2025/05/08 更新

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写真a

カトウ ユリ
加藤 百合
KATO YURI
所属
薬学研究院 臨床薬学部門 講師
薬学部 臨床薬学科(併任)
薬学府 臨床薬学専攻(併任)
職名
講師
連絡先
メールアドレス
電話番号
0926426668
外部リンク

研究分野

  • ライフサイエンス / 薬系衛生、生物化学

学位

  • 博士(薬科学)

経歴

  • 2014.1-2019.12 岡山大学 ゲノム・プロテオーム解析部門 特任助教   

研究テーマ・研究キーワード

  • 研究テーマ: 膜タンパク質に着目した生理的、病的条件での機能解明と薬理的応用

    研究キーワード: トランスポーター、チャネル、筋萎縮

    研究期間: 2020年1月

受賞

  • 2023年度 入澤宏・彩記念若手研究奨励賞

    2024年3月   日本生理学会  

  • 令和5年度生化学会九州支部学術奨励賞

    2023年6月   生化学会九州支部  

  • Young Investigator Award

    2023年1月   日本循環薬理学会  

  • 最優秀発表賞

    2022年10月   日本薬理学会西南部会  

論文

  • Polysulfur-based bulking of dynamin-related protein 1 prevents ischemic sulfide catabolism and heart failure in mice

    Nishimura A., Ogata S., Tang X., Hengphasatporn K., Umezawa K., Sanbo M., Hirabayashi M., Kato Y., Ibuki Y., Kumagai Y., Kobayashi K., Kanda Y., Urano Y., Shigeta Y., Akaike T., Nishida M.

    Nature Communications   16 ( 1 )   276   2025年1月   eISSN:2041-1723

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

    The presence of redox-active molecules containing catenated sulfur atoms (supersulfides) in living organisms has led to a review of the concepts of redox biology and its translational strategy. Glutathione (GSH) is the body’s primary detoxifier and antioxidant, and its oxidized form (GSSG) has been considered as a marker of oxidative status. However, we report that GSSG, but not reduced GSH, prevents ischemic supersulfide catabolism-associated heart failure in male mice by electrophilic modification of dynamin-related protein (Drp1). In healthy exercised hearts, the redox-sensitive Cys644 of Drp1 is highly S-glutathionylated. Nearly 40% of Cys644 is normally polysulfidated, which is a preferential target for GSSG-mediated S-glutathionylation. Cys644 S-glutathionylation is resistant to Drp1 depolysulfidation-dependent mitochondrial hyperfission and myocardial dysfunction caused by hypoxic stress. MD simulation of Drp1 structure and site-directed mutagenetic analysis reveal a functional interaction between Cys644 and a critical phosphorylation site Ser637, through Glu640. Bulky modification at Cys644 via polysulfidation or S-glutathionylation reduces Drp1 activity by disrupting Ser637-Glu640-Cys644 interaction. Disruption of Cys644 S-glutathionylation nullifies the cardioprotective effect of GSSG against heart failure after myocardial infarction. Our findings suggest a therapeutic potential of supersulfide-based Cys bulking on Drp1 for ischemic heart disease.

    DOI: 10.1038/s41467-024-55661-5

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  • Inorganic sulfides prevent osimertinib-induced mitochondrial dysfunction in human iPS cell-derived cardiomyocytes 査読

    Kondo, M; Nakamura, Y; Kato, Y; Nishimura, A; Fukata, M; Moriyama, S; Ito, T; Umezawa, K; Urano, Y; Akaike, T; Akashi, K; Kanda, Y; Nishida, M

    JOURNAL OF PHARMACOLOGICAL SCIENCES   156 ( 2 )   69 - 76   2024年10月   ISSN:1347-8613 eISSN:1347-8648

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    記述言語:英語   出版者・発行元:Journal of Pharmacological Sciences  

    Despite the widespread recognition of the global concern regarding the onset of cardiovascular diseases in a significant number of patients following cancer treatment, definitive strategies for prevention and treatment remain elusive. In this study, we established systems to evaluate the influence of anti-cancer drugs on the quality control of mitochondria, pivotal for energy metabolism, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor used for treatment in lung cancer, reportedly increases the risk of cardiovascular disease. However, its underlying mechanism is largely unknown. Here, we found that the treatment of hiPSC-CMs with osimertinib and doxorubicin, but not trastuzumab and cisplatin, revealed a concentration-dependent impairment of respiratory function accompanied by mitochondrial fission. We previously reported the significant role of sulfur metabolism in maintaining mitochondrial quality in the heart. Co-treatment with various inorganic sulfur donors (Na2S, Na2S2, Na2S3) alongside anti-cancer drugs demonstrated that Na2S attenuated the cardiotoxicity of osimertinib but not doxorubicin. Osimertinib decreased intracellular reduced sulfur levels, while Na2S treatment suppressed the sulfur leakage, suggesting its potential in mitigating osimertinib-induced cardiotoxicity. These results imply the prospect of inorganic sulfides, such as Na2S, as a seed for precision pharmacotherapy to alleviate osimertinib's cardiotoxic effects.

    DOI: 10.1016/j.jphs.2024.07.007

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  • Diabetic Mice Spleen Vulnerability Contributes to Decreased Persistence of Antibody Production after SARS-CoV-2 Vaccine 国際誌

    Atef Y., Ito T., Masuda A., Kato Y., Nishimura A., Kanda Y., Kunisawa J., Kusakabe T., Nishida M.

    International Journal of Molecular Sciences   25 ( 19 )   2024年9月   ISSN:16616596 eISSN:1422-0067

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Molecular Sciences  

    During the COVID-19 pandemic, diabetic and obese patients experienced higher rates of hospital admissions, severe illness, and mortality. However, vaccinations failed to provide those vulnerable populations the same level of protection against COVID-19 severity as those without diabetic and obese phenotypes. Our study aimed to investigate how diabetes mellitus (DM) impacts the immune response following vaccination including the artificially designed trimeric SARS-CoV-2 spike (S)-protein. By using two diabetic mouse models, ob/ob mice (obese, hyperglycemic, and insulin-resistant) and STZ-treated mice (insulin-deficient and hyperglycemic), we observed a significant reduction in S-protein-specific IgG antibody titer post-vaccination in both diabetic models compared to wild-type (WT) mice. Both diabetic mouse models exhibited significant abnormalities in spleen tissue, including marked reductions in splenic weight and the size of the white pulp regions. Furthermore, the splenic T-cell and B-cell zones were notably diminished, suggesting an underlying immune dysfunction that could contribute to impaired antibody production. Notably, vaccination with the S-protein, when paired with an optimal adjuvant, did not exacerbate diabetic cardiomyopathy, blood glucose levels, or liver function, providing reassurance about the vaccine′s safety. These findings offer valuable insights into potential mechanisms responsible for the decreased persistence of antibody production in diabetic patients.

    DOI: 10.3390/ijms251910379

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  • Inhibition of dynamin-related protein 1-filamin interaction improves systemic glucose metabolism 査読

    Kato, Y; Ariyoshi, K; Nohara, Y; Matsunaga, N; Shimauchi, T; Shindo, N; Nishimura, A; Mi, XY; Kim, SG; Ide, T; Kawanishi, E; Ojida, A; Nakashima, N; Mori, Y; Nishida, M

    BRITISH JOURNAL OF PHARMACOLOGY   181 ( 21 )   4328 - 4347   2024年7月   ISSN:0007-1188 eISSN:1476-5381

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    記述言語:英語   出版者・発行元:British Journal of Pharmacology  

    Background and purpose: Maintaining mitochondrial quality is attracting attention as a new strategy to treat diabetes and diabetic complications. We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin-related protein (Drp) 1 and filamin, mediates chronic heart failure and cilnidipine, initially developed as an L/N-type Ca2+ channel blocker, improves heart failure by inhibiting Drp1-filamin protein complex. We investigated whether cilnidipine improves hyperglycaemia of various diabetic mice models. Experimental Approach: Retrospective analysis focusing on haemoglobin A1c (HbA1c) was performed in hypertensive and hyperglycaemic patients taking cilnidipine and amlodipine. After developing diabetic mice by streptozotocin (STZ) treatment, an osmotic pump including drug was implanted intraperitoneally, followed by weekly measurements of blood glucose levels. Mitochondrial morphology was analysed by electron microscopy. A Ca2+ channel-insensitive cilnidipine derivative (1,4-dihydropyridine [DHP]) was synthesized and its pharmacological effect was evaluated using obese (ob/ob) mice fed with high-fat diet (HFD). Key Results: In patients, cilnidipine was superior to amlodipine in HbA1c lowering effect. Cilnidipine treatment improved systemic hyperglycaemia and mitochondrial morphological abnormalities in STZ-exposed mice, without lowering blood pressure. Cilnidipine failed to improve hyperglycaemia of ob/ob mice, with suppressing insulin secretion. 1,4-DHP improved hyperglycaemia and mitochondria abnormality in ob/ob mice fed HFD. 1,4-DHP and cilnidipine improved basal oxygen consumption rate of HepG2 cells cultured under 25 mM glucose. Conclusion and implications: Inhibition of Drp1-filamin protein complex formation becomes a new strategy for type 2 diabetes treatment.

    DOI: 10.1111/bph.16487

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  • Inhibition of Drp1-Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria-Lipid Droplet Contact 査読 国際誌

    Ariyoshi, K; Nishiyama, K; Kato, Y; Mi, XY; Ito, T; Azuma, YT; Nishimura, A; Nishida, M

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   25 ( 10 )   2024年5月   ISSN:1661-6596 eISSN:1422-0067

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Molecular Sciences  

    Lipid droplet (LD) accumulation in hepatocytes is one of the major symptoms associated with fatty liver disease. Mitochondria play a key role in catabolizing fatty acids for energy production through β-oxidation. The interplay between mitochondria and LD assumes a crucial role in lipid metabolism, while it is obscure how mitochondrial morphology affects systemic lipid metabolism in the liver. We previously reported that cilnidipine, an already existing anti-hypertensive drug, can prevent pathological mitochondrial fission by inhibiting protein–protein interaction between dynamin-related protein 1 (Drp1) and filamin, an actin-binding protein. Here, we found that cilnidipine and its new dihydropyridine (DHP) derivative, 1,4-DHP, which lacks Ca2+ channel-blocking action of cilnidipine, prevent the palmitic acid-induced Drp1–filamin interaction, LD accumulation and cytotoxicity of human hepatic HepG2 cells. Cilnidipine and 1,4-DHP also suppressed the LD accumulation accompanied by reducing mitochondrial contact with LD in obese model and high-fat diet-fed mouse livers. These results propose that targeting the Drp1–filamin interaction become a new strategy for the prevention or treatment of fatty liver disease.

    DOI: 10.3390/ijms25105446

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  • Pharmacological Activation of TRPC6 Channel Prevents Colitis Progression. 査読 国際誌

    Kazuhiro Nishiyama, Yuri Kato, Akiyuki Nishimura, Xinya Mi, Ryu Nagata, Yasuo Mori, Yasu-Taka Azuma, Motohiro Nishida

    International journal of molecular sciences   25 ( 4 )   2024年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn2+ homeostasis in the heart. Zn2+ has also been implicated in the regulation of intestinal redox and microbial homeostasis. This study aims to investigate the role of TRPC6-mediated Zn2+ influx in the stress resistance of the intestine. The expression profile of TRPC1-C7 mRNAs in the actively inflamed mucosa from inflammatory bowel disease (IBD) patients was analyzed using the GEO database. Systemic TRPC3 knockout (KO) and TRPC6 KO mice were treated with dextran sulfate sodium (DSS) to induce colitis. The Zn2+ concentration and the mRNA expression levels of oxidative/inflammatory markers in colon tissues were quantitatively analyzed, and gut microbiota profiles were compared. TRPC6 mRNA expression level was increased in IBD patients and DSS-treated mouse colon tissues. DSS-treated TRPC6 KO mice, but not TRPC3 KO mice, showed severe weight loss and increased disease activity index compared with DSS-treated WT mice. The mRNA abundances of antioxidant proteins were basically increased in the TRPC6 KO colon, with changes in gut microbiota profiles. Treatment with TRPC6 activator prevented the DSS-induced colitis progression accompanied by increasing Zn2+ concentration. We suggest that TRPC6-mediated Zn2+ influx activity plays a key role in stress resistance against IBD, providing a new strategy for treating colitis.

    DOI: 10.3390/ijms25042401

  • Supersulfide prevents cigarette smoke extract-induced mitochondria hyperfission and cardiomyocyte early senescence by inhibiting Drp1-filamin complex formation. 査読

    Akiyuki Nishimura, Liuchenzi Zhou, Yuri Kato, Xinya Mi, Tomoya Ito, Yuko Ibuki, Yasunari Kanda, Motohiro Nishida

    Journal of pharmacological sciences   154 ( 2 )   127 - 135   2024年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Smoking is one of the most serious risk factors for cardiovascular diseases. Although cigarette mainstream and sidestream smoke are significant contributors to increased cardiovascular mortality and morbidity, the underlying mechanism is still unclear. Here, we report that exposure of rat neonatal cardiomyocytes to cigarette smoke extract (CSE) induces mitochondrial hyperfission-mediated myocardial senescence. CSE leads to mitochondrial fission and reactive oxygen species (ROS) production through the complex formation between mitochondrial fission factor Drp1 and actin-binding protein, filamin A. Pharmacological perturbation of interaction between Drp1 and filamin A by cilnidipine and gene knockdown of Drp1 or filamin A inhibited CSE-induced mitochondrial hyperfission and ROS production as well as myocardial senescence. We previously reported that Drp1 activity is controlled by supersulfide-induced Cys644 polysulfidation. The redox-sensitive Cys644 was critical for CSE-mediated interaction with filamin A. The administration of supersulfide donor, Na2S3 also improved mitochondrial hyperfission-mediated myocardial senescence induced by CSE. Our results suggest the important role of Drp1-filamin A complex formation on cigarette smoke-mediated cardiac risk and the contribution of supersulfide to mitochondrial fission-associated myocardial senescence.

    DOI: 10.1016/j.jphs.2023.12.008

  • Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction 査読 国際誌

    Ogawa, A; Ohira, S; Kato, Y; Ikuta, T; Yanagida, S; Mi, XY; Ishii, Y; Kanda, Y; Nishida, M; Inoue, A; Wei, FY

    COMMUNICATIONS BIOLOGY   6 ( 1 )   511 - 511   2023年5月   eISSN:2399-3642

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

    Remdesivir is an antiviral drug used for COVID-19 treatment worldwide. Cardiovascular side effects have been associated with remdesivir; however, the underlying molecular mechanism remains unknown. Here, we performed a large-scale G-protein-coupled receptor screening in combination with structural modeling and found that remdesivir is a selective, partial agonist for urotensin-II receptor (UTS2R) through the Gαi/o-dependent AKT/ERK axis. Functionally, remdesivir treatment induced prolonged field potential and APD90 in human induced pluripotent stem cell (iPS)-derived cardiomyocytes and impaired contractility in both neonatal and adult cardiomyocytes, all of which mirror the clinical pathology. Importantly, remdesivir-mediated cardiac malfunctions were effectively attenuated by antagonizing UTS2R signaling. Finally, we characterized the effect of 110 single-nucleotide variants in UTS2R gene reported in genome database and found four missense variants that show gain-of-function effects in the receptor sensitivity to remdesivir. Collectively, our study illuminates a previously unknown mechanism underlying remdesivir-related cardiovascular events and that genetic variations of UTS2R gene can be a potential risk factor for cardiovascular events during remdesivir treatment, which collectively paves the way for a therapeutic opportunity to prevent such events in the future.

    DOI: 10.1038/s42003-023-04888-x

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  • Knockout of Purinergic P2Y<sub>6</sub> Receptor Fails to Improve Liver Injury and Inflammation in Non-Alcoholic Steatohepatitis 査読 国際誌

    Nishiyama, K; Ariyoshi, K; Nishimura, A; Kato, Y; Mi, XY; Kurose, H; Kim, SG; Nishida, M

    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES   24 ( 4 )   2023年2月   ISSN:16616596 eISSN:1422-0067

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Molecular Sciences  

    Nonalcoholic steatohepatitis (NASH) is a disease that progresses from nonalcoholic fatty liver (NAFL) and which is characterized by inflammation and fibrosis. The purinergic P2Y6 receptor (P2Y6R) is a pro-inflammatory Gq/G12 family protein-coupled receptor and reportedly contributes to intestinal inflammation and cardiovascular fibrosis, but its role in liver pathogenesis is unknown. Human genomics data analysis revealed that the liver P2Y6R mRNA expression level is increased during the progression from NAFL to NASH, which positively correlates with inductions of C-C motif chemokine 2 (CCL2) and collagen type I α1 chain (Col1a1) mRNAs. Therefore, we examined the impact of P2Y6R functional deficiency in mice crossed with a NASH model using a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Feeding CDAHFD for 6 weeks markedly increased P2Y6R expression level in mouse liver, which was positively correlated with CCL2 mRNA induction. Unexpectedly, the CDAHFD treatment for 6 weeks increased liver weights with severe steatosis in both wild-type (WT) and P2Y6R knockout (KO) mice, while the disease marker levels such as serum AST and liver CCL2 mRNA in CDAHFD-treated P2Y6R KO mice were rather aggravated compared with those of CDAHFD-treated WT mice. Thus, P2Y6R may not contribute to the progression of liver injury, despite increased expression in NASH liver.

    DOI: 10.3390/ijms24043800

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  • Echinochrome Prevents Sulfide Catabolism-Associated Chronic Heart Failure after Myocardial Infarction in Mice 査読 国際誌

    Tang, XK; Nishimura, A; Ariyoshi, K; Nishiyama, K; Kato, Y; Vasileva, EA; Mishchenko, NP; Fedoreyev, SA; Stonik, VA; Kim, HK; Han, J; Kanda, Y; Umezawa, K; Urano, Y; Akaike, T; Nishida, M

    MARINE DRUGS   21 ( 1 )   2023年1月   eISSN:1660-3397

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

    Abnormal sulfide catabolism, especially the accumulation of hydrogen sulfide (H2S) during hypoxic or inflammatory stresses, is a major cause of redox imbalance-associated cardiac dysfunction. Polyhydroxynaphtoquinone echinochrome A (Ech-A), a natural pigment of marine origin found in the shells and needles of many species of sea urchins, is a potent antioxidant and inhibits acute myocardial ferroptosis after ischemia/reperfusion, but the chronic effect of Ech-A on heart failure is unknown. Reactive sulfur species (RSS), which include catenated sulfur atoms, have been revealed as true biomolecules with high redox reactivity required for intracellular energy metabolism and signal transduction. Here, we report that continuous intraperitoneal administration of Ech-A (2.0 mg/kg/day) prevents RSS catabolism-associated chronic heart failure after myocardial infarction (MI) in mice. Ech-A prevented left ventricular (LV) systolic dysfunction and structural remodeling after MI. Fluorescence imaging revealed that intracellular RSS level was reduced after MI, while H2S/HS- level was increased in LV myocardium, which was attenuated by Ech-A. This result indicates that Ech-A suppresses RSS catabolism to H2S/HS- in LV myocardium after MI. In addition, Ech-A reduced oxidative stress formation by MI. Ech-A suppressed RSS catabolism caused by hypoxia in neonatal rat cardiomyocytes and human iPS cell-derived cardiomyocytes. Ech-A also suppressed RSS catabolism caused by lipopolysaccharide stimulation in macrophages. Thus, Ech-A has the potential to improve chronic heart failure after MI, in part by preventing sulfide catabolism.

    DOI: 10.3390/md21010052

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  • TRPC3-Nox2 Protein Complex Formation Increases the Risk of SARS-CoV-2 Spike Protein-Induced Cardiomyocyte Dysfunction through ACE2 Upregulation. 査読 国際誌

    Yuri Kato, Kazuhiro Nishiyama, Jae Man Lee, Yuko Ibuki, Yumiko Imai, Takamasa Noda, Noriho Kamiya, Takahiro Kusakabe, Yasunari Kanda, Motohiro Nishida

    International journal of molecular sciences   24 ( 1 )   2022年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Myocardial damage caused by the newly emerged coronavirus (SARS-CoV-2) infection is one of the key determinants of COVID-19 severity and mortality. SARS-CoV-2 entry to host cells is initiated by binding with its receptor, angiotensin-converting enzyme (ACE) 2, and the ACE2 abundance is thought to reflect the susceptibility to infection. Here, we report that ibudilast, which we previously identified as a potent inhibitor of protein complex between transient receptor potential canonical (TRPC) 3 and NADPH oxidase (Nox) 2, attenuates the SARS-CoV-2 spike glycoprotein pseudovirus-evoked contractile and metabolic dysfunctions of neonatal rat cardiomyocytes (NRCMs). Epidemiologically reported risk factors of severe COVID-19, including cigarette sidestream smoke (CSS) and anti-cancer drug treatment, commonly upregulate ACE2 expression level, and these were suppressed by inhibiting TRPC3-Nox2 complex formation. Exposure of NRCMs to SARS-CoV-2 pseudovirus, as well as CSS and doxorubicin (Dox), induces ATP release through pannexin-1 hemi-channels, and this ATP release potentiates pseudovirus entry to NRCMs and human iPS cell-derived cardiomyocytes (hiPS-CMs). As the pseudovirus entry followed by production of reactive oxygen species was attenuated by inhibiting TRPC3-Nox2 complex in hiPS-CMs, we suggest that TRPC3-Nox2 complex formation triggered by panexin1-mediated ATP release participates in exacerbation of myocardial damage by amplifying ACE2-dependent SARS-CoV-2 entry.

    DOI: 10.3390/ijms24010102

  • Myocardial TRPC6-mediated Zn2+ influx induces beneficial positive inotropy through β-adrenoceptors. 査読 国際誌

    Sayaka Oda, Kazuhiro Nishiyama, Yuka Furumoto, Yohei Yamaguchi, Akiyuki Nishimura, Xiaokang Tang, Yuri Kato, Takuro Numaga-Tomita, Toshiyuki Kaneko, Supachoke Mangmool, Takuya Kuroda, Reishin Okubo, Makoto Sanbo, Masumi Hirabayashi, Yoji Sato, Yasuaki Nakagawa, Koichiro Kuwahara, Ryu Nagata, Gentaro Iribe, Yasuo Mori, Motohiro Nishida

    Nature communications   13 ( 1 )   6374 - 6374   2022年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Baroreflex control of cardiac contraction (positive inotropy) through sympathetic nerve activation is important for cardiocirculatory homeostasis. Transient receptor potential canonical subfamily (TRPC) channels are responsible for α1-adrenoceptor (α1AR)-stimulated cation entry and their upregulation is associated with pathological cardiac remodeling. Whether TRPC channels participate in physiological pump functions remains unclear. We demonstrate that TRPC6-specific Zn2+ influx potentiates β-adrenoceptor (βAR)-stimulated positive inotropy in rodent cardiomyocytes. Deletion of trpc6 impairs sympathetic nerve-activated positive inotropy but not chronotropy in mice. TRPC6-mediated Zn2+ influx boosts α1AR-stimulated βAR/Gs-dependent signaling in rat cardiomyocytes by inhibiting β-arrestin-mediated βAR internalization. Replacing two TRPC6-specific amino acids in the pore region with TRPC3 residues diminishes the α1AR-stimulated Zn2+ influx and positive inotropic response. Pharmacological enhancement of TRPC6-mediated Zn2+ influx prevents chronic heart failure progression in mice. Our data demonstrate that TRPC6-mediated Zn2+ influx with α1AR stimulation enhances baroreflex-induced positive inotropy, which may be a new therapeutic strategy for chronic heart failure.

    DOI: 10.1038/s41467-022-34194-9

  • Inhibition of transient receptor potential cation channel 6 promotes capillary arterialization during post-ischaemic blood flow recovery. 査読 国際誌

    Numaga-Tomita, T; Shimauchi, T; Kato, Y; Nishiyama, K; Nishimura, A; Sakata, K; Inada, H; Kita, S; Iwamoto, T; Nabekura, J; Birnbaumer, L; Mori, Y; Nishida, M

    BRITISH JOURNAL OF PHARMACOLOGY   180 ( 1 )   94 - 110   2022年9月   ISSN:0007-1188 eISSN:1476-5381

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:British Journal of Pharmacology  

    BACKGROUND AND PURPOSE: Capillary arterialization, characterized by the coverage of pre-existing or nascent capillary vessels with vascular smooth muscle cells (VSMCs), is critical for the development of collateral arterioles to improve post-ischaemic blood flow. We previously demonstrated that the inhibition of transient receptor potential 6 subfamily C, member 6 (TRPC6) channels facilitate contractile differentiation of VSMCs under ischaemic stress. We here investigated whether TRPC6 inhibition promotes post-ischaemic blood flow recovery through capillary arterialization in vivo. EXPERIMENTAL APPROACH: Mice were subjected to hindlimb ischaemia by ligating left femoral artery. The recovery rate of peripheral blood flow was calculated by the ratio of ischaemic left leg to non-ischaemic right one. The number and diameter of blood vessels were analysed by immunohistochemistry. Expression and phosphorylation levels of TRPC6 proteins were determined by western blotting and immunohistochemistry. KEY RESULTS: Although the post-ischaemic blood flow recovery is reportedly dependent on endothelium-dependent relaxing factors, systemic TRPC6 deletion significantly promoted blood flow recovery under the condition that nitric oxide or prostacyclin production were inhibited, accompanying capillary arterialization. Cilostazol, a clinically approved drug for peripheral arterial disease, facilitates blood flow recovery by inactivating TRPC6 via phosphorylation at Thr69 in VSMCs. Furthermore, inhibition of TRPC6 channel activity by pyrazole-2 (Pyr2; BTP2; YM-58483) promoted post-ischaemic blood flow recovery in Apolipoprotein E-knockout mice. CONCLUSION AND IMPLICATIONS: Suppression of TRPC6 channel activity in VSMCs could be a new strategy for the improvement of post-ischaemic peripheral blood circulation.

    DOI: 10.1111/bph.15942

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  • Drug repurposing for the treatment of COVID-19 査読

    Kato, Y; Nishiyama, K; Nishimura, A; Noda, T; Okabe, K; Kusakabe, T; Kanda, Y; Nishida, M

    JOURNAL OF PHARMACOLOGICAL SCIENCES   149 ( 3 )   108 - 114   2022年7月   ISSN:1347-8613 eISSN:1347-8648

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Pharmacological Sciences  

    Coronavirus disease 2019 (COVID-19) remains prevalent worldwide since its onset was confirmed in Wuhan, China in 2019. Vaccines against the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have shown a preventive effect against the onset and severity of COVID-19, and social and economic activities are gradually recovering. However, the presence of vaccine-resistant variants has been reported, and the development of therapeutic agents for patients with severe COVID-19 and related sequelae remains urgent. Drug repurposing, also called drug repositioning or eco-pharma, is the strategy of using previously approved and safe drugs for a therapeutic indication that is different from their original indication. The risk of severe COVID-19 and mortality increases with advancing age, cardiovascular disease, hypertension, diabetes, and cancer. We have reported three protein-protein interactions that are related to heart failure, and recently identified that one mechanism increases the risk of SARS-CoV-2 infection in mammalian cells. This review outlines the global efforts and outcomes of drug repurposing research for the treatment of severe COVID-19. It also discusses our recent finding of a new protein-protein interaction that is common to COVID-19 aggravation and heart failure.

    DOI: 10.1016/j.jphs.2022.04.007

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  • Vesicular nucleotide transporter is a molecular target of eicosapentaenoic acid for neuropathic and inflammatory pain treatment. 査読 国際誌

    Yuri Kato, Kengo Ohsugi, Yuto Fukuno, Ken Iwatsuki, Yuika Harada, Takaaki Miyaji

    Proceedings of the National Academy of Sciences of the United States of America   119 ( 30 )   e2122158119   2022年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Eicosapentaenoic acid (EPA), an omega-3 (ω-3) polyunsaturated fatty acid, is an essential nutrient that exhibits antiinflammatory, neuroprotective, and cardiovascular-protective activities. Although EPA is used as a nutrient-based pharmaceutical agent or dietary supplement, its molecular target(s) is debatable. Here, we showed that EPA and its metabolites strongly and reversibly inhibit vesicular nucleotide transporter (VNUT), a key molecule for vesicular storage and release of adenosine triphosphate (ATP) in purinergic chemical transmission. In vitro analysis showed that EPA inhibits human VNUT-mediated ATP uptake at a half-maximal inhibitory concentration (IC50) of 67 nM, acting as an allosteric modulator through competition with Cl-. EPA impaired vesicular ATP release from neurons without affecting the vesicular release of other neurotransmitters. In vivo, VNUT-/- mice showed a delay in the onset of neuropathic pain and resistance to both neuropathic and inflammatory pain. EPA potently attenuated neuropathic and inflammatory pain in wild-type mice but not in VNUT-/- mice without affecting the basal nociception. The analgesic effect of EPA was canceled by the intrathecal injection of purinoceptor agonists and was stronger than that of existing drugs used for neuropathic pain treatment, with few side effects. Neuropathic pain impaired insulin sensitivity in previous studies, which was improved by EPA in the wild-type mice but not in the VNUT-/- mice. Our results showed that VNUT is a molecular target of EPA that attenuates neuropathic and inflammatory pain and insulin resistance. EPA may represent a unique nutrient-based treatment and prevention strategy for neurological, immunological, and metabolic diseases by targeting purinergic chemical transmission.

    DOI: 10.1073/pnas.2122158119

  • A TRPC3/6 Channel Inhibitor Promotes Arteriogenesis after Hind-Limb Ischemia 査読 国際誌

    Shimauchi, T; Numaga-Tomita, T; Kato, Y; Morimoto, H; Sakata, K; Matsukane, R; Nishimura, A; Nishiyama, K; Shibuta, A; Horiuchi, Y; Kurose, H; Kim, SG; Urano, Y; Ohshima, T; Nishida, M

    CELLS   11 ( 13 )   2022年6月   eISSN:2073-4409

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

    Retarded revascularization after progressive occlusion of large conductance arteries is a major cause of bad prognosis for peripheral artery disease (PAD). However, pharmacological treatment for PAD is still limited. We previously reported that suppression of transient receptor potential canonical (TRPC) 6 channel activity in vascular smooth muscle cells (VSMCs) facilitates VSMC differentiation without affecting proliferation and migration. In this study, we found that 1-benzilpiperadine derivative (1-BP), a selective inhibitor for TRPC3 and TRPC6 channel activities, induced VSMC differentiation. 1-BP-treated mice showed increased capillary arterialization and improvement of peripheral circulation and skeletal muscle mass after hind-limb ischemia (HLI) in mice. 1-BP had no additive effect on the facilitation of blood flow recovery after HLI in TRPC6-deficient mice, suggesting that suppression of TRPC6 underlies facilitation of the blood flow recovery by 1-BP. 1-BP also improved vascular nitric oxide bioavailability and blood flow recovery after HLI in hypercholesterolemic mice with endothelial dysfunction, suggesting the retrograde interaction from VSMCs to endothelium. These results suggest that 1-BP becomes a potential seed for PAD treatments that target vascular TRPC6 channels.

    DOI: 10.3390/cells11132041

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  • Optimization of SARS-CoV-2 Spike Protein Expression in the Silkworm and Induction of Efficient Protective Immunity by Inoculation With Alum Adjuvants 査読

    Masuda, A; Lee, JM; Miyata, T; Mon, H; Sato, K; Oyama, K; Sakurai, Y; Yasuda, J; Takahashi, D; Ueda, T; Kato, Y; Nishida, M; Karasaki, N; Kakino, K; Ebihara, T; Nagasato, T; Hino, M; Nakashima, A; Suzuki, K; Tonooka, Y; Tanaka, M; Moriyama, T; Nakatake, H; Fujita, R; Kusakabe, T

    FRONTIERS IN IMMUNOLOGY   12   803647   2022年1月   ISSN:1664-3224

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    記述言語:英語   出版者・発行元:Frontiers in Immunology  

    The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing a spread of coronavirus disease 2019 (COVID-19) globally. In order to end the COVID-19 pandemic, an effective vaccine against SARS-CoV-2 must be produced at low cost and disseminated worldwide. The spike (S) protein of coronaviruses plays a pivotal role in the infection to host cells. Therefore, targeting the S protein is one of the most rational approaches in developing vaccines and therapeutic agents. In this study, we optimized the expression of secreted trimerized S protein of SARS-CoV-2 using a silkworm-baculovirus expression vector system and evaluated its immunogenicity in mice. The results showed that the S protein forming the trimeric structure was the most stable when the chicken cartilage matrix protein was used as the trimeric motif and could be purified in large amounts from the serum of silkworm larvae. The purified S protein efficiently induced antigen-specific antibodies in mouse serum without adjuvant, but its ability to induce neutralizing antibodies was low. After examining several adjuvants, the use of Alum adjuvant was the most effective in inducing strong neutralizing antibody induction. We also examined the adjuvant effect of paramylon from Euglena gracilis when administered with the S protein. Our results highlight the effectiveness and suitable construct design of the S protein produced in silkworms for the subunit vaccine development against SARS-CoV-2.

    DOI: 10.3389/fimmu.2021.803647

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  • Redox-dependent internalization of the purinergic P2Y6 receptor limits colitis progression. 査読 国際誌

    Kazuhiro Nishiyama, Akiyuki Nishimura, Kakeru Shimoda, Tomohiro Tanaka, Yuri Kato, Takahiro Shibata, Hiroshi Tanaka, Hitoshi Kurose, Yasu-Taka Azuma, Hideshi Ihara, Yoshito Kumagai, Takaaki Akaike, Philip Eaton, Koji Uchida, Motohiro Nishida

    Science signaling   15 ( 716 )   eabj0644   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    After ligand stimulation, many G protein–coupled receptors (GPCRs) undergo β-arrestin–dependent desensitization, during which they are internalized and either degraded or recycled to the plasma membrane. Some GPCRs are not subject to this type of desensitization because they lack the residues required to interact with β-arrestins. We identified a mechanism of redox-dependent alternative internalization (REDAI) that promotes the internalization and degradation of the purinergic P2Y6 receptor (P2Y6R). Synthetic and natural compounds containing electrophilic isothiocyanate groups covalently modified P2Y6R at Cys220, which promoted the ubiquitylation of Lys137 and receptor internalization and degradation in various mouse and human cultured cell lines. Endogenous electrophiles also promoted ligand-dependent P2Y6R internalization and degradation. P2Y6R is highly abundant in inflammatory cells and promotes the pathogenesis of colitis. Deficiency in P2Y6R protected mice against experimentally induced colitis, and mice expressing a form of P2Y6R in which Cys220 was mutated to nonmodifiable serine were more sensitive to the induction of colitis. Several other GPCRs, including A2BAR, contain cysteine and lysine residues at the appropriate positions to mediate REDAI, and isothiocyanate stimulated the internalization of A2BAR and of a form of P2Y2R with insertions of the appropriate residues. Thus, endogenous and exogenous electrophiles may limit colitis progression through cysteine modification of P2Y6R and may also mediate internalization of other GPCRs.

    DOI: 10.1126/scisignal.abj0644

  • Cardiac robustness regulated by reactive sulfur species 査読

    Nishimura, A; Tanaka, T; Kato, Y; Nishiyama, K; Nishida, M

    Journal of Clinical Biochemistry and Nutrition   70 ( 1 )   1 - 6   2022年1月   ISSN:09120009 eISSN:18805086

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:一般社団法人 日本酸化ストレス学会  

    The human myocardium contains robust cells that constantly beat from birth to death without being replaced, even when exposed to various environmental stresses. Myocardial robustness is thought to depend primarily on the strength of the reducing power to protect the heart from oxidative stress. Myocardial antioxidant systems are controlled by redox reactions, primarily via the redox reaction of Cys sulfhydryl groups, such as found in thioredoxin and glutathione. However, the specific molecular entities that regulate myocardial reducing power have long been debated. Recently, reactive sulfide species, with excellent electron transfer ability, consisting of a series of multiple sulfur atoms, i.e., Cys persulfide and Cys polysulfides, have been found to play an essential role in maintaining mitochondrial quality and function, as well as myocardial robustness. This review presents the latest findings on the molecular mechanisms underlying mitochondrial energy metabolism and the maintenance of quality control by reactive sulfide species and provides a new insight for the prevention of chronic heart failure.

    DOI: 10.3164/jcbn.21-84

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  • Clomipramine suppresses ACE2-mediated SARS-CoV-2 entry 国際誌

    Yuri Kato, Shigeru Yamada, Kazuhiro Nishiyama, Ayano Satsuka, Suyong Re, Daiki Tomokiyo, Jae Man Lee,Tomohiro Tanaka, Akiyuki Nishimura, Kenzo Yonemitsu, Hiroshi Asakura, Yuko Ibuki, Yumiko Imai, Noriho Kamiya, Kenji Mizuguchi, Takahiro Kusakabe, Yasunari Kanda, Motohiro Nishida

    bioRxiv preprint   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: https://doi.org/10.1101/2021.03.13.435221

  • Node-Localized Transporters of Phosphorus Essential for Seed Development in Rice. 査読

    Jing Che, Naoki Yamaji, Takaaki Miyaji, Namiki Mitani-Ueno, Yuri Kato, Ren Fang Shen, Jian Feng Ma

    Plant & cell physiology   61 ( 8 )   1387 - 1398   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    About 60-85&#37; of total phosphorus (P) in cereal crops is finally allocated to seeds, where it is required for seed development, germination and early growth. However, little is known about the molecular mechanisms underlying P allocation to seeds. Here, we found that two members (OsPHO1;1 and OsPHO1;2) of the PHO1 gene family are involved in the distribution of P to seeds in rice. Both OsPHO1;1 and OsPHO1;2 were localized to the plasma membrane and showed influx transport activities for inorganic phosphate. At the reproductive stage, both OsPHO1;1 and OsPHO1;2 showed higher expression in node I, the uppermost node connecting to the panicle. OsPHO1;1 was mainly localized at the phloem region of diffuse vascular bundles (DVBs) of node I, while OsPHO1;2 was expressed in the xylem parenchyma cells of the enlarged vascular bundles (EVBs). In addition, they were also expressed in the ovular vascular trace, the outer layer of the inner integument (OsPHO1;1) and in the nucellar epidermis (OsPHO1;2) of caryopses. Knockout of OsPHO1;2, as well as OsPHO1;1 to a lesser extent, decreased the distribution of P to the seed, resulting in decreased seed size and delayed germination. Taken together, OsPHO1;2 expressed in node I is responsible for the unloading of P from the xylem of EVBs, while OsPHO1;1 is involved in reloading P into the phloem of DVBs for subsequent allocation of P to seeds. Furthermore, OsPHO1;1 and OsPHO1;2 expression in the caryopsis is important for delivering P from the maternal tissues to the filial tissues for seed development.

    DOI: 10.1093/pcp/pcaa074

  • Modulation of P2Y6R expression exacerbates pressure overload-induced cardiac remodeling in mice. 査読 国際誌

    Kakeru Shimoda, Akiyuki Nishimura, Caroline Sunggip, Tomoya Ito, Kazuhiro Nishiyama, Yuri Kato, Tomohiro Tanaka, Hidetoshi Tozaki-Saitoh, Makoto Tsuda, Motohiro Nishida

    Scientific reports   10 ( 1 )   13926 - 13926   2020年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y6 receptor (P2Y6R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y6R prevents or promotes heart failure. We demonstrate that inhibition of P2Y6R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y6R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y6R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y6R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y6R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y6R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y6R exacerbates pressure overload-induced heart failure in mice, although P2Y6R in cardiomyocytes contributes to the progression of cardiac fibrosis.

    DOI: 10.1038/s41598-020-70956-5

  • Efficient Mass Spectral Analysis of Active Transporters Overexpressed in Escherichia coli 査読

    Mamiyo Kawakami, Narinobu Juge, Yuri Kato, Hiroshi Omote, Yoshinori Moriyama, Takaaki Miyaji

    Journal of Proteome Research   17 ( 3 )   1108 - 1119   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Structural analysis of purified active membrane proteins can be performed by mass spectrometry (MS). However, no large-scale expression systems for active eukaryotic membrane proteins are available. Moreover, because membrane proteins cannot easily be digested by trypsin and ionized, they are difficult to analyze by MS. We developed a method for mass spectral analysis of eukaryotic membrane proteins combined with an overexpression system in Escherichia coli. Vesicular glutamate transporter 2 (VGLUT2/SLC17A6) with a soluble α-helical protein and histidine tag on the N- and C-terminus, respectively, was overexpressed in E. coli, solubilized with detergent, and purified by Ni-NTA affinity chromatography. Proteoliposomes containing VGLUT2 retained glutamate transport activity. For MS analysis, the detergent was removed from purified VGLUT2 by trichloroacetic acid precipitation, and VGLUT2 was then subjected to reductive alkylation and tryptic digestion. The resulting peptides were detected with 88% coverage by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) MS with or without liquid chromatography. Vesicular excitatory amino acid transporter and vesicular acetylcholine transporter were also detected with similar coverage by the same method. Thus this methodology could be used to analyze purified eukaryotic active transporters. Structural analysis with chemical modifiers by MS could have applications in functional binding analysis for drug discovery.

    DOI: 10.1021/acs.jproteome.7b00777

  • Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain 査読

    Yuri Kato, Miki Hiasa, Reiko Ichikawa, Nao Hasuzawa, Atsushi Kadowaki, Ken Iwatsuki, Kazuhiro Shima, Yasuo Endo, Yoshiro Kitahara, Tsuyoshi Inoue, Masatoshi Nomura, Hiroshi Omote, Yoshinori Moriyama, Takaaki Miyaji

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   114 ( 31 )   E6297 - E6305   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Despite the high incidence of neuropathic and inflammatory pain worldwide, effective drugs with few side effects are currently unavailable for the treatment of chronic pain. Recently, researchers have proposed that inhibitors of purinergic chemical transmission, which plays a key role in the pathological pain response, may allow for targeted treatment of pathological neuropathic and inflammatory pain. However, such therapeutic analgesic agents have yet to be developed. In the present study, we demonstrated that clodronate, a first-generation bisphosphonate with comparatively fewer side effects than traditional treatments, significantly attenuates neuropathic and inflammatory pain unrelated to bone abnormalities via inhibition of vesicular nucleotide transporter (VNUT), a key molecule for the initiation of purinergic chemical transmission. In vitro analyses indicated that clodronate inhibits VNUT at a half-maximal inhibitory concentration of 15.6 nM without affecting other vesicular neurotransmitter transporters, acting as an allosteric modulator through competition with Cl-. A low concentration of clodronate impaired vesicular ATP release from neurons, microglia, and immune cells. In vivo analyses revealed that clodronate is more effective than other therapeutic agents in attenuating neuropathic and inflammatory pain, as well as the accompanying inflammation, in wild-type but not VNUT-/- mice, without affecting basal nociception. These findings indicate that clodronate may represent a unique treatment strategy for chronic neuropathic and inflammatory pain via inhibition of vesicular ATP release.

    DOI: 10.1073/pnas.1704847114

  • Inhibitors of ATP release inhibit vesicular nucleotide transporter 査読

    Yuri Kato, Hiroshi Omote, Takaaki Miyaji

    Biological and Pharmaceutical Bulletin   36 ( 11 )   1688 - 1691   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Vesicular nucleotide transporter (VNUT) is responsible for vesicular ATP storage in ATP-secreting cells. In the present study, we examined the effects on VNUT-mediated transport of ATP release inhibitors such as ATP-binding cassette (ABC) proteins, hemichannels, maxi anion channels and P2X7 receptor. The ATP transport activity of proteoliposomes containing purified human VNUT was blocked by glibenclamide, carbenoxolone, 18 á-glycyrrhetinic acid, flufenamic acid, arachidonic acid and A438079 without the formation of Äø (positive inside) as a driving force being affected. Thus, inhibitors of ATP release may inhibit VNUT and subsequent ATP release, since the previous works proved that inhibitors of ATP release blocked VNUT-mediated ATP release at the cell level. © 2013 The Pharmaceutical Society of Japan.

    DOI: 10.1248/bpb.b13-00544

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講演・口頭発表等

  • The role of TRPC6 channel in arteriogenesis after hind-limb ischemia. 国際会議

    Kato Yuri, Shimauchi Tsukasa, Numaga-Tomita Takuro, Nishiyama Kazuhiro, Nishimura Akiyuki, Nishida Motohiro

    World Congress of Basic & Clinical Pharmacology 2023  2023年7月 

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    開催年月日: 2023年7月

    記述言語:英語  

    開催地:glasgow   国名:グレートブリテン・北アイルランド連合王国(英国)  

  • 新型コロナウイルス感染に対する新規治療標的の提案とその薬理学的応用

    加藤百合, 西山和宏, 友清大樹, 田中智弘, 西村明幸, 西田基宏

    日本薬理学会西南部会  2020年11月 

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    開催年月日: 2021年11月

    記述言語:日本語  

    国名:日本国  

  • Regulation of myocardial atrophy by TRPC3-Nox2 complex formation

    Yuri Kato, Kazuhiro Nishiyama, Tomohiro Tanaka, Akiyuki Nishimura, Motohiro Nishida

    第98回 生理学会年会  2021年8月 

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    開催年月日: 2021年7月

    記述言語:英語  

    国名:日本国  

  • Eco-pharma research aimed at developing COVID-19 therapeutic agent

    Yuri Kato, Motohiro Nishida

    第94回薬理学会年会  2021年3月 

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    開催年月日: 2021年3月

    記述言語:日本語  

    国名:日本国  

  • 低濃度有機水銀曝露による新型コロナウイルス感染増悪

    加藤百合

    令和2年度メチル水銀研究ミーティング  2021年1月 

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    開催年月日: 2021年1月

    記述言語:日本語  

    国名:日本国  

  • 小胞型ヌクレオチドトランスポーター特異的阻害剤を用いたプリン作動性化学伝達のin vivo制御

    加藤 百合, 日浅 未来, 門脇 敦志, 島 和弘, 市川 玲子, 岩槻 健, 北原 吉朗, 井上 剛, 遠藤 康男, 表 弘志, 森山 芳則, 宮地 孝明

    日本生化学会大会  2016年9月 

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    記述言語:日本語  

    国名:日本国  

    小胞型ヌクレオチドトランスポーター特異的阻害剤を用いたプリン作動性化学伝達のin vivo制御

  • 骨粗鬆症症治療薬クロドロン酸は小胞型ヌクレオチドトランスポーターを標的として慢性疼痛を改善する

    加藤 百合, 日浅 未来, 市川 玲子, 蓮澤 奈央, 門脇 敦史, 岩槻 健, 島 和弘, 遠藤 康男, 北原 吉郎, 井上 剛, 野村 政壽, 表 弘志, 森山 芳則, 宮地 孝明

    生命科学系学会合同年次大会  2017年12月 

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    記述言語:日本語  

    国名:日本国  

    骨粗鬆症症治療薬クロドロン酸は小胞型ヌクレオチドトランスポーターを標的として慢性疼痛を改善する

  • 神経因性・炎症性疼痛に有効な小胞型ヌクレオチドトランスポーターの特異的阻害剤の同定

    加藤 百合, 日浅 未来, 市川 玲子, 蓮澤 奈央, 門脇 敦志, 岩槻 健, 島 和弘, 遠藤 康男, 北原 吉朗, 井上 剛, 野村 政壽, 表 弘志, 森山 芳則, 宮地 孝明

    脂質生化学研究  2018年5月 

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    記述言語:日本語  

    国名:日本国  

    神経・内分泌細胞は分泌小胞に充填したATPを開口放出し、プリン受容体を介して痛覚等の多彩な生理機能を制御する。我々は、ATPを分泌小胞に充填する小胞型ヌクレオチドトランスポーター(VNUT)を同定し、VNUTはプリン作動性化学伝達の必須因子であること、VNUTには塩素イオン(ON)とケトン体(OFF)によるアロステリックな代謝スイッチがあることを見出した。このスイッチを特異的にOFFできる化合物は画期的な鎮痛薬になると期待できる。骨粗鬆症治療薬の第一世代ビスホスホネート製剤は骨吸収抑制作用や副作用が弱く、鎮痛効果があることが報告されていたが、その作用機構は不明であった。我々は、このうちクロドロン酸が低濃度でVNUTを阻害することを見出した。興味深いことに、クロドロン酸はVNUTの代謝スイッチを選択的にOFFするアロステリック薬剤であった。神経因性と炎症性疼痛モデルマウスにクロドロン酸を投与したところ、鎮痛効果と抗炎症効果を発揮することを見出した。VNUT-/-マウスではクロドロン酸の効果が消失していた。以上より、クロドロン酸の鎮痛・抗炎症効果の分子標的はVNUTであり、クロドロン酸は副作用の少ない神経因性・炎症性疼痛の画期的治療薬になると期待できる。今後、ドラッグリポジショニングによる新規鎮痛薬のトランスポーター創薬が期待される。(著者抄録)

  • 硫黄の化学的理解に立脚したカルコゲン・バイオロジー 活性イオウによる心筋の頑健性制御

    西村 明幸, 西田 基宏, 西山 和弘, 加藤 百合, 田中 智弘

    日本生化学会大会  2020年9月 

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    記述言語:日本語  

    国名:日本国  

  • ミトコンドリア品質管理を標的とした炎症性腸疾患治療

    阿部 愛杜, 西山 和宏, 田中 智弘, 加藤 百合, 西村 明幸, 西田 基宏

    臨床薬理学会  2020年10月 

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    記述言語:日本語  

    国名:日本国  

  • プリン作動性P2Y6受容体数の変調は圧負荷誘導性心不全を増悪させる

    下田 翔, 西村 明幸, 西山 和宏, 加藤 百合, 田中 智弘, 齊藤 秀俊, 津田 誠, 西田 基宏

    臨床薬理学会  2020年10月 

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    記述言語:日本語  

    国名:日本国  

  • タバコ副流煙による心筋早期老化の誘導機構

    後藤 拓実, 友清 大樹, 加藤 百合, 西山 和宏, 西村 明幸, 西田 基宏

    臨床薬理学会  2020年10月 

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    記述言語:日本語  

    国名:日本国  

  • Covid-19感染重症化の予防・治療を見据えたエコファーマ研究

    友清 大樹, 後藤 拓実, 遠山 千恵実, 西山 和宏, 加藤 百合, 田中 智弘, 西村 明幸, 西田 基宏

    臨床薬理学会  2020年10月 

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    記述言語:日本語  

    国名:日本国  

  • 先端的医薬品開発を目指す薬理学・臨床薬理学研究 筋萎縮性疾患治療薬を指向したエコファーマ研究

    西田 基宏, 西山 和宏, 加藤 百合, 小谷 さゆみ, 田中 智弘, 西村 明幸

    臨床薬理学会  2021年3月 

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    記述言語:日本語  

    国名:日本国  

  • Covid-19感染重症化におけるACE2発現制御機構の解明及び新規治療薬の探索

    友清 大樹, 加藤 百合, 西山 和宏, 西村 明幸, 田中 智弘, 日下部 宜宏, 神谷 典穂, 今井 由美子, 朝倉 宏, 諫田 泰成, 西田 基宏

    日本薬学会  2021年3月 

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    記述言語:日本語  

    国名:日本国  

  • 筋萎縮性疾患治療薬を指向したエコファーマ研究

    西田 基宏, 西山 和宏, 加藤 百合, 小谷 さゆみ, 田中 智弘, 西村 明幸

    臨床薬理学会  2021年3月 

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    記述言語:日本語  

    国名:日本国  

    4. Eco-pharma Research Aimed at Therapeutic Agents for Amyotrophic Diseases

  • 次世代薬理研究者による創薬研究ブレイクスルーへの挑戦 システイン修飾を介したGPCRの内在化機構の解明

    西山 和宏, 西村 明幸, 加藤 百合, 下田 翔, 西田 基宏

    日本薬学会  2022年3月 

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    記述言語:日本語  

    国名:日本国  

  • マウス下肢虚血後の毛細血管動脈化におけるTRPC6チャネルの役割

    酒田 康介, 島内 司, 冨田 拓郎, 加藤 百合, 西山 和宏, 西村 明幸, 西田 基宏

    日本薬学会  2022年3月 

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    記述言語:日本語  

    国名:日本国  

  • 横紋筋の萎縮におけるTRPC3-Nox2複合体の関与

    加藤 百合, 西山 和宏, 西村 明幸, 西田 基宏

    日本心脈管作動物質学会  2022年6月 

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    記述言語:日本語  

    国名:日本国  

  • 代謝制御と変容、その生物学的意義-心不全治療法開発に向けたアイデア- ミトコンドリア硫黄代謝制御による心不全治療

    西田 基宏, 西村 明幸, 下田 翔, 加藤 百合, 西山 和宏

    日本心脈管作動物質学会  2022年6月 

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    記述言語:日本語  

    国名:日本国  

  • システイン修飾を介したGPCRの内在化機構の解明

    西山 和宏, 西村 明幸, 下田 翔, 加藤 百合, 西田 基宏

    日本心脈管作動物質学会  2022年6月 

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    記述言語:日本語  

    国名:日本国  

  • TRPC6チャネル阻害は末梢循環障害を改善する

    加藤 百合、島内 司、冨田 拓郎、酒田 康介、西山 和宏、西村 明幸、岩本 隆宏、森 泰生、西田 基宏

    日本薬理学会西南部会  2022年10月 

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    記述言語:日本語  

    国名:日本国  

  • 超硫黄生物学が切り拓く生命原理変革 超硫黄分子による心臓の虚血ストレス抵抗性制御

    西田 基宏, 西村 明幸, 西山 和宏, 加藤 百合

    日本生化学会大会  2022年11月 

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    記述言語:日本語  

    国名:日本国  

  • 肺高血圧症治療の新戦略 TRPC3/6タンパク質のアイソフォーム特異的な役割を標的とする創薬

    西田 基宏, 西山 和宏, 加藤 百合, Mi Xinya, 西村 明幸

    日本心脈管作動物質学会  2023年1月 

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    記述言語:日本語  

    国名:日本国  

  • TRPC6チャネル阻害における末梢循環障害改善効果の検討

    加藤 百合, 島内 司, 冨田 拓郎, 酒田 康介, 西山 和宏, 西村 明幸, 岩本 隆宏, 森 泰生, 西田 基宏

    日本循環薬理学会  2023年1月 

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    記述言語:日本語  

    国名:日本国  

  • ミトコンドリア品質管理を標的とした炎症性腸疾患治療

    西山 和宏, 西村 明幸, 加藤 百合, 川西 英治, 王子田 彰夫, 西田 基宏

    日本循環薬理学会  2023年1月 

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    記述言語:日本語  

    国名:日本国  

  • Drp1グルタチオン化は硫黄代謝異常によって引き起こされるミトコンドリア過剰分裂および心筋細胞老化を改善する

    西村 明幸, Tang Xiaokang, Hengphasat Kowit, 西山 和宏, 加藤 百合, 重田 育照, 西田 基宏

    日本循環薬理学会  2023年1月 

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    記述言語:日本語  

    国名:日本国  

  • 末梢循環障害における脂質作動性TRPCチャネルの関与

    加藤 百合, 冨田 拓郎[沼賀], 島内 司, 酒田 康介, 西山 和宏, 西村 明幸, 岩本 隆宏, 森 泰生, 西田 基宏

    脂質生化学研究  2023年5月 

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    記述言語:日本語  

    国名:日本国  

▼全件表示

MISC

  • 骨粗鬆症治療薬クロドロン酸は小胞型ヌクレオチドトランスポーターを標的として慢性疼痛を改善する

    加藤 百合, 日浅 未来, 市川 玲子, 蓮澤 奈央, 門脇 敦史, 岩槻 健, 島 和弘, 遠藤 康男, 北原 吉郎, 井上 剛, 野村 政壽, 表 弘志, 森山 芳則, 宮地 孝明

    生命科学系学会合同年次大会   2017年12月

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    記述言語:日本語  

    骨粗鬆症治療薬クロドロン酸は小胞型ヌクレオチドトランスポーターを標的として慢性疼痛を改善する

  • 小胞型ヌクレオチドトランスポーター特異的阻害剤の同定とプリン作動性化学伝達のin vivo制御

    加藤 百合, 日浅 未来, 門脇 敦志, 島 和弘, 市川 玲子, 岩槻 健, 北原 吉朗, 井上 剛, 遠藤 康男, 表 弘志, 森山 芳則, 宮地 孝明

    日本薬学会年会要旨集   2016年3月

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    記述言語:日本語  

    小胞型ヌクレオチドトランスポーター特異的阻害剤の同定とプリン作動性化学伝達のin vivo制御

  • Inhibitors of ATP release inhibit vesicular nucleotide transporter

    Yuri Kato, Hiroshi Omote, Takaaki Miyaji

    PURINERGIC SIGNALLING   2014年12月

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    記述言語:英語  

産業財産権

特許権   出願件数: 1件   登録件数: 0件
実用新案権   出願件数: 0件   登録件数: 0件
意匠権   出願件数: 0件   登録件数: 0件
商標権   出願件数: 0件   登録件数: 0件

所属学協会

  • 日本循環薬理学会

  • 日本毒性学会

  • 日本生理学会

  • 日本薬理学会

  • 日本生化学会

  • 日本薬学会

▼全件表示

共同研究・競争的資金等の研究課題

  • 超硫黄分子トランスポーターの探索と骨格筋における硫黄代謝の生理的意義の解明

    研究課題/領域番号:23K06164  2023年 - 2025年

    日本学術振興会  科学研究費助成事業  基盤研究(C)

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    担当区分:研究代表者  資金種別:科研費

  • 代謝活性化を介した民生品のタンパク質付加体形成によるエピジェネティクス変化

    研究課題/領域番号:23H03547  2023年 - 2025年

    日本学術振興会  科学研究費助成事業  基盤研究(B)

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    担当区分:研究分担者  資金種別:科研費

  • 非天然α-アミノ酸を用いた中分子ペプチド医薬品創成

    2021年 - 2023年

    科学研究費助成事業 

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    担当区分:研究分担者  資金種別:科研費以外の競争的資金

  • 木下基礎科学研究基金/COVID-19治療候補薬クロミプラミンの作用標的の探索と重症化機構の解明

    2021年

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    資金種別:寄附金

  • COVID-19治療候補薬クロミプラミンの作用標的の同定と重症化メカニズムの解明

    2021年

    QRプログラム わかばチャレンジ

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    担当区分:研究代表者  資金種別:学内資金・基金等

  • 細胞特異的なプリン作動性化学伝達の出力系の生理的意義の解明と応用

    研究課題/領域番号:20K15993  2020年 - 2022年

    日本学術振興会  科学研究費助成事業  若手研究

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    担当区分:研究代表者  資金種別:科研費

  • 研究奨励金 / ACE2に着目したCOVID-19重症化機構の解明とその応用

    2020年

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    資金種別:寄附金

  • 新型コロナウイルス感染症に対する新規治療標的の提案とその薬理学的応用

    2020年

    QRプログラム わかばチャレンジ

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    担当区分:研究代表者  資金種別:学内資金・基金等

  • 薬学系研究助成/プリン作動性化学伝達を標的とした慢性疼痛抑制メカニズムの解明

    2019年

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    資金種別:寄附金

  • プリン作動性化学伝達の遮断による慢性疼痛の抑制メカニズムの解明と薬学的応用

    研究課題/領域番号:18K14903  2018年 - 2019年

    日本学術振興会  科学研究費助成事業  若手研究

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    担当区分:研究代表者  資金種別:科研費

  • ショウジョウバエVNUTの同定とその生理的意義

    研究課題/領域番号:26893154  2014年 - 2015年

    日本学術振興会  科学研究費助成事業  研究活動スタート支援

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    担当区分:研究代表者  資金種別:科研費

▼全件表示

担当授業科目

  • 薬理・疾患治療

    2025年10月 - 2026年3月   後期

  • 薬学基礎実習Ⅳ

    2025年6月 - 2025年8月   夏学期

  • 薬物治療学Ⅰ

    2025年4月 - 2025年6月   春学期

学内運営に関わる各種委員・役職等

  • 2023年4月 - 現在   その他 動物実験委員会委員

  • 2020年1月 - 現在   その他 X線取扱主任者