Research Experience 【 display / non-display 】

Research Experience 【 display / non-display 】

• 2022.09

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  Sapporo Medical University   Department of Cardiovascular, Renal and Metabolic Medicine   Professor

Professional Memberships 【 display / non-display 】

Professional Memberships 【 display / non-display 】

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  THE JAPANESE CIRCULATION SOCIETY

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  日本動脈硬化学会

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  日本分子生物学会

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  THE JAPANESE SOCIETY OF INTERNAL MEDICINE

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  日本心臓病学会

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Research Areas 【 display / non-display 】

Research Areas 【 display / non-display 】

• Life sciences   Cardiology  

• Life sciences   Metabolism and endocrinology  

Affiliation 【 display / non-display 】

Affiliation 【 display / non-display 】

• Sapporo Medical University   Department of Cardiovascular, Renal and Metabolic Medicine   Professor  

Research Interests 【 display / non-display 】

Research Interests 【 display / non-display 】

• 慢性炎症

• 耐糖能異常

• Adipokine

• 動脈硬化

• 糖尿病

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Papers 【 display / non-display 】

Papers 【 display / non-display 】

• Associations between in‐hospital daily protein intake and adverse clinical outcomes in older patients with heart failure

  Satoshi Katano, Toshiyuki Yano, Kotaro Yamano, Ryo Numazawa, Ryohei Nagaoka, Suguru Honma, Yusuke Fujisawa, Katsuhiko Ohori, Hidemichi Kouzu, Hayato Kunihara, Hiroya Fujisaki, Masaki Katayose, Akiyoshi Hashimoto, Masato Furuhashi

  ESC Heart Failure ( Wiley )   2024.05

  　View Summary

  Abstract Aims The adverse effects of low daily protein intake (DPI) on clinical outcomes in patients with heart failure (HF) are known; however, an optimal DPI to predict event adverse outcomes remains undetermined. Moreover, whether protein restriction therapy for chronic kidney disease is applicable in patients with HF and renal dysfunction remains unclear. Methods and results In this single‐centre, ambispective cohort study, we included 405 patients with HF aged ≥65 years (mean age, 78.6 ± 7.5 years; 50% women). DPI was estimated from consumption over three consecutive days before discharge and normalized relative to the ideal body weight [IBW, 22 kg/m² × height (m)²]. The primary outcome was a composite of all‐cause mortality and HF‐related readmission within the 2 year post‐discharge period. Results During an average follow‐up period of 1.49 ± 0.74 years, 100 patients experienced composite events. Kaplan–Meier survival curves revealed a significantly lower composite event‐free rate in patients within the lowest quartile of DPI than in the upper quartiles (log‐rank test, P = 0.02). A multivariate Cox proportional hazards analysis after adjusting for established prognostic markers and non‐proteogenic energy intake revealed that patients in the lowest DPI quartile faced a two‐fold higher risk of composite events than those in the highest quartile [hazard ratio (HR), 2.03; 95% confidence interval (CI), 1.08–3.82; P = 0.03]. The composite event risk linearly increased as DPI decreased (P for nonlinearity = 0.90), with each standard deviation (0.26 g/kg IBW/day) decrease in DPI associated with a 32% increase in composite event risk (HR, 1.32; 95% CI, 1.10–1.71; P = 0.04). There was significant heterogeneity in the effect of DPI, with the possible disadvantage of lower DPI in patients with HF with cystatin C‐based estimated glomerular filtration rate <30 mL/min/1.73 m². The cutoff value of DPI for predicting the occurrence of composite events calculated from the Youden index was 1.12 g/kg IBW/day. Incorporating a DPI < 1.12 g/kg IBW/day into the baseline model significantly improved the prediction of post‐discharge composite events (continuous net reclassification improvement, 0.294; 95% CI, 0.072–0.516; P = 0.01). Conclusions Lower DPI during hospitalization is associated with an increased risk of mortality and HF readmission independent of non‐proteogenic energy intake, and the possible optimal DPI for predicting adverse clinical outcomes is >1.12 g/kg IBW/day in older patients with HF. Caution is warranted when protein restriction therapy is administered to older patients with HF and renal dysfunction.

  DOI

• Deciphering metabolic dysfunction-associated steatotic liver disease: insights from predictive modeling and clustering analysis.

  Kazuma Mori, Yukinori Akiyama, Marenao Tanaka, Tatsuya Sato, Keisuke Endo, Itaru Hosaka, Nagisa Hanawa, Naoya Sakamoto, Masato Furuhashi

  Journal of gastroenterology and hepatology    2024.04  [International journal]

  　View Summary

  BACKGROUND AND AIM: 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 investigated clustering analyses to decipher the complex landscape of SLD pathologies including the former nomenclature of nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: Japanese individuals who received annual health checkups including abdominal ultrasonography (n = 15 788, men/women: 10 250/5538, mean age: 49 years) were recruited. RESULTS: The numbers of individuals with SLD, MASLD, MetALD, ALD, NAFLD, and MAFLD were 5603 (35.5%), 4227 (26.8%), 795 (5.0%), 324 (2.1%), 3982 (25.8%), and 4946 (31.3%), respectively. Clustering analyses using t-distributed stochastic neighbor embedding and K-means to visually represent interconnections in SLDs uncovered five cluster formations. MASLD and NAFLD mainly shared three clusters including (i) low alcohol intake with relatively low-grade obesity; (ii) obesity with dyslipidemia; and (iii) dysfunction of glucose metabolism. Both MetALD and ALD displayed one distinct cluster intertwined with alcohol consumption. MAFLD widely shared all of the five clusters. In machine learning-based analyses using algorithms of random forest and extreme gradient boosting and receiver operating characteristic curve analyses, fatty liver index (FLI), calculated by body mass index, waist circumference, and levels of γ-glutamyl transferase and triglycerides, was selected as a useful feature for SLDs. CONCLUSIONS: The new nomenclature of SLDs is useful for obtaining a better understanding of liver pathologies and for providing valuable insights into predictive factors and the dynamic interplay of diseases. FLI may be a noninvasive predictive marker for detection of SLDs.

  DOI PubMed

• Which came first: Sarcopenia or weight loss?

  Katsuhiko Ohori, Toshiyuki Yano, Satoshi Katano, Ryohei Nagaoka, Ryo Numazawa, Kotaro Yamano, Yusuke Fujisawa, Hidemichi Kouzu, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Wataru Ohwada, Masato Furuhashi

  Geriatrics &amp; Gerontology International ( Wiley )   2024.04

  DOI

• Differential Effects of Benzalkonium Chloride on Human Trabecular Meshwork Cells Not Treated or Treated with Transforming Growth Factor-β2 or Dexamethasone.

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

  Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics    2024.03  [International journal]

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  Purpose: The objective of the present study was to evaluate the effects of low concentrations of benzalkonium chloride (BAC) (10-7%, 10-6%, or 10-5%) on healthy and glaucomatous human trabecular meshwork (HTM) cells. For this purpose, we used in vitro models replicating a healthy HTM and HTM with primary open-angle glaucoma (POAG) or steroid-induced glaucoma (SG) using two-dimensional (2D) cultures of HTM cells not treated or treated with a 5 ng/mL solution of transforming growth factor-β2 or 250 nM dexamethasone (DEX). Methods: Analyses were carried out for (1) the intercellular affinity function of 2D HTM monolayers, as determined by transepithelial electrical resistance (TEER) measurements; (2) cell viability; (3) cellular metabolism by using a Seahorse bioanalyzer; and (4) expression of extracellular matrix (ECM) molecules, an ECM modulator, and cell junction-related molecules. Results: In the absence and presence of BAC (10-7% or 10-5%), intercellular affinity function determined by TEER and cellular metabolic activities were significantly and dose dependently affected in both healthy and glaucomatous HTM cells despite the fact that there was no significant decrease in cell viabilities. However, the effects based on TEER values were significantly greater in the healthy HTM. The mRNA expression of several molecules that were tested was not substantially modulated by these concentrations of BAC. Conclusions: The findings reported herein suggest that low concentrations of BAC may have unfavorable adverse effects on cellular metabolic capacity by inducing increases in the intercellular affinity properties of the HTM, but those effects of BAC were different in healthy and glaucomatous HTM cells.

  DOI PubMed

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

  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 ( MDPI AG )  25 ( 5 ) 2905 - 2905  2024.03

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  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

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Misc 【 display / non-display 】

Misc 【 display / non-display 】

• CKD発症予測におけるfatty liver indexの意義

  高橋 聖子, 田中 希尚, 古橋 眞人, 長南 新太, 宮森 大輔, 後町 結, 塙 なぎさ, 茂庭 仁人, 大西 浩文, 三浦 哲嗣

  日本腎臓学会誌 ( (一社)日本腎臓学会 )  63 ( 4 ) 453 - 453  2021.06

• CKDモデルの造影剤腎症におけるネクロプトーシスの役割

  柴田 智, 茂庭 仁人, 木村 歩, 後町 結, 田中 希尚, 古橋 眞人, 三浦 哲嗣

  日本腎臓学会誌 ( (一社)日本腎臓学会 )  63 ( 4 ) 447 - 447  2021.06

• 血液透析患者におけるビタミンDの季節変動に関する検討

  田中 希尚, 後町 結, 菅原 浩仁, 茂庭 仁人, 山下 智久, 古橋 眞人, 滝沢 英毅, 向 博也, 大野 紘平, 三浦 哲嗣

  日本透析医学会雑誌 ( (一社)日本透析医学会 )  54 ( Suppl.1 ) 379 - 379  2021.05

• 経口ブドウ糖負荷試験で診断し得た機能性低血糖症の1例

  寺沢 誠, 長南 新太, 佐藤 達也, 原田 なお, 川原田 航, 箱崎 頌平, 後町 結, 茂庭 仁人, 矢野 俊之, 古橋 眞人, 丹野 雅也, 三浦 哲嗣

  日本内分泌学会雑誌 ( (一社)日本内分泌学会 )  96 ( 3 ) 596 - 596  2021.01

• PGI2製剤使用中に甲状腺機能亢進症を合併し治療に難渋した特発性肺動脈性肺高血圧症例

  土田 輝, 小山 雅之, 大和田 渉, 西川 諒, 永野 伸卓, 神津 英至, 村中 敦子, 矢野 俊之, 古橋 眞人, 橋本 暁佳, 櫻井 晃洋, 三浦 哲嗣

  日本内分泌学会雑誌 ( (一社)日本内分泌学会 )  96 ( 3 ) 595 - 595  2021.01

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Awards 【 display / non-display 】

Awards 【 display / non-display 】

• 五島雄一郎賞

  2018   第50回日本動脈硬化学会  

  Winner： 古橋 眞人

• 学術奨励賞

  2014   第35回日本肥満学会  

  Winner： 古橋眞人

• 学術賞

  2013   第36回日本高血圧学会  

  Winner： 古橋眞人

• 高峰譲吉研究奨励賞

  2012   第16回日本心血管内分泌代謝学会  

  Winner： 古橋眞人

• Scholarship Award.

  2008   Keystone Symposia. Molecular Control of Adipogenesis and Obesity.  

  Winner： 古橋眞人

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Research Projects 【 display / non-display 】

Research Projects 【 display / non-display 】

• 脂質シャペロンと代謝性脂肪肝疾患が関わる腎臓病発症機序の解明

  基盤研究(C)

  Project Year :

  2022.04

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  2025.03

   

  田中 希尚, 古橋 眞人

• The association of PCSK7 with coronary calcification

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2020.04

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  2024.03

   

  片岡 有, 古橋 眞人, 小倉 正恒

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  心筋梗塞の原因となる冠動脈石灰化の特徴を解析し、論文報告した。 Atherosclerosis. 2021 Feb;318:70-75. 675例の心筋梗塞症例を解析した。 心筋梗塞を引き起こす冠動脈石灰化は、心臓死や再狭窄、心筋梗塞再発リスクが高いことを報告した。 JACC Case Rep. 2020 Sep 2;2(12):1872-1878.

• Elucidation of intracellular actions of fatty acid-binding protein family and application to clinical therapies

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2020.04

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  2023.03

   

  古橋 眞人

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  1.ヒト脂肪組織由来幹細胞にリコンビナントFABP4を外因性に投与し、RNA-seqを行った。蛋白~蛋白相互作用カスケード解析から様々な転写因子および 各種キナーゼとの相互作用が認められた。 2.ヒト脂肪組織由来幹細胞にリコンビナントFABP4を外因性に投与し、CE-TOFMSおよびLC-TOFMSを用いてメタボローム解析を行った。FABP4の外因性投与により、 様々な細胞内メタボライトの変化が認められ、FABP4が脂肪細胞由来の生理活性物質であるアディポカインとして働くことが確認された。 3.リコンビナントFABP4に対する各種脂肪酸(パルミチン酸、パルミトレイン酸、ステアリン酸、オレイン酸、リノール酸、αリノレイン酸、アラキドン酸、エ イコサペンタエン酸、ドコサヘキサエン酸)に対する脂肪酸結合親和性を1-anilinonapthalene 8-sulfonic acid (1,8 ANS)を用いて行ったところ、通常状態で は脂肪酸結合親和性は必須脂肪酸で、多価不飽和脂肪酸であるリノール酸やαリノレイン酸に親和性が高く、飽和脂肪酸であるパルミチン酸とは親和性が低かった。また、酸化ストレスを模倣するフリーラジカルジェネレーターである2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH)の存在下ではパルミチン酸 以外の脂肪酸はKd値が上昇し、親和性が相対的に低くなったが、パルミチン酸とのKd値は変化がなかった。 4. リコンビナントFABP4を各種細胞に投与して、炎症関連分子の変化を確認した。 5.疫学調査 (端野・壮瞥町研究) でFABP4濃度を測定し、12年間のフォロー期間中の心血管死と関連することを見出した。 6.ヒトの心臓手術時に採取した心外膜脂肪組織や血管周囲脂肪組織の検討からFABP4の発現を確認した。

• Elucidation of underlying mechanism of the onset and renal deterioration of kidney disease contributed by lipid chaperones

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2019.04

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  2022.03

   

  Marenao Tanaka

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  In a renal biopsy cohort, urinary FABP4 excretion was associated with renal function, urinary protein levels and deterioration of renal function after 1 year. In a general population cohort, a high LDL-cholesterol level was negatively associated with change in eGFR during 10-year follow-up period and was a risk factor for the development of CKD in males. In IgA nephropathy and gddY, a IgAN-prone mouse model, expression of FABP4 was ectopically induced by glomerular injury in cells of the glomerulus including glomerular endothelial cells and macrophages, and the extent of glomerular FABP4 expression was associated with proteinuria and renal dysfunction. Expression of ER stress markers were present on the cells in glomerulus in IgAN and in gddY. In human renal glomerular endothelial cells, FABP4 was induced by treatment with VEGF and was secreted from cells. Treatment of podocytes with FABP4 significantly increased gene expression of inflammatory cytokines and ER stress markers.

• Elucidation of ectopic expression of fatty acid-binding protein 4 in endovascular injury and application to clinical therapies

  Grant-in-Aid for Scientific Research (C)

  Project Year :

  2017.04

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  2020.03

   

  Furuhashi Masato

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  Fatty acid-binding protein 4 (FABP4) is expressed in adipocytes and macrophages and plays significant roles in the development of insulin resistance and atherosclerosis. The present study demonstrated that FABP4 was ectopically induced in endothelial cells by cellular senescence and vascular injury. Furthermore, secreted FABP4 from injured vascular endothelial cells promoted inflammatory response in several cells, proliferation and migration in vascular smooth muscle cells, and endothelial dysfunction in vascular endothelial cells, leading to the development of neointima formation after vascular injury.

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