Updated on 2025/04/17

Information

 

写真a

 
MI XINYA
 
Organization
Faculty of Pharmaceutical Sciences Department of Pharmaceutical Health Care and Sciences Assistant Professor
Title
Assistant Professor
External link

Research Areas

  • Life Science / Physiology

Degree

  • Medical PhD

Research History

  • Kyushu University School of Pharmaceutical Sciences Assistant Professor 

    2022.4 - Present

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  • Shiga University of Medical Science Molecular Neuroscience Research Center Specially Appointed Assistant Professor 

    2021.10 - 2022.3

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Education

  • Shiga University of Medical Science    

    2017.10 - 2022.3

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Research Interests・Research Keywords

  • Research theme: 心筋

    Keyword: 心筋

    Research period: 2024

  • Research theme: 受容体

    Keyword: 受容体

    Research period: 2024

  • Research theme: パッチクランプ

    Keyword: パッチクランプ

    Research period: 2024

  • Research theme: イオンチャネル

    Keyword: イオンチャネル

    Research period: 2024

Papers

  • Activation of the urotensin-II receptor by remdesivir induces cardiomyocyte dysfunction Reviewed International journal

    Akiko Ogawa 1,8, Seiya Ohira 1,2,8, Yuri Kato 3, Tatsuya Ikuta 4, Shota Yanagida 5 6, Xinya Mi 3, Yukina Ishii 3, Yasunari Kanda 5, Motohiro Nishida3,7, Asuka Inoue4, Fan-Yan Wei 1

    Communications biology   6 ( 1 )   511   2023.3   eISSN:2399-3642

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

    Abstract

    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 Gα<sub>i/o</sub>-dependent AKT/ERK axis. Functionally, remdesivir treatment induced prolonged field potential and APD<sub>90</sub> 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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    Other Link: https://www.nature.com/articles/s42003-023-04888-x

  • Knockout of Purinergic P2Y6 Receptor Fails to Improve Liver Injury and Inflammation in Non-Alcoholic Steatohepatitis Reviewed International journal

    Kazuhiro Nishiyama 1, Kohei Ariyoshi 1, Akiyuki Nishimura 2 3, Yuri Kato 1, Xinya Mi 1, Hitoshi Kurose 1, Sang Geon Kim 4, Motohiro Nishida 1 2 3

    International Journal of Molecular Sciences   24 ( 4 )   2023.2   ISSN:16616596 eISSN:1422-0067

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    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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  • 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 Reviewed

    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   2023.1

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

    DOI: SN : 0911-4637医中誌Web ID : X522520015

  • Propofol, an Anesthetic Agent, Inhibits HCN Channels through the Allosteric Modulation of the cAMP-Dependent Gating Mechanism. Reviewed International journal

    Morihiro Shimizu, Xinya Mi, Futoshi Toyoda, Akiko Kojima, Wei-Guang Ding, Yutaka Fukushima, Mariko Omatsu-Kanbe, Hirotoshi Kitagawa, Hiroshi Matsuura

    Biomolecules   12 ( 4 )   2022.4

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    Propofol is a broadly used intravenous anesthetic agent that can cause cardiovascular effects, including bradycardia and asystole. A possible mechanism for these effects is slowing cardiac pacemaker activity due to inhibition of the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. However, it remains unclear how propofol affects the allosteric nature of the voltage- and cAMP-dependent gating mechanism in HCN channels. To address this aim, we investigated the effect of propofol on HCN channels (HCN4 and HCN2) in heterologous expression systems using a whole-cell patch clamp technique. The extracellular application of propofol substantially suppressed the maximum current at clinical concentrations. This was accompanied by a hyperpolarizing shift in the voltage dependence of channel opening. These effects were significantly attenuated by intracellular loading of cAMP, even after considering the current modification by cAMP in opposite directions. The differential degree of propofol effects in the presence and absence of cAMP was rationalized by an allosteric gating model for HCN channels, where we assumed that propofol affects allosteric couplings between the pore, voltage-sensor, and cyclic nucleotide-binding domain (CNBD). The model predicted that propofol enhanced autoinhibition of pore opening by unliganded CNBD, which was relieved by the activation of CNBD by cAMP. Taken together, these findings reveal that propofol acts as an allosteric modulator of cAMP-dependent gating in HCN channels, which may help us to better understand the clinical action of this anesthetic drug.

    DOI: 10.3390/biom12040570

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  • Atypically Shaped Cardiomyocytes (ACMs): The Identification, Characterization and New Insights into a Subpopulation of Cardiomyocytes Reviewed International journal

    Mariko Omatsu-Kanbe 1, Ryo Fukunaga 1, Xinya Mi 1, Hiroshi Matsuura 1

    Biomolecules   12 ( 7 )   896 - 896   2022.1   eISSN:2218-273X

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

    In the adult mammalian heart, no data have yet shown the existence of cardiomyocyte-differentiable stem cells that can be used to practically repair the injured myocardium. Atypically shaped cardiomyocytes (ACMs) are found in cultures of the cardiomyocyte-removed fraction obtained from cardiac ventricles from neonatal to aged mice. ACMs are thought to be a subpopulation of cardiomyocytes or immature cardiomyocytes, most closely resembling cardiomyocytes due to their spontaneous beating, well-organized sarcomere and the expression of cardiac-specific proteins, including some fetal cardiac gene proteins. In this review, we focus on the characteristics of ACMs compared with ventricular myocytes and discuss whether these cells can be substitutes for damaged cardiomyocytes. ACMs reside in the interstitial spaces among ventricular myocytes and survive under severely hypoxic conditions fatal to ventricular myocytes. ACMs have not been observed to divide or proliferate, similar to cardiomyocytes, but they maintain their ability to fuse with each other. Thus, it is worthwhile to understand the role of ACMs and especially how these cells perform cell fusion or function independently in vivo. It may aid in the development of new approaches to cell therapy to protect the injured heart or the clarification of the pathogenesis underlying arrhythmia in the injured heart.

    DOI: 10.3390/biom12070896

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  • Selective activation of adrenoceptors potentiates IKs current in pulmonary vein cardiomyocytes through the protein kinase A and C signaling pathways. Reviewed International journal

    Xinya Mi, Wei-Guang Ding, Futoshi Toyoda, Akiko Kojima, Mariko Omatsu-Kanbe, Hiroshi Matsuura

    Journal of molecular and cellular cardiology   161   86 - 97   2021.12

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    Delayed rectifier K+ current (IKs) is a key contributor to repolarization of action potentials. This study investigated the mechanisms underlying the adrenoceptor-induced potentiation of IKs in pulmonary vein cardiomyocytes (PVC). PVC were isolated from guinea pig pulmonary vein. The action potentials and IKs current were recorded using perforated and conventional whole-cell patch-clamp techniques. The expression of IKs was examined using immunocytochemistry and Western blotting. KCNQ1, a IKs pore-forming protein was detected as a signal band approximately 100 kDa in size, and its immunofluorescence signal was found to be mainly localized on the cell membrane. The IKs current in PVC was markedly enhanced by both β1- and β2-adrenoceptor stimulation with a negative voltage shift in the current activation, although the potentiation was more effectively induced by β2-adrenoceptor stimulation than β1-adrenoceptor stimulation. Both β-adrenoceptor-mediated increases in IKs were attenuated by treatment with the adenylyl cyclase (AC) inhibitor or protein kinase A (PKA) inhibitor. Furthermore, the IKs current was increased by α1-adrenoceptor agonist but attenuated by the protein kinase C (PKC) inhibitor. PVC exhibited action potentials in normal Tyrode solution which was slightly reduced by HMR-1556 a selective IKs blocker. However, HMR-1556 markedly reduced the β-adrenoceptor-potentiated firing rate. The stimulatory effects of β- and α1-adrenoceptor on IKs in PVC are mediated via the PKA and PKC signal pathways. HMR-1556 effectively reduced the firing rate under β-adrenoceptor activation, suggesting that the functional role of IKs might increase during sympathetic excitation under in vivo conditions.

    DOI: 10.1016/j.yjmcc.2021.08.004

  • Characterization and functional role of rapid- and slow-activating delayed rectifier K+ currents in atrioventricular node cells of guinea pigs. Reviewed International journal

    Mayumi Yuasa, Akiko Kojima, Xinya Mi, Wei-Guang Ding, Mariko Omatsu-Kanbe, Hirotoshi Kitagawa, Hiroshi Matsuura

    Pflugers Archiv : European journal of physiology   473 ( 12 )   1885 - 1898   2021.12

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    The atrioventricular (AV) node is the only conduction pathway where electrical impulse can pass from atria to ventricles and exhibits spontaneous automaticity. This study examined the function of the rapid- and slow-activating delayed rectifier K+ currents (IKr and IKs) in the regulation of AV node automaticity. Isolated AV node cells from guinea pigs were current- and voltage-clamped to record the action potentials and the IKr and IKs current. The expression of IKr or IKs was confirmed in the AV node cells by immunocytochemistry, and the positive signals of both channels were localized mainly on the cell membrane. The basal spontaneous automaticity was equally reduced by E4031 and HMR-1556, selective blockers of IKr and IKs, respectively. The nonselective β-adrenoceptor agonist isoproterenol markedly increased the firing rate of action potentials. In the presence of isoproterenol, the firing rate of action potentials was more effectively reduced by the IKs inhibitor HMR-1556 than by the IKr inhibitor E4031. Both E4031 and HMR-1556 prolonged the action potential duration and depolarized the maximum diastolic potential under basal and β-adrenoceptor-stimulated conditions. IKr was not significantly influenced by β-adrenoceptor stimulation, but IKs was concentration-dependently enhanced by isoproterenol (EC50: 15 nM), with a significant negative voltage shift in the channel activation. These findings suggest that both the IKr and IKs channels might exert similar effects on regulating the repolarization process of AV node action potentials under basal conditions; however, when the β-adrenoceptor is activated, IKs modulation may become more important.

    DOI: 10.1007/s00424-021-02617-z

  • Elevation of propofol sensitivity of cardiac IKs channel by KCNE1 polymorphism D85N. Reviewed International journal

    Akiko Kojima, Xinya Mi, Yutaka Fukushima, Wei-Guang Ding, Mariko Omatsu-Kanbe, Hiroshi Matsuura

    British journal of pharmacology   178 ( 13 )   2690 - 2708   2021.7

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    BACKGROUND AND PURPOSE: The slowly activating delayed rectifier K+ channel (IKs ), composed of pore-forming KCNQ1 α-subunits and ancillary KCNE1 β-subunits, regulates ventricular repolarization in human heart. Propofol, at clinically used concentrations, modestly inhibits the intact (wild-type) IKs channels and is therefore unlikely to appreciably prolong QT interval in ECG during anaesthesia. However, little information is available concerning the inhibitory effect of propofol on IKs channel associated with its gene variants implicated in QT prolongation. The KCNE1 single nucleotide polymorphism leading to D85N is associated with drug-induced QT prolongation and therefore regarded as a clinically important genetic variant. This study examined whether KCNE1-D85N affects the sensitivity of IKs to inhibition by propofol. EXPERIMENTAL APPROACH: Whole-cell patch-clamp and immunostaining experiments were conducted in HEK293 cells and/or mouse cardiomyocyte-derived HL-1 cells, transfected with wild-type KCNQ1, wild-type or variant KCNE1 cDNAs. KEY RESULTS: Propofol inhibited KCNQ1/KCNE1-D85N current more potently than KCNQ1/KCNE1 current in HEK293 cells and HL-1 cells. Immunostaining experiments in HEK293 cells revealed that pretreatment with propofol (10 μM) did not appreciably affect cell membrane expression of KCNQ1 and KCNE1 proteins in KCNQ1/KCNE1 and KCNQ1/KCNE1-D85N channels. CONCLUSION AND IMPLICATIONS: The KCNE1 polymorphism D85N significantly elevates the sensitivity of IKs to inhibition by propofol. This study detects a functionally important role of KCNE1-D85N polymorphism in conferring genetic susceptibility to propofol-induced QT prolongation and further suggests the possibility that the inhibitory action of anaesthetics on ionic currents becomes exaggerated in patients carrying variants in genes encoding ion channels.

    DOI: 10.1111/bph.15460

  • An Antegrade Perfusion Method for Cardiomyocyte Isolation from Mice. Reviewed International journal

    Mariko Omatsu-Kanbe, Ryo Fukunaga, Xinya Mi, Hiroshi Matsuura

    Journal of visualized experiments : JoVE   ( 171 )   2021.5

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    In basic research using mouse heart, isolating viable individual cardiomyocytes is a crucial technical step to overcome. Traditionally, isolating cardiomyocytes from rabbits, guinea pigs or rats has been performed via retrograde perfusion of the heart with enzymes using a Langendorff apparatus. However, a high degree of skill is required when this method is used with a small mouse heart. An antegrade perfusion method that does not use a Langendorff apparatus was recently reported for the isolation of mouse cardiomyocytes. We herein report a complete protocol for the improved antegrade perfusion of the excised heart to isolate individual heart cells from adult mice (8 - 108 weeks old). Antegrade perfusion is performed by injecting perfusate near the apex of the left ventricle of the excised heart, the aorta of which was clamped, using an infusion pump. All procedures are carried out on a pre-warmed heater mat under a microscope, which allows for the injection and perfusion processes to be monitored. The results suggest that ventricular and atrial myocytes, and fibroblasts can be well isolated from a single adult mouse simultaneously.

    DOI: 10.3791/61866

  • Positive Inotropic Effects of ATP Released via the Maxi-Anion Channel in Langendorff-Perfused Mouse Hearts Subjected to Ischemia-Reperfusion Reviewed International journal

    Hiroshi Matsuura 1, Akiko Kojima 2, Yutaka Fukushima 2, Yu Xie 1, Xinya Mi 1, Ravshan Z Sabirov 3, Yasunobu Okada 4 5 6

    Front Cell Dev Biol   2021.1

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    DOI: 10.3389/fcell.2021.597997

  • Open-channel blocking action of volatile anaesthetics desflurane and sevoflurane on human voltage-gated Kv 1.5 channel. Reviewed International journal

    Yutaka Fukushima, Akiko Kojima, Xinya Mi, Wei-Guang Ding, Hirotoshi Kitagawa, Hiroshi Matsuura

    British journal of pharmacology   177 ( 16 )   3811 - 3827   2020.8

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    BACKGROUND AND PURPOSE: Volatile anaesthetics have been shown to differentially modulate mammalian Shaker-related voltage-gated potassium (Kv 1.x) channels. This study was designed to investigate molecular and cellular mechanisms underlying the modulatory effects of desflurane or sevoflurane on human Kv 1.5 (hKv 1.5) channels. EXPERIMENTAL APPROACH: Thirteen single-point mutations were constructed within pore domain of hKv 1.5 channel using site-directed mutagenesis. The effects of desflurane or sevoflurane on heterologously expressed wild-type and mutant hKv 1.5 channels were examined by whole-cell patch-clamp technique. A computer simulation was conducted to predict the docking pose of desflurane or sevoflurane within hKv 1.5 channel. KEY RESULTS: Both desflurane and sevoflurane increased hKv 1.5 current at mild depolarizations but decreased it at strong depolarizations, indicating that these anaesthetics produce both stimulatory and inhibitory actions on hKv 1.5 channels. The inhibitory effect of desflurane or sevoflurane on hKv 1.5 channels arose primarily from its open-channel blocking action. The inhibitory action of desflurane or sevoflurane on hKv 1.5 channels was significantly attenuated in T480A, V505A, and I508A mutant channels, compared with wild-type channel. Computational docking simulation predicted that desflurane or sevoflurane resides within the inner cavity of channel pore and has contact with Thr479, Thr480, Val505, and Ile508. CONCLUSION AND IMPLICATIONS: Desflurane and sevoflurane exert an open-channel blocking action on hKv 1.5 channels by functionally interacting with specific amino acids located within the channel pore. This study thus identifies a novel molecular basis mediating inhibitory modulation of hKv 1.5 channels by desflurane and sevoflurane.

    DOI: 10.1111/bph.15105

  • Ligand-Independent Spontaneous Activation of Purinergic P2Y(6) Receptor Under Cell Culture Soft Substrate.

    Nishimura A, Nishiyama K, Ito T, Mi X, Kato Y, Inoue A, Aoki J, Nishida M

    Cells   14 ( 3 )   2025.2

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    DOI: 10.3390/cells14030216

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  • Supersulfide catabolism participates in maladaptive remodeling of cardiac cells Reviewed

    Liuchenzi Zhou, Akiyuki Nishimura, Keitaro Umezawa, Yuri Kato, Xinya Mi, Tomoya Ito, Yasuteru Urano, Takaaki Akaike, Motohiro Nishida

    Journal of Pharmacological Sciences   155 ( 4 )   121 - 130   2024.8   ISSN:1347-8613 eISSN:1347-8648

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    The atrophic myocardium resulting from mechanical unloading and nutritional deprivation is considered crucial as maladaptive remodeling directly associated with heart failure, as well as interstitial fibrosis. Conversely, myocardial hypertrophy resulting from hemodynamic loading is perceived as compensatory stress adaptation. We previously reported the abundant presence of highly redox-active polysulfide molecules, termed supersulfide, with two or more sulfur atoms catenated in normal hearts, and the supersulfide catabolism in pathologic hearts after myocardial infarction correlated with worsened prognosis of heart failure. However, the impact of supersulfide on myocardial remodeling remains unclear. Here, we investigated the involvement of supersulfide metabolism in cardiomyocyte remodeling, using a model of adenosine 5′-triphosphate (ATP) receptor-stimulated atrophy and endothelin-1 receptor-stimulated hypertrophy in neonatal rat cardiomyocytes. Results revealed contrasting changes in intracellular supersulfide and its catabolite, hydrogen sulfide (H2S), between cardiomyocyte atrophy and hypertrophy. Stimulation of cardiomyocytes with ATP decreased supersulfide activity, while H2S accumulation itself did not affect cardiomyocyte atrophy. This supersulfide catabolism was also involved in myofibroblast formation of neonatal rat cardiac fibroblasts. Thus, unraveling supersulfide metabolism during myocardial remodeling may lead to the development of novel therapeutic strategies to improve heart failure.

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  • Supersulfide catabolism participates in maladaptive remodeling of cardiac cells(タイトル和訳中)

    Zhou Liuchenzi, Nishimura Akiyuki, Umezawa Keitaro, Kato Yuri, Mi Xinya, Ito Tomoya, Urano Yasuteru, Akaike Takaaki, Nishida Motohiro

    Journal of Pharmacological Sciences   155 ( 4 )   121 - 130   2024.8   ISSN:1347-8613

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

    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   2024.7   ISSN:0007-1188 eISSN:1476-5381

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    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.

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  • Inhibition of Drp1-Filamin Protein Complex Prevents Hepatic Lipid Droplet Accumulation by Increasing Mitochondria-Lipid Droplet Contact. Reviewed International journal

    Kohei Ariyoshi, Kazuhiro Nishiyama, Yuri Kato, Xinya Mi, Tomoya Ito, Yasu-Taka Azuma, Akiyuki Nishimura, Motohiro Nishida

    International journal of molecular sciences   25 ( 10 )   2024.5   ISSN:1661-6596 eISSN:1422-0067

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    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.

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  • Cardiac remodeling: novel pathophysiological mechanisms and therapeutic strategies. Reviewed International journal

    Motohiro Nishida, Xinya Mi, Yukina Ishii, Yuri Kato, Akiyuki Nishimura

    Journal of biochemistry   176 ( 4 )   255 - 262   2024.3   ISSN:0021-924X eISSN:1756-2651

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    Morphological and structural remodeling of the heart, including cardiac hypertrophy and fibrosis, has been considered as a therapeutic target for heart failure for approximately three decades. Groundbreaking heart failure medications demonstrating reverse remodeling effects have contributed significantly to medical advancements. However, nearly 50% of heart failure patients still exhibit drug resistance, posing a challenge to the healthcare system. Recently, characteristics of heart failure resistant to ARBs and β-blockers have been defined, highlighting preserved systolic function despite impaired diastolic function, leading to the classification of heart failure with preserved ejection fraction (HFpEF). The pathogenesis and aetiology of HFpEF may be related to metabolic abnormalities, as evidenced by its mimicry through endothelial dysfunction and excessive intake of high-fat diets. Our recent findings indicate a significant involvement of mitochondrial hyper-fission in the progression of heart failure. This mitochondrial pathological remodeling is associated with redox imbalance, especially hydrogen sulphide accumulation due to abnormal electron leak in myocardium. In this review, we also introduce a novel therapeutic strategy for heart failure from the current perspective of mitochondrial redox-metabolic remodeling.

    DOI: 10.1093/jb/mvae031

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  • Supersulfide prevents cigarette smoke extract-induced mitochondria hyperfission and cardiomyocyte early senescence by inhibiting Drp1-filamin complex formation Invited Reviewed International journal

    Akiyuki Nishimura 1, Liuchenzi Zhou 2, Yuri Kato 3, Xinya Mi 3, Tomoya Ito 2, Yuko Ibuki 4, Yasunari Kanda 5, Motohiro Nishida 6

    2024.2

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  • Pharmacological Activation of TRPC6 Channel Prevents Colitis Progression Reviewed International journal

    Kazuhiro Nishiyama 1 2, Yuri Kato 1, Akiyuki Nishimura 3 4 5, Xinya Mi 1, Ryu Nagata 6, Yasuo Mori 7, Yasu-Taka Azuma 2, Motohiro Nishida 1 3 4 5 8

    2024.2

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    DOI: DOI: 10.3390/ijms25042401

  • Pharmacological Activation of TRPC6 Channel Prevents Colitis Progression. Reviewed International journal

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

    International journal of molecular sciences   25 ( 4 )   2024.2   ISSN:1661-6596 eISSN:1422-0067

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    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.

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  • Supersulfide prevents cigarette smoke extract-induced mitochondria hyperfission and cardiomyocyte early senescence by inhibiting Drp1-filamin complex formation(タイトル和訳中)

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

    Journal of Pharmacological Sciences   154 ( 2 )   127 - 135   2024.2   ISSN:1347-8613

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    Language:English   Publisher:(公社)日本薬理学会  

    ラット新生仔の心筋細胞にタバコ煙抽出物(CSE)を曝露すると、ミトコンドリア(MT)過剰分裂を介して心筋細胞老化が誘発された。CSEはMT分裂因子Drp1とアクチン結合蛋白質であるフィラミンA(FIL-A)との複合体形成を介して、MT分裂と活性酸素種(ROS)産生を引き起こした。シルニジピンやDrp1またはFIL-Aの遺伝子ノックダウンによりDrp1とFIL-Aの相互作用が変化し、CSE誘発性MT過剰分裂とROS産生、および心筋細胞老化を阻害した。Drp1活性の中心である酸化還元感受性をもったCys644について、CSEを介したFIL-Aとの相互作用において重要な役割を果たしていた。超硫黄分子(SS)供与体Na2S3の投与により、CSE誘発性MT過剰分裂を介して心筋細胞老化を改善した。以上より、Drp1-FIL-A複合体形成がタバコ煙介在性心リスクにおいて重要な役割を果たしており、MT分裂関連心筋細胞老化に対するSSの寄与が考えられた。

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

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

    Journal of Pharmacological Sciences   154 ( 2 )   127 - 135   2024.2   ISSN:1347-8613 eISSN:1347-8648

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

    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

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  • Supersulfide metabolism participates in regulating cardiomyocyte morphology

    ZHOU Liuchenzi, NISHIMURA Akiyuki, TANG Xiaokang, KATO Yuri, MI Xinya, NISHIDA Motohiro

    Annual Meeting of the Japanese Society of Toxicology   51.1 ( 0 )   P-12S   2024

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    Language:Japanese   Publisher:The Japanese Society of Toxicology  

    <p>Cardiac remodeling involves compensatory alterations in heart mass, geometry, and function in response to hemodynamic stress or cardiac injury. Previous studies have attributed myocardial variations to the size of cardiomyocytes. Recently, supersulfide, a sulfur-catenated molecule, has emerged as a crucial regulator of cardiac robustness. Our earlier findings revealed a heightened presence of supersulfide in healthy mouse hearts, which undergoes catabolism to hydrogen sulfide (H2S) following myocardial infarction. Despite these observations, the precise role of supersulfide metabolism in governing cardiac cellular functions remains elusive. In this study, we use cardiomyocytes isolated from ventricular of neonatal rat cardiomyocytes (NRCMs). We found that supersulfide, but not H2S, positively regulates the size of cardiomyocytes. qPCR results elucidated supersulfide anabolism related gene, Solute carrier family 7 member 11 (Slc7A11), may have involved in regulating size of cardiomyocytes. Slc7A11 gene knockdown efficiently induced cardiomyocyte atrophy. These findings suggest that supersulfide plays a key role in regulating cardiac cell remodeling induced by receptor stimulation. The anabolism and catabolism of supersulfide in cardiac cells could provide a new strategy for the treatment of pathological cardiac remodeling.</p>

    DOI: 10.14869/toxpt.51.1.0_p-12s

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  • Involvement of TRPC3-Nox2 complex formation in the progression of striated muscle atrophy

    WU Di, AYUKAWA Koichi, KATO Yuri, MI Xinya, NISHIYAMA Kazuhiro, NISHIMURA Akiyuki, NISHIDA Motohiro

    Annual Meeting of the Japanese Society of Toxicology   51.1 ( 0 )   P-5S   2024

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    Language:Japanese   Publisher:The Japanese Society of Toxicology  

    <p>Striated muscles, including cardiac muscle and red skeletal muscle which abundantly express myoglobin, play a crucial role not only in systemic motor function but also in the homeostasis of energy metabolism. The muscle atrophy that comes with age and disease will reduce systemic function. We have previously shown that the onset and progression of myocardial atrophy induced by the anticancer drug doxorubicin are mediated through the functional interactions between transient receptor potential canonical (TRPC) 3 protein and the ROS-producing NADPH oxidase 2 (Nox2), which is responsible for ROS production, on the cardiac myocyte membrane. We also identified ibudilast, a bronchodilator, can inhibit TRPC3-Nox2 complex formation and reduced the systemic muscle weight loss induced by doxorubicin. In this study, we investigated whether TRPC3/Nox2 complex formation is a therapeutic target for skeletal muscle atrophy in muscular dystrophy. In the skeletal muscle of Duchenne muscular dystrophy (mdx) model mice, TRPC3-Nox2 protein complex formation was markedly observed, and pharmacological inhibition of this complex formation by ibudilast attenuated skeletal muscle atrophy and motor functional loss in mdx mice. Furthermore, administration of pyrazole-3 (Pyr3), a TRPC3-selective inhibitor, to mdx mice similarly attenuated muscle atrophy and weakness. Oxidative stress caused in atrophied muscle cells was also suppressed by preventing TRPC3-Nox2 interaction. These results suggest that TRPC3-Nox2 complex formation may be a new therapeutic target for preventing myopathic muscle atrophy.</p>

    DOI: 10.14869/toxpt.51.1.0_p-5s

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  • Supersulfide catabolism underlies cardiac vulnerability to ischemic and electrophilic stress

    NISHIMURA Akiyuki, TANG Xiaokang, KATO Yuri, MI Xinya, NISHIDA Motohiro

    Annual Meeting of the Japanese Society of Toxicology   51.1 ( 0 )   S2-2   2024

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    Language:Japanese   Publisher:The Japanese Society of Toxicology  

    <p>The robustness of cardiomyocytes is supported by their superior redox homeostasis, and disruption of redox homeostasis leads to the onset and progression of cardiac disease. Supersulfides, which include catenated sulfur atoms (R-S<sub>n</sub>SH) such as cysteine persulfide (Cys-SSH), have been recently identified as highly reactive sulfur metabolites and recognized as a key molecule to regulate redox homeostasis. This study aimed to elucidate the role of sulfur metabolism in maintaining cardiac robustness, and the impact of abnormal sulfur metabolism on ischemic and electrophilic stress-mediated cardiac dysfunction.</p><p>Supersulfides are reduced to hydrogen sulfides in cardiomyocytes after ischemic and electrophilic stress. This supersulfide catabolism decreased the contractile function of cardiomyocytes through mitochondrial hyperfission. We also found that the depletion of supersulfides promotes mitochondrial fission by decreasing polysulfidation of mitochondrial fission factor Drp1 at Cys644.</p><p>Our results suggest that the redox modification of Drp1 Cys644 has a pivotal role in the ischemic and electrophilic tolerance of cardiomyocytes. We found that this polysulfidated Cys644 is modified by S-glutathionylation. Drp1 was glutathionylated by oxidized GSSG but not reduced GSH. GSSG-mediated Drp1 glutathionylation protected cardiac function against ischemic and electrophilic stress in vitro and in vivo. These results suggest that sulfur metabolism has a pivotal role in ischemic and electrophilic stress-mediated cardiac dysfunction through Drp1 Cys644 redox modification.</p>

    DOI: 10.14869/toxpt.51.1.0_s2-2

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  • Systemic glucose metabolism disorders caused by formation of Drp1-filamin protein complex

    KATO Yuri, ARIYOSHI Kohei, SHIMAUCHI Tsukasa, NISHIMURA Akiyuki, MI Xinya, KIM Sang Geon, MORI Yasuo, NISHIDA Motohiro

    Annual Meeting of the Japanese Society of Toxicology   51.1 ( 0 )   S8-4   2024

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    Language:Japanese   Publisher:The Japanese Society of Toxicology  

    <p>Diabetes is a chronic metabolic disorder that affects nearly 10% of adult people worldwide. It is characterized by high levels of blood glucose, which can lead to a range of complications, such as cardiovascular disease, neuropathy, and retinopathy. Recently, mitochondrial quality control has been highlighted as a potential therapeutic target for treating diabetes and its complications. We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin-related protein (Drp) 1 and filamin A (FLNa), mediates chronic heart failure and cilnidipine, developed as an L/N-type Ca<sup>2+</sup> channel blocker, improves heart failure by inhibiting Drp1-FLNa protein complex. Therefore, we investigated whether cilnidipine improves hyperglycemia of various diabetic model mice.</p><p>Cilnidipine treatment improved systemic hyperglycemia and mitochondrial morphological abnormalities in STZ-exposed mice, without lowering blood pressure. In contrast, cilnidipine failed to improve hyperglycemia of <i> ob/ob</i> mice, by suppressing insulin secretion. Therefore, we have identified a Ca<sup>2+ </sup>channel-insensitive cilnidipine derivative (1,4-DHP) that does not inhibit insulin release. 1,4-DHP improved hyperglycemia and mitochondria morphology abnormality in <i> ob/ob</i> mice fed high-fat diet. These results suggested that maintaining mitochondrial quality by inhibition of Drp1-FLNa becomes a new strategy for diabetes treatment to treat diabetes and diabetic complications.</p>

    DOI: 10.14869/toxpt.51.1.0_s8-4

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  • Evaluation of Cardiotoxicity by Anticancer Drugs Focusing on Mitochondrial Function

    KONDO Moe, NAKAMURA Yuya, KATO Yuri, FUKATA Mitsuhiro, MI Xinya, ITO Tomoya, NISHIMURA Akiyuki, AKASHI Koichi, KANDA Yasunari, NISHIDA Motohiro

    Annual Meeting of the Japanese Society of Toxicology   51.1 ( 0 )   P-139   2024

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    Language:Japanese   Publisher:The Japanese Society of Toxicology  

    <p>The number of cancer patients worldwide is increasing every year. On the other hand, there are still many unknowns regarding the development of cardiovascular disease in cancer patients. Osimertinib is used for treatment of epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer and significantly improves the prognosis. However, heart failure is observed in 1-5% of patients during treatment and QT prolongation in 10%, with a lethal course in some cases, but the mechanism of cardiotoxicity caused by osimertinib has not been elucidated.</p><p>In this study, we focused on the mitochondria of human iPS-derived cardiomyocytes (hiPSC-CMs) to analyze the cardiotoxicity mechanism of osimertinib. Exposure of hiPSC-CMs to anticancer drugs (osimertinib, doxorubicin, and trastuzumab) induced mitochondrial hyperfission and suppressed respiratory capacity. Our laboratory has previously found that sulfur metabolism plays an important role in maintaining mitochondrial quality in cardiomyocytes. When sulfur molecular donors (Na<sub>2</sub>S, Na<sub>2</sub>S<sub>2</sub>, and Na<sub>2</sub>S<sub>3</sub>) were added, Na<sub>2</sub>S most strongly inhibited osimertinib-induced mitochondrial dysfunction. Intracellular imaging using a sulfur molecular detection probe showed that osimertinib reduced intracellular H<sub>2</sub>S concentrations, which were restored by Na<sub>2</sub>S exposure.</p><p>These results indicate that osimertinib reduces intracellular H<sub>2</sub>S levels concurrently with mitochondrial dysfunction in myocardium. Our results also indicate that maintenance of intracellular H<sub>2</sub>S levels may contribute to the mitigation of osimertinib cardiotoxicity.</p>

    DOI: 10.14869/toxpt.51.1.0_p-139

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  • Pharmacological activation of TRPC6 channels improves heart failure

    SU Chenlin, MI Xinya, KATO Yuri, NISHIMURA Akiyuki, UMEZAWA Keitaro, URANO Yasuteru, NAGATA Ryu, MORI Yasuo, AKAIKE Takaaki, NISHIDA Motohiro

    Annual Meeting of the Japanese Society of Toxicology   51.1 ( 0 )   P-4S   2024

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    Language:Japanese   Publisher:The Japanese Society of Toxicology  

    <p>A growing body of evidence suggests that transient receptor potential canonical (TRPC) 3 and 6 channels are involved in developing pathological remodeling of the heart. However, we found that activation of TRPC6 channel enhances β adrenoceptor (βAR)-stimulated myocardial positive inotropy and prevents chronic heart failure in mice by enhancing Zn<sup>2+</sup> dynamics. This study aims to investigate whether TRPC6-mediated Zn<sup>2+</sup> influx suppresses sympathetic overactivity-induced chronic heart failure in mice. </p><p>Chronic stimulation of βAR with isoproterenol (ISO; 30 mg/kg/day) for 4 weeks caused myocardial dysfunction in WT mice and Zn<sup>2+</sup> permeation-dead (PD) TRPC6 mutant-expressing mice. Treatment with 2-[4-(2,3-dimethylphenyl)-piperazin-1-yl]-N- (2-ethoxyphenyl) acetamide (PPZ2), a TRPC3/6/7 channel activator, improved ISO-induced heart failure in WT mice but failed in TRPC6 (PD) mice. Zinpyr-1 imaging revealed that PPZ2 increased the intracellular Zn<sup>2+</sup> pool in ISO-treated WT hearts, while this increase was not observed in ISO-treated TRPC6 (PD) hearts. In addition, the electrophysiological study demonstrated that TRPC6 (PD) mutant could permeate Na<sup>+</sup>, Ca<sup>2+</sup> and K<sup>+</sup> as much as WT, but failed to permeate Zn<sup>2+</sup> after PPZ2 stimulation. PPZ2 improved ISO-induced impairment of L-type Ca<sup>2+</sup> channel current. Furthermore, PPZ2 attenuated ISO-induced oxidative stress and supersulfide catabolism. In conclusion, these results suggest that activating TRPC6-mediated Zn<sup>2+</sup> influx improves chronic heart failure by maintaining redox homeostasis.</p>

    DOI: 10.14869/toxpt.51.1.0_p-4s

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  • 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 Reviewed

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

    血管   46 ( 1 )   38 - 38   2023.1   ISSN:0911-4637

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    Language:Japanese   Publisher:日本心脈管作動物質学会  

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