Updated on 2025/09/15

写真a

 
KUNO Atsushi
 
Organization
School of Medicine Department of Pharmacology Professor
Title
Professor
External link

Degree

  • 医学博士 ( 札幌医科大学 )

Research Areas

  • Life Science / Pharmacology

Professional Memberships

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Papers

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

    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

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    Language：English   Publishing type：Research paper (scientific journal)  

    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： 10.3389/fpsyt.2025.1615497

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  • Resveratrol promotes autophagosome elimination via SIRT1 in cardiomyocytes. Reviewed

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

    Journal of Pharmacological Sciences   2024.11

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    Authorship：Lead author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.jphs.2024.11.006

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

    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   2024.9

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    Language：English   Publishing type：Research paper (scientific journal)  

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

    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 )   2905 - 2905   2024.3

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    Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

    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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  • Role of AMP deaminase in diabetic cardiomyopathy Reviewed

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

    Molecular and Cellular Biochemistry   2024.2

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    Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    Other Link： https://link.springer.com/article/10.1007/s11010-024-04951-z/fulltext.html

    DOI： 10.1007/s11010-024-04951-z

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  • Transcriptional dysregulation of autophagy in the muscle of a mouse model of Duchenne muscular dystrophy. Reviewed International journal

    Ryuta Nakashima, Ryusuke Hosoda, Yuki Tatekoshi, Naotoshi Iwahara, Yukika Saga, Atsushi Kuno

    Scientific reports   14 ( 1 )   1365 - 1365   2024.1

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    Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    It has been reported that autophagic activity is disturbed in the skeletal muscles of dystrophin-deficient mdx mice and patients with Duchenne muscular dystrophy (DMD). Transcriptional regulations of autophagy by FoxO transcription factors (FoxOs) and transcription factor EB (TFEB) play critical roles in adaptation to cellular stress conditions. Here, we investigated whether autophagic activity is dysregulated at the transcription level in dystrophin-deficient muscles. Expression levels of autophagy-related genes were globally decreased in tibialis anterior and soleus muscles of mdx mice compared with those of wild-type mice. DNA microarray data from the NCBI database also showed that genes related to autophagy were globally downregulated in muscles from patients with DMD. These downregulated genes are known as targets of FoxOs and TFEB. Immunostaining showed that nuclear localization of FoxO1 and FoxO3a was decreased in mdx mice. Western blot analyses demonstrated increases in phosphorylation levels of FoxO1 and FoxO3a in mdx mice. Nuclear localization of TFEB was also reduced in mdx mice, which was associated with elevated phosphorylation levels of TFEB. Collectively, the results suggest that autophagy is disturbed in dystrophin-deficient muscles via transcriptional downregulation due to phosphorylation-mediated suppression of FoxOs and TFEB.

    DOI： 10.1038/s41598-024-51746-9

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  • Circulating level of β-aminoisobutyric acid (BAIBA), a novel myokine-like molecule, is inversely associated with fat mass in patients with heart failure Reviewed

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

    Heart and Vessels   2023.9

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    Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    Other Link： https://link.springer.com/article/10.1007/s00380-023-02308-y/fulltext.html

    DOI： 10.1007/s00380-023-02308-y

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  • Resveratrol, a SIRT1 activator, attenuates aging-associated alterations in skeletal muscle and heart in mice. Reviewed

    Ryusuke Hosoda, Ryuta Nakashima, Masaki Yano, Naotoshi Iwahara, Seidai Asakura, Iyori Nojima, Yukika Saga, Risa Kunimoto, Yoshiyuki Horio, Atsushi Kuno

    Journal of Pharmacological Sciences   2023.4

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    Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.jphs.2023.04.001

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

    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   2023.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    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.

    DOI： 10.1111/jdi.13982

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  • Downregulation of extramitochondrial BCKDH and its uncoupling from AMP deaminase in type 2 diabetic OLETF rat hearts Reviewed International journal

    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   2023.2

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

    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   2023.2

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    Language：English   Publishing type：Research paper (scientific journal)  

    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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  • No sex differences in the acute effects of caffeine on mental calculation and pulse rate in healthy college students. Reviewed

    Nobuyuki Kurokawa, Rumi Niwa, Kouhei Tada, Ryusuke Hosoda, Naotoshi Iwahara, Yoshiyuki Horio, Atsushi Kuno

    Clinical Nutrition Open Science   2023.2

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    Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.nutos.2023.01.004

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  • Elevated circulating level of β-aminoisobutyric acid (BAIBA) in heart failure patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitors Reviewed

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

    Cardiovascular Diabetology   21 ( 1 )   2022.12

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    Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    Abstract

    Aims

    The mechanism by which a sodium-glucose cotransporter inhibitor (SGLT2i) induces favorable effects on diabetes and cardiovascular diseases including heart failure (HF) remains poorly understood. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiles are modulated by SGLT2i use in HF patients with type 2 diabetes mellitus (T2DM).

    Methods

    We retrospectively examined 81 HF patients with T2DM (68 ± 11 years old; 78% male). Plasma amino acid concentrations in a fasting state after stabilization of HF were determined using ultraperformance liquid chromatography. To minimize potential selection bias in the retrospective analyses, the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an inverse probability of treatment weighting (IPTW)-adjusted analysis.

    Results

    Of amino acids measurable in the present assay, plasma β-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule also known as 3-aminoisobutyric acid or 3-amino-2-methyproponic acid, was detected in 77% of all patients and the proportion of patients in whom plasma BAIBA was detected was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (93% vs. 67%, p = 0.01). Analyses in patients in whom plasma BAIBA was detected showed that plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (6.76 ± 4.72 vs. 4.56 ± 2.93 nmol/ml, p = 0.03). In multivariate logistic regression analyses that were adjusted for age and sex, SGLT2i use was independently associated with BAIBA detection. The independent association between BAIBA and SGLT2i use remained after inclusion of body mass index, HF with reduced ejection fraction, ischemic etiology, renal function, NT-proBNP, albumin, hemoglobin, and HbA1c into the Cox proportional hazards model. When the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an IPTW-adjusted analysis, least squares mean of plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i.

    Conclusion

    SGLT2i use is closely associated with increased circulating BAIBA concentration in HF patients with T2DM.

    Other Link： https://link.springer.com/article/10.1186/s12933-022-01727-x/fulltext.html

    DOI： 10.1186/s12933-022-01727-x

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  • Activation of SIRT1 promotes membrane resealing via cortactin. Reviewed International journal

    Naotoshi Iwahara, Kuya Azekami, Ryusuke Hosoda, Iyori Nojima, Shin Hisahara, Atsushi Kuno

    Scientific reports   12 ( 1 )   15328 - 15328   2022.9

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    Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

    Abstract

    Muscular dystrophies are inherited myopathic disorders characterized by progressive muscle weakness. Recently, several gene therapies have been developed; however, the treatment options are still limited. Resveratrol, an activator of SIRT1, ameliorates muscular function in muscular dystrophy patients and dystrophin-deficient mdx mice, although its mechanism is still not fully elucidated. Here, we investigated the effects of resveratrol on membrane resealing. We found that resveratrol promoted membrane repair in C2C12 cells via the activation of SIRT1. To elucidate the mechanism by which resveratrol promotes membrane resealing, we focused on the reorganization of the cytoskeleton, which occurs in the early phase of membrane repair. Treatment with resveratrol promoted actin accumulation at the injured site. We also examined the role of cortactin in membrane resealing. Cortactin accumulated at the injury site, and cortactin knockdown suppressed membrane resealing and reorganization of the cytoskeleton. Additionally, SIRT1 deacetylated cortactin and promoted the interaction between cortactin and F-actin, thus possibly enhancing the accumulation of cortactin at the injury site. Finally, we performed a membrane repair assay using single fiber myotubes from control and resveratrol-fed mice, where the oral treatment with resveratrol promoted membrane repair ex vivo. These findings suggest that resveratrol promotes membrane repair via the SIRT1/cortactin axis.

    Other Link： https://www.nature.com/articles/s41598-022-19136-1

    DOI： 10.1038/s41598-022-19136-1

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  • Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy. Reviewed International journal

    Yugo Fujita, Toshiyuki Yano, Hiromitsu Kanamori, Daigo Nagahara, Atsuko Muranaka, Hidemichi Kouzu, Atsushi Mochizuki, Masayuki Koyama, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Naoyuki Kamiyama, Marenao Tanaka, Atsushi Kuno, Masaya Tanno, Tetsuji Miura

    ESC heart failure   9 ( 5 )   3435 - 3451   2022.7

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

    AIMS: The role of necroptosis in dilated cardiomyopathy (DCM) remains unclear. Here, we examined whether phosphorylation of mixed lineage kinase domain-like protein (MLKL), an indispensable event for execution of necroptosis, is associated with the progression of DCM. METHODS AND RESULTS: Patients with DCM (n = 56, 56 ± 15 years of age; 68% male) were enrolled for immunohistochemical analyses of biopsies. Adverse events were defined as a composite of death or admission for heart failure or ventricular arrhythmia. Compared with the normal myocardium, increased signals of MLKL phosphorylation were detected in the nuclei, cytoplasm, and intercalated discs of cardiomyocytes in biopsy samples from DCM patients. The phosphorylated MLKL (p-MLKL) signal was increased in enlarged nuclei or nuclei with bizarre shapes in hypertrophied cardiomyocytes. Nuclear p-MLKL level was correlated negatively with septal peak myocardial velocity during early diastole (r = -0.327, P = 0.019) and was correlated positively with tricuspid regurgitation pressure gradient (r = 0.339, P = 0.023), while p-MLKL level in intercalated discs was negatively correlated with mean left ventricular wall thickness (r = -0.360, P = 0.014). During a median follow-up period of 3.5 years, 10 patients (18%) had adverse events. To examine the difference in event rates according to p-MLKL expression levels, patients were divided into two groups by using the median value of nuclear p-MLKL or intercalated disc p-MLKL. A group with high nuclear p-MLKL level (H-nucMLKL group) had a higher adverse event rate than did a group with low nuclear p-MLKL level (L-nucMLKL group) (32% vs. 4%, P = 0.012), and Kaplan-Meier survival curves showed that the adverse event-free survival rate was lower in the H-nucMLKL group than in the L-nucMLKL group (P = 0.019 by the log-rank test). Such differences were not detected between groups divided by a median value of intercalated disc p-MLKL. In δ-sarcoglycan-deficient (Sgcd-/- ) mice, a model of DCM, total p-MLKL and nuclear p-MLKL levels were higher than in wild-type mice. CONCLUSION: The results suggest that increased localization of nuclear p-MLKL in cardiomyocytes is associated with left ventricular diastolic dysfunction and future adverse events in DCM.

    Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ehf2.14059

    DOI： 10.1002/ehf2.14059

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  • Downregulation of IGFBP5 contributes to replicative senescence via ERK2 activation in mouse embryonic fibroblasts. Reviewed International journal

    Iyori Nojima, Ryusuke Hosoda, Yuki Toda, Yoshiki Saito, Naohiro Ueda, Kouhei Horimoto, Naotoshi Iwahara, Yoshiyuki Horio, Atsushi Kuno

    Aging   14 ( 7 )   2966 - 2988   2022.4

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    Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Insulin-like growth factor (IGF)-binding proteins (IGFBPs) are secretory proteins that regulate IGF signaling. In this study, we investigated the role of IGFBP5 in replicative senescence in embryonic mouse fibroblasts (MEFs). During passages according to the 3T3 method, MEFs underwent senescence after the 5th passage (P5) based on cell growth arrest, an increase in the number of cells positive for senescence-associated β-galactosidase (SA-β-GAL) staining, and upregulation of p16 and p19. In P8 MEFs, IGFBP5 mRNA level was markedly reduced compared with that in P2 MEFs. Downregulation of IGFBP5 via siRNA in P2 MEFs increased the number of SA-β-GAL-positive cells, upregulated p16 and p19, and inhibited cell growth. Incubation of MEFs with IGFBP5 during serial passage increased the cumulative population doubling and decreased SA-β-GAL positivity compared with those in vehicle-treated cells. IGFBP5 knockdown in P2 MEFs increased phosphorylation levels of ERK1 and ERK2. Silencing of ERK2, but not that of ERK1, blocked the increase in the number of SA-β-GAL-positive cells in IGFBP5-knockdown cells. The reduction in the cell number and upregulation of p16 and p21 in IGFBP5-knockdown cells were attenuated by ERK2 knockdown. Our results suggest that downregulation of IGFBP5 during serial passage contributes to replicative senescence via ERK2 in MEFs.

    DOI： 10.18632/aging.203999

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  • SIRT1 in the cardiomyocyte counteracts doxorubicin-induced cardiotoxicity via regulating histone H2AX. Reviewed International journal

    Atsushi Kuno, Ryusuke Hosoda, Miki Tsukamoto, Tatsuya Sato, Hiromi Sakuragi, Nami Ajima, Yukika Saga, Kouhei Tada, Yoshiki Taniguchi, Naotoshi Iwahara, Yoshiyuki Horio

    Cardiovascular research   2022.3

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    AIMS: Cardiotoxicity by doxorubicin predicts worse prognosis of patients. Accumulation of damaged DNA has been implicated in doxorubicin-induced cardiotoxicity. SIRT1, an NAD+-dependent histone/protein deacetylase, protects cells by deacetylating target proteins. We investigated whether SIRT1 counteracts doxorubicin-induced cardiotoxicity by mediating Ser139 phosphorylation of histone H2AX, a critical signal of the DNA damage response. METHODS AND RESULTS: Doxorubicin (5 mg/kg per week, x4) was administered to mice with intact SIRT1 (Sirt1f/f) and mice that lack SIRT1 activity in cardiomyocytes (Sirt1f/f; MHCcre/+). Reductions in left ventricular fractional shortening and ejection fraction by doxorubicin treatment were more severe in Sirt1f/f; MHCcre/+ than in Sirt1f/f. Myocardial expression level of type-B natriuretic peptide was 2.5-fold higher in Sirt1f/f; MHCcre/+ than in Sirt1f/f after doxorubicin treatment. Sirt1f/f; MHCcre/+ showed larger fibrotic areas and higher nitrotyrosine levels in the heart after doxorubicin treatment. Although doxorubicin-induced DNA damage evaluated by TUNEL staining was enhanced in Sirt1f/f; MHCcre/+, the myocardium from Sirt1f/f; MHCcre/+ showed blunted Ser139 phosphorylation of H2AX by doxorubicin treatment. In H9c2 cardiomyocytes, SIRT1 knockdown attenuated Ser139 phosphorylation of H2AX, increased DNA damage, and enhanced caspase-3 activation under doxorubicin treatment. Immunostaining revealed that acetylation level of H2AX at Lys5 was higher in hearts from Sirt1f/f; MHCcre/+. In H9c2 cells, acetyl-Lys5-H2AX level was increased by SIRT1 knockdown and reduced by SIRT1 overexpression. Ser139 phosphorylation in response to doxorubicin treatment was blunted in a mutant H2AX with substitution of Lys5 to Gln (K5Q) that mimics acetylated lysine compared with that in wild-type H2AX. Expression of K5Q-H2AX as well as S139A-H2AX, which cannot be phosphorylated at Ser139, augmented doxorubicin-induced caspase-3 activation. Treatment of mice with resveratrol, a SIRT1 activator, attenuated doxorubicin-induced cardiac dysfunction, which was associated with a reduction in acetyl-Lys5-H2AX level and a preserved phospho-Ser139-H2AX level. CONCLUSION: These findings suggest that SIRT1 counteracts doxorubicin-induced cardiotoxicity by mediating H2AX phosphorylation through its deacetylation in cardiomyocytes. TRANSLATIONAL PERSPECTIVE: Doxorubicin-induced cardiotoxicity limits the further use of doxorubicin for cancer treatment and determines prognosis of patients. This work shows for the first time the protective effect of SIRT1, an NAD+-dependent deacetylase, on doxorubicin-induced cardiotoxicity using a genetically modified mouse model. We identified histone H2AX as a target of SIRT1 for proper DNA damage response. Therefore, DNA repair by SIRT1 could be a potential therapeutic target to attenuate doxorubicin cardiotoxicity. SIRT1 activity may also help to predict a risk of developing cardiotoxicity in patients treated with doxorubicin.

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  • Diabetes modulation of the myocardial infarction-acute kidney injury axis. Reviewed International journal

    Tetsuji Miura, Atsushi Kuno, Marenao Tanaka

    American journal of physiology. Heart and circulatory physiology   322 ( 3 )   H394-H405   2022.3

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    As there is cross talk in functions of the heart and kidney, acute or chronic injury in one of the two organs provokes adaptive and/or maladaptive responses in both organs, leading to cardiorenal syndrome (CRS). Acute kidney injury (AKI) induced by acute heart failure is referred to as type 1 CRS, and a frequent cause of this type of CRS is acute myocardial infarction (AMI). Diabetes mellitus increases the risk of AMI and also the risk of AKI of various causes. However, there have been only a few studies in which animal models of diabetes were used to examine how diabetes modulates AMI-induced AKI. In this review, we summarize findings regarding the mechanisms of type 1 CRS and the impact of diabetes on both AMI and renal susceptibility to AKI and we discuss mechanisms by which diabetes modulates AMI-induced AKI. Hemodynamic alterations induced by AMI could be augmented by diabetes via its detrimental effect on infarct size and contractile function of the noninfarcted region in the heart. Diabetes increases susceptibility of renal cells to hypoxia and oxidative stress by modulation of signaling pathways that regulate cell survival and autophagy. Recent studies have shown that diabetes mellitus even at early stage of cardiomyopathy/nephropathy predisposes the kidney to AMI-induced AKI, in which activation of Toll-like receptors and reactive oxygen species derived from NADPH oxidases are involved. Further analysis of cross talk between diabetic cardiomyopathy and diabetic kidney disease is necessary for obtaining a more comprehensive understanding of modulation of the AMI-AKI axis by diabetes.

    DOI： 10.1152/ajpheart.00639.2021

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  • Ubiquitin-dependent rapid degradation conceals a cell-protective function of cytoplasmic SIRT3 against oxidative stress. Reviewed International journal

    Takashi Hayashi, Takashi Matsushita, Shin Hisahara, Naotoshi Iwahara, Atsushi Kuno, Risa Kunimoto, Ryusuke Hosoda, Masaya Tanno, Shun Shimohama, Yoshiyuki Horio

    Journal of biochemistry   171 ( 2 )   201 - 213   2022.2

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    SIRT3 is an NAD+-dependent protein deacetylase localized in mitochondria. Several studies reported localization of SIRT3 in the cytoplasm or nucleus, but data of these studies were not consistent. We detected expression of mitochondrial (SIRT3mt) and cytoplasmic (SIRT3ct) Sirt3 mRNAs in the mouse brain, and we also found SIRT3 immunostaining of mitochondria and cytoplasm in the brain and cultured neural cells. However, expression levels of SIRT3ct in COS cells transfected with SIRT3ct cDNA were much lower than those of SIRT3mt. We found that SIRT3ct but not SIRT3mt was promptly degraded by ubiquitin-dependent degradation, in which SIRT3ct degradation was mediated mainly by ubiquitination of NH2-terminal methionine and partly by that of lysine residues of SIRT3ct. SIRT3ct expression level was significantly enhanced by the treatment of cells with staurosporine or H2O2. H2O2 treatment promoted nuclear translocation of SIRT3ct and induced histone H3 deacetylation and superoxide dismutase 2 expression. Overexpression of SIRT3ct decreased cell death caused by H2O2 at levels similar to those achieved by overexpression of SIRT3mt. Knockdown of Sirt3 mRNA increased cell death caused by amyloid-β (Aβ), and overexpression of SIRT3ct suppressed the toxic function of Aβ in PC12 cells. These results indicate that SIRT3ct promotes cell survival under physiological and pathological conditions.

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  • Aging-associated inflammation and fibrosis in arachnoid membrane. Reviewed International journal

    Hime Suzuki, Takeshi Mikami, Naotoshi Iwahara, Yukinori Akiyama, Masahiko Wanibuchi, Katsuya Komatsu, Rintaro Yokoyama, Tsukasa Hirano, Ryusuke Hosoda, Yoshiyuki Horio, Atsushi Kuno, Nobuhiro Mikuni

    BMC neurology   21 ( 1 )   169 - 169   2021.4

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    BACKGROUND: The physiological and pathological significance of the arachnoid membrane (AM) is still unknown. In this study, we investigated various characteristics of the AM, focusing on the influence of inflammation and fibrosis. METHODS: Small pieces of AM sample were obtained during neurosurgical procedures from 74 cases. The clinical and pathological characteristics of the hyperplastic AM group (≥ 50 μm) and the non-hyperplastic AM group (< 50 μm) were compared. Then, potential correlations between AM thickness and clinical characteristics were analyzed. Moreover, VEGFα, TGFβ, and TGFα levels were quantitated by real time PCR. Then, the potential correlations between AM thickness and these inflammatory or anti-inflammatory markers, and the influence of the original disease were calculated. RESULTS: The median age of the patients in hyperplastic AM group was significantly older than that of the non-hyperplastic AM group. Moreover, the number of fibroblasts, CD68+ cells, CD86+ cells, and CD206+ cells in the hyperplastic AM group was significantly higher than that in the non-hyperplastic AM group. The AM thickness was significantly correlated to age and number of fibroblasts, CD68+ cells, CD86+ cells, and CD206+ cells. The thickness of the AM was significantly correlated to the messenger RNA expression levels of VEGFα (ρ = 0.337), and the VEGFα expression levels were significantly correlated with TGFβ and TNFα. CONCLUSIONS: The AM hyperplasia was influenced by aging and could be a result of inflammation and fibrosis through cytokine secretion from the inflammatory cells and fibroblasts in the AM.

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  • Involvement of necroptosis in contrast-induced nephropathy in a rat CKD model. Reviewed

    Satoru Shibata, Norihito Moniwa, Atsushi Kuno, Ayumu Kimura, Wataru Ohwada, Hirohito Sugawara, Yufu Gocho, Marenao Tanaka, Toshiyuki Yano, Masato Furuhashi, Masaya Tanno, Takayuki Miki, Tetsuji Miura

    Clinical and experimental nephrology   25 ( 7 )   708 - 717   2021.3

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    BACKGROUND: The risk of contrast-induced nephropathy (CIN) is high in patients with chronic kidney disease (CKD). However, the mechanism of CIN in CKD is not fully understood. Here, we prepared a clinically relevant model of CIN and examined the role of necroptosis, which potentially cross-talks with autophagy, in CIN. METHODS: In Sprague-Dawley rats, CKD was induced by subtotal nephrectomy (SNx, 5/6 nephrectomy) 4 weeks before induction of CIN. CIN was induced by administration of a contrast medium (CM), iohexol, following administration of indomethacin and N-omega-Nitro-L-arginine methyl ester. Renal function and tissue injuries were assessed 48 h after CM injection. RESULTS: Serum creatinine (s-Cre) and BUN were increased from 0.28 ± 0.01 to 0.52 ± 0.02 mg/dl and from 15.1 ± 0.7 to 29.2 ± 1.2 mg/dl, respectively, after SNx alone. CM further increased s-Cre and BUN to 0.69 ± 0.03 and 37.2 ± 2.1, respectively. In the renal tissue after CM injection, protein levels of receptor-interacting serine/threonine-protein kinase (RIP) 1, RIP3, cleaved caspase 3, and caspase 8 were increased by 64 ~ 212%, while there was reduction in LC3-II and accumulation of p62. Necrostatin-1, an RIP1 inhibitor, administered before and 24 h after CM injection significantly suppressed elevation of s-Cre, BUN and urinary albumin levels, kidney injury molecule-1 expression and infiltration of CD68-positive macrophages in renal tissues after CM injection. CONCLUSION: The results suggest that necroptosis of proximal tubular cells contributes to CIN in CKD and that suppression of protective autophagy by pro-necroptotic signaling may also be involved.

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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. Reviewed International journal

    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   2021.2

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    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.

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  • Activation of the angiotensin II receptor promotes autophagy in renal proximal tubular cells and affords protection from ischemia/reperfusion injury Reviewed

    Hirohito Sugawara, Norihito Moniwa, Atsushi Kuno, Wataru Ohwada, Arata Osanami, Satoru Shibata, Yukishige Kimura, Koki Abe, Yufu Gocho, Masaya Tanno, Tetsuji Miura

    Journal of Pharmacological Sciences   145 ( 2 )   187 - 197   2021.2

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    Roles of the renin-angiotensin system in autophagy and ischemia/reperfusion (I/R) injury in the kidney have not been fully characterized. Here we examined the hypothesis that modest activation of the angiotensin II (Ang II) receptor upregulates autophagy and increases renal tolerance to I/R injury. Sprague-Dawley rats were assigned to treatment with a vehicle or a non-pressor dose of Ang II (200 ng/kg/min) for 72 h before 30-min renal I/R. LC3-immunohistochemistry showed that Ang II treatment increased autophagosomes in proximal tubular cells by 2.7 fold. In Ang II-pretreated rats, autophagosomes were increased by 2.5 fold compared to those in vehicle-treated rats at 4 h after I/R, when phosphorylation of Akt and S6 was suppressed and ULK1-Ser555 phosphorylation was increased. Serum creatinine and urea nitrogen levels, incidence of oliguria, and histological score of tubular necrosis at 24 h after I/R were attenuated by Ang II-pretreatment. In NRK-52E cells, Ang II induced LC3-II upregulation, which was inhibited by losartan but not by A779. The results indicate that a non-pressor dose of Ang-II promotes autophagy via ULK1-mediated signaling in renal tubular cells and attenuates renal I/R injury. The AT1 receptor, but not the Mas receptor, contributes to Ang-II-induced autophagy and presumably also to the renoprotection.

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  • Different anti-oxidative and anti-apoptotic effects of piceatannol and resveratrol. Reviewed International journal

    Ryusuke Hosoda, Hiroki Hamada, Daisuke Uesugi, Naotoshi Iwahara, Iyori Nojima, Yoshiyuki Horio, Atsushi Kuno

    Journal of Pharmacology and Experimental Therapeutics   376 ( 3 )   JPET - AR   2020.12

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    Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Pharmacology & Experimental Therapeutics (ASPET)  

    Resveratrol affords protection against reactive oxygen species (ROS)-related diseases via activation of SIRT1, an NAD+-dependent deacetylase. However, the low bioavailability of resveratrol limits its therapeutic applications. Since piceatannol is a hydroxyl analog of resveratrol with higher bioavailability, it could be an alternative to resveratrol. In this study, we compared the cytotoxicity, antioxidative activity, and mechanisms of cytoprotection of piceatannol with those of resveratrol. In C2C12 cells incubated with piceatannol, electrospray ionization mass spectrometry analysis showed that piceatannol was present in the intracellular fraction. A high concentration (50 μM) of piceatannol, but not resveratrol, induced mitochondrial depolarization and apoptosis. However, piceatannol at 10 μM inhibited the increase in mitochondrial ROS level induced by antimycin A, and this ROS reduction was greater than that by resveratrol. The reduction in hydrogen peroxide-induced ROS by piceatannol was also greater than that by resveratrol or vitamin C. Piceatannol reduced antimycin A-induced apoptosis more than did resveratrol. SIRT1 knockdown abolished the antiapoptotic activity of resveratrol, whereas it blocked only half of the antiapoptotic activity of piceatannol. Piceatannol, but not resveratrol, induced heme oxygenase-1 (HO1) expression, which was blocked by knockdown of the transcription factor NRF2, but not by SIRT1 knockdown. HO1 knockdown partially blocked the reduction of ROS by piceatannol. Furthermore, the antiapoptotic action of piceatannol was abolished by HO1 knockdown. Our results suggest that the therapeutic dose of piceatannol protects cells against mitochondrial ROS more than does resveratrol via SIRT1- and NRF2/HO1-dependent mechanisms. The activation of NRF2/HO1 could be an advantage of piceatannol compared with resveratrol for cytoprotection. SIGNIFICANCE STATEMENT: This study showed that piceatannol and resveratrol were different in cytotoxicity, oxidant-scavenging activities, and mechanisms of cytoprotection. Protection by piceatannol against apoptosis induced by reactive oxygen species was superior to that by resveratrol. In addition to the sirtuin 1-dependent pathway, piceatannol exerted nuclear factor erythroid 2-related factor 2/heme oxygenase-1-mediated antioxidative and antiapoptotic effects, which could be an advantage of piceatannol compared with resveratrol.

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  • Resveratrol improves motor function in patients with muscular dystrophies: an open-label, single-arm, phase IIa study Reviewed International journal

    Kentaro Kawamura, Shinobu Fukumura, Koki Nikaido, Nobutada Tachi, Naoki Kozuka, Tsugumi Seino, Kingya Hatakeyama, Mitsuru Mori, Yoichi M. Ito, Akiyoshi Takami, Shiro Hinotsu, Atsushi Kuno, Yukihiko Kawasaki, Yoshiyuki Horio, Hiroyuki Tsutsumi

    Scientific Reports   10 ( 1 )   20585 - 20585   2020.12

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    <title>Abstract</title>Muscular dystrophies (MDs) are inherited disorders characterized by progressive muscle weakness. Previously, we have shown that resveratrol (3,5,4′-trihydroxy-trans-stilbene), an antioxidant and an activator of the protein deacetylase SIRT1, decreases muscular and cardiac oxidative damage and improves pathophysiological conditions in animal MD models. To determine whether resveratrol provides therapeutic benefits to patients with MDs, an open-label, single-arm, phase IIa trial of resveratrol was conducted in 11 patients with Duchenne, Becker or Fukuyama MD. The daily dose of resveratrol was 500 mg/day, which was increased every 8 weeks to 1000 and then 1500 mg/day. Primary outcomes were motor function, evaluated by a motor function measure (MFM) scale, muscular strength, monitored with quantitative muscle testing (QMT), and serum creatine kinase (CK) levels. Adverse effects and tolerability were evaluated as secondary outcomes. Despite the advanced medical conditions of the patients, the mean MFM scores increased significantly from 34.6 to 38.4 after 24 weeks of medication. A twofold increase was found in the mean QMT scores of scapula elevation and shoulder abduction. Mean CK levels decreased considerably by 34%. Diarrhoea and abdominal pain was noted in six and three patients, respectively. Resveratrol may provide some benefit to MD patients.

    Other Link： http://www.nature.com/articles/s41598-020-77197-6

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  • Distinct intra-mitochondrial localizations of pro-survival kinases and regulation of their functions by DUSP5 and PHLPP-1 Reviewed International journal

    Wataru Ohwada, Masaya Tanno, Toshiyuki Yano, Sang-Bing Ong, Koki Abe, Tatsuya Sato, Atsushi Kuno, Takayuki Miki, Hirohito Sugawara, Yusuke Igaki, Tetsuji Miura

    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease   1866 ( 10 )   165851 - 165851   2020.10

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    ERK and Akt have been shown to regulate cell sensitivity to death-inducing stress by phosphorylating GSK-3β, a major modulator of the threshold for mitochondrial permeability transition. Here we examined intra-mitochondrial localization of the pro-survival kinases and their regulation by phosphatases. Stepwise trypsin digestion of mitochondria isolated from HEK293 or H9c2 cells was performed, and immunoblotting revealed that GSK-3β and ERK localized dominantly in the outer membrane (OM), while Akt resided at comparable levels in OM, the inner membrane (IM) and the matrix. Treatment with IGF-1 increased the protein level of Akt in the matrix, while ERK and GSK-3β protein levels were increased in OM. Simultaneously, IGF-1 treatment elevated the level of Thr202/Tyr204-phospho-ERK in IM and matrix and levels of Ser473-phospho-Akt and Ser9-phospho-GSK-3β in OM, IM and matrix. Exposing cells to reactive oxygen species (ROS) by using antimycin A increased the levels of DUSP5 and PHLPP-1 mainly in OM and induced dephosphorylation of Akt, ERK and GSK-3β. The mitochondrial localization of DUSP5 was confirmed by experiments with mitochondria purified by Percoll gradient centrifugation and by transfection of cells with GFP-tagged DUSP5. Knockdown of either DUSP5 or PHLPP-1 increased the levels of both Thr202/Tyr204-phospho-ERK and Ser473-phospho-Akt in mitochondria. Cell death induced by antimycin A was suppressed by siRNA-mediated knockdown of DUSP5. The results suggest that Akt and ERK in mitochondria show distinct intra-mitochondrial localization and crosstalk in GSK-3β regulation and that recruitment of DUSP5 as well as PHLPP-1 to mitochondria contributes to ROS-induced termination of the protective signaling.

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  • Empagliflozin attenuates acute kidney injury after myocardial infarction in diabetic rats. Reviewed International journal

    Atsushi Kuno, Yukishige Kimura, Masashi Mizuno, Hiroto Oshima, Tatsuya Sato, Norihito Moniwa, Marenao Tanaka, Toshiyuki Yano, Masaya Tanno, Takayuki Miki, Tetsuji Miura

    Scientific reports   10 ( 1 )   7238 - 7238   2020.4

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    Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

    Acute kidney injury (AKI) predicts poor prognosis in patients with acute myocardial infarction (MI) and diabetes mellitus (DM) is an independent risk factor of AKI. Recent clinical studies have shown the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular and renal outcomes in patients with DM. We recently reported that canagliflozin normalized susceptibility of diabetic rats to AKI after acute MI via β-hydroxybutyrate-mediated suppression of NOX expression. Here we examined whether the same renoprotective effect is shared by empagliflozin. Serum creatinine levels were not changed by MI induced by coronary artery occlusion in LETO, non-diabetic control rats, and OLETF, obese type 2 diabetic rats. However, immunohistochemistry revealed that MI increased renal expression of NGAL and KIM-1, early markers of tubular injury, by 3.2-fold and 2.6-fold, respectively, in OLETF. These increases in injury markers were not observed in LETO. Pretreatment with empagliflozin of OLETF for 2 weeks improved hyperglycemia, increased blood β-hydroxybutyrate level, and suppressed MI-induced expression of NGAL and KIM-1. Empagliflozin suppressed upregulation of NOX2 and NOX4 in the kidney of OLETF. Taken together with the results of our previous study, it was concluded that treatment with the SGLT2 inhibitor protects the diabetic kidney from MI-induced AKI.

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  • Deletion of SIRT1 in the skeletal muscle decreases type IIa oxidative muscle fiber in mice.

    Ryusuke Hosoda, Atsushi Kuno, Seidai Asakura, Yoshiyuki Horio

    The FASEB Journal   34 ( S1 )   1 - 1   2020.4

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    DOI： 10.1096/fasebj.2020.34.s1.02823

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  • mTORC1 inhibition attenuates necroptosis through RIP1 inhibition-mediated TFEB activation Reviewed International journal

    Abe K, Yano T, Tanno M, Miki T, Kuno A, Sato T, Kouzu H, Nakata K, Ohwada W, Kimura Y, Sugawara H, Shibata S, Igaki Y, Ino S, Miura T

    BBA Molecular Basis of Disease   1865 ( 12 )   165552 - 165552   2019.12

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    Accumulating evidence indicates that necroptosis contributes to cardiovascular diseases. We recently reported suppression of autophagy by necroptotic signals in cardiomyocytes and protective action of rapamycin. Here we examined the mechanism by which mTORC1 inhibition protects cardiomyocytes from necroptosis. Necroptosis of H9c2 cells was induced by treatment with tumor necrotic factor-α (TNF) and z-VAD-fmk (zVAD), and the extent of necroptosis was determined as the level of LDH release (as % of total). TNF/zVAD increased RIP1-RIP3 interaction and LDH release from 3.4 ± 1.3% to 46.1 ± 2.3%. The effects of TNF/zVAD were suppressed by an mTORC1 inhibitor, rapamycin, and an mTORC1/2 inhibitor, Ku-0063794, but not by a p70s6K inhibitor, PF-4708671. Protection by rapamycin was not abolished by inhibitors of TAK1, IKKα/β, and cIAP, endogenous necroptosis suppressors upstream of RIP1. Rapamycin and Ku-0063794 suppressed TNF/zVAD-induced RIP1-Ser166 phosphorylation and increased phosphorylation of RIP1-Ser320, an inhibitory phosphorylation site, though such an effect on RIP1-Ser320 was not observed for PF-4708671. Protective effects of rapamycin on TNF/zVAD-induced RIP1-RIP3 binding and necroptosis were undetected in cells transfected with RIP1-S320A. In TNF/zVAD-treated cells, rapamycin and a RIP1 inhibitor, necrostatin-1, increased nuclear localization of transcriptional factor EB (TFEB) and promoted autolysosome formation from autophagosomes in a TFEB-dependent manner. Knockdown of TFEB expression attenuated rapamycin-induced protection from necroptosis in TNF/zVAD-treated cells. The results suggest that mTORC1 inhibition promotes autophagy and protects cardiomyocytes from necroptosis by a TFEB-dependent mechanism and that inhibition of RIP1 by increased phosphorylation at Ser320 is crucial in the cardiomyocyte protection afforded by mTORC1 inhibition.

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  • Canagliflozin, an SGLT2 inhibitor, normalizes renal susceptibility to type 1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats. Reviewed

    Kimura Y, Kuno A, Tanno M, Sato T, Ohno K, Shibata S, Nakata K, Sugawara H, Abe K, Igaki Y, Yano T, Miki T, Miura T

    Journal of Diabetes Investigation   10 ( 4 )   933 - 946   2019.7

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    AIMS/INTRODUCTION: Type 2 diabetes mellitus is a risk factor of acute kidney injury after myocardial infarction (MI), a form of cardiorenal syndrome. Recent clinical trials have shown that a sodium-glucose cotransporter 2 (SGLT2) inhibitor improved both cardiac and renal outcomes in patients with type 2 diabetes mellitus, but effects of an SGLT2 inhibitor on cardiorenal syndrome remain unclear. MATERIALS AND METHODS: Type 2 diabetes mellitus (Otsuka Long-Evans Tokushima Fatty rats [OLETF]) and control (Long-Evans Tokushima Otsuka rats [LETO]) were treated with canagliflozin, an SGLT2 inhibitor, for 2 weeks. Renal tissues were analyzed at 12 h after MI with or without preoperative fasting. RESULTS: Canagliflozin reduced blood glucose levels in OLETF, and blood β-hydroxybutyrate levels were increased by canagliflozin only with fasting. MI increased neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 protein levels in the kidney by 3.2- and 1.6-fold, respectively, in OLETF, but not in LETO. The renal messenger ribonucleic acid level of Toll-like receptor 4 was higher in OLETF than in LETO after MI, whereas messenger ribonucleic acid levels of cytokines/chemokines were not significantly different. Levels of lipid peroxides, nicotinamide adenine dinucleotide phosphate oxidase (NOX)2 and NOX4 proteins after MI were significantly higher in OLETF than in LETO. Canagliflozin with pre-MI fasting suppressed MI-induced renal expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in OLETF, together with reductions in lipid peroxides and NOX proteins in the kidney. Blood β-hydroxybutyrate levels before MI were inversely correlated with neutrophil gelatinase-associated lipocalin protein levels in OLETF. Pre-incubation with β-hydroxybutyrate attenuated angiotensin II-induced upregulation of NOX4 in NRK-52E cells. CONCLUSIONS: The findings suggest that SGLT2 inhibitor treatment with a fasting period protects kidneys from MI-induced cardiorenal syndrome, possibly by β-hydroxybutyrate-mediated reduction of NOXs and oxidative stress, in type 2 diabetic rats.

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  • SIRT1 deficiency interferes with membrane resealing after cell membrane injury. Reviewed

    Fujiwara D, Iwahara N, Sebori R, Hosoda R, Shimohama S, Kuno A, Horio Y

    PloS one   14 ( 6 )   e0218329 - e0218329   2019.6

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  • Empagliflozin, an SGLT2 inhibitor, reduced the mortality rate after acute myocardial infarction with modification of cardiac metabolomes and anti-oxidants in diabetic rats. Reviewed International journal

    Oshima H, Miki T, Kuno A, Mizuno M, Sato T, Tanno M, Yano T, Nakata K, Kimura Y, Abe K, Ohwada W, Miura T

    The Journal of pharmacology and experimental therapeutics   368 ( 3 )   524 - 534   2019.3

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    The mechanism by which SGLT2 inhibitors reduce cardiac events in diabetic patients remains unclear. Here, we examined the effects of an SGLT2 inhibitor on the acute survival rate after myocardial infarction (MI) in an animal model of type 2 diabetes mellitus (DM) and the possible involvement of modification of cardiac metabolomes and antioxidative proteins. MI was induced in DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) control rats. Treatment with empagliflozin (10 mg/kg per day, 14 days) before MI reduced blood glucose and increased blood and myocardial β-hydroxybutyrate (βOHB) levels in OLETF. Survival rate at 48 hours after MI was significantly lower in OLETF rats than in LETO rats (40% vs. 84%), and empagliflozin significantly improved the survival rate in OLETF rats to 70%, although the sizes of MI were comparable. Patterns of metabolomes and gene expression in the noninfarcted myocardium of OLETF rats were consistent with increased fatty acid oxidation and decreased glucose oxidation. The patterns were modified by empagliflozin, suggesting both increased glucose oxidation and ketone utilization in OLETF rats. Empagliflozin prevented reduction of ATP level in the noninfarcted myocardium after MI and significantly increased myocardial levels of Sirt3 and superoxide dismutase 2 in OLETF rats. Administration of βOHB partially mimicked the effects of empagliflozin in OLETF rats. The results suggest that empagliflozin prevents DM-induced increase in post-MI mortality, possibly by protective modification of cardiac energy metabolism and antioxidant proteins.

    DOI： 10.1124/jpet.118.253666

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  • Resveratrol Decreases Oxidative Stress by Restoring Mitophagy and Improves the Pathophysiology of Dystrophin-Deficient <i>mdx</i> Mice. Reviewed

    Sebori R, Kuno A, Hosoda R, Hayashi T, Horio Y

    Oxidative medicine and cellular longevity   2018   9179270 - 13   2018.10

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    We previously showed that treatment with resveratrol (3,5,4-trihydroxy-trans-stilbene), an activator of the NAD<sup>+</sup>-dependent deacetylase SIRT1 at 4 g/kg food for 32 weeks, significantly decreased the muscular reactive oxygen species (ROS) levels and ameliorated the pathology of mdx mice, an animal model of Duchenne muscular dystrophy (DMD). Here, we treated mdx mice with various doses of resveratrol (0.04, 0.4, and 4 g/kg food) for 56 weeks and examined the effects on serum creatine kinase levels and physical activities. Because resveratrol promotes autophagy, we also investigated whether autophagy including mitochondrial autophagy (mitophagy) is involved in resveratrol’s effects. Autophagy/mitophagy-related genes and autophagic flux were downregulated in the muscle of mdx mice, and these phenomena were reversed by resveratrol with significant ROS reduction. Resveratrol at 4 g/kg food reduced the number of immature myofibers containing central nuclei and fine fibers &lt; 400 μm<sup>2</sup> and increased that of thicker myofibers in the quadriceps, suggesting that resveratrol decreased myofiber wasting and promoted muscular maturation. Accordingly, resveratrol at 0.4 g/kg food reduced the creatine kinase levels to one-third of those in untreated mdx mice and significantly increased the animals’ physical activities. In C2C12 myoblast cells, resveratrol promoted mitophagy and eliminated mitochondria containing high superoxide levels. The clearance of damaged mitochondria and ROS reduction by resveratrol was completely suppressed by an autophagy inhibitor (chloroquine) and by knocking down Atg5 or Pink1, essential genes for autophagy and mitophagy, respectively. Thus, resveratrol is a potential therapeutic agent for DMD, and the clearance of damaged mitochondria probably contributes to its action.

    Other Link： http://downloads.hindawi.com/journals/omcl/2018/9179270.xml

    DOI： 10.1155/2018/9179270

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  • Resveratrol Ameliorates Mitophagy Disturbance and Improves Cardiac Pathophysiology of Dystrophin-deficient mdx Mice. Reviewed

    Kuno A, Hosoda R, Sebori R, Hayashi T, Sakuragi H, Tanabe M, Horio Y

    Scientific Reports   8 ( 1 )   15555   2018.10

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    DOI： 10.1038/s41598-018-33930-w.

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  • Does p53 Inhibition Suppress Myocardial Ischemia–Reperfusion Injury? Reviewed

    Toshiyuki Yano, Koki Abe, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Tetsuji Miura, Charles Steenbergen

    Journal of Cardiovascular Pharmacology and Therapeutics   23 ( 4 )   350 - 357   2018.7

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    DOI： 10.1177/1074248418763612

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  • Translational regulation by miR-301b upregulates AMP deaminase in diabetic hearts Reviewed

    Yuki Tatekoshi, Masaya Tanno, Hidemichi Kouzu, Koki Abe, Takayuki Miki, Atsushi Kuno, Toshiyuki Yano, Satoko Ishikawa, Wataru Ohwada, Tatsuya Sato, Takeshi Niinuma, Hiromu Suzuki, Tetsuji Miura

    Journal of Molecular and Cellular Cardiology   119   138 - 146   2018.6

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    DOI： 10.1016/j.yjmcc.2018.05.003

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  • Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts Reviewed

    Masashi Mizuno, Atsushi Kuno, Toshiyuki Yano, Takayuki Miki, Hiroto Oshima, Tatsuya Sato, Kei Nakata, Yukishige Kimura, Masaya Tanno, Tetsuji Miura

    Physiological Reports   6 ( 12 )   e13741   2018.6

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    DOI： 10.14814/phy2.13741

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  • Diabetes increases the susceptibility to acute kidney injury after myocardial infarction through augmented activation of renal Toll-like receptors in rats Reviewed

    Kouhei Ohno, Atsushi Kuno, Hiromichi Murase, Shingo Muratsubaki, Takayuki Miki, Masaya Tanno, Toshiyuki Yano, Satoko Ishikawa, Tomohisa Yamashita, Tetsuji Miura

    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY   313 ( 6 )   H1130 - H1142   2017.12

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    DOI： 10.1152/ajpheart.00205.2017

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  • Suppression of autophagic flux contributes to cardiomyocyte death by activation of necroptotic pathways Reviewed

    Makoto Ogasawara, Toshiyuki Yano, Masaya Tanno, Koki Abe, Satoko Ishikawa, Takayuki Mild, Atsushi Kuno, Toshiyuki Tobisawa, Shingo Muratsubaki, Kouhei Ohno, Yuki Tatekoshi, Kei Nakata, Wataru Ohwada, Tetsuji Miura

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   108   203 - 213   2017.7

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    DOI： 10.1016/j.yjmcc.2017.06.008

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  • Suppressed autophagic response underlies augmentation of renal ischemia/reperfusion injury by type 2 diabetes Reviewed

    Shingo Muratsubaki, Atsushi Kuno, Masaya Tanno, Takayuki Miki, Toshiyuki Yano, Hirohito Sugawara, Satoru Shibata, Koki Abe, Satoko Ishikawa, Kouhei Ohno, Yukishige Kimura, Yuki Tatekoshi, Kei Nakata, Wataru Ohwada, Masashi Mizuno, Tetsuji Miura

    SCIENTIFIC REPORTS   7 ( 1 )   5311   2017.7

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    DOI： 10.1038/s41598-017-05667-5

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  • Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55 alpha contributes to enlargement of infarct size by chronic kidney disease Reviewed

    Toshiyuki Tobisawa, Toshiyuki Yano, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Yukishige Kimura, Satoko Ishikawa, Hidemichi Kouzu, Keitaro Nishizawa, Hideaki Yoshida, Tetsuji Miura

    BASIC RESEARCH IN CARDIOLOGY   112 ( 3 )   31   2017.5

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    DOI： 10.1007/s00395-017-0621-6

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  • Biochemical effects of the flavanol-rich lychee fruit extract on the melanin biosynthesis and reactive oxygen species Reviewed

    Kazuya Hagiwara, Masae Okura, Yasuyuki Sumikawa, Tokimasa Hida, Atsushi Kuno, Yoshiyuki Horio, Toshiharu Yamashita

    Journal of Dermatology   43 ( 10 )   1174 - 1183   2016.10

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    DOI： 10.1111/1346-8138.13326

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  • Chronic Treatment With an Erythropoietin Receptor Ligand Prevents Chronic Kidney Disease-Induced Enlargement of Myocardial Infarct Size Reviewed

    Keitaro Nishizawa, Toshiyuki Yano, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Toshiyuki Tobisawa, Makoto Ogasawara, Shingo Muratsubaki, Kouhei Ohno, Satoko Ishikawa, Tetsuji Miura

    HYPERTENSION   68 ( 3 )   697 - +   2016.9

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    DOI： 10.1161/HYPERTENSIONAHA.116.07480

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  • Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Reviewed International journal

    Daniel J Klionsky, Kotb Abdelmohsen, Akihisa Abe, Md Joynal Abedin, Hagai Abeliovich, Abraham Acevedo Arozena, Hiroaki Adachi, Christopher M Adams, Peter D Adams, Khosrow Adeli, Peter J Adhihetty, Sharon G Adler, Galila Agam, Rajesh Agarwal, Manish K Aghi, Maria Agnello, Patrizia Agostinis, Patricia V Aguilar, Julio Aguirre-Ghiso, Edoardo M Airoldi, Slimane Ait-Si-Ali, Takahiko Akematsu, Emmanuel T Akporiaye, Mohamed Al-Rubeai, Guillermo M Albaiceta, Chris Albanese, Diego Albani, Matthew L Albert, Jesus Aldudo, Hana Algül, Mehrdad Alirezaei, Iraide Alloza, Alexandru Almasan, Maylin Almonte-Beceril, Emad S Alnemri, Covadonga Alonso, Nihal Altan-Bonnet, Dario C Altieri, Silvia Alvarez, Lydia Alvarez-Erviti, Sandro Alves, Giuseppina Amadoro, Atsuo Amano, Consuelo Amantini, Santiago Ambrosio, Ivano Amelio, Amal O Amer, Mohamed Amessou, Angelika Amon, Zhenyi An, Frank A Anania, Stig U Andersen, Usha P Andley, Catherine K Andreadi, Nathalie Andrieu-Abadie, Alberto Anel, David K Ann, Shailendra Anoopkumar-Dukie, Manuela Antonioli, Hiroshi Aoki, Nadezda Apostolova, Saveria Aquila, Katia Aquilano, Koichi Araki, Eli Arama, Agustin Aranda, Jun Araya, Alexandre Arcaro, Esperanza Arias, Hirokazu Arimoto, Aileen R Ariosa, Jane L Armstrong, Thierry Arnould, Ivica Arsov, Katsuhiko Asanuma, Valerie Askanas, Eric Asselin, Ryuichiro Atarashi, Sally S Atherton, Julie D Atkin, Laura D Attardi, Patrick Auberger, Georg Auburger, Laure Aurelian, Riccardo Autelli, Laura Avagliano, Maria Laura Avantaggiati, Limor Avrahami, Suresh Awale, Neelam Azad, Tiziana Bachetti, Jonathan M Backer, Dong-Hun Bae, Jae-Sung Bae, Ok-Nam Bae, Soo Han Bae, Eric H Baehrecke, Seung-Hoon Baek, Stephen Baghdiguian, Agnieszka Bagniewska-Zadworna, Hua Bai, Jie Bai, Xue-Yuan Bai, Yannick Bailly, Kithiganahalli Narayanaswamy Balaji, Walter Balduini, Andrea Ballabio, Rena Balzan, Rajkumar Banerjee, Gábor Bánhegyi, Haijun Bao, Benoit Barbeau, Maria D Barrachina, Esther Barreiro, Bonnie Bartel, Alberto Bartolomé, Diane C Bassham, Maria Teresa Bassi, Robert C Bast Jr, Alakananda Basu, Maria Teresa Batista, Henri Batoko, Maurizio Battino, Kyle Bauckman, Bradley L Baumgarner, K Ulrich Bayer, Rupert Beale, Jean-François Beaulieu, George R Beck Jr, Christoph Becker, J David Beckham, Pierre-André Bédard, Patrick J Bednarski, Thomas J Begley, Christian Behl, Christian Behrends, Georg Mn Behrens, Kevin E Behrns, Eloy Bejarano, Amine Belaid, Francesca Belleudi, Giovanni Bénard, Guy Berchem, Daniele Bergamaschi, Matteo Bergami, Ben Berkhout, Laura Berliocchi, Amélie Bernard, Monique Bernard, Francesca Bernassola, Anne Bertolotti, Amanda S Bess, Sébastien Besteiro, Saverio Bettuzzi, Savita Bhalla, Shalmoli Bhattacharyya, Sujit K Bhutia, Caroline Biagosch, Michele Wolfe Bianchi, Martine Biard-Piechaczyk, Viktor Billes, Claudia Bincoletto, Baris Bingol, Sara W Bird, Marc Bitoun, Ivana Bjedov, Craig Blackstone, Lionel Blanc, Guillermo A Blanco, Heidi Kiil Blomhoff, Emilio Boada-Romero, Stefan Böckler, Marianne Boes, Kathleen Boesze-Battaglia, Lawrence H Boise, Alessandra Bolino, Andrea Boman, Paolo Bonaldo, Matteo Bordi, Jürgen Bosch, Luis M Botana, Joelle Botti, German Bou, Marina Bouché, Marion Bouchecareilh, Marie-Josée Boucher, Michael E Boulton, Sebastien G Bouret, Patricia Boya, Michaël Boyer-Guittaut, Peter V Bozhkov, Nathan Brady, Vania Mm Braga, Claudio Brancolini, Gerhard H Braus, José M Bravo-San Pedro, Lisa A Brennan, Emery H Bresnick, Patrick Brest, Dave Bridges, Marie-Agnès Bringer, Marisa Brini, Glauber C Brito, Bertha Brodin, Paul S Brookes, Eric J Brown, Karen Brown, Hal E Broxmeyer, Alain Bruhat, Patricia Chakur Brum, John H Brumell, Nicola Brunetti-Pierri, Robert J Bryson-Richardson, Shilpa Buch, Alastair M Buchan, Hikmet Budak, Dmitry V Bulavin, Scott J Bultman, Geert Bultynck, Vladimir Bumbasirevic, Yan Burelle, Robert E Burke, Margit Burmeister, Peter Bütikofer, Laura Caberlotto, Ken Cadwell, Monika Cahova, Dongsheng Cai, Jingjing Cai, Qian Cai, Sara Calatayud, Nadine Camougrand, Michelangelo Campanella, Grant R Campbell, Matthew Campbell, Silvia Campello, Robin Candau, Isabella Caniggia, Lavinia Cantoni, Lizhi Cao, Allan B Caplan, Michele Caraglia, Claudio Cardinali, Sandra Morais Cardoso, Jennifer S Carew, Laura A Carleton, Cathleen R Carlin, Silvia Carloni, Sven R Carlsson, Didac Carmona-Gutierrez, Leticia Am Carneiro, Oliana Carnevali, Serena Carra, Alice Carrier, Bernadette Carroll, Caty Casas, Josefina Casas, Giuliana Cassinelli, Perrine Castets, Susana Castro-Obregon, Gabriella Cavallini, Isabella Ceccherini, Francesco Cecconi, Arthur I Cederbaum, Valentín Ceña, Simone Cenci, Claudia Cerella, Davide Cervia, Silvia Cetrullo, Hassan Chaachouay, Han-Jung Chae, Andrei S Chagin, Chee-Yin Chai, Gopal Chakrabarti, Georgios Chamilos, Edmond Yw Chan, Matthew Tv Chan, Dhyan Chandra, Pallavi Chandra, Chih-Peng Chang, Raymond Chuen-Chung Chang, Ta Yuan Chang, John C Chatham, Saurabh Chatterjee, Santosh Chauhan, Yongsheng Che, Michael E Cheetham, Rajkumar Cheluvappa, Chun-Jung Chen, Gang Chen, Guang-Chao Chen, Guoqiang Chen, Hongzhuan Chen, Jeff W Chen, Jian-Kang Chen, Min Chen, Mingzhou Chen, Peiwen Chen, Qi Chen, Quan Chen, Shang-Der Chen, Si Chen, Steve S-L Chen, Wei Chen, Wei-Jung Chen, Wen Qiang Chen, Wenli Chen, Xiangmei Chen, Yau-Hung Chen, Ye-Guang Chen, Yin Chen, Yingyu Chen, Yongshun Chen, Yu-Jen Chen, Yue-Qin Chen, Yujie Chen, Zhen Chen, Zhong Chen, Alan Cheng, Christopher Hk Cheng, Hua Cheng, Heesun Cheong, Sara Cherry, Jason Chesney, Chun Hei Antonio Cheung, Eric Chevet, Hsiang Cheng Chi, Sung-Gil Chi, Fulvio Chiacchiera, Hui-Ling Chiang, Roberto Chiarelli, Mario Chiariello, Marcello Chieppa, Lih-Shen Chin, Mario Chiong, Gigi Nc Chiu, Dong-Hyung Cho, Ssang-Goo Cho, William C Cho, Yong-Yeon Cho, Young-Seok Cho, Augustine Mk Choi, Eui-Ju Choi, Eun-Kyoung Choi, Jayoung Choi, Mary E Choi, Seung-Il Choi, Tsui-Fen Chou, Salem Chouaib, Divaker Choubey, Vinay Choubey, Kuan-Chih Chow, Kamal Chowdhury, Charleen T Chu, Tsung-Hsien Chuang, Taehoon Chun, Hyewon Chung, Taijoon Chung, Yuen-Li Chung, Yong-Joon Chwae, Valentina Cianfanelli, Roberto Ciarcia, Iwona A Ciechomska, Maria Rosa Ciriolo, Mara Cirone, Sofie Claerhout, Michael J Clague, Joan Clària, Peter Gh Clarke, Robert Clarke, Emilio Clementi, Cédric Cleyrat, Miriam Cnop, Eliana M Coccia, Tiziana Cocco, Patrice Codogno, Jörn Coers, Ezra Ew Cohen, David Colecchia, Luisa Coletto, Núria S Coll, Emma Colucci-Guyon, Sergio Comincini, Maria Condello, Katherine L Cook, Graham H Coombs, Cynthia D Cooper, J Mark Cooper, Isabelle Coppens, Maria Tiziana Corasaniti, Marco Corazzari, Ramon Corbalan, Elisabeth Corcelle-Termeau, Mario D Cordero, Cristina Corral-Ramos, Olga Corti, Andrea Cossarizza, Paola Costelli, Safia Costes, Susan L Cotman, Ana Coto-Montes, Sandra Cottet, Eduardo Couve, Lori R Covey, L Ashley Cowart, Jeffery S Cox, Fraser P Coxon, Carolyn B Coyne, Mark S Cragg, Rolf J Craven, Tiziana Crepaldi, Jose L Crespo, Alfredo Criollo, Valeria Crippa, Maria Teresa Cruz, Ana Maria Cuervo, Jose M Cuezva, Taixing Cui, Pedro R Cutillas, Mark J Czaja, Maria F Czyzyk-Krzeska, Ruben K Dagda, Uta Dahmen, Chunsun Dai, Wenjie Dai, Yun Dai, Kevin N Dalby, Luisa Dalla Valle, Guillaume Dalmasso, Marcello D'Amelio, Markus Damme, Arlette Darfeuille-Michaud, Catherine Dargemont, Victor M Darley-Usmar, Srinivasan Dasarathy, Biplab Dasgupta, Srikanta Dash, Crispin R Dass, Hazel Marie Davey, Lester M Davids, David Dávila, Roger J Davis, Ted M Dawson, Valina L Dawson, Paula Daza, Jackie de Belleroche, Paul de Figueiredo, Regina Celia Bressan Queiroz de Figueiredo, José de la Fuente, Luisa De Martino, Antonella De Matteis, Guido Ry De Meyer, Angelo De Milito, Mauro De Santi, Wanderley de Souza, Vincenzo De Tata, Daniela De Zio, Jayanta Debnath, Reinhard Dechant, Jean-Paul Decuypere, Shane Deegan, Benjamin Dehay, Barbara Del Bello, Dominic P Del Re, Régis Delage-Mourroux, Lea Md Delbridge, Louise Deldicque, Elizabeth Delorme-Axford, Yizhen Deng, Joern Dengjel, Melanie Denizot, Paul Dent, Channing J Der, Vojo Deretic, Benoît Derrien, Eric Deutsch, Timothy P Devarenne, Rodney J Devenish, Sabrina Di Bartolomeo, Nicola Di Daniele, Fabio Di Domenico, Alessia Di Nardo, Simone Di Paola, Antonio Di Pietro, Livia Di Renzo, Aaron DiAntonio, Guillermo Díaz-Araya, Ines Díaz-Laviada, Maria T Diaz-Meco, Javier Diaz-Nido, Chad A Dickey, Robert C Dickson, Marc Diederich, Paul Digard, Ivan Dikic, Savithrama P Dinesh-Kumar, Chan Ding, Wen-Xing Ding, Zufeng Ding, Luciana Dini, Jörg Hw Distler, Abhinav Diwan, Mojgan Djavaheri-Mergny, Kostyantyn Dmytruk, Renwick Cj Dobson, Volker Doetsch, Karol Dokladny, Svetlana Dokudovskaya, Massimo Donadelli, X Charlie Dong, Xiaonan Dong, Zheng Dong, Terrence M Donohue Jr, Kelly S Doran, Gabriella D'Orazi, Gerald W Dorn 2nd, Victor Dosenko, Sami Dridi, Liat Drucker, Jie Du, Li-Lin Du, Lihuan Du, André du Toit, Priyamvada Dua, Lei Duan, Pu Duann, Vikash Kumar Dubey, Michael R Duchen, Michel A Duchosal, Helene Duez, Isabelle Dugail, Verónica I Dumit, Mara C Duncan, Elaine A Dunlop, William A Dunn Jr, Nicolas Dupont, Luc Dupuis, Raúl V Durán, Thomas M Durcan, Stéphane Duvezin-Caubet, Umamaheswar Duvvuri, Vinay Eapen, Darius Ebrahimi-Fakhari, Arnaud Echard, Leopold Eckhart, Charles L Edelstein, Aimee L Edinger, Ludwig Eichinger, Tobias Eisenberg, Avital Eisenberg-Lerner, N Tony Eissa, Wafik S El-Deiry, Victoria El-Khoury, Zvulun Elazar, Hagit Eldar-Finkelman, Chris Jh Elliott, Enzo Emanuele, Urban Emmenegger, Nikolai Engedal, Anna-Mart Engelbrecht, Simone Engelender, Jorrit M Enserink, Ralf Erdmann, Jekaterina Erenpreisa, Rajaraman Eri, Jason L Eriksen, Andreja Erman, Ricardo Escalante, Eeva-Liisa Eskelinen, Lucile Espert, Lorena Esteban-Martínez, Thomas J Evans, Mario Fabri, Gemma Fabrias, Cinzia Fabrizi, Antonio Facchiano, Nils J Færgeman, Alberto Faggioni, W Douglas Fairlie, Chunhai Fan, Daping Fan, Jie Fan, Shengyun Fang, Manolis Fanto, Alessandro Fanzani, Thomas Farkas, Mathias Faure, Francois B Favier, Howard Fearnhead, Massimo Federici, Erkang Fei, Tania C Felizardo, Hua Feng, Yibin Feng, Yuchen Feng, Thomas A Ferguson, Álvaro F Fernández, Maite G Fernandez-Barrena, Jose C Fernandez-Checa, Arsenio Fernández-López, Martin E Fernandez-Zapico, Olivier Feron, Elisabetta Ferraro, Carmen Veríssima Ferreira-Halder, Laszlo Fesus, Ralph Feuer, Fabienne C Fiesel, Eduardo C Filippi-Chiela, Giuseppe Filomeni, Gian Maria Fimia, John H Fingert, Steven Finkbeiner, Toren Finkel, Filomena Fiorito, Paul B Fisher, Marc Flajolet, Flavio Flamigni, Oliver Florey, Salvatore Florio, R Andres Floto, Marco Folini, Carlo Follo, Edward A Fon, Francesco Fornai, Franco Fortunato, Alessandro Fraldi, Rodrigo Franco, Arnaud Francois, Aurélie François, Lisa B Frankel, Iain Dc Fraser, Norbert Frey, Damien G Freyssenet, Christian Frezza, Scott L Friedman, Daniel E Frigo, Dongxu Fu, José M Fuentes, Juan Fueyo, Yoshio Fujitani, Yuuki Fujiwara, Mikihiro Fujiya, Mitsunori Fukuda, Simone Fulda, Carmela Fusco, Bozena Gabryel, Matthias Gaestel, Philippe Gailly, Malgorzata Gajewska, Sehamuddin Galadari, Gad Galili, Inmaculada Galindo, Maria F Galindo, Giovanna Galliciotti, Lorenzo Galluzzi, Luca Galluzzi, Vincent Galy, Noor Gammoh, Sam Gandy, Anand K Ganesan, Swamynathan Ganesan, Ian G Ganley, Monique Gannagé, Fen-Biao Gao, Feng Gao, Jian-Xin Gao, Lorena García Nannig, Eleonora García Véscovi, Marina Garcia-Macía, Carmen Garcia-Ruiz, Abhishek D Garg, Pramod Kumar Garg, Ricardo Gargini, Nils Christian Gassen, Damián Gatica, Evelina Gatti, Julie Gavard, Evripidis Gavathiotis, Liang Ge, Pengfei Ge, Shengfang Ge, Po-Wu Gean, Vania Gelmetti, Armando A Genazzani, Jiefei Geng, Pascal Genschik, Lisa Gerner, Jason E Gestwicki, David A Gewirtz, Saeid Ghavami, Eric Ghigo, Debabrata Ghosh, Anna Maria Giammarioli, Francesca Giampieri, Claudia Giampietri, Alexandra Giatromanolaki, Derrick J Gibbings, Lara Gibellini, Spencer B Gibson, Vanessa Ginet, Antonio Giordano, Flaviano Giorgini, Elisa Giovannetti, Stephen E Girardin, Suzana Gispert, Sandy Giuliano, Candece L Gladson, Alvaro Glavic, Martin Gleave, Nelly Godefroy, Robert M Gogal Jr, Kuppan Gokulan, Gustavo H Goldman, Delia Goletti, Michael S Goligorsky, Aldrin V Gomes, Ligia C Gomes, Hernando Gomez, Candelaria Gomez-Manzano, Rubén Gómez-Sánchez, Dawit Ap Gonçalves, Ebru Goncu, Qingqiu Gong, Céline Gongora, Carlos B Gonzalez, Pedro Gonzalez-Alegre, Pilar Gonzalez-Cabo, Rosa Ana González-Polo, Ing Swie Goping, Carlos Gorbea, Nikolai V Gorbunov, Daphne R Goring, Adrienne M Gorman, Sharon M Gorski, Sandro Goruppi, Shino Goto-Yamada, Cecilia Gotor, Roberta A Gottlieb, Illana Gozes, Devrim Gozuacik, Yacine Graba, Martin Graef, Giovanna E Granato, Gary Dean Grant, Steven Grant, Giovanni Luca Gravina, Douglas R Green, Alexander Greenhough, Michael T Greenwood, Benedetto Grimaldi, Frédéric Gros, Charles Grose, Jean-Francois Groulx, Florian Gruber, Paolo Grumati, Tilman Grune, Jun-Lin Guan, Kun-Liang Guan, Barbara Guerra, Carlos Guillen, Kailash Gulshan, Jan Gunst, Chuanyong Guo, Lei Guo, Ming Guo, Wenjie Guo, Xu-Guang Guo, Andrea A Gust, Åsa B Gustafsson, Elaine Gutierrez, Maximiliano G Gutierrez, Ho-Shin Gwak, Albert Haas, James E Haber, Shinji Hadano, Monica Hagedorn, David R Hahn, Andrew J Halayko, Anne Hamacher-Brady, Kozo Hamada, Ahmed Hamai, Andrea Hamann, Maho Hamasaki, Isabelle Hamer, Qutayba Hamid, Ester M Hammond, Feng Han, Weidong Han, James T Handa, John A Hanover, Malene Hansen, Masaru Harada, Ljubica Harhaji-Trajkovic, J Wade Harper, Abdel Halim Harrath, Adrian L Harris, James Harris, Udo Hasler, Peter Hasselblatt, Kazuhisa Hasui, Robert G Hawley, Teresa S Hawley, Congcong He, Cynthia Y He, Fengtian He, Gu He, Rong-Rong He, Xian-Hui He, You-Wen He, Yu-Ying He, Joan K Heath, Marie-Josée Hébert, Robert A Heinzen, Gudmundur Vignir Helgason, Michael Hensel, Elizabeth P Henske, Chengtao Her, Paul K Herman, Agustín Hernández, Carlos Hernandez, Sonia Hernández-Tiedra, Claudio Hetz, P Robin Hiesinger, Katsumi 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Shu, Deepak Shukla, Andriy A Sibirny, Valentina Sica, Christina J Sigurdson, Einar M Sigurdsson, Puran Singh Sijwali, Beata Sikorska, Wilian A Silveira, Sandrine Silvente-Poirot, Gary A Silverman, Jan Simak, Thomas Simmet, Anna Katharina Simon, Hans-Uwe Simon, Cristiano Simone, Matias Simons, Anne Simonsen, Rajat Singh, Shivendra V Singh, Shrawan K Singh, Debasish Sinha, Sangita Sinha, Frank A Sinicrope, Agnieszka Sirko, Kapil Sirohi, Balindiwe Jn Sishi, Annie Sittler, Parco M Siu, Efthimios Sivridis, Anna Skwarska, Ruth Slack, Iva Slaninová, Nikolai Slavov, Soraya S Smaili, Keiran Sm Smalley, Duncan R Smith, Stefaan J Soenen, Scott A Soleimanpour, Anita Solhaug, Kumaravel Somasundaram, Jin H Son, Avinash Sonawane, Chunjuan Song, Fuyong Song, Hyun Kyu Song, Ju-Xian Song, Wei Song, Kai Y Soo, Anil K Sood, Tuck Wah Soong, Virawudh Soontornniyomkij, Maurizio Sorice, Federica Sotgia, David R Soto-Pantoja, Areechun Sotthibundhu, Maria João Sousa, Herman P Spaink, Paul N Span, Anne Spang, Janet D Sparks, Peter G Speck, Stephen A Spector, Claudia D Spies, Wolfdieter Springer, Daret St Clair, Alessandra Stacchiotti, Bart Staels, Michael T Stang, Daniel T Starczynowski, Petro Starokadomskyy, Clemens Steegborn, John W Steele, Leonidas Stefanis, Joan Steffan, Christine M Stellrecht, Harald Stenmark, Tomasz M Stepkowski, Stęphan T Stern, Craig Stevens, Brent R Stockwell, Veronika Stoka, Zuzana Storchova, Björn Stork, Vassilis Stratoulias, Dimitrios J Stravopodis, Pavel Strnad, Anne Marie Strohecker, Anna-Lena Ström, Per Stromhaug, Jiri Stulik, Yu-Xiong Su, Zhaoliang Su, Carlos S Subauste, Srinivasa Subramaniam, Carolyn M Sue, Sang Won Suh, Xinbing Sui, Supawadee Sukseree, David Sulzer, Fang-Lin Sun, Jiaren Sun, Jun Sun, Shi-Yong Sun, Yang Sun, Yi Sun, Yingjie Sun, Vinod Sundaramoorthy, Joseph Sung, Hidekazu Suzuki, Kuninori Suzuki, Naoki Suzuki, Tadashi Suzuki, Yuichiro J Suzuki, Michele S Swanson, Charles Swanton, Karl Swärd, Ghanshyam Swarup, Sean T Sweeney, Paul W Sylvester, Zsuzsanna Szatmari, Eva Szegezdi, Peter W Szlosarek, Heinrich Taegtmeyer, Marco Tafani, Emmanuel Taillebourg, Stephen Wg Tait, Krisztina Takacs-Vellai, Yoshinori Takahashi, Szabolcs Takáts, Genzou Takemura, Nagio Takigawa, Nicholas J Talbot, Elena Tamagno, Jerome Tamburini, Cai-Ping Tan, Lan Tan, Mei Lan Tan, Ming Tan, Yee-Joo Tan, Keiji Tanaka, Masaki Tanaka, Daolin Tang, Dingzhong Tang, Guomei Tang, Isei Tanida, Kunikazu Tanji, Bakhos A Tannous, Jose A Tapia, Inmaculada Tasset-Cuevas, Marc Tatar, Iman Tavassoly, Nektarios Tavernarakis, Allen Taylor, Graham S Taylor, Gregory A Taylor, J Paul Taylor, Mark J Taylor, Elena V Tchetina, Andrew R Tee, Fatima Teixeira-Clerc, Sucheta Telang, Tewin Tencomnao, Ba-Bie Teng, Ru-Jeng Teng, Faraj Terro, Gianluca Tettamanti, Arianne L Theiss, Anne E Theron, Kelly Jean Thomas, Marcos P Thomé, Paul G Thomes, Andrew Thorburn, Jeremy Thorner, Thomas Thum, Michael Thumm, Teresa Lm Thurston, Ling Tian, Andreas Till, Jenny Pan-Yun Ting, Vladimir I Titorenko, Lilach Toker, Stefano Toldo, Sharon A Tooze, Ivan Topisirovic, Maria Lyngaas Torgersen, Liliana Torosantucci, Alicia Torriglia, Maria Rosaria Torrisi, Cathy Tournier, Roberto Towns, Vladimir Trajkovic, Leonardo H Travassos, Gemma Triola, Durga Nand Tripathi, Daniela Trisciuoglio, Rodrigo Troncoso, Ioannis P Trougakos, Anita C Truttmann, Kuen-Jer Tsai, Mario P Tschan, Yi-Hsin Tseng, Takayuki Tsukuba, Allan Tsung, Andrey S Tsvetkov, Shuiping Tu, Hsing-Yu Tuan, Marco Tucci, David A Tumbarello, Boris Turk, Vito Turk, Robin Fb Turner, Anders A Tveita, Suresh C Tyagi, Makoto Ubukata, Yasuo Uchiyama, Andrej Udelnow, Takashi Ueno, Midori Umekawa, Rika Umemiya-Shirafuji, Benjamin R Underwood, Christian Ungermann, Rodrigo P Ureshino, Ryo Ushioda, Vladimir N Uversky, Néstor L Uzcátegui, Thomas Vaccari, Maria I Vaccaro, Libuše Váchová, Helin Vakifahmetoglu-Norberg, Rut Valdor, Enza Maria Valente, Francois Vallette, Angela M Valverde, Greet Van den Berghe, Ludo Van Den Bosch, Gijs R van den Brink, F Gisou van der Goot, Ida J van der Klei, Luc Jw van der Laan, Wouter G van Doorn, Marjolein van Egmond, Kenneth L van Golen, Luc Van Kaer, Menno van Lookeren Campagne, Peter Vandenabeele, Wim Vandenberghe, Ilse Vanhorebeek, Isabel Varela-Nieto, M Helena Vasconcelos, Radovan Vasko, Demetrios G Vavvas, Ignacio Vega-Naredo, Guillermo Velasco, Athanassios D Velentzas, Panagiotis D Velentzas, Tibor Vellai, Edo Vellenga, Mikkel Holm Vendelbo, Kartik Venkatachalam, Natascia Ventura, Salvador Ventura, Patrícia St Veras, Mireille Verdier, Beata G Vertessy, Andrea Viale, Michel Vidal, Helena L A Vieira, Richard D Vierstra, Nadarajah Vigneswaran, Neeraj Vij, Miquel Vila, Margarita Villar, Victor H Villar, Joan Villarroya, Cécile Vindis, Giampietro Viola, Maria Teresa Viscomi, Giovanni Vitale, Dan T Vogl, Olga V Voitsekhovskaja, Clarissa von Haefen, Karin von Schwarzenberg, Daniel E Voth, Valérie Vouret-Craviari, Kristina Vuori, Jatin M Vyas, Christian Waeber, Cheryl Lyn Walker, Mark J Walker, Jochen Walter, Lei Wan, Xiangbo Wan, Bo Wang, Caihong Wang, Chao-Yung Wang, Chengshu Wang, Chenran Wang, Chuangui Wang, Dong Wang, Fen Wang, Fuxin Wang, Guanghui Wang, Hai-Jie Wang, Haichao Wang, Hong-Gang Wang, Hongmin Wang, Horng-Dar Wang, Jing Wang, Junjun Wang, Mei Wang, Mei-Qing Wang, Pei-Yu Wang, Peng Wang, Richard C Wang, Shuo Wang, Ting-Fang Wang, Xian Wang, Xiao-Jia Wang, Xiao-Wei Wang, Xin Wang, Xuejun Wang, Yan Wang, Yanming Wang, Ying Wang, Ying-Jan Wang, Yipeng Wang, Yu Wang, Yu Tian Wang, Yuqing Wang, Zhi-Nong Wang, Pablo Wappner, Carl Ward, Diane McVey Ward, Gary Warnes, Hirotaka Watada, Yoshihisa Watanabe, Kei Watase, Timothy E Weaver, Colin D Weekes, Jiwu Wei, Thomas Weide, Conrad C Weihl, Günther Weindl, Simone Nardin Weis, Longping Wen, Xin Wen, Yunfei Wen, Benedikt Westermann, Cornelia M Weyand, Anthony R White, Eileen White, J Lindsay Whitton, Alexander J Whitworth, Joëlle Wiels, Franziska Wild, Manon E Wildenberg, Tom Wileman, Deepti Srinivas Wilkinson, Simon Wilkinson, Dieter Willbold, Chris Williams, Katherine Williams, Peter R Williamson, Konstanze F Winklhofer, Steven S Witkin, Stephanie E Wohlgemuth, Thomas Wollert, Ernst J Wolvetang, Esther Wong, G William Wong, Richard W Wong, Vincent Kam Wai Wong, Elizabeth A Woodcock, Karen L Wright, Chunlai Wu, Defeng Wu, Gen Sheng Wu, Jian Wu, Junfang Wu, Mian Wu, Min Wu, Shengzhou Wu, William Kk Wu, Yaohua Wu, Zhenlong Wu, Cristina Pr Xavier, Ramnik J Xavier, Gui-Xian Xia, Tian Xia, Weiliang Xia, Yong Xia, Hengyi Xiao, Jian Xiao, Shi Xiao, Wuhan Xiao, Chuan-Ming Xie, Zhiping Xie, Zhonglin Xie, Maria Xilouri, Yuyan Xiong, Chuanshan Xu, Congfeng Xu, Feng Xu, Haoxing Xu, Hongwei Xu, Jian Xu, Jianzhen Xu, Jinxian Xu, Liang Xu, Xiaolei Xu, Yangqing Xu, Ye Xu, Zhi-Xiang Xu, Ziheng Xu, Yu Xue, Takahiro Yamada, Ai Yamamoto, Koji Yamanaka, Shunhei Yamashina, Shigeko Yamashiro, Bing Yan, Bo Yan, Xianghua Yan, Zhen Yan, Yasuo Yanagi, Dun-Sheng Yang, Jin-Ming Yang, Liu Yang, Minghua Yang, Pei-Ming Yang, Peixin Yang, Qian Yang, Wannian Yang, Wei Yuan Yang, Xuesong Yang, Yi Yang, Ying Yang, Zhifen Yang, Zhihong Yang, Meng-Chao Yao, Pamela J Yao, Xiaofeng Yao, Zhenyu Yao, Zhiyuan Yao, Linda S Yasui, Mingxiang Ye, Barry Yedvobnick, Behzad Yeganeh, Elizabeth S Yeh, Patricia L Yeyati, Fan Yi, Long Yi, Xiao-Ming Yin, Calvin K Yip, Yeong-Min Yoo, Young Hyun Yoo, Seung-Yong Yoon, Ken-Ichi Yoshida, Tamotsu Yoshimori, Ken H Young, Huixin Yu, Jane J Yu, Jin-Tai Yu, Jun Yu, Li Yu, W Haung Yu, Xiao-Fang Yu, Zhengping Yu, Junying Yuan, Zhi-Min Yuan, Beatrice Yjt Yue, Jianbo Yue, Zhenyu Yue, David N Zacks, Eldad Zacksenhaus, Nadia Zaffaroni, Tania Zaglia, Zahra Zakeri, Vincent Zecchini, Jinsheng Zeng, Min Zeng, Qi Zeng, Antonis S Zervos, Donna D Zhang, Fan Zhang, Guo Zhang, Guo-Chang Zhang, Hao Zhang, Hong Zhang, Hong Zhang, Hongbing Zhang, Jian Zhang, Jian Zhang, Jiangwei Zhang, Jianhua Zhang, Jing-Pu Zhang, Li Zhang, Lin Zhang, Lin Zhang, Long Zhang, Ming-Yong Zhang, Xiangnan Zhang, Xu Dong Zhang, Yan Zhang, Yang Zhang, Yanjin Zhang, Yingmei Zhang, Yunjiao Zhang, Mei Zhao, Wei-Li Zhao, Xiaonan Zhao, Yan G Zhao, Ying Zhao, Yongchao Zhao, Yu-Xia Zhao, Zhendong Zhao, Zhizhuang J Zhao, Dexian Zheng, Xi-Long Zheng, Xiaoxiang Zheng, Boris Zhivotovsky, Qing Zhong, Guang-Zhou Zhou, Guofei Zhou, Huiping Zhou, Shu-Feng Zhou, Xu-Jie Zhou, Hongxin Zhu, Hua Zhu, Wei-Guo Zhu, Wenhua Zhu, Xiao-Feng Zhu, Yuhua Zhu, Shi-Mei Zhuang, Xiaohong Zhuang, Elio Ziparo, Christos E Zois, Teresa Zoladek, Wei-Xing Zong, Antonio Zorzano, Susu M Zughaier

    Autophagy   12 ( 1 )   1 - 222   2016

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  • SIRT1: A Novel Target for the Treatment of Muscular Dystrophies Reviewed

    Atsushi Kuno, Yoshiyuki Horio

    OXIDATIVE MEDICINE AND CELLULAR LONGEVITY   2016   6714686   2016

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  • Inhibition of DPP-4 reduces acute mortality after myocardial infarction with restoration of autophagic response in type 2 diabetic rats Reviewed

    Hiromichi Murase, Atsushi Kuno, Takayuki Miki, Masaya Tanno, Toshiyuki Yano, Hidemichi Kouzu, Satoko Ishikawa, Toshiyuki Tobisawa, Makoto Ogasawara, Keitaro Nishizawa, Tetsuji Miura

    CARDIOVASCULAR DIABETOLOGY   14   103   2015.8

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    DOI： 10.1186/s12933-015-0264-6

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  • Chloroquine potentiates temozolomide cytotoxicity by inhibiting mitochondrial autophagy in glioma cells Reviewed

    Yusuke S. Hori, Ryusuke Hosoda, Yukinori Akiyama, Rio Sebori, Masahiro Wanibuchi, Takeshi Mikami, Toshiya Sugino, Kengo Suzuki, Mitsuhisa Maruyama, Miki Tsukamoto, Nobuhiro Mikuni, Yoshiyuki Horio, Atsushi Kuno

    JOURNAL OF NEURO-ONCOLOGY   122 ( 1 )   11 - 20   2015.3

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  • Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart Reviewed

    Hidemichi Kouzu, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Toshiyuki Yano, Takahito Itoh, Tatsuya Sato, Daisuke Sunaga, Hiromichi Murase, Toshiyuki Tobisawa, Makoto Ogasawara, Satoko Ishikawa, Tetsuji Miura

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   80   136 - 145   2015.3

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  • The effects of resveratrol and SIRT1 activation on dystrophic cardiomyopathy Invited Reviewed

    Atsushi Kuno, Masaya Tanno, Yoshiyuki Horio

    Annals of the New York Academy of Sciences   1348 ( 1 )   46 - 54   2015

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  • Accelerated Recovery of Mitochondrial Membrane Potential by GSK-3 beta Inactivation Affords Cardiomyocytes Protection from Oxidant-Induced Necrosis Reviewed

    Daisuke Sunaga, Masaya Tanno, Atsushi Kuno, Satoko Ishikawa, Makoto Ogasawara, Toshiyuki Yano, Takayuki Miki, Tetsuji Miura

    PLOS ONE   9 ( 11 )   e112529   2014.11

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  • Translocation of Glycogen Synthase Kinase-3 beta (GSK-3 beta), a Trigger of Permeability Transition, Is Kinase Activity-dependent and Mediated by Interaction with Voltage-dependent Anion Channel 2 (VDAC2) Reviewed

    Masaya Tanno, Atsushi Kuno, Satoko Ishikawa, Takayuki Miki, Hidemichi Kouzu, Toshiyuki Yano, Hiromichi Murase, Toshiyuki Tobisawa, Makoto Ogasawara, Yoshiyuki Horio, Tetsuji Miura

    JOURNAL OF BIOLOGICAL CHEMISTRY   289 ( 42 )   29285 - 29296   2014.10

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    DOI： 10.1074/jbc.M114.563924

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  • Does glycemic control reverse dispersion of ventricular repolarization in type 2 diabetes? Reviewed

    Takayuki Miki, Toshiyuki Tobisawa, Tatsuya Sato, Masaya Tanno, Toshiyuki Yano, Hiroshi Akasaka, Atsushi Kuno, Makoto Ogasawara, Hiromichi Murase, Shigeyuki Saitoh, Tetsuji Miura

    CARDIOVASCULAR DIABETOLOGY   13   125   2014.8

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    DOI： 10.1186/s12933-014-0125-8

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  • Pivotal Role of mTORC2 and Involvement of Ribosomal Protein S6 in Cardioprotective Signaling Reviewed

    Toshiyuki Yano, Marcella Ferlito, Angel Aponte, Atsushi Kuno, Tetsuji Miura, Elizabeth Murphy, Charles Steenbergen

    CIRCULATION RESEARCH   114 ( 8 )   1268 - 1280   2014.4

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    DOI： 10.1161/CIRCRESAHA.114.303562

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  • Type 2 diabetes induces subendocardium-predominant reduction in transient outward K+ current with downregulation of Kv4.2 and KChIP2 Reviewed

    Tatsuya Sato, Takeshi Kobayashi, Atsushi Kuno, Takayuki Miki, Masaya Tanno, Hidemichi Kouzu, Takahito Itoh, Satoko Ishikawa, Takashi Kojima, Tetsuji Miura, Noritsugu Tohse

    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY   306 ( 7 )   H1054 - H1065   2014.4

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    DOI： 10.1152/ajpheart.00414.2013

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  • Reversal of metabolic shift in post-infarct-remodelled hearts: possible novel therapeutic approach Reviewed

    Masaya Tanno, Atsushi Kuno

    CARDIOVASCULAR RESEARCH   97 ( 2 )   195 - 196   2013.2

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  • Resveratrol Improves Cardiomyopathy in Dystrophin-deficient Mice through SIRT1 Protein-mediated Modulation of p300 Protein Reviewed

    Atsushi Kuno, Yusuke S. Hori, Ryusuke Hosoda, Masaya Tanno, Tetsuji Miura, Kazuaki Shimamoto, Yoshiyuki Horio

    JOURNAL OF BIOLOGICAL CHEMISTRY   288 ( 8 )   5963 - 5972   2013.2

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    DOI： 10.1074/jbc.M112.392050

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  • Differential cell-protective function of two resveratrol (trans-3,5,4'-trihydroxystilbene) glucosides against oxidative stress. Reviewed International journal

    Ryusuke Hosoda, Atsushi Kuno, Yusuke S Hori, Katsuki Ohtani, Nobutaka Wakamiya, Azusa Oohiro, Hiroki Hamada, Yoshiyuki Horio

    The Journal of pharmacology and experimental therapeutics   344 ( 1 )   124 - 32   2013.1

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    Resveratrol (trans-3,5,4'-trihydroxystilbene; RSV), a natural polyphenol, exerts a beneficial effect on health and diseases. RSV targets and activates the NAD(+)-dependent protein deacetylase SIRT1; in turn, SIRT1 induces an intracellular antioxidative mechanism by inducing mitochondrial superoxide dismutase (SOD2). Most RSV found in plants is glycosylated, and the effect of these glycosylated forms on SIRT1 has not been studied. In this study, we compared the effects of RSV and two glycosyl RSVs, resveratrol-3-O-β-d-glucoside (3G-RSV; polydatin/piceid) and resveratrol-4'-O-β-d-glucoside (4'G-RSV), at the cellular level. In oxygen radical absorbance capacity and 2,2-diphenyl-1-picrylhydrazyl radical scavenging assays, the antioxidant activity of 3G-RSV was comparable to that of RSV, whereas the radical-scavenging efficiency of 4'G-RSV was less than 50% of that of RSV. However, 4'G-RSV, but not 3G-RSV, induced SIRT1-dependent histone H3 deacetylation and SOD2 expression in mouse C2C12 skeletal myoblasts; as with RSV, SIRT1 knockdown blunted these effects. RSV and 4'G-RSV, but not 3G-RSV, mitigated oxidative stress-induced cell death in C2C12 cells and primary neonatal rat cardiomyocytes. RSV and 4'G-RSV inhibited C2C12 cell proliferation, but 3G-RSV did not. RSV was found in both the intracellular and extracellular fractions of C2C12 cells that had been incubated with 4'G-RSV, indicating that 4'G-RSV was extracellularly deglycosylated to RSV, which was then taken up by the cells. C2C12 cells did not deglycosylate 3G-RSV. Our results point to 4'G-RSV as a useful RSV prodrug with high water solubility. These data also show that the in vitro antioxidative activity of these molecules did not correlate with their ability to protect cells from oxidative stress-induced apoptosis.

    DOI： 10.1124/jpet.112.198937

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  • Regulation of FOXOs and p53 by SIRT1 modulators under oxidative stress. Reviewed

    Hori YS, Kuno A, Hosoda R, Horio Y

    PloS one   8 ( 9 )   e73875 - e73875   2013

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  • Cytoprotective regulation of the mitochondrial permeability transition pore is impaired in type 2 diabetic Goto-Kakizaki rat hearts Reviewed

    Takahito Itoh, Hidemichi Kouzu, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Tatsuya Sato, Daisuke Sunaga, Hiromichi Murase, Tetsuji Miura

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   53 ( 6 )   870 - 879   2012.12

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    DOI： 10.1016/j.yjmcc.2012.10.001

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  • Emerging beneficial roles of sirtuins in heart failure Reviewed

    Masaya Tanno, Atsushi Kuno, Yoshiyuki Horio, Tetsuji Miura

    BASIC RESEARCH IN CARDIOLOGY   107 ( 4 )   273   2012.7

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  • Role of connexin-43 in protective PI3K-Akt-GSK-3 beta signaling in cardiomyocytes Reviewed

    Satoko Ishikawa, Atsushi Kuno, Masaya Tanno, Takayuki Miki, Hidemichi Kouzu, Takahito Itoh, Tatsuya Sato, Daisuke Sunaga, Hiromichi Murase, Tetsuji Miura

    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY   302 ( 12 )   H2536 - H2544   2012.6

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    DOI： 10.1152/ajpheart.00940.2011

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  • Role of ER Stress in Ventricular Contractile Dysfunction in Type 2 Diabetes Reviewed

    Akifumi Takada, Takayuki Miki, Atsushi Kuno, Hidemichi Kouzu, Daisuke Sunaga, Takahito Itoh, Masaya Tanno, Toshiyuki Yano, Tatsuya Sato, Satoko Ishikawa, Tetsuji Miura

    PLOS ONE   7 ( 6 )   e39893   2012.6

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  • Cellular and molecular effects of sirtuins in health and disease Reviewed

    Yoshiyuki Horio, Takashi Hayashi, Atsushi Kuno, Risa Kunimoto

    CLINICAL SCIENCE   121 ( 5-6 )   191 - 203   2011.9

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  • Resveratrol Ameliorates Muscular Pathology in the Dystrophic mdx Mouse, a Model for Duchenne Muscular Dystrophy Reviewed

    Yusuke S. Hori, Atsushi Kuno, Ryusuke Hosoda, Masaya Tanno, Tetsuji Miura, Kazuaki Shimamoto, Yoshiyuki Horio

    JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS   338 ( 3 )   784 - 794   2011.9

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    DOI： 10.1124/jpet.111.183210

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  • A(2B) adenosine receptors inhibit superoxide production from mitochondrial complex I in rabbit cardiomyocytes via a mechanism sensitive to Pertussis toxin Reviewed

    Xiulan Yang, Wenkuan Xin, Xi-Ming Yang, Atsushi Kuno, Thomas C. Rich, Michael V. Cohen, James M. Downey

    BRITISH JOURNAL OF PHARMACOLOGY   163 ( 5 )   995 - 1006   2011.7

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    DOI： 10.1111/j.1476-5381.2011.01288.x

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  • Hypertensive Hypertrophied Myocardium Is Vulnerable to Infarction and Refractory to Erythropoietin-Induced Protection Reviewed

    Toshiyuki Yano, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Takahito Itoh, Akifumi Takada, Tatsuya Sato, Hidemichi Kouzu, Kazuaki Shimamoto, Tetsuji Miura

    HYPERTENSION   57 ( 1 )   110 - U291   2011.1

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    DOI： 10.1161/HYPERTENSIONAHA.110.158469

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  • Roles of phospho-GSK-3 beta in myocardial protection afforded by activation of the mitochondrial K-ATP channel Reviewed

    Yoshiaki Terashima, Tatsuya Sato, Toshiyuki Yano, Ole Maas, Takahito Itoh, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Kazuaki Shimamoto, Tetsuji Miura

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   49 ( 5 )   762 - 770   2010.11

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    DOI： 10.1016/j.yjmcc.2010.08.001

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  • Protein deacetylase SIRT1 in the cytoplasm promotes nerve growth factor-induced neurite outgrowth in PC12 cells. Reviewed International journal

    Toshiya Sugino, Mitsuhisa Maruyama, Masaya Tanno, Atsushi Kuno, Kiyohiro Houkin, Yoshiyuki Horio

    FEBS letters   584 ( 13 )   2821 - 6   2010.7

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    SIRT1, a NAD(+)-dependent protein deacetylase, is known to have neural functions. However, despite its cytoplasmic expression in some neural cells, its cytoplasmic function, if any, is unknown. Here we found that PC12 (pheochromocytoma) cells expressed SIRT1 in the cytoplasm. Nerve growth factor (NGF)-induced neurite outgrowth of these cells was promoted by activators of SIRT1, while inhibitors of SIRT1 or SIRT1-siRNA significantly inhibited it. The overexpression of a mutant SIRT1 that localised to the cytoplasm but not the nucleus enhanced the NGF-dependent neurite outgrowth, and a cytoplasmic dominant-negative SIRT1 suppressed it. Thus, cytoplasmic SIRT1 increases the NGF-induced neurite outgrowth of PC12 cells.

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  • Induction of Manganese Superoxide Dismutase by Nuclear Translocation and Activation of SIRT1 Promotes Cell Survival in Chronic Heart Failure Reviewed

    Masaya Tanno, Atsushi Kuno, Toshiyuki Yano, Tetsuji Miura, Shin Hisahara, Satoko Ishikawa, Kazuaki Shimamoto, Yoshiyuki Horio

    JOURNAL OF BIOLOGICAL CHEMISTRY   285 ( 11 )   8375 - 8382   2010.3

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    DOI： 10.1074/jbc.M109.090266

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  • Angiotensin II Type 1 Receptor-Mediated Upregulation of Calcineurin Activity Underlies Impairment of Cardioprotective Signaling in Diabetic Hearts Reviewed

    Hiroyuki Hotta, Tetsuji Miura, Takayuki Miki, Nobuhiko Togashi, Takuto Maeda, Seok Jai Kim, Masaya Tanno, Toshiyuki Yano, Atsushi Kuno, Takahito Itoh, Takahiro Satoh, Yoshiaki Terashima, Satoko Ishikawa, Kazuaki Shimamoto

    CIRCULATION RESEARCH   106 ( 1 )   129 - U260   2010.1

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    DOI： 10.1161/CIRCRESAHA.109.205385

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  • [Anti-aging drugs]. Reviewed

    Kuno A, Horio Y

    Nihon rinsho. Japanese journal of clinical medicine   67 ( 7 )   1384 - 1388   2009.7

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  • Infarct limitation by a protein kinase G activator at reperfusion in rabbit hearts is dependent on sensitizing the heart to A(2b) agonists by protein kinase C Reviewed

    Atsushi Kuno, Nataliya V. Solenkova, Victoriya Solodushko, Turhan Dost, Yanping Liu, Xi-Ming Yang, Michael V. Cohen, James M. Downey

    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY   295 ( 3 )   H1288 - H1295   2008.9

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    DOI： 10.1152/ajpheart.00209.2008

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  • Protein kinase C protects preconditioned rabbit hearts by increasing sensitivity of adenosine A(2b)-dependent signaling during early reperfusion Reviewed

    Atsushi Kuno, Stuart D. Critz, Lin Cui, Victoriya Solodushko, Xi-Ming Yang, Thomas Krahn, Barbara Albrecht, Sebastian Philipp, Michael V. Cohen, James M. Downey

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   43 ( 3 )   262 - 271   2007.9

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    DOI： 10.1016/j.yjmcc.2007.05.016

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  • The beta-opioid receptor agonist DADLE at reperfusion protects the heart through activation of pro-survival kinases via EGF receptor transactivation Reviewed

    Karina Foerster, Atsushi Kuno, Natalia Solenkova, Stephan B. Felix, Thomas Krieg

    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY   293 ( 3 )   H1604 - H1608   2007.9

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    DOI： 10.1152/ajpheart.00418.2007

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  • Preconditioning-mimetics bradykinin and DADLE activate PI3-kinase through divergent pathways Reviewed

    Michael V. Cohen, Sebastian Philipp, Thomas Krieg, Lin Cui, Atsushi Kuno, Viktoriya Solodushko, James M. Downey

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   42 ( 4 )   842 - 851   2007.4

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    DOI： 10.1016/j.yjmcc.2007.01.004

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  • Total liquid ventilation provides ultra-fast cardioprotective cooling Reviewed

    Renaud Tissier, Kazutoshl Hamanaka, Atsushi Kuno, James C. Parker, Michael V. Cohen, James M. Downey

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   49 ( 5 )   601 - 605   2007.2

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    DOI： 10.1016/j.jacc.2006.09.041

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  • Nicorandil opens mitochondrial K-ATP channels not only directly but also through a NO-PKG-dependent pathway Reviewed

    Atsushi Kuno, Stuart D. Critz, Michael V. Cohen, James M. Downey

    BASIC RESEARCH IN CARDIOLOGY   102 ( 1 )   73 - 79   2007.1

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    DOI： 10.1007/s00395-006-0612-5

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  • Protective role of gap junctions in preconditioning against myocardial infarction Reviewed

    T Miura, Y Ohnuma, A Kuno, M Tanno, Y Ichikawa, Y Nakamura, T Yano, T Miki, J Sakamoto, K Shimamoto

    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY   286 ( 1 )   H214 - H221   2004.1

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    DOI： 10.1152/ajpheart.00441.2003

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  • Interruption of signal transduction between G protein and PKC-epsilon underlies the impaired myocardial response to ischemic preconditioning in postinfarct remodeled hearts Reviewed

    T Miki, T Miura, M Tanno, J Sakamoto, A Kuno, S Genda, T Matsumoto, Y Ichikawa, K Shimamoto

    MOLECULAR AND CELLULAR BIOCHEMISTRY   247 ( 1-2 )   185 - 193   2003.5

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    DOI： 10.1023/A:1024124016053

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  • Infarct size limitation by nicorandil: Roles of mitochondrial K-ATP channels, sarcolemmal K-ATP channels, and protein kinase C Reviewed

    A Tsuchida, T Miura, M Tanno, J Sakamoto, T Miki, A Kuno, T Matsumoto, Y Ohnuma, Y Ichikawa, K Shimamoto

    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY   40 ( 8 )   1523 - 1530   2002.10

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    DOI： 10.1016/S0735-1097(02)02268-4

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  • Opening of mitochondrial K-ATP channel occurs downstream of PKC-epsilon activation in the mechanism of preconditioning Reviewed

    Y Ohnuma, T Miura, T Miki, M Tanno, A Kuno, A Tsuchida, K Shimamoto

    AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY   283 ( 1 )   H440 - H447   2002.7

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    DOI： 10.1152/ajpheart.00434.2001

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  • Blockade of angiotensin II type 1 receptors suppressed free radical production and preserved coronary endothelial function in the rabbit heart after myocardial infarction Reviewed

    A Kuno, T Miura, A Tsuchida, T Hasegawa, T Miki, Y Nishino, K Shimamoto

    JOURNAL OF CARDIOVASCULAR PHARMACOLOGY   39 ( 1 )   49 - 57   2002.1

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    DOI： 10.1097/00005344-200201000-00006

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  • Critical timing of mitochondrial KATP channel opening for enhancement of myocardial tolerance against infarction Reviewed

    Akihito Tsuchida, Tetsuji Miura, Takayuki Miki, Atsushi Kuno, Masaya Tanno, Yukinaga Nozawa, Satoshi Genda, Tomoaki Matsumoto, Kazuaki Shimamoto

    Basic Research in Cardiology   96 ( 5 )   446 - 453   2001

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    DOI： 10.1007/s003950170026

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  • Endothelium-dependent coronary response is impaired in the myocardium at an early phase of post-infarct remodeling Reviewed

    T Hasegawa, T Miura, A Tsuchida, T Miki, A Nakano, A Kuno, K Shimamoto

    JAPANESE HEART JOURNAL   41 ( 6 )   743 - 755   2000.11

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    DOI： 10.1536/jhj.41.743

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  • Mobile intracardiac calcinosis: a new risk of thromboembolism in patients with haemodialysed end stage renal disease Reviewed

    K Tsuchihashi, A Nozawa, S Marusaki, N Moniwa, Y Oh-numa, A Kuno, S Takagi, H Takizawa, N Ura, K Shimamoto

    HEART   82 ( 5 )   638 - 640   1999.11

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  • Sustained right ventricular dyskinesis complicated by right ventricular infarction Reviewed

    T Nakata, A Hashimoto, A Kuno, K Tsuchihashi, S Yonekura, K Shimamoto

    JOURNAL OF NUCLEAR MEDICINE   38 ( 9 )   1421 - 1423   1997.9

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  • Low Plasma Branched-chain Amino Acids under SGLT2 Inhibitor Administration Predict Poor Prognosis in Heart Failure Patients

    神津英至, 矢野俊之, 片野唆敏, 沼澤瞭, 大堀克彦, 川原田航, 小川俊史, 小川俊史, 舘越勇輝, 舘越勇輝, 佐藤達也, 佐藤達也, 久野篤史, 久野篤史, 丹野雅也, 丹野雅也, 古橋眞人

    日本循環器学会学術集会(Web)   89th   2025

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  • SIRT1活性化薬はドキソルビシンによる腎尿細管のミトコンドリア形態異常を抑制する

    齊藤圭司, 細田隆介, 岩原直敏, 野島伊世里, 嵯峨幸夏, 久野篤史

    日本薬理学雑誌   159 ( Supplement )   2024

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  • NAD<sup>+</sup>前駆体ニコチンアミド・モノヌクレオチドの投与はドキソルビシンによる心・腎障害とカヘキシアを軽減する

    久野篤史, 齊藤圭司, 細田隆介, 舘越勇輝, 嵯峨幸夏

    日本腫瘍循環器学会学術集会抄録集(Web)   7th   2024

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  • Administration of Nicotinamide Mononucleotide, a Precursor of NAD+, Attenuates Doxorubicin-induced Cardiotoxicity and Renal Tubular Injury in Mice

    齊藤圭司, 細田隆介, 嵯峨幸夏, 舘越勇輝, 久野篤史

    日本循環器学会学術集会(Web)   88th   2024

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  • Impact of Mitochondrial Dynamics on Necroptosis in Cardiomyocytes

    戸田悠貴, 矢野俊之, 久野篤史, 久野篤史, 丹野雅也, 丹野雅也, 神津英至, 佐藤達也, 佐藤達也, 大和田渉, 舘越勇輝, 舘越勇輝, 小川俊史, 小川俊史, 清水将輝, 古橋眞人

    日本循環器学会学術集会(Web)   88th   2024

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  • レスベラトロールによるSIRT1活性化はドキソルビシンによる骨格筋萎縮を改善する

    岩舩令佳, 細田隆介, 中島龍汰, 岩原直敏, 野島伊世里, 久野篤史

    日本分子生物学会年会プログラム・要旨集(Web)   47th   2024

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  • 加齢による皮膚菲薄化に対するSIRT1活性化薬レスベラトロールの効果

    田村楓佳, 細田隆介, 野島伊世里, 久野篤史

    日本分子生物学会年会プログラム・要旨集(Web)   47th   2024

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  • NAD<sup>+</sup>の前駆体であるニコチンアミドモノヌクレオチドの投与は,ドキソルビシンによる心臓および腎臓の毒性を抑制する

    宮崎瑞菜, 斉藤圭司, 細田隆介, 嵯峨幸夏, 舘越勇輝, 久野篤史

    日本分子生物学会年会プログラム・要旨集(Web)   47th   2024

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  • サルコペニアの骨格筋において亢進するアセチル化蛋白の同定とそれらの機能的意義

    細田隆介, 中島龍汰, 岩原直敏, 野島伊世里, 久野篤史

    日本分子生物学会年会プログラム・要旨集(Web)   47th   2024

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  • SIRT1によるオートリソソーム形成の制御におけるRab7の役割解明

    嵯峨幸夏, 細田隆介, 久野篤史

    日本分子生物学会年会プログラム・要旨集(Web)   47th   2024

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  • 糖尿病心におけるβ酸化の候補制御因子としてのアセチル化電子伝達フラビンタンパク質αの同定

    矢野雅貴, 舘越勇輝, 細田隆介, 嵯峨幸夏, 久野篤史

    日本分子生物学会年会プログラム・要旨集(Web)   47th   2024

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  • 糖尿病腎における虚血再灌流時のオートファジー障害とネクロプトーシス経路亢進の関連

    高橋怜央, 嵯峨幸夏, 細田隆介, 舘越勇輝, 久野篤史

    日本分子生物学会年会プログラム・要旨集(Web)   47th   2024

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  • 糖尿病腎におけるオートファジー障害はネクロプトーシス経路を亢進させる

    高橋怜央, 嵯峨幸夏, 細田隆介, 舘越勇輝, 久野篤史

    日本薬理学雑誌   159 ( Supplement )   2024

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  • 加齢によるサルコペニアの骨格筋で増加するアセチル化蛋白の網羅的解析

    細田隆介, 中島龍汰, 岩原直敏, 野島伊世里, 久野篤史

    日本薬理学雑誌   159 ( Supplement )   2024

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  • ドキソルビシンによる臓器毒性はニコチンアミド・モノヌクレオチドにより軽減する

    久野篤史, 細田隆介, 岩原直敏, 野島伊世里, 嵯峨幸夏, 齊藤圭司

    日本薬理学雑誌   158 ( Supplement )   2023

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  • Analysis of acetylated proteins in the skeletal muscle increased by aging and SIRT1 knockout.

    細田隆介, 中島龍汰, 岩原直敏, 野島伊世里, 久野篤史

    日本分子生物学会年会プログラム・要旨集(Web)   46th   2023

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  • 骨格筋におけるSIRT1の活性化はオートファジー活性を維持して加齢によるサルコペニアを改善する

    細田隆介, 久野篤史, 中島龍汰, 岩原直敏, 野島伊世里

    日本薬理学雑誌   158 ( Supplement )   2023

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  • Duchenne型筋ジストロフィーの骨格筋では転写因子TFEBの活性低下によりオートファジーが障害される

    中島龍汰, 細田隆介, 久野篤史

    日本薬理学雑誌   158 ( Supplement )   2023

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  • 2型糖尿病の心臓におけるミトコンドリア型サーチュインSIRT3の役割

    矢野雅貴, 谷口祥貴, 細田隆介, 岩原直敏, 久野篤史

    日本薬理学雑誌   158 ( Supplement )   2023

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  • 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   86回   PJ21 - 1   2022.3

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  • 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   2022.1

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  • Roles of an NAD<sup>+</sup>-dependent protein deacetylase SIRT1 and protein acetylation in aging-associated sarcopenia

    久野篤史, 細田隆介, 岩原直敏

    代謝異常治療研究基金研究業績集   45   2022

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  • 【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   13 ( 11 )   86 - 93   2021.11

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  • 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   36 ( 9 )   910 - 914   2021.8

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  • 【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   93 ( 1 )   100 - 108   2021.2

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  • Novel microRNA-mediated Regulation of AMP Deaminase, a Key Player in Diabetic Cardiomyopathy

    TANNO Masaya, TATEKOSHI Yuki, KOUZU Hidemichi, KUNO Atsushi, YANO Toshiyuki, MIKI Takayuki, MIURA Tetsuji

    日本循環器学会学術集会(Web)   83rd   2019

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  • 【心不全(第2版)上-最新の基礎・臨床研究の進歩-】心不全の基礎研究 心不全の分子機序 心筋リモデリング DNA・転写制御障害 Sirtuin

    丹野 雅也, 久野 篤史

    日本臨床   76 ( 増刊9 心不全(上) )   325 - 330   2018.12

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  • レスベラトロールによる筋ジストロフィーの治療

    堀尾 嘉幸, 久野 篤史, 川村 健太郎, 堤 裕幸

    BIO Clinica   33 ( 8 )   770 - 775   2018.7

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  • SIRT1は老化関連タンパクPrl2C3を負に制御する(SIRT1 negatively regulates the expression of Prl2C3, a senescence-associated protein)

    堀本 浩平, 國本 梨沙, 橋本 梨沙, 上田 直弘, 細田 隆介, 久野 篤史, 山下 利春, 堀尾 嘉幸

    札幌医学雑誌   86 ( 1-6 )   63 - 71   2017.12

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  • Dysregulation of miR-301b Contributes to Diabetic Cardiomyopathy via Upregulation of AMP Deaminase in the Vicinity of the Sarcoplasmic Reticulum

    Yuki Tatekoshi, Masaya Tanno, Takayuki Miki, Atsushi Kuno, Toshiyuki Yano, Wataru Ohwada, Koki Abe, Yusuke Igaki, Yugo Fujita, Tetsuji Miura

    CIRCULATION   136   2017.11

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  • Empagliflozin, an SGLT2 inhibitor, improves survival after myocardial infarction in diabetic rats by up-regulating anti-oxidative stress proteins

    H. Oshima, M. Mizuno, T. Miki, A. Kuno, K. Nakata, Y. Kimura, T. Yano, M. Tanno, T. Miura

    DIABETOLOGIA   60   S32 - S32   2017.9

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  • 長寿遺伝子SIRT1活性化による筋ジストロフィーの治療

    久野 篤史, 川村 健太郎, 堀尾 嘉幸

    臨床薬理の進歩   ( 38 )   79 - 86   2017.6

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  • 筋ジストロフィーの新治療法の開発

    久野 篤史, 細田 隆介, 堀尾 嘉幸

    Medical Science Digest   42 ( 13 )   642 - 646   2016.12

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  • ROS-Induced Mitochondrial Translocation of Phosphatases Cancels Cell-Protective Signals Activated by Phosphorylation of Mitochondrial Protective Kinases

    Wataru Ohwada, Masaya Tanno, Toshiyuki Yano, Atsushi Kuno, Takayuki Miki, Satoko Ishikawa, Yuki Tatekoshi, Koki Abe, Kouhei Ohno, Masashi Mizuno, Kei Nakata, Tetsuji Miura

    CIRCULATION   134   2016.11

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  • Impaired Autophagy Induced by Activated mTORC1 Underlies Development of Dystrophic Cardiomyopathy.

    Atsushi Kuno, Ryusuke Hosoda, Rio Sebori

    CIRCULATION   134   2016.11

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  • 【超高齢化時代の呼吸器診療】 基礎医学とのダイアローグ 長寿遺伝子サーチュイン

    堀尾 嘉幸, 久野 篤史, 國本 梨沙

    THE LUNG-perspectives   24 ( 3 )   303 - 306   2016.8

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  • Upregulation of AMP deaminase activity in diabetic hearts by decreased interaction with phosphoglucomutase-1 and depletion of fructose 1,6-diphosphate: a novel mechanism for diabetic cardiomyopathy

    Y. Tatekoshi, M. Tanno, H. Kouzu, T. Miki, A. Kuno, S. Ishikawa, T. Yano, W. Ohwada, K. Ohno, M. Mizuno, K. Nishizawa, K. Nakata, T. Miura

    EUROPEAN HEART JOURNAL   37   1037 - 1038   2016.8

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  • Restoration of the intra-mitochondrial interplay between protective signals and malate-aspartate shuttle by continuous erythropoietin receptor activation prevents CKD-induced infarct size enlargement

    K. Nishizawa, T. Yano, T. Miki, M. Tanno, A. Kuno, T. Tobisawa, M. Ogasawara, S. Muratsubaki, K. Ohno, M. Mizuno, W. Ohwada, S. Ishikawa, T. Miura

    EUROPEAN HEART JOURNAL   37   522 - 523   2016.8

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  • Sequestration of p62 by RIP1 promotes necroptosis through suppression of autophagic flux in cardiomyocytes; a novel cross-talk between autophagy and necroptosis

    T. Yano, M. Ogasawara, T. Miki, M. Tanno, A. Kuno, K. Ohno, K. Nishizawa, W. Owada, M. Mizuno, H. Sugawara, Y. Takekoshi, K. Nakata, S. Ishikawa, T. Miura

    EUROPEAN HEART JOURNAL   37   307 - 307   2016.8

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  • Excessive ROS production in mitochondria switches off protective mitochondrial kinase signaling

    M. Tanno, W. Ohwada, T. Yano, T. Miki, A. Kuno, S. Ishikawa, Y. Tatekoshi, K. Nishizawa, M. Mizuno, T. Miura

    CARDIOVASCULAR RESEARCH   111   S1 - S1   2016.7

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  • ピセアタンノールとレスベラトロールの酸化ストレスに対する細胞保護効果の比較

    細田 隆介, 久野 篤史, 瀬堀 理生, 濱田 博喜, 堀尾 嘉幸

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   88回・38回   [3P0135] - [3P0135]   2015.12

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    Ichushi

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  • SIRT1 in the Cardiomyocyte Counteracts Doxorubicin Cardiotoxicity in vivo

    Miki Tsukamoto, Atsushi Kuno, Ryusuke Hosoda, Rio Sebori, Yoshiyuki Horio

    CIRCULATION   132   2015.11

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  • Regulation of Mitochondrial Functions by Sirtuin Proteins in Heart Failure

    Masaya Tanno, Atsushi Kuno, Yoshiyuki Horio, Tetsuji Miura

    JOURNAL OF CARDIAC FAILURE   21 ( 10 )   S158 - S159   2015.10

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  • Enlargement of Infarct Size by CKD is Preventable by Consistent Activation of the Erythropoietin Receptor

    Keitaro Nishizawa, Toshiyuki Yano, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Hidemichi Kouzu, Toshiyuki Tobisawa, Tetsuji Miura

    JOURNAL OF CARDIAC FAILURE   21 ( 10 )   S180 - S180   2015.10

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  • Continuous erythropoietin receptor activation reverses increased myocardial susceptibility to ischemia/reperfusion injury in chronic renal failure

    K. Nishizawa, T. Yano, T. Miki, M. Tanno, A. Kuno, H. Kouzu, T. Tobisawa, M. Mizuno, H. Sugawara, T. Miura

    EUROPEAN HEART JOURNAL   36   378 - 378   2015.8

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  • Dysregulation of two phosphorylation sites in Akt, Thr308 and Ser473, upon reperfusion mediates enlargement of myocardial infarct size by chronic renal failure

    T. Tobisawa, T. Yano, T. Miki, A. Kuno, M. Tanno, H. Kouzu, M. Ogasawara, S. Muratsubaki, K. Ohno, T. Miura

    EUROPEAN HEART JOURNAL   36   170 - 170   2015.8

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  • Resveratrol ameliorates dystrophic cardiomyopathy by activating FoxO transcription factors

    A. Kuno, T. Miura, Y. Horio

    EUROPEAN HEART JOURNAL   36   670 - 670   2015.8

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  • Dysregulation of intramolecular interplay between two phosphorylation sites in Akt contributes to enlargement of infarct size by chronic renal failure

    TOBISAWA Toshiyuki, YANO Toshiyuki, MIKI Takayuki, TANNO Masaya, KUNO Atsushi, KOUZU Hidemichi, OGASAWARA Makoto, MIURA Tetsuji

    日本血管生物医学会学術集会プログラム・抄録集   23rd   2015

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  • Disruption of mTORC2 Integrity Underlies Increased Myocardial Susceptibility to Ischemia/reperfusion Injury in Chronic Renal Failure

    Toshiyuki Tobisawa, Toshiyuki Yano, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Hidemichi Kouzu, Hiromichi Murase, Makoto Ogasawara, Shingo Muratsubaki, Masashi Mizuno, Keitaro Nishizawa, Satoko Ishikawa, Hideaki Yoshida, Tetsuji Miura

    CIRCULATION   130   2014.11

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  • Role of FOXO Transcription Factors in the Protective Mechanism by Resveratrol Against Cardiomyopathy in the Dystrophin-deficient Mdx Mouse

    Atsushi Kuno, Rio Sebori, Tetsuji Miura, Yoshiyuki Horio

    CIRCULATION   130   2014.11

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  • Accumulation of P62 by Dysregulation of Autophagy Induces Rip1-dependent Necroptosis in Cardiomyocytes: a Novel Interplay Between Autophagy and Necroptosis

    Makoto Ogasawara, Toshiyuki Yano, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Hidemichi Kouzu, Hiromichi Murase, Toshiyuki Tobisawa, Shingo Muratsubaki, Keitaro Nishizawa, Masashi Mizuno, Satoko Ishikawa, Tetsuji Miura

    CIRCULATION   130   2014.11

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  • Role of FOXO Transcription Factors in the Protective Mechanism by Resveratrol Against Cardiomyopathy in the Dystrophin-deficient Mdx Mouse

    Atsushi Kuno, Rio Sebori, Yoshiyuki Horio, Tetsuji Miura

    JOURNAL OF CARDIAC FAILURE   20 ( 10 )   S199 - S199   2014.10

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  • Insufficient ATP supply due to excessive degradation of adenine nucleotides by AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart

    H. Kouzu, T. Miki, M. Tanno, A. Kuno, T. Yano, H. Murase, T. Tobisawa, M. Ogasawara, S. Muratsubaki, T. Miura

    EUROPEAN HEART JOURNAL   35   327 - 327   2014.9

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  • Inhibition of DPP-4 restores myocardial autophagic flux and reduces mortality after myocardial infarction in diabetic rats

    H. Murase, A. Kuno, T. Miki, M. Tanno, T. Yano, H. Kouzu, T. Tobisawa, M. Ogasawara, S. Ishikawa, T. Miura

    EUROPEAN HEART JOURNAL   35   443 - 444   2014.9

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  • Mitochondrial translocation of GSK-3beta, a trigger of mitochondrial permeability transition, is mediated by its N-terminal domain and promoted by interaction with VDAC2.

    M. Tanno, T. Miura, T. Miki, A. Kuno, S. Ishikawa, T. Yano, H. Kouzu

    CARDIOVASCULAR RESEARCH   103   2014.7

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    DOI： 10.1093/cvr/cvu076.2

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  • A novel interplay between RIP1-dependent necroptosis and autophagy in cardiomyocytes.

    OGASAWARA Makoto, YANO Toshiyuki, MIKI Takayuki, TANNO Masaya, KUNO Atsushi, KOUZU Hidemichi, ISHIKAWA Satoko, MIURA Tetsuji

    International Society for Heart Research Annual Meeting of the Japanese Section. Program and Abstracts   31st   2014

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  • Chloroquine enhances temozolomide cytotoxicity in glioma cells by inducing mitochondrial ROS via blocking mitochondrial autophagy

    Atsushi Kuno, Yusuke Hori, Ryusuke Hosoda, Yoshiyuki Horio

    JOURNAL OF PHARMACOLOGICAL SCIENCES   124   171P - 171P   2014

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  • DPP-4 inhibition restores myocardial autophagic flux through attenuation of Bcl2-beclin-1 interaction and improves survival after myocardial infarction in diabetic rats.

    MURASE Hiromichi, KUNO Atsushi, MIKI Takayuki, TANNO Masaya, YANO Toshiyuki, KOUZU Hidemichi, ISHIKAWA Satoko, MIURA Tetsuji

    International Society for Heart Research Annual Meeting of the Japanese Section. Program and Abstracts   31st   2014

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  • Activation of the Glucagon-Like Peptide-1 Receptor Restores Myocardial Autophagic Flux and Reduces Mortality After Myocardial Infarction in Diabetic Rats

    Hiromichi Murase, Atsushi Kuno, Takayuki Miki, Masaya Tanno, Toshiyuki Yano, Hidemichi Kouzu, Toshiyuki Tobisawa, Makoto Ogasawara, Satoko Ishikawa, Tetsuji Miura

    CIRCULATION   128 ( 22 )   2013.11

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  • The Role of mTORC2 and Ribosomal Protein S6 in Cardioprotective Signaling

    Toshiyuki Yano, Marcella Ferlito, Toshiyuki Tobisawa, Atsushi Ogasawara, Hiromichi Murase, Atsushi Kuno, Masaya Tanno, Takayuki Miki, Charles Steenbergen, Tetsuji Miura

    JOURNAL OF CARDIAC FAILURE   19 ( 10 )   S138 - S138   2013.10

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  • Type 2 diabetes induces ventricular electrical remodeling with a transmural gradient

    T. Tobisawa, T. Sato, S. Yuda, T. Miki, M. Tanno, A. Kuno, T. Kobayashi, H. Akasaka, N. Tohse, T. Miura

    EUROPEAN HEART JOURNAL   34   926 - 926   2013.8

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  • Mechanisms Underlying Mitochondrial Translocation Of GSK-3 beta, A Crucial Inducer Of Mitochondrial Permeability Transition: GSK-3 beta Activity, Interaction With VDAC2 And A Mitochondrial Targeting Sequence

    Masaya Tanno, Atsushi Kuno, Satoko Ishikawa, Makoto Ogasawara, Toshiyuki Tobisawa, Hiromichi Murase, Tatsuya Sato, Hidemichi Kouzu, Takayuki Miki, Tetsuji Miura

    CIRCULATION RESEARCH   113 ( 4 )   2013.8

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  • 酸化ストレスによるミトコンドリア透過性遷移に対するニコランジルの効果

    須永 大介, 石川 聡子, 神津 英至, 久野 篤史, 丹野 雅也, 三木 隆幸, 三浦 哲嗣

    Therapeutic Research   34 ( 3 )   296,304 - 299,304   2013.3

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  • Type 2 diabetes induces subendocardium-predominant reduction of transient outward K<sup>+</sup> current via downregulation of Kv4.2 and KChIP2.

    SATO Tatsuya, KOBAYASHI Takeshi, KUNO Atsushi, MURASE Hiromichi, ISHIKAWA Satoko, KOUZU Hidemichi, TANNO Masaya, MIKI Takayuki, MIURA Tetsuji, TOHSE Noritsugu

    International Society for Heart Research Annual Meeting of the Japanese Section. Program and Abstracts   30th   2013

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  • Roles of insulin-like growth factor binding protein 5 (IGFBP5) in cellular senescence

    Yuki Toda, Atsushi Kuno, Rio Sebori, Kouki Abe, Yusuke Hori, Ryusuke Hosoda, Takashi Hayashi, Yoshiyuki Horio

    JOURNAL OF PHARMACOLOGICAL SCIENCES   121   92P - 92P   2013

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  • Mechanisms of mPTP re-closure by activation of the mitochondrical ATP-sensitive K<sup>+</sup> channel: suppression of GSK-3β-Rieske interaction and ROS production after oxidative stress

    SUNAGA Daisuke, TANNO Masaya, ISHIKAWA Satoko, KUNO Atsushi, SATO Tatsuya, KOUZU Hidemichi, MIKI Takayuki, MIURA Tetsuji

    International Society for Heart Research Annual Meeting of the Japanese Section. Program and Abstracts   30th   2013

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  • 【レスベラトロール】 レスベラトロールの筋肉・神経疾患への応用

    堀尾 嘉幸, 久野 篤史

    アンチ・エイジング医学   8 ( 6 )   906 - 912   2012.12

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    Ichushi

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  • Facilitated Re-Closure of the Mitochondrial Permeability Transition Pore Underlies Protection of Cardiomyocytes from ROS-Induced Necrosis by Activation of the Mitochondrial ATP-Sensitive K+ Channel

    Daisuke Sunaga, Atsushi Kuno, Satoko Ishikawa, Takayuki Miki, Masaya Tannno, Hidemichi Kouzu, Takahito Itoh, Tatsuya Sato, Hiromichi Murase, Tetsuji Miura

    CIRCULATION   126 ( 21 )   2012.11

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  • Titin-isoform Shift May Underlie Distinct Ventricular Responses to Pressure and Volume Overloads in Type 2 Diabetic Heart

    Hidemichi Kouzu, Atsushi Kuno, Takayuki Miki, Masaya Tanno, Takahito Itoh, Tatsuya Sato, Daisuke Sunaga, Hiromichi Murase, Tetsuji Miura

    CIRCULATION   126 ( 21 )   2012.11

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  • Resveratrol, a SIRT1 activator, prevents cardiomyopathy in dystrophin-deficient mice by down-regulation of p300

    A. Kuno, M. Tanno, T. Miki, S. Ishikawa, Y. Horio, T. Miura

    EUROPEAN HEART JOURNAL   33   803 - 803   2012.8

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  • Modified interaction of inorganic phosphate carrier with cyclophilin D underlies impaired response of diabetic heart to cardioprotection

    T. Itoh, T. Miki, M. Tanno, A. Kuno, H. Kouzu, T. Sato, D. Sunaga, H. Murase, S. Ishikawa, T. Miura

    EUROPEAN HEART JOURNAL   33   109 - 109   2012.8

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  • 【がん疼痛の管理 アセトアミノフェンとNSAIDs】 アセトアミノフェンとNSAIDsが及ぼす副作用リスクとその対応 NSAIDsと心・脳血管障害

    久野 篤史, 三浦 哲嗣

    薬局   63 ( 6 )   2321 - 2326   2012.5

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    Ichushi

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  • Ser9位のGSK-3βのリン酸化はミトコンドリアへの移行を阻害し、ミトコンドリアによる致死性ROS産生を減弱する(Phosphorylation of GSK-3β at Ser9 Inhibits Its Translocation to Mitochondria and Attenuates Lethal ROS Production by Mitochondria)

    Tanno Masaya, Miki Takayuki, Kuno Atsushi, Kouzu Hidemichi, Itoh Takahito, Satoh Tatsuya, Ishikawa Satoko, Sunaga Daisuke

    Circulation Journal   76 ( Suppl.I )   943 - 943   2012.3

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    Ichushi

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  • Transient Outward K+ Current (I-To) is Reduced Especially in the Suben-docardium via Downregulation of Kv4.2 and KChIP2 Gene Expression in Obese Type2 Diabetic Rat Hearts

    Tatsuya Sato, Takeshi Kobayashi, Atsushi Kuno, Takayuki Miki, Masaya Tanno, Tetsuji Miura, Noritsugu Tohse

    BIOPHYSICAL JOURNAL   102 ( 3 )   339A - 340A   2012.1

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  • 糖尿病心筋の心保護機構破綻の分子メカニズムにおけるSIRT1の意義

    久野 篤史

    医科学応用研究財団研究報告   31   269 - 271   2012

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  • SIRT1 suppresses cardiac hypertrophy by downregulating p300 via the ubiquitin-proteasome pathway

    Atsushi Kuno, Tetsuji Miura, Kazuaki Shimamoto, Yoshiyuki Horio

    JOURNAL OF PHARMACOLOGICAL SCIENCES   118   199P - 199P   2012

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  • Activation of the Mitochondrial Atp-Sensitive K<sup>+</sup> Channel Promotes Re-Closure of the Mitochondrial Permeability Transition Pore and Protects Cardiomyocytes from Oxidant Stress-Induced Necrosis

    SUNAGA Daisuke, KUNO Atsushi, ISHIKAWA Satoko, MIKI Takayuki, TANNO Masayuki, KOUZU Hidemichi, ITOH Takahito, SATO Tatsuya, MURASE Hiromichi, MIURA Tetsuji

    International Society for Heart Research Annual Meeting of the Japanese Section. Program and Abstracts   29th   2012

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  • Increased Interaction of Inorganic Phosphate Carrier with Cyclophilin D Underlies Impaired Cardioprotection in Diabetic Heart

    ITOH Takahito, MIKI Takayuki, TANNO Masaya, KUNO Atsushi, KOUZU Hidemichi, SATO Tatsuya, SUNAGA Daisuke, MURASE Hiromichi, ISHIKAWA Satoko, MIURA Tetsuji

    International Society for Heart Research Annual Meeting of the Japanese Section. Program and Abstracts   29th   2012

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  • SIRT1 activation by resveratrol ameliorates dystrophic muscle pathology in mdx mice

    Yusuke Hori, Atsushi Kuno, Ryusuke Hosoda, Masaya Tanno, Tetsuji Miura, Kazuaki Shimamoto, Yoshiyuki Horio

    JOURNAL OF PHARMACOLOGICAL SCIENCES   118   72P - 72P   2012

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  • 心臓老化Cardiac agingの研究 : 長寿遺伝子Sirtuinの心臓における働きと老化

    久野 篤史

    福田記念医療技術振興財団情報   ( 24 )   55 - 57   2011.12

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  • UPR In Endoplasmic Reticulum vs. UPR In Mitochondria In Diabetic Myocardium: Which Is Responsible For Deficient Regulation Of Mitochondrial Permeability Transition Pores?

    Takahito Itoh, Hidemichi Kouzu, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Tatsuya Sato, Daisuke Sunaga, Satoko Ishikawa, Tetsuji Miura

    CIRCULATION   124 ( 21 )   2011.11

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  • Long-Term Treatment with the SIRT1 Activator Resveratrol Ameliorates Cardiomyopathy in Dystrophin-Deficient Mice

    Atsushi Kuno, Yusuke Hori, Masaya Tanno, Hidemichi Kouzu, Takahito Itoh, Daisuke Sunaga, Yoshiyuki Horio, Tetsuji Miura

    CIRCULATION   124 ( 21 )   2011.11

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  • GSK-3 beta Translocates to Mitochondria by Oxidant Stress in a Kinase Activity-Dependent Manner and Contributes to Lethal ROS Production

    Masaya Tanno, Takayuki Miki, Atsushi Kuno, Hidemichi Kouzu, Takahito Itoh, Tatsuya Sato, Satoko Ishikawa, Daisuke Sunaga, Tetsuji Miura

    CIRCULATION   124 ( 21 )   2011.11

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  • Treatment with a Sirt1 Activator Resveratrol Prevents Cardiomyopathy in Dystrophin-Deficient Mice

    Atsushi Kuno, Yusuke Hori, Tatsuya Sato, Hidemichi Kouzu, Masaya Tanno, Takayuki Miki, Yoshiyuki Horio, Tetsuji Miura

    JOURNAL OF CARDIAC FAILURE   17 ( 9 )   S149 - S149   2011.9

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  • 肥満2型糖尿病ラットの心臓における左室収縮および活動電位の特徴(Characteristics of Left Ventricular Contractility and Action Potential in Heart of Obese Type2 Diabetes Rats)

    Sato Tatsuya, Takada Akifumi, Hotta Hiroyuki, Miki Takayuki, Tanno Masaya, Kobayashi Takeshi, Maeda Sachiko, Ichise Nobutoshi, Kuno Atsushi, Kohzu Hidemichi, Itoh Takahito, Sunaga Daisuke, Ishikawa Satoko, Miura Tetsuji, Tohse Noritsugu

    Circulation Journal   75 ( Suppl.I )   3 - 3   2011.3

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    Ichushi

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  • Resveratrol ameliorates cardiomyopathy in dystrophin-deficient mice

    Atsushi Kuno, Yusuke Hori, Ryusuke Hosoda, Tetsuji Miura, Yoshiyuki Horio

    JOURNAL OF PHARMACOLOGICAL SCIENCES   115   204P - 204P   2011

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  • Resveratrol, a SIRT1 activator, inhibits muscle fibrosis in mdx mouse

    Yusuke Hori, Atsushi Kuno, Ryusuke Hosoda, Yoshiyuki Horio

    JOURNAL OF PHARMACOLOGICAL SCIENCES   115   65P - 65P   2011

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  • Dysregulation of the mitochondrial permeability transition pore by increased UPRs in the ER and mitochondria underlies loss of protection in diabetic hearts.

    ITOH Takahito, KOUZU Hidemichi, MIKI Takayuki, TANNO Masaya, KUNO Atsushi, SATO Tatsuya, SUNAGA Daisuke, ISHIKAWA Satoko, MIURA Tetsuji

    International Society for Heart Research Annual Meeting of the Japanese Section. Program and Abstracts   28th   2011

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  • Connexin-43 Contributes to Transmission of MitoK(ATP) Channel-Derived Redox Signal to Akt-GSK-3 beta Pathway in Cardiomyocyte Protection Afforded by G-protein Coupled Receptors

    Satoko Ishikawa, Atsushi Kuno, Takayuki Miki, Masaya Tanno, Toshiyuki Yano, Hidemichi Kouzu, Tatsuya Sato, Daisuke Sunaga, Tetsuji Miura

    CIRCULATION   122 ( 21 )   2010.11

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  • Activation of Sirt1 Suppresses Hypertrophic Response of Cardiomyocytes by Inhibition of H3K9 Acetylation via Proteasome-mediated p300 Degradation.

    Atsushi Kuno, Masaya Tanno, Satoko Ishikawa, Yoshiyuki Horio, Tetsuji Miura

    CIRCULATION   122 ( 21 )   2010.11

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  • Apparently Slight Ventricular Dysfunction Predisposes Obese Type 2 Diabetic Rats to High Mortality After Myocardial Infarction

    Hidemichi Kouzu, Akifumi Takada, Takayuki Miki, Masaya Tanno, Toshiyuki Yano, Atsushi Kuno, Takahito Itoh, Tatsuya Satoh, Tetsuji Miura

    JOURNAL OF CARDIAC FAILURE   16 ( 9 )   S169 - S169   2010.9

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  • Resveratrol inhibits cell death caused by oxidative stress through SIRT1 in p53-dependent and p53-independent pathway

    Yu-suke Hori, Atsushi Kuno, Ryusuke Hosoda, Yoshiyuki Horio

    JOURNAL OF PHARMACOLOGICAL SCIENCES   112   57P - 57P   2010

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  • Activation of SIRT1 modifies histone acetylation/methylation and attenuates cardiomyocyte hypertrophy

    Atsushi Kuno, Masaya Tanno, Yoshiyuki Horio

    JOURNAL OF PHARMACOLOGICAL SCIENCES   112   200P - 200P   2010

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  • ROS-mediated Dysregulation of Mitochondrial Permeability Transition Pore Underlies Increased Susceptibility of Hypertensive Hypertrophied Hearts to Ischemia/reperfusion Injury

    Toshiyuki Yano, Tetsuji Miura, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Takahito Itoh, Akifumi Takada, Tatsuya Satoh, Kazuaki Shimamoto

    CIRCULATION   120 ( 18 )   S784 - S784   2009.11

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  • The SIRT1 Activator Resveratrol Suppresses Cardiomyocyte Hypertrophy by Promoting Histone H3 Lys9 Deacetylation and Tri-methylation

    Atsushi Kuno, Masaya Tanno, Toshiyuku Yano, Akifumi Takada, Satoko Ishikawa, Tetsuji Miura, Yoshiyuki Horio, Kazuaki Shimamoto

    CIRCULATION   120 ( 18 )   S617 - S617   2009.11

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  • Activation of histone/protein deacetylase SIRT1 by resveratrol induces MnSOD up-regulation via FOXO3a and improves survival of heart failure animals

    A. Kuno, M. Tanno, T. Miura, Y. Horio, K. Shimamoto

    EUROPEAN HEART JOURNAL   30   421 - 421   2009.9

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  • 【アンチエイジング医学 基礎・臨床研究の進歩】 臨床研究の進歩 老化抑制と健康寿命延長の方法論 薬剤によるアンチエイジング 老化抑制薬

    久野 篤史, 堀尾 嘉幸

    日本臨床   67 ( 7 )   1384 - 1388   2009.7

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    Other Link:： http://search.jamas.or.jp/link/ui/2009259934

    Ichushi

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  • Adenosine A(2b) receptors unexpectedly activate cardioprotective kinases through G(i) rather than G(s)

    Atsushi Kuno, Sheree Walker, Turhan Dost, Michael V. Cohen, James M. Downey

    FASEB JOURNAL   23   2009.4

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  • PE-545 Distinct Roles of FOXO Subtypes in SIRT1-mediated Mn-SOD Up-regulation under Oxidative Stress(PE091,Molecular Biology (M),Poster Session (English),The 73rd Annual Scientific Meeting of the Japanese Circulation Society)

    Kuno Atsushi, Tanno Masaya, Miura Tetsuji, Horio Yoshiyuki, Shimamoto Kazuaki

    Circulation journal : official journal of the Japanese Circulation Society   73   537 - 537   2009.3

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  • DPE-012 Activation of SIRT1, a Histone/Protein Deacetylase, by Resveratrol Up-regulates MnSOD and Suppresses the Progression of Heart Failure(DPE02,Heart Failure, Basic (M),Digital Poster Session (English),The 73rd Annual Scientific Meeting of The Japanese Circulation Society)

    Tanno Masaya, Kuno Atsushi, Ishikawa Satoko, Miura Tetsuji, Miki Takayuki, Horio Yoshiyuki, Shimamoto Kazuaki

    Circulation journal : official journal of the Japanese Circulation Society   73   358 - 359   2009.3

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  • Activation of SIRT1 by resveratrol prevents progression of heart failure and improves the survival in cardiomyopathic hamsters by upregulating MnSOD

    Atsushi Kuno, Masaya Tanno, Yoshiyuki Horio

    JOURNAL OF PHARMACOLOGICAL SCIENCES   109   112P - 112P   2009

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  • Role of GSK-3 beta modulation in cytoprotective regulation of mitochondrial permeability transition pores by mitochondrial K-ATP channel activation

    Yoshiaki Terashima, Tetsuji Miura, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Toshiyuki Yano, Hiroyuki Hotta, Satoko Ishikawa, Kazuaki Shimamoto

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   45   S22 - S22   2008.10

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    DOI： 10.1016/j.yjmcc.2008.09.662

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  • ER Stress Contributes to Dysregulation Of GSK-3 beta-mediated Suppression of Mitochondrial Permeability Transition in Diabetic Hearts

    Takayuki Miki, Masaya Tanno, Atsushi Kuno, Toshiyuki Yano, Takahiro Sato, Hiroyuki Hotta, Satoko Ishikawa, Tetsuji Miura

    CIRCULATION   118 ( 18 )   S290 - S291   2008.10

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  • Resveratrol activates protein deacetylase SIRT1 and prolongs the survival of heart failure animals by up-regulating MnSOD through transactivation of FOXO3a

    Atsushi Kuno, Masaya Tanno, Tetsuji Miura, Yoshiyuki Horio, Kazuaki Shimamoto

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   45   S19 - S19   2008.10

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    DOI： 10.1016/j.yjmcc.2008.09.651

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  • Activation of a Protein Deacetylase, SIRT1, by Resveratrol Suppresses Progression of Heart Failure and Improves Survival by Up-Regulation of Mn-SOD

    Masaya Tanno, Atsushi Kuno, Takayuki Miki, Tetsuji Miura, Yoshiyuki Horio, Kazuaki Shimamoto

    CIRCULATION   118 ( 18 )   S388 - S388   2008.10

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  • Rasveratrol, an Activator of Protein Deacetylase SIRT1, Suppresses Oxidative Stress-Induced Call Death by Upregulating MnSOD Expression through Transactivation of FOXO3a

    Atsushi Kuno, Masaya Tanno, Tetsuji Miura, Yoshiyuki Horio, Kazuaki Shimamoto

    CIRCULATION   118 ( 18 )   S391 - S391   2008.10

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  • Connexin43-dependent And -independent Mechanisms Of Mitochondrial GSK-3 beta Phosphorylation In Protection Of Cardiomyocyte Against Necrosis

    Satoko Ishilkawa, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Takahiro Sato, Hiroyuki Hotta, Yoshiaki Terashima, Tetsuji Miura

    CIRCULATION   118 ( 18 )   S355 - S355   2008.10

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  • PJ-725 Cardioprotection by a PKG Activatior Given at Reperfusion is Dependent on Adenosine A_<2b> Receptors Sensitized by PKC in Rabbit Hearts(Myocardial ischemia / reperfusion, basic / clinical(04)(IHD),Poster Session(Japanese),The 72nd Annual Scientific Meeting of the Japanese Circulation Society)

    Kuno Atsushi, Shimamoto Kazuaki, Cohen Michael, Downey James

    Circulation journal : official journal of the Japanese Circulation Society   72   694 - 694   2008.3

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  • Resveratrol, an activator of longevity protein SIRT1, suppresses progression of heart failure through SIRT1-mediated cardiomyocyte protection against oxidant stress

    Atsushi Kuno, Masaya Tanno, Yoshiyuki Horio

    JOURNAL OF PHARMACOLOGICAL SCIENCES   106   213P - 213P   2008

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  • Cardioprotection from GSK-3 beta inhibition requires activation of PI-3 kinase and Src but not Akt, PKC, or ERK

    Thomas Krieg, Heike Richter, Atsushi Kuno, Karina Foerster, Michael V. Cohen, James M. Downey, Stephan B. Felix

    CIRCULATION   116 ( 16 )   164 - 164   2007.10

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  • PKC enhances adenosine A(2b) receptor sensitivity in preconditioned rabbit hearts

    Atsushi Kuno, Lin Cui, Michael V. Cohen, James M. Downey

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   42   S178 - S179   2007.6

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    DOI： 10.1016/j.yjmcc.2007.03.547

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  • Cardioprotection from GSK-beta p inhibition requires activation of PI-3 kinase and src but not akt, PKC, or ERK

    Thomas Krieg, Heike Richter, Atsushi Kuno, Karina Foerster, Stephan Felix

    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY   42   S53 - S53   2007.6

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    DOI： 10.1016/j.yjmcc.2007.03.151

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  • Effects of ischemic preconditioning on interactions between Connexin43 and protein kinases during myocardial ischemia

    K Naito, T Yano, T Miki, J Sakamoto, M Tanno, A Kuno, Y Ikeda, T Miura

    CIRCULATION   112 ( 17 )   U284 - U284   2005.10

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  • 甲状腺機能亢進症を伴う冠動脈攣縮性狭心症の1例

    加藤 伸郎, 久野 篤史, 百石 雅哉, 中野 淳, 長谷川 亨

    道南医学会誌   ( 40 )   131 - 133   2005.3

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  • 膝窩動脈アプローチにより経皮的下肢動脈形成術が可能となった大腿動脈閉塞性動脈硬化症の1例

    百石 雅哉, 久野 篤史, 中野 淳, 長谷川 亨

    道南医学会誌   ( 40 )   128 - 131   2005.3

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  • 心不全を契機に初めて診断された成人発症型ネマリンミオパチーの1症例

    中野 淳, 吉岡 拓司, 百石 雅哉, 久野 篤史, 長谷川 亨, 佐藤 達郎

    心臓   37 ( 2 )   150 - 154   2005.2

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    DOI： 10.11281/shinzo1969.37.2_150

    Ichushi

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  • 25) Nemalin myopathyによる肺胞低換気にて心不全を発症し,夜間のBiPAP療法が有効であると考えられた1症例(第91回日本循環器学会北海道地方会)

    中野 淳, 吉岡 拓司, 久野 篤史, 長谷川 亨

    Circulation journal : official journal of the Japanese Circulation Society   68   866 - 866   2004.10

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  • DDDペースメーカー植え込みを施行したHOCM患者の8年の経過

    吉岡 拓司, 中村 裕一, 久野 篤史, 中野 淳, 長谷川 亨

    道南医学会誌   ( 39 )   170 - 172   2004.4

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  • 当院で経験した,たこつぼ型心筋症の3例(第89回日本循環器学会北海道地方会)

    久野 篤史, 中村 裕一, 中野 淳, 長谷川 亨

    Circulation journal : official journal of the Japanese Circulation Society   67   884 - 884   2003.10

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  • 閉塞性肥大型心筋症に対する経皮的中隔心筋焼灼術 術後8ヵ月の効果

    久野 篤史, 西里 仁男, 中野 淳, 長谷川 亨, 榊原 亨

    道南医学会誌   ( 38 )   110 - 112   2003.7

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  • 左室流出路狭窄を呈したたこつぼ型心筋症の1例

    西里 仁男, 久野 篤史, 中野 淳, 長谷川 亨

    道南医学会誌   ( 38 )   89 - 91   2003.7

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  • Gap Junction Is an End-Effector of Cardioprotection in Ischemic Preconditioning

    Ohnuma Yoshito, Miura Tetsuji, Kuno Atsushi, Miki Takayuki, Nakamura Yuichi, Shimamoto Kazuaki

    Circulation journal : official journal of the Japanese Circulation Society   67   190 - 190   2003.3

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  • Hypercholesterolemia enhances the no-reflow phenomenon after reperfusion by impairing K-ATP channel activity and delays healing of myocardial intarct

    S Genda, T Miki, A Nakano, A Kuno, Y Nishino, T Miura

    CIRCULATION   106 ( 19 )   246 - 246   2002.11

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  • Contribution of gap junction communication to myocardial necrosis during ischemia/reperfusion

    Kuno Atsushi, Miura Tetsuji, Genda Satoshi, Matsumoto Tomoaki, Nakano Atsushi, Miki Takayuki, Shimamoto Kazuaki

    Circulation journal : official journal of the Japanese Circulation Society   66   217 - 217   2002.3

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  • Opening of the mitochondrial K-ATP channel is downstream of protein kinase C-epsilon activation in the cardioprotective mechanism of ischemic preconditioning

    Y Ohnuma, T Miki, M Tanno, S Genda, A Kuno, T Miura

    CIRCULATION   104 ( 17 )   16 - 16   2001.10

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  • Failure of adenosine receptors to activate PKC-epsilon is responsible for loss of cardioprotection of preconditioning in the myocardium undergoing post-infarct remodeling

    T Miki, T Miura, A Tsuchida, J Sakamoto, M Tanno, A Kuno, Y Nishino, K Shimamoto

    CIRCULATION   104 ( 17 )   209 - 209   2001.10

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  • Progression of ventricular remodelling after infarction is accompanied by loss of PKC-epsilon activation and cardioprotection by ischaemic preconditioning

    T Miki, T Miura, A Tsuchida, J Sakamoto, A Kuno, K Shimamoto, S Genda

    EUROPEAN HEART JOURNAL   22   383 - 383   2001.9

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  • Opening of the mitochondrial KATP channel occurs downstream of protein kinase C in the cardioprotective mechanism of ischaemic preconditioning

    T Miki, T Miura, Y Ohnuma, M Tanno, A Kuno, T Matsumoto, K Shimamoto

    EUROPEAN HEART JOURNAL   22   669 - 669   2001.9

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  • 22) インフルエンザA型H3N2による急性心筋炎の二例

    中村 裕一, 現田 聡, 久野 篤史, 国分 宣明, 百石 雅哉, 山口 康一, 高木 覚, 橋本 暁佳, 島本 和明, 小林 史, 続 雅博, 若林 央

    Japanese circulation journal   64   844 - 844   2000.10

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  • Blockade of the Na+/Ca2+ exchanger is more efficient than is blockade of the Na+/H+ exchanger for protection of the myocardium from lethal reperfusion injury

    T Matsumoto, T Miura, A Tsuchida, Y Nishino, S Genda, A Kuno, K Shimamoto

    CIRCULATION   102 ( 18 )   137 - 137   2000.10

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  • Subtypes of ATP-sensitive potassium channels (KATP) affording anti-infarct tolerance in the heart: mitochondrial KATP versus sarcolemmal KATP

    M Tanno, T Miura, A Kuno, T Miki, A Tsuchida, K Shimamoto

    EUROPEAN HEART JOURNAL   21   669 - 669   2000.8

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  • IS073 Infarct Size-limiting Effect of Ischemic Preconditioning is Disturbed by Post-infarct Ventricular Remodeling via Angiotensin II Type 1 Receptor Activation

    Miki Takayuki, Miura Tetsuji, Tsuchida Akihito, Hasegawa Tohru, Fukuma Takayuki, Genda Satoshi, Kuno Atsushi, Shimamoto Kazuaki

    Japanese circulation journal   64   143 - 143   2000.3

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  • 0787 梗塞後リモデリング心での冠動脈内皮障害におけるAT_1受容体ならびに活性酸素の役割

    久野 篤史, 三浦 哲嗣, 長谷川 徹, 福真 隆行, 坂本 淳, 三木 隆幸, 土田 哲人, 島本 和明

    Japanese circulation journal   64   383 - 383   2000.3

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  • Critical timing of mitochondrial K-ATP channel opening for enhancement of myocardial tolerance against infarction

    A Tsuchida, A Kuno, M Tanno, Y Nozawa, T Miura

    CIRCULATION   100 ( 18 )   631 - 631   1999.11

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  • 人工血管再狭窄病変に対しStent植え込みが有用であった閉塞性動脈硬化症の1例

    久野 篤史, 老松 寛, 土井 敦

    道南医学会誌   32 ( 32 )   41 - 42   1997.7

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  • 当院にて最近経験したシングルパスリードVDDペースメーカー植え込みの7例

    土井 敦, 老松 寛, 久野 篤史

    道南医学会誌   ( 32 )   38 - 40   1997.7

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  • 当院での急性冠症候群(Acute Coronary Syndrome)における冠動脈ステント植え込みの成績

    遠藤 明太, 老松 寛, 久野 篤史

    道南医学会誌   ( 32 )   58 - 60   1997.7

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  • Bail-out stentに成功した対角枝早期複雑再狭窄病変の1例

    長尾 和彦, 老松 寛, 久野 篤史

    道南医学会誌   ( 32 )   43 - 44   1997.7

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  • Parallel wire techniqueにて静脈グラフト屈曲病変へのステント植え込みに成功した不安定狭心症の一例

    遠藤 明太, 老松 寛, 久野 篤史

    函館五稜郭病院医誌   5   91 - 96   1997.5

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  • 28) 慢性血液透析患者のPTCA後再狭窄に対しWIKTORステントを使用した一例

    北 宏之, 老松 寛, 久野 篤史, 中原 学史, 長尾 和彦, 遠藤 明太, 岩倉 雅弘, 高田 徹, 高田 竹人

    Japanese circulation journal   60   682 - 682   1997.1

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Presentations

  • Impaired Autophagy Induced by Activated mTORC1 Underlies Development of Dystrophic Cardiomyopathy. International conference

    Atsushi Kuno

    American Heart Association Scientific Sessions 2016  2016.11 

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  • 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  2016.9 

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  • Deletion of SIRT1 in the cardiomyocyte worsens doxorubicin-induced cardiac dysfunction in mice. International conference

    Atsushi Kuno

    European Society of Cardiology Congress 2016  2016.8 

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  • Role of impaired autophagy caused by aberrant activation of mTORC1 in dystrophic cardiomyopathy. International conference

    Atsushi Kuno

    Keystone Symposia Conference: Aging and Mechanisms of Aging-Related Disease  2017.5 

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  • Resveratrolrestores autophagy and improves cardiac dysfunction in a mouse model of Duchenne muscular dystrophy.

    Atsushi Kuno

    2017.3 

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  • Protective roles of SIRT1 in the cardiomyocyte in doxorubicin-induce cardiotoxicity.

    Atsushi Kuno

    ISHR2016  2016.12 

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  • 筋ジストロフィーの心筋障害におけるオートファジー不全の意義

    久野 篤史

    第39回 日本分子生物学会  2016.11 

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  • Role of autophagy-mediated clearance of mitochondria in cardioprotection afforded by the protein deacetylase SIRT1 in dystrophin-deficient mdx mice. International conference

    久野 篤史

    Keystone Symposia Conference: Mitochondrial Biology  2018.4 

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

    Atsushi Kuno

    ISHR2017  2017.12 

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  • 筋ジストロフィー心筋におけるオートファジー不全の意義

    久野 篤史

    第68回 日本薬理学会北部会  2017.9 

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  • Sirt1 Activation Restores Mitophagy-Mediated Clearance of Damaged Mitochondria and Ameliorates Dystrophic Cardiomyopathy in Mice International conference

    Atsushi Kuno

    米国心臓協会学術集会2018  2018.11 

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  • Resveratrol, a SIRT1 activator, restores autophagy-mediated clearance of damaged mitochondria and ameliorates dystrophic cardiomyopathy in mice.

    久野 篤史

    第22回 日本心不全学会学術集会  2018.10 

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  • レスベラトロールによる筋ジストロフィー治療

    久野 篤史

    第69回 日本薬理学会北部  2018.9 

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  • The SIRT1 activator resveratrol ameliorates dystrophic cardiomyopathy by promoting mitophagy. International conference

    Atsushi Kuno

    European Society of Cardiology Congress 2018  2018.8 

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  • Protective Role of SIRT1, a Protein Deacetylase, in Doxorubicin-induced Cardiotoxicity.

    久野 篤史

    第83回日本循環器学会学術集会  2019.3 

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  • 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  2019.3 

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  • 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  2018.11 

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  • SIRT1 Protects against Doxorubicin Cardiotoxicity In Vivo.

    Atsushi Kuno

    2016.3 

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Industrial property rights

Research Projects

  • 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

    Grant number：23K06152  2023.4 - 2026.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    久野 篤史

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    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

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

    Grant number：17K08600  2017.4 - 2020.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Kuno Atsushi

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    Authorship：Principal investigator 

    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

    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.

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  • サルコペニアにおけるミトコンドリア蛋白アセチル化修飾の役割解明

    Grant number：25K09985  2025.4 - 2028.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    細田 隆介, 藤谷 直樹, 野島 伊世里, 久野 篤史

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    Authorship：Coinvestigator(s) 

    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

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  • Myokine BAIBA as a Therapeutic Modulator in Heart Failure

    Grant number：25K11368  2025.4 - 2028.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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    Grant amount：\4680000 （ Direct Cost: \3600000 、 Indirect Cost：\1080000 ）

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  • 心筋分岐鎖アミノ酸代謝を標的とした心不全治療の開発

    Grant number：23K07481  2023.4 - 2026.3

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    神津 英至, 久野 篤史, 佐藤 達也

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    Authorship：Coinvestigator(s) 

    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

    申請者らはラット心筋細胞において、分枝鎖アミノ酸(BCAA)の代謝律速酵素である分枝鎖α-ケト酸脱水素酵素(BCKDH)がミトコンドリアのみならず筋小胞体に高発現し、AMP deaminase 3(AMPD3)との直接結合にて活性修飾を受けていること、AMPD3-BCKDHの発現不均衡が糖尿病性心筋症の発症に関与していることを最近報告した。本研究においてこれまで、BCKDHの筋小胞体における高発現およびAMPD3との直接結合がマウスの心筋でも再現されることを確認した。さらに、AMPD1が主要なアイソフォームとされる骨格筋において、下肢挙上による筋萎縮の誘導がAMPD3の発現を有意に上昇させること、BCKDHがAMPD1とではなくAMPD3と直接結合していることを同定した。これらの結果から、筋組織のBCAA代謝におけるAMPD3の特異的な役割が示唆された。
    AMPD3全身ノックアウトマウスは、非負荷時には明らかな表現型を認めなかったが、横行大動脈縮窄(TAC)による心不全の誘導が増悪する傾向にあった。一方、下肢挙上による筋萎縮の誘導においては、AMPD3欠損により前脛骨筋およびヒラメ筋の筋重量減少が抑制される傾向がみられた。これらの結果から、AMPD3の欠損により誘導される代謝変化の影響は、心筋と骨格筋では異なる可能性が示唆された。
    臨床研究では、心不全症例において末梢血アミノ酸プロファイリングを行い、BCAAを含む予後不良なアミノ酸プロファイルが、骨格筋の脂肪変性と関連することを見出した。
    また、糖尿病性心筋症におけるAMPD3の関与について、申請者らのこれまでの報告をまとめ、総説を発表した。

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  • 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

    2022.12 - 2023.11

    日本糖尿病財団  ノボノルディスクファーマ研究助成 

    久野 篤史

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    Authorship：Principal investigator 

    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

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  • 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

    2022.8 - 2023.3

    ノーステック財団  イノベーション創出研究支援事業：研究成果展開 （発展・橋渡し研究）補助金 

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    Authorship：Principal investigator 

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  • 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

    Grant number：22K08189  2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    矢野 俊之, 丹野 雅也, 久野 篤史

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    Authorship：Coinvestigator(s) 

    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

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  • 蛋白アセチル化修飾を標的としたサルコペニア発症機序の解明と治療法開発

    Grant number：22K06632  2022.4 - 2025.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    細田 隆介, 岩原 直敏, 藤谷 直樹, 野島 伊世里, 久野 篤史, 山田 崇史

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    Authorship：Coinvestigator(s) 

    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

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  • AMPデアミナーゼ活性制御機構の解明と糖尿病性心筋症治療への応用

    Grant number：21K08110  2021.4 - 2024.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    丹野 雅也, 久野 篤史, 矢野 俊之

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    Authorship：Coinvestigator(s) 

    Grant amount：\4160000 （ Direct Cost: \3200000 、 Indirect Cost：\960000 ）

    糖尿病性心筋症は発症早期には左室拡張機能障害を呈する。我々は肥満2型糖尿病モデルラットであるOLETFの左室心筋を用い、糖尿病合併心筋において、AMP deaminase (AMPD) 活性亢進によるATPレベルの低下と酸化ストレス増加が拡張能機能障害に寄与することから、AMPD活性制御が糖尿病性心筋症の新たな治療標的になり得ることを報告した。本研究ではAMPDの細胞内局在に着目して検討を行なっている。
    左室心筋各細胞分画におけるAMPDの局在をウェステンブロット法で解析したところ、主要なアイソフォームである90-kDa AMPD3はOLETFにおいて非糖尿病対照ラットであるLETOと比較して小胞体や小胞体-ミトコンドリア接触(MAM)領域においてその発現レベルが有意に上昇していた。電子顕微鏡による観察では心筋のMAM領域はOLETFにおいてLETOと比較して有意に広かった。また、H9c2細胞においてFLAG-AMPD3をトランスフェクションしたところ、対照ベクターと比較して有意にMAM領域が広くなったことから、OLETFにおけるMAM領域の拡大はAMPD3発現増加が関与する可能性が示唆された。左室後負荷を増大させた状態で採取した心筋ミトコンドリアのCa2+濃度はOLETFにおいてLETOよりも有意に高く、AMPD3を過剰発現したH9c2細胞のミトコンドリアにおいてもCa2+濃度が上昇した。さらに、H9c2細胞において過酸化水素暴露によるミトコンドリア膜電位の低下はAMPD3の過剰発現で増悪し、発現抑制で軽減した。細胞外フラックスアナライザーを用いた解析ではAMPD過剰発現によりミトコンドリア呼吸鎖複合体Iの機能異常が生じた。これらの成績からMAMに局在するAMPD3は、そのレベルが過剰になるとミトコンドリアカルシウム負荷による機能異常を惹起すると考えられる。

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  • アミノ酸ー核酸代謝連関の制御による心不全の新規治療開発

    Grant number：20K08452  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    神津 英至, 久野 篤史, 矢野 俊之

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    Authorship：Coinvestigator(s) 

    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    ラット心筋におけるプロテオミクス解析において、AMPD3と分枝鎖アミノ酸(BCAA)の代謝律速酵素である分枝鎖α-ケト酸脱水素酵素(BCKDH)が直接結合していることを同定し、BCAA代謝の制御にAMPD3が関与していることを同定した。さらに細胞分画実験において、この結合が主に小胞体分画で見られることを同定し、心筋においてBCAAがミトコンドリア外でも代謝されている可能性を見出した。AMPD3-BCKDH結合は新生ラット初代心筋細胞(NRCM)、ラット心臓筋芽細胞(H9c2)、ヒト胎児腎細胞293(HEK293)でも見られ、細胞に共通した代謝機構であることが示唆された。In vitroにて遺伝的BCKDH発現抑制はAMPD3の発現を亢進させ、2型糖尿病モデルラット(OLETF)心で見られたBCKDH-AMPD3結合不均衡を再現した。In vitroにてAMPD3の過剰発現はBCKDH活性を上昇させ、逆に発現抑制は同活性を低下させることから、AMPD3はBCKDH活性を正に制御していることが示唆された。
    NRCMにおいて、遺伝的BCKDH発現抑制は脂肪酸負荷時の脂肪滴合成能障害および、ミトコンドリアでの脂肪酸酸化能を低下させたが、グルコース酸化能には影響を与えなかった。以上より、心筋細胞においてBCAA代謝が脂肪酸代謝に対して促進的に働いており、BCAA代謝障害は糖尿病における心筋代謝障害に寄与している可能性が考えられた。
    また臨床研究では心不全症例において血中アミノ酸プロファイリングを行い、骨格筋分解マーカーである3-methylhistidineの上昇および、BCAAであるバリンの低下が、既存の危険因子と独立して予後を予測することを見出し、論文を発表した。

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  • 心不全におけるオートファジー障害の機序解明と治療への応用

    Grant number：20K07068  2020.4 - 2023.3

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    久野 篤史, 藤谷 直樹, 野島 伊世里, 堀尾 嘉幸, 矢野 俊之

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    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    令和3年度の本研究の目的は、1) SIRT1によるオートファジー調節の分子機序を明らかにすること、2) ヒト病的心におけるSIRT1活性やオートファジー活性の評価、である。
    1) これまでの申請者による研究成果により、SIRT1はオートファゴソームの分解、つまりオートファゴソームとリソソームの融合の調節に重要な枠割を果たすことがわかっていた。従って、H9c2心筋細胞においてSIRT1と既知のオートファゴソーム・リソソーム融合に関わる因子の結合を評価した。(A) SIRT1とUVRAGの結合は確認できた。しかしSIRT1をノックダウンしてもUVRAGの機能調節に重要なリン酸化のレベルは変化しなかった。またSIRT1によるUVRAGの脱アセチル化が確認できなかった。以上から、SIRT1のオートファジー調節にUVRAGが関与する可能性が少ないことが示唆された。(B)免疫沈降法を用いて、SIRT1とオートファゴソーム・リソソーム融合に関与する既知の蛋白が結合するかを評価した。いくつかSIRT1と結合する蛋白を同定できた。
    2) ヒト心筋組織切片（正常心および弁膜症などの病的心）を入手して、SIRT1の免疫染色を行った。病的心でもSIRT1の発現はある程度保たれているが、定量性に課題が残った。またオートファジーの指標の一つでもあるp62の染色にも成功したが、どのように定量を行うかの検討を行う必要があった。

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  • Necroptosis-tartgeted therapy for heart failure

    Grant number：19K08544  2019.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Yano Toshiyuki

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    Authorship：Coinvestigator(s) 

    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    We found increased cardiomyocyte expression of nuclear p-MLKL, an executor of necroptosis, in patients with nonischemic dilated cardiomyopathy (NICM), but its clinical significance remains unclear. Endomyocardial biopsy specimens were obtained from 57 patients with NICM (56±15 years old, 68% male). Nuclear p-MLKL levels were determined by immunostaining against phospho-Ser358-MLKL. Using median nuclear p-MLKL expression levels, patients were classified into a high nuclear p-MLKL group and a low nuclear p-MLKL group. Adverse event was defined as composite of death or admission for heart failure or ventricular arrhythmia. Results of Kaplan-Meier survival curve analyses showed that the adverse event-free survival rate was lower in the high nuclear p-MLKL group than in the low nuclear p-MLKL group (4% vs. 31%, p=0.021). Enhanced expression of nuclear p-MLKL in cardiomyocytes predicts future adverse events, suggesting possible involvement of necroptosis in progression of NICM.

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  • Development of a novel therapeutics for muscular dystrophy by targeting mitophagy.

    Grant number：19K07102  2019.4 - 2022.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Hosoda Ryusuke

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    Authorship：Coinvestigator(s) 

    Grant amount：\4290000 （ Direct Cost: \3300000 、 Indirect Cost：\990000 ）

    This study was conducted to elucidate the relationship between the pathogenesis of Duchenne muscular dystrophy (DMD) and impaired mitochondria. mitochondrial DNA from skeletal muscle of DMD model mice was analyzed by next-generation sequencing, but deletion sites could not be identified. On the other hand, the nuclear localization of TFEB, an autophagy-related factor, was significantly reduced in the skeletal muscle of DMD model mice. In the future, we will clarify whether SIRT1 activation shifts the localization of TFEB to the nucleus in DMD. We will then elucidate the mitophagy-promoting mechanism via SIRT1 activation to develop a mitophagy-targeted therapy for muscular dystrophy.

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  • Functional roles of SIRT1 in the differentiation of neural cells

    Grant number：22590245  2010 - 2012

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    HORIO Yoshiyuki, HAYASHI Takashi, KUNO Atsushi, KUNIMOTO Risa

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    Authorship：Coinvestigator(s) 

    Grant amount：\4550000 （ Direct Cost: \3500000 、 Indirect Cost：\1050000 ）

    We found that SIRT1, an homologue of yeast longevity gene Sir2, bound and deacetylated p300, a co-activator for Notch-intracellular domain, resulting in the ubiquitination and degradation of p300. We found that SIRT1 promoted neurite formation and extension ofPC12 pheochromocytoma cells. We also found that SIRT1 was necessary for lamellipodium formation and migration of B16F1 melanoma cells. Because melanoma cells are derived from neural crest cells, similar mechanism may regulate neural cell migration.

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