneous transcatheter biopsy under the guidance of intracardiac echocardiography was useful for diagnosis of IgG4-RD manifested as an intracavitary right atrial mass, extending into the superior vena cava. Successful transcatheter diagnosis of myocardial involvement of IgG4-RD led to immediate favorable response to steroid therapy. Including the present case, previous IgG4-RD cases with myocardial involvement are reviewed to delineate its clinical characteristics.

    DOI: 10.1536/ihj.17-467

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MISC

  • 腹腔鏡下胃スリーブ状切除術によりインスリン抵抗性-インスリン必要量増加-体重増加の悪循環を脱し、肥満関連合併症の改善が得られた1例

    小川 俊史, 佐藤 達也, 大久保 武志, 寺沢 誠, 中田 圭, 隅田 健太郎, 神津 英至, 矢野 俊之, 矢島 諒人, 伊東 竜哉, 竹政 伊知朗, 古橋 眞人

    日本内分泌学会雑誌   100 ( 4 )   805 - 805   2024年12月

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    記述言語:日本語   出版者・発行元:(一社)日本内分泌学会  

    医中誌

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  • セマグルチド注射薬により20年間のインスリン強化療法から離脱できた2型糖尿病の1例

    寺沢 誠, 中田 圭, 大久保 武志, 小川 俊史, 隅田 健太郎, 佐藤 達也, 神津 英至, 矢野 俊之, 古橋 眞人

    糖尿病   67 ( 12 )   511 - 511   2024年12月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

    医中誌

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  • Impact of Mitochondrial Dynamics on Necroptosis in Cardiomyocytes(タイトル和訳中)

    戸田 悠貴, 矢野 俊之, 久野 篤史, 丹野 雅也, 神津 英至, 佐藤 達也, 大和田 渉, 舘越 勇輝, 小川 俊史, 清水 将輝, 古橋 眞人

    日本循環器学会学術集会抄録集   88回   PJ080 - 3   2024年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

    医中誌

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  • Contribution of MLKL to the Development of Doxorubicin-induced Cardiomyopathy(タイトル和訳中)

    清水 将輝, 大和田 渉, 矢野 俊之, 神津 英至, 佐藤 達也, 長南 新太, 小川 俊史, 戸田 悠貴, 久野 篤史, 丹野 雅也, 古橋 眞人

    日本循環器学会学術集会抄録集   88回   PJ073 - 1   2024年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

    医中誌

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  • 中枢性尿崩症合併糖尿病患者に対するSGLT2阻害薬+経口GLP1製剤による治療の1例

    中田 圭, 佐藤 達也, 小川 俊史, 大和田 渉, 隅田 健太郎, 神津 英至, 矢野 俊之, 古橋 眞人

    糖尿病   67 ( 1 )   40 - 40   2024年1月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

    医中誌

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  • 肥満減量術後慢性期の血糖コントロール悪化にセマグルチドが著効した2型糖尿病の症例

    赤澤 史子, 小川 俊史, 中田 圭, 佐藤 達也, 伊東 竜哉, 竹政 伊知朗, 古橋 眞人

    糖尿病   67 ( 1 )   37 - 37   2024年1月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

    医中誌

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  • チルゼパチドが著効した後腹膜滑膜肉腫合併の若年肥満2型糖尿病の症例

    大久保 武志, 佐藤 達也, 小川 俊史, 中田 圭, 大和田 渉, 隅田 健太郎, 神津 英至, 矢野 俊之, 古橋 眞人

    糖尿病   67 ( 1 )   38 - 38   2024年1月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

    医中誌

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  • 末梢性疲労モデルラットと中枢性疲労モデルラットにおける鉄代謝の特徴の検討

    唐牛拓郎, 佐藤達也, 一瀬信敏, 房川祐頼, 小川俊史, 當瀬規嗣

    日本疲労学会誌   20 ( 1 )   2024年

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  • 腹部大動脈瘤拡大因子としての瘤壁三次リンパ組織形成および濾胞関連新規リンパ球サブセットの解明

    保坂到, 池上一平, 三上拓真, 佐藤達也, 小川俊文, 武川慶, 田中希尚, 遠藤圭佑, 秋山幸功, 大川陽史, 仲澤順二, 柴田豪, 中島智博, 伊庭裕, 高野賢一, 一宮慎吾, 川原田修義, 古橋眞人

    脈管学(Web)   64 ( Supplement )   2024年

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  • Graph based clusteringを用いた腹部大動脈瘤拡大因子としての濾胞関連新規リンパ球サブセットの同定と機能的意義の解明

    保坂到, 池上一平, 三上拓真, 佐藤達也, 小川俊文, 田中希尚, 遠藤圭佑, 秋山幸功, 大川陽史, 仲澤順二, 柴田豪, 中島智博, 伊庭裕, 高野賢一, 一宮慎吾, 川原田修義, 古橋眞人

    脈管学(Web)   64 ( Supplement )   2024年

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  • 日本人2型糖尿病患者においてペマフィブラートの12ヵ月投与が血中脂質と脂肪肝指数に与える影響の検討

    鈴木亨, 鈴木亨, 佐藤達也, 佐藤達也, 田中希尚, 田中希尚, 遠藤圭佑, 中田圭, 小川俊史, 小川俊史, 保坂致, 秋山幸功, 梅津新矢

    日本動脈硬化学会総会・学術集会プログラム・抄録集(Web)   56th   2024年

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  • 心臓血管外科における未来医療を目指して:予測医学・シミュレーションを用いたPrecision medicine Random survival forest法を用いた機械学習による術後予後予測の有用性に関する検討 生存時間解析における古典的Cox比例ハザードモデルとの比較と課題

    保坂 到, 田中 希尚, 秋山 幸功, 佐藤 亮太, 森 和真, 小川 俊史, 梅津 新矢, 遠藤 圭佑, 三上 拓真, 佐藤 達也, 梅田 璃子, 宇塚 武司, 古橋 眞人, 川原田 修義

    日本胸部外科学会定期学術集会   76回   CSY3 - 4   2023年10月

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    記述言語:日本語   出版者・発行元:(一社)日本胸部外科学会  

    医中誌

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  • Fatty Liver Indexを用いて高血圧発症を予測する機械学習モデルの構築

    田中 希尚, 秋山 幸功, 佐藤 亮太, 保坂 到, 三上 拓真, 遠藤 圭佑, 梅津 新矢, 小川 俊史, 森 和真, 佐藤 達也, 塙 なぎさ, 古橋 眞人

    日本高血圧学会総会プログラム・抄録集   45回   391 - 391   2023年9月

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    記述言語:日本語   出版者・発行元:(NPO)日本高血圧学会  

    医中誌

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  • BCKDH活性のダウンレギュレーションとAMPデアミナーゼとのアンカップリングが2型糖尿病性心臓における基質柔軟性の欠如を引き起こす(Downregulation of BCKDH Activity and Uncoupling from AMP Deaminase Underlie Substrate Inflexibility in Type 2 Diabetic Hearts)

    小川 俊史, 神津 英至, 長南 新太, 清水 将輝, 戸田 悠貴, 大和田 渉, 佐藤 達也, 矢野 俊之, 久野 篤史, 丹野 雅也, 三浦 哲嗣, 古橋 眞人

    日本循環器学会学術集会抄録集   87回   OJ03 - 2   2023年3月

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    記述言語:英語   出版者・発行元:(一社)日本循環器学会  

    医中誌

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  • 非弁膜症性心房細動患者における抗凝固薬(DOAC)の適正使用に対する薬学的介入効果の検討

    安田 祐也, 長谷川 功, 一村 真希, 小川 俊史, 大沼 義人, 吉岡 拓司, 冨樫 信彦, 長谷川 徹, 吉田 英昭

    日本腎臓病薬物療法学会誌   11 ( 特別号 )   S185 - S185   2022年10月

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    記述言語:日本語   出版者・発行元:日本腎臓病薬物療法学会  

    医中誌

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  • AMPデアミナーゼの役割 2型糖尿病合併心不全の新しい治療標的

    丹野 雅也, 長南 新太, 小川 俊史, 神津 英至

    BIO Clinica   37 ( 10 )   940 - 945   2022年9月

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    記述言語:日本語   出版者・発行元:(株)北隆館  

    医中誌

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  • 糖尿病性心筋症におけるAMPデアミナーゼの役割

    丹野 雅也, 長南 新太, 小川 俊史, 神津 英至

    BIO Clinica   36 ( 8 )   762 - 767   2021年7月

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    記述言語:日本語   出版者・発行元:(株)北隆館  

    医中誌

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  • 非専門医の外来診療における慢性合併症評価率の年次変化

    小川 俊史, 佐藤 達也, 三木 隆幸, 東浦 幸村, 伊野 祥哉, 矢野 俊之, 古橋 眞人, 神津 英至, 丹野 雅也, 斎藤 重幸, 三浦 哲嗣

    糖尿病   63 ( Suppl.1 )   S - 204   2020年8月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

    医中誌

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  • 糖尿病外来診療における慢性合併症評価の実態調査

    小川 俊史, 佐藤 達也, 東浦 幸村, 伊野 祥哉, 矢野 俊之, 古橋 眞人, 丹野 雅也, 三木 隆幸, 斎藤 重幸, 三浦 哲嗣

    糖尿病   63 ( 5 )   356 - 356   2020年5月

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    記述言語:日本語   出版者・発行元:(一社)日本糖尿病学会  

    医中誌

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  • SDB治療フロンティア 陽圧換気療法の新展開(第9回) 睡眠呼吸障害と血糖変動

    中田 圭, 小川 俊史

    睡眠医療   12 ( 3 )   409 - 417   2018年9月

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    記述言語:日本語   出版者・発行元:(株)ライフ・サイエンス  

    医中誌

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  • 高度腎機能障害で発症したが自然軽快したTINU症候群の一例

    小川 俊史, 山下 智久, 田中 希尚, 茂庭 仁人, 古橋 眞人, 小川 弥生, 三浦 哲嗣

    日本腎臓学会誌   59 ( 6 )   895 - 895   2017年9月

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    記述言語:日本語   出版者・発行元:(一社)日本腎臓学会  

    医中誌

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  • 急激に進行し経過不良であった再発粘液性境界悪性卵巣腫瘍の一例

    小川 俊史, 郷久 晴朗, 岩崎 雅宏, 田中 綾一, 寺本 瑞絵, 竹浪 奈穂子, 伊坂 五沙, 齋藤 豪

    北日本産科婦人科学会総会・学術講演会プログラム・抄録集   63回   58 - 58   2015年9月

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    記述言語:日本語   出版者・発行元:東北連合産科婦人科学会・北日本産科婦人科学会  

    医中誌

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▼全件表示

共同研究・競争的資金等の研究課題

  • 心血管・腎・代謝 (CKM) 症候群の病態基盤における脂肪性肝疾患のフェロトーシスの役割

    研究課題/領域番号:25K11392  2025年4月 - 2028年3月

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    佐藤達也, 渡部恵, 一瀬信敏, 小川俊史

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  • AMPデアミナーゼを介する代謝の再配線に着目したサルコペニアの病態の解明

    研究課題/領域番号:24K19004  2024年4月 - 2027年3月

    日本学術振興会  科学研究費助成事業  若手研究

    小川 俊史

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    配分額:4550000円 ( 直接経費:3500000円 、 間接経費:1050000円 )

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