KUNO Atsushi

写真a

Affiliation

School of Medicine, Department of Pharmacology

Job title

Professor
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Degree 【 display / non-display 】

  • 札幌医科大学   医学博士

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Professional Memberships 【 display / non-display 】

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    THE JAPANESE PHARMACOLOGICAL SOCIETY

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    THE MOLECULAR BIOLOGY SOCIETY OF JAPAN

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    米国心臓協会

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    国際心臓研究学会

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    THE JAPANESE SOCIETY OF INTERNAL MEDICINE

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Research Areas 【 display / non-display 】

  • Life sciences   Pharmacology  

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Affiliation 【 display / non-display 】

  • Sapporo Medical University   医学部薬理学講座   教授  

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Papers 【 display / non-display 】

  • Mapping research trends in obsessive-compulsive disorder before and after the COVID-19 pandemic: a bibliometric analysis focusing on its molecular mechanisms.

    Yuito Inoue, Nobutoshi Ichise, Wataru Ukai, Jun Shinozaki, Toshifumi Ogawa, Takuro Karaushi, Marenao Tanaka, Yukinori Akiyama, Masato Furuhashi, Atsushi Kuno, Tatsuya Sato

    Frontiers in psychiatry   16   1615497 - 1615497  2025  [Refereed]  [International journal]

    　View Summary

    Obsessive-compulsive disorder (OCD) is a psychiatric disorder that primarily develops during adolescence, and is characterized by obsessive thoughts and compulsive behaviors. Although multiple factors including heredity, environment, and abnormalities in neural networks and synapses are involved in the onset and exacerbation of OCD, their underlying molecular mechanisms have not been fully elucidated. In addition, recent studies have demonstrated that the novel coronavirus disease (COVID-19) pandemic worsened OCD phenotypes. Hence, this global crisis may have changed the field of molecular-focused OCD research. We conducted a brief bibliometric analysis to investigate changes in prevalent topics in molecular-focused OCD research before (2015-2019) and after (2020-2025) the COVID-19 pandemic using Web of Science and VOSviewer. "Schizophrenia" and "metaanalysis" remained highly ranked terms in molecular-focused OCD research. In terms of neurotransmitters, the term "serotonin" became more prevalent than "dopamine" after the COVID-19 pandemic. In addition, research interest shifted toward younger populations, and there was a noticeable increase in terms related to neural networks such as "connectivity". However, only a few specific molecular mechanisms or cellular physiological pathways by which COVID-19 exacerbates OCD have been identified. To address this gap, an additional post hoc analysis focusing on inflammation-related terms was conducted, revealing the emergence of "oxidative stress" and "c-reactive protein" in studies published after the COVID-19 pandemic. The findings of this study highlight several potential clues for elucidating the pathophysiology of OCD and identifying aggravating factors such as COVID-19, while also emphasizing the importance of continued molecular-focused research to establish novel therapeutic targets.

    DOI PubMed

  • Resveratrol promotes autophagosome elimination via SIRT1 in cardiomyocytes.

    Atsushi Kuno, Ryusuke Hosoda, Yukika Saga, Naotoshi Iwahara, Yuki Tatekoshi, Ryo Numazawa, Yoshiyuki Horio

    Journal of Pharmacological Sciences ( Elsevier BV )   2024.11  [Refereed]

    Authorship：   Lead author  , Corresponding author

    DOI

  • 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  2024.09  [Refereed]  [Domestic journal]

    　View Summary

    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 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  [Refereed]

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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

  • Role of AMP deaminase in diabetic cardiomyopathy

    Tetsuji Miura, Hidemichi Kouzu, Masaya Tanno, Yuki Tatekoshi, Atsushi Kuno

    Molecular and Cellular Biochemistry ( Springer Science and Business Media LLC )   2024.02  [Refereed]

    DOI

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Misc 【 display / non-display 】

  • SIRT1は脱アセチル化を介してヒストンH2AXのリン酸化を媒介しドキソルビシン誘発性心毒性を弱める(SIRT1 Mediates Histone H2AX Phosphorylation via Its Deacetylation and Counteracts Doxorubicin-induced Cardiotoxicity)

    久野 篤史, 細田 隆介

    日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  86回   PJ21 - 1  2022.03

  • 健康食品とサーチュイン遺伝子（長寿遺伝子）：総論

    久野 篤史

    日本食品安全協会会誌   17 ( 1 ) 3 - 9  2022.01

    Authorship：   Lead author  , Corresponding author

  • 【目標を見据えた高齢者糖尿病管理〜実態の理解から薬物療法まで〜】糖尿病・血糖降下薬と長寿遺伝子サーチュイン

    久野 篤史

    月刊糖尿病 ( (株)医学出版 )  13 ( 11 ) 86 - 93  2021.11

  • レスベラトロールによる筋ジストロフィーの治療

    福村 忍, 川村 健太郎, 山本 晃代, 堀尾 嘉幸, 久野 篤史, 堤 裕幸

    BIO Clinica ( (株)北隆館 )  36 ( 9 ) 910 - 914  2021.08

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    レスベラトロールはDuchenne型筋ジストロフィーモデルのmdxマウスに対して、組織の酸化ストレス低下、筋蛋白質量の増加、線維化の抑制、骨格筋と心筋機能の低下抑制とクレアチンキナーゼ低下作用を示した。筋ジストロフィーを対象とした臨床研究ではレスベラトロールによる有意な運動機能の向上と筋力増加を確認した。レスベラトロールは筋ジストロフィー治療薬として有用と考えられる。(著者抄録)

  • 【食・栄養から健康を拓く生化学】レスベラトロールの生体作用とその標的SIRT1

    久野 篤史, 堀尾 嘉幸

    生化学 ( (公社)日本生化学会 )  93 ( 1 ) 100 - 108  2021.02

    　View Summary

    レスベラトロールはブドウの果皮や赤ワインなどに豊富に含まれるポリフェノールである.NAD+依存性タンパク質脱アセチル化酵素SIRT1を活性化させる植物由来物質としてレスベラトロールが同定されて以来,レスベラトロールは種々の疾患への治療薬となる可能性があるとして注目を集めてきた.我々はレスベラトロールの持つ細胞保護効果に着目し,心疾患および骨格筋疾患モデルにおける有効性と,その機序におけるSIRT1の役割を検討してきた.本稿では,レスベラトロールの生体における作用をその主な標的分子であるSIRT1との関連から概説し,我々のレスベラトロールの心疾患・骨格筋疾患に対する治療効果に関する研究成果を紹介する.レスベラトロールはさまざまな疾患の予防や治療において期待のできる植物由来物質である.(著者抄録)

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Industrial Property Rights 【 display / non-display 】

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Research Projects 【 display / non-display 】

  • 糖尿病による急性腎障害の増悪におけるオートファジー・ネクロプトーシスの役割

    基盤研究(C)

    Project Year :

    2023.04
    -
    2026.03
     

    久野 篤史

  • Novel role of SIRT1 in regulation of autophagy and its role in heart failure

    Grant-in-Aid for Scientific Research (C)

    Project Year :

    2017.04
    -
    2020.03
     

    Kuno Atsushi

    　View Summary

    We investigated how SIRT1 regulates autophagy/mitophagy and its role in heart diseases. We found that administration of the SIRT1 activator to mdx mice, a model of muscular dystrophy, restored mitophagy in the heart and led to the improvement in cardiac function. In cardiomyocytes, knockdown of SIRT1 blocked CCCP-induced mitophagy and interrupted fusion of autophagosomes and lysosomes. These results suggest that SIRT1 is involved in autophagosome-lysosome fusion to promotes autophagy/mitophagy and protects the heart via autophagy/mitophagy activation.

  • 糖尿病による急性腎障害増悪におけるオートファジー・ネ クロプトーシス連関の役割解明

    Project Year :

    2022.12
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    2023.11
     

    久野 篤史

    Authorship： Principal investigator

  • スチルベノイド含有植物素材による筋萎縮予防の実用化に向けた研究

    Project Year :

    2022.08
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    2023.03
     

    Authorship： Principal investigator

  • ネクロプトーシス実行因子MLKLを標的とした心不全治療の開発

    基盤研究(C)

    Project Year :

    2022.04
    -
    2025.03
     

    矢野 俊之, 丹野 雅也, 久野 篤史

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Presentations 【 display / non-display 】

  • 筋ジストロフィー心筋障害におけるオートファジー不全の意義とレスベラトロールによる治療効果

    久野 篤史

    第67回 日本薬理学会北部会 

    Presentation date： 2016.09

  • ドキソルビシンによる心障害はSIRT1の欠損により増悪する

    久野 篤史

    第92回日本薬理学会年会 

    Presentation date： 2019.03

  • Restoration of impaired autophagosome clearance underlies amelioration of cardiomyopathy afforded by SIRT1 activation in dystrophin-deficient mice.

    Atsushi Kuno

    ISHR2017 

    Presentation date： 2017.12

  • SIRT1 Protects against Doxorubicin Cardiotoxicity In Vivo.

    Atsushi Kuno

    第80回 日本循環器学会 

    Presentation date： 2016.03

  • SIRT1の活性化はマイトファジーにより障害ミトコンドリアを除去して筋ジストロフィー心筋障害を軽減する

    久野 篤史

    第41回日本分子生物学会年会 

    Presentation date： 2018.11

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