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

DOI： 10.1126/scisignal.aac9187

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

DOI： 10.1038/NCHEMBIO.1018

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DOI： 10.1073/pnas.1017640108

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DOI： 10.1038/emboj.2008.237

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DOI： 10.1038/sj.emboj.7601417

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In non-excitable cells, receptor-activated Ca2+ signalling comprises initial transient responses followed by a Ca2+ entry-dependent sustained and/or oscillatory phase. Here, we describe the molecular mechanism underlying the second phase linked to signal amplification. An in vivo inositol 1,4,5-trisphosphate (IP3) sensor revealed that in B lymphocytes, receptor-activated and store-operated Ca2+ entry greatly enhanced IP3 production, which terminated in phospholipase Cγ2 (PLCγ2)-deficient cells. Association between receptor-activated TRPC3 Ca2+ channels and PLCγ2, which cooperate in potentiating Ca2+ responses, was demonstrated by co-immunoprecipitation. PLCγ2-deficient cells displayed diminished Ca2+ entry-induced Ca2+ responses. However, this defect was canceled by suppressing IP3-induced Ca2+ release, implying that IP3 and IP3 receptors mediate the second Ca2+ phase. Furthermore, confocal visualization of PLCγ2 mutants demonstrated that Ca2+ entry evoked a C2 domain-mediated PLCγ2 translocation towards the plasma membrane in a lipase-independent manner to activate PLCγ2. Strikingly, Ca2+ entry-activated PLCγ2 maintained Ca2+ oscillation and extracellular signal-regulated kinase activation downstream of protein kinase C. We suggest that coupling of Ca 2+ entry with PLCγ2 translocation and activation controls the amplification and co-ordination of receptor signalling.

DOI： 10.1093/emboj/cdg457

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

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

DOI： 10.1016/j.jphs.2024.07.007

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DOI： 10.1016/j.jphs.2024.05.002

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Authorship：Corresponding author   Language：English   Publisher：Journal of Pharmacological Sciences  

Sulfur-based redox signaling has long attracted attention as critical mechanisms underlying the development of cardiac diseases and resultant heart failure. Especially, post-translational modifications of cysteine (Cys) thiols in proteins mediate oxidative stress-dependent cardiac remodeling including myocardial hypertrophy, senescence, and interstitial fibrosis. However, we recently revealed the existence of Cys persulfides and Cys polysulfides in cells and tissues, which show higher redox activities than Cys and substantially contribute to redox signaling and energy metabolism. We have established simple evaluation methods that can detect polysulfides in proteins and inorganic polysulfides in cells and revealed that polysulfides abundantly expressed in normal hearts are dramatically catabolized by exposure to ischemic/hypoxic and environmental electrophilic stress, which causes vulnerability of the heart to mechanical load. Accumulation of hydrogen sulfide, a nucleophilic catabolite of persulfides/polysulfides, may lead to reductive stress in ischemic hearts, and perturbation of polysulfide catabolism can improve chronic heart failure after myocardial infarction in mice. This review focuses on the (patho)physiological role of sulfur metabolism in hearts, and proposes that sulfur catabolism during ischemic/hypoxic stress has great potential as a new therapeutic strategy for the treatment of ischemic heart failure.

DOI： 10.1016/j.jphs.2024.04.005

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While cysteine (CysSH) is known to be exported into the extracellular space, its biological significance is not well understood. The present study examined the movement of extracellular CysSH using stable isotope-labeled cystine (CysSSCys), which is transported into cells and reduced to CysSH. Exposure of HepG2 cells to 100 µM stable isotope-labeled CysSSCys resulted in 70 µM labeled CysSH in cell medium 1 h after CysSSCys exposure. When the cell medium was collected and incubated with either hydrogen peroxide (H2O2) or atmospheric electrophiles, such as 1,2-naphthoquinone, 1,4-naphthoquinone and 1,4-benzoquinone, CysSH in the cell medium was almost completely consumed. In contrast, extracellular levels of CysSH were unaltered during exposure of HepG2 cells to H2O2 for up to 2 h, suggesting redox cycling of CysSSCys/CysSH in the cell system. Experiments with and without changing cell medium containing CysSH from HepG2 cells revealed that oxidative and electrophilic modifications of cellular proteins, caused by exposure to H2O2 and 1,2-naphthoquinone, were significantly repressed by CysSH in the medium. We also examined participation of enzymes and/or antioxidants in intracellular reduction of CysSSCys to CysSH. These results provide new findings that extracellular CysSH derived from CysSSCys plays a role in the regulation of oxidative and electrophilic stress.

DOI： 10.1080/10715762.2024.2350524

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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.

DOI： 10.3390/ijms25105446

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BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which is associated with various neurological symptoms, including nausea, dizziness, headache, encephalitis, and epileptic seizures. SARS-CoV-2 is considered to affect the central nervous system (CNS) by interacting with the blood-brain barrier (BBB), which is defined by tight junctions that seal paracellular gaps between brain microvascular endothelial cells (BMECs). Although SARS-CoV-2 infection of BMECs has been reported, the detailed mechanism has not been fully elucidated. METHODS: Using the original strain of SARS-CoV-2, the infection in BMECs was confirmed by a detection of intracellular RNA copy number and localization of viral particles. BMEC functions were evaluated by measuring transendothelial electrical resistance (TEER), which evaluates the integrity of tight junction dynamics, and expression levels of proinflammatory genes. BMEC signaling pathway was examined by comprehensive RNA-seq analysis. RESULTS: We observed that iPSC derived brain microvascular endothelial like cells (iPSC-BMELCs) were infected with SARS-CoV-2. SARS-CoV-2 infection resulted in decreased TEER. In addition, SARS-CoV-2 infection decreased expression levels of tight junction markers CLDN3 and CLDN11. SARS-CoV-2 infection also increased expression levels of proinflammatory genes, which are known to be elevated in patients with COVID-19. Furthermore, RNA-seq analysis revealed that SARS-CoV-2 dysregulated the canonical Wnt signaling pathway in iPSC-BMELCs. Modulation of the Wnt signaling by CHIR99021 partially inhibited the infection and the subsequent inflammatory responses. CONCLUSION: These findings suggest that SARS-CoV-2 infection causes BBB dysfunction via Wnt signaling. Thus, iPSC-BMELCs are a useful in vitro model for elucidating COVID-19 neuropathology and drug development.

DOI： 10.1186/s12987-024-00533-9

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DOI： 10.1093/jb/mvae031

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Reactive sulfane sulfur species such as persulfides (RSSH) and H2S2 are important redox regulators and closely linked to H2S signaling. However, the study of these species is still challenging due to their instability, high reactivity, and the lack of suitable donors to produce them. Herein we report a unique compound, 2H-thiopyran-2-thione sulfine (TTS), which can specifically convert H2S to HSOH, and then to H2S2 in the presence of excess H2S. Meanwhile, the reaction product 2H-thiopyran-2-thione (TT) can be oxidized to reform TTS by biological oxidants. The reaction mechanism of TTS is studied experimentally and computationally. TTS can be conjugated to proteins to achieve specific delivery, and the combination of TTS and H2S leads to highly efficient protein persulfidation. When TTS is applied in conjunction with established H2S donors, the corresponding donors of H2S2 (or its equivalents) are obtained. Cell-based studies reveal that TTS can effectively increase intracellular sulfane sulfur levels and compensate for certain aspects of sulfide:quinone oxidoreductase (SQR) deficiency. These properties make TTS a conceptually new strategy for the design of donors of reactive sulfane sulfur species.

DOI： 10.1038/s41467-024-46652-7

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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.

DOI： 10.3390/ijms25042401

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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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Authorship：Last author,　Corresponding author   Language：English  

DOI： 10.1111/bph.16487

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Authorship：Corresponding author   Language：English   Publisher： Int. J Mol Sci.  

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

For decades, the major focus of redox biology has been oxygen, the most abundant element on Earth. Molecular oxygen functions as the final electron acceptor in the mitochondrial respiratory chain, contributing to energy production in aerobic organisms. In addition, oxygen-derived reactive oxygen species including hydrogen peroxide and nitrogen free radicals, such as superoxide, hydroxyl radical and nitric oxide radical, undergo a complicated sequence of electron transfer reactions with other biomolecules, which lead to their modified physiological functions and diverse biological and pathophysiological consequences (e.g. oxidative stress). What is now evident is that oxygen accounts for only a small number of redox reactions in organisms and knowledge of biological redox reactions is still quite limited. This article reviews a new aspects of redox biology which is governed by redox-active sulfur-containing molecules-supersulfides. We define the term 'supersulfides' as sulfur species with catenated sulfur atoms. Supersulfides were determined to be abundant in all organisms, but their redox biological properties have remained largely unexplored. In fact, the unique chemical properties of supersulfides permit them to be readily ionized or radicalized, thereby allowing supersulfides to actively participate in redox reactions and antioxidant responses in cells. Accumulating evidence has demonstrated that supersulfides are indispensable for fundamental biological processes such as energy production, nucleic acid metabolism, protein translation and others. Moreover, manipulation of supersulfide levels was beneficial for pathogenesis of various diseases. Thus, supersulfide biology has opened a new era of disease control that includes potential applications to clinical diagnosis, prevention and therapeutics of diseases.

DOI： 10.1111/bph.16271

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

DOI： https://doi.org/10.1126/sciadv.adg8631

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

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

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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Language：Others   Publisher：Cold Spring Harbor Laboratory  

The elucidation of gene-silencing mechanisms by RNA interference (RNAi) and antisense oligomers has drawn increasing attention to nucleic acid medicine. However, several challenges remain to be overcome, such as in vivo stability, target selectivity, drug delivery, and induced innate immunity. Here, we report a new, versatile, and highly-selective method to hack RNA by controlling RNA structure using short oligonucleotides (RNA hacking: RNAh) in living cells. The oligonucleotide, named Staple oligomer, hybridizes specifically to a target mRNA and artificially induces an RNA higher-order structure, RNA G-quadruplex (RGq), on the mRNA. As a result, the RGq allows effective suppression of the target protein translation. This technology does not require cooperation with bioprocesses including enzymatic reactions as in RNAi or antisense technologies, permitting the introduction of artificial nucleic acids into Staple oligomers to increase their in vivo stability without compromising their effectiveness. The method was validated by translational regulation of the mRNAs of TPM3, MYD88, and TRPC6, in a cell-free system and in living mammalian cells. In vivo application of the technology to TRPC6 mRNA allowed us to prevent cardiac hypertrophy in transverse aortic constriction (TAC)-treated mice with no detectable off-target effects. This technology provides new insights into gene therapy after RNAi and antisense technologies.

DOI： 10.1101/2023.04.18.537290

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

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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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

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Reactive sulfur species (RSS) play a role in redox homeostasis; however, adaptive cell responses to excessive intracellular RSS are not well understood. Therefore, in this study, we generated transgenic (Tg) mice overexpressing cystathionine gamma-lyase (CSE) to produce excessive RSS. Contrary to expectations, tissue concentrations of RSS, such as cysteine persulfide (CysSSH), were comparable in both wild-type and CSE Tg mice, but the plasma concentrations of CysSSH were significantly higher in CSE Tg mice than in wild-type mice. This export of surplus intracellular RSS was also observed in primary hepatocytes of CSE Tg mice. Exposure of primary hepatocytes to the RSS generator sodium tetrasulfide (Na2S4) resulted in an initial increase in the intracellular concentration of RSS, which later returned to basal levels after export into the extracellular space. Interestingly, among all amino acids, cystine (CysSSCys) was found to be essential for CysSSH export from primary mouse hepatocytes, HepG2 cells, and HEK293 cells during Na2S4 exposure, suggesting that the cystine/glutamate transporter (SLC7A11) contributes, at least partially, to CysSSH export. We established HepG2 cell lines with knockout and overexpression of SLC7A11 and used them to confirm SLC7A11 as the predominant antiporter of CysSSCys and CysSSH. We observed that the poor efflux of excess CysSSH from the cell enhanced cellular stresses induced by Na2S4 exposure, such as polysulfidation of intracellular proteins, mitochondrial damage, and cytotoxicity. These results suggest the presence of a cellular response to excess intracellular RSS that involves the extracellular efflux of excess CysSSH by a cystine-dependent transporter to maintain intracellular redox homeostasis.

DOI： 10.1016/j.redox.2022.102514

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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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DOI： 10.1016/j.jphs.2022.04.010.

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

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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Although the number of patients with heart failure is increasing, a sufficient treatment agent has not been established. Oxidative stress and inflammation play important roles in the development of myocardial remodeling. When thioredoxin (Trx), an endogenous anti-oxidative and inflammatory modulator with a molecular weight of 12 kDa, is exogenously administered, it disappears rapidly from the blood circulation. In this study, we prepared a long-acting Trx, by fusing human Trx (HSA-Trx) with human serum albumin (HSA) and evaluated its efficacy in treating drug-induced heart failure. Drug-induced cardiomyopathy was created by intraperitoneally administering doxorubicin (Dox) to mice three times per week. A decrease in heart weight, increased myocardial fibrosis and markers for myocardial damage that were observed in the Dox group were suppressed by HSA-Trx administration. HSA-Trx also suppressed the expression of atrogin-1 and myostatin, myocardial atrophy factors in addition to suppressing oxidative stress and inflammation. In the Dox group, a decreased expression of endogenous Trx in cardiac tissue and an increased expression of macrophage migration inhibitory factor were observed, but these changes were restored to normal levels by HSA-Trx administration. These findings suggest that HSA-Trx improves the pathological condition associated with Dox-induced cardiomyopathy by its anti-oxidative/anti-inflammatory and myocardial atrophy inhibitory action.

DOI： 10.3390/pharmaceutics14030562

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Triple-negative breast cancer (TNBC) is a highly aggressive cancer for which targeted therapeutic agents are limited. Growing evidence suggests that TNBC originates from breast cancer stem cells (BCSCs), and elucidation of the molecular mechanisms controlling BCSC proliferation will be crucial for new drug development. We have previously reported that the lysosphingolipid sphingosine-1-phosphate mediates the CSC phenotype, which can be identified as the ALDH-positive cell population in several types of human cancer cell lines. In this study, we have investigated additional lipid receptors upregulated in BCSCs. We found that lysophosphatidic acid (LPA) receptor 3 was highly expressed in ALDH-positive TNBC cells. The LPAR3 antagonist inhibited the increase in ALDH-positive cells after LPA treatment. Mechanistically, the LPA-induced increase in ALDH-positive cells was dependent on intracellular calcium ion (Ca2+), and the increase in Ca2+ was suppressed by a selective inhibitor of transient receptor potential cation channel subfamily C member 3 (TRPC3). Moreover, IL-8 production was involved in the LPA response via the activation of the Ca2+-dependent transcriptional factor nuclear factor of activated T cells. Taken together, our findings provide new insights into the lipid-mediated regulation of BCSCs via the LPA-TRPC3 signaling axis and suggest several potential therapeutic targets for TNBC.

DOI： 10.3390/ijms23041967

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Language：English   Publisher：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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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOCIETY FOR FREE RADICAL RESEARCH JAPAN  

<p>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.</p>

DOI： 10.3164/jcbn.21-84

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DOI： 10.1038/s41467-021-26633-w

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DOI： 10.1038/s41467-021-23363-x

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

Cold atmospheric plasma (CAP) has attracted much attention in the fields of biotechnology and medicine owing to its potential utility in clinical applications. Recently accumulating evidence has demonstrated that CAP influences protein structures. However, there remain open questions regarding the molecular mechanisms behind the CAP-induced structural perturbations of biomacromolecules. Here, we investigated the potential effects of CAP irradiation of amyloid β (Aβ), an amyloidogenic protein associated with Alzheimer’s disease. Using nuclear magnetic resonance spectroscopy, we observed gradual spectral changes in Aβ after a 10 s CAP pretreatment, which also suppressed its fibril formation, as revealed by thioflavin T assay. As per mass spectrometric analyses, these effects were attributed to selective oxidation of the methionine residue (Met) at position 35. Interestingly, this modification occurred when Aβ was dissolved into a pre-irradiated buffer, indicating that some reactive species oxidize the Met residue. Our results strongly suggest that the H2O2 generated in the solution by CAP irradiation is responsible for Met oxidation, which inhibits Aβ amyloid formation. The findings of the present study provide fundamental insights into plasma biology, giving clues for developing novel applications of CAP.

DOI： 10.3390/ijms22063116

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

DOI： 10.1038/s41598-020-70956-5

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

DOI： 10.1016/j.jaci.2020.06.039

Authorship：Last author,　Corresponding author   Language：English  

DOI： 10.2174/1874467213666200407090121

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

DOI： 10.1248/bpb.b20-00903

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

DOI： 10.1038/s41598-019-46252-2

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

Ibudilast attenuates doxorubicin-induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes.
BACKGROUND AND PURPOSE: Doxorubicin is a highly effective anticancer agent but eventually induces cardiotoxicity associated with increased production of ROS. We previously reported that a pathological protein interaction between TRPC3 channels and NADPH oxidase 2 (Nox2) contributed to doxorubicin-induced cardiac atrophy in mice. Here we have investigated the effects of ibudilast, a drug already approved for clinical use and known to block doxorubicin-induced cytotoxicity, on the TRPC3-Nox2 complex. We specifically sought evidence that this drug attenuated doxorubicin-induced systemic tissue wasting in mice. EXPERIMENTAL APPROACH: We used the RAW264.7 macrophage cell line to screen 1,271 clinically approved chemical compounds, evaluating functional interactions between TRPC3 channels and Nox2, by measuring Nox2 protein stability and ROS production, with and without exposure to doxorubicin. In male C57BL/6 mice, samples of cardiac and gastrocnemius muscle were taken and analysed with morphometric, immunohistochemical, RT-PCR and western blot methods. In the passive smoking model, cells were exposed to DMEM containing cigarette sidestream smoke. KEY RESULTS: Ibudilast, an anti-asthmatic drug, attenuated ROS-mediated muscle toxicity induced by doxorubicin treatment or passive smoking, by inhibiting the functional interactions between TRPC3 channels and Nox2, without reducing TRPC3 channel activity. CONCLUSIONS AND IMPLICATIONS: These results indicate a common mechanism underlying induction of systemic tissue wasting by doxorubicin. They also suggest that ibudilast could be repurposed to prevent muscle toxicity caused by anticancer drugs or passive smoking.

DOI： 10.1111/bph.14777

Language：English  

TRPC6 regulates phenotypic switching of vascular smooth muscle cells through plasma membrane potential-dependent coupling with PTEN.
Vascular smooth muscle cells (VSMCs) play critical roles in the stability and tonic regulation of vascular homeostasis. VSMCs can switch back and forth between highly proliferative synthetic and fully differentiated contractile phenotypes in response to changes in the vessel environment. Although abnormal phenotypic switching of VSMCs is a hallmark of vascular disorders such as atherosclerosis and restenosis after angioplasty, how control of VSMC phenotypic switching is dysregulated in pathologic conditions remains obscure. We found that inhibition of canonical transient receptor potential 6 (TRPC6) channels facilitated contractile differentiation of VSMCs through plasma membrane hyperpolarization. TRPC6-deficient VSMCs exhibited more polarized resting membrane potentials and higher protein kinase B (Akt) activity than wild-type VSMCs in response to TGF-β1 stimulation. Ischemic stress elicited by oxygen-glucose deprivation suppressed TGF-β1-induced hyperpolarization and VSMC differentiation, but this effect was abolished by TRPC6 deletion. TRPC6-mediated Ca2+ influx and depolarization coordinately promoted the interaction of TRPC6 with lipid phosphatase and tensin homolog deleted from chromosome 10 (PTEN), a negative regulator of Akt activation. Given the marked up-regulation of TRPC6 observed in vascular disorders, our findings suggest that attenuation of TRPC6 channel activity in pathologic VSMCs could be a rational strategy to maintain vascular quality control by fine-tuning of VSMC phenotypic switching.-Numaga-Tomita, T., Shimauchi, T., Oda, S., Tanaka, T., Nishiyama, K., Nishimura, A., Birnbaumer, L., Mori, Y., Nishida, M. TRPC6 regulates phenotypic switching of vascular smooth muscle cells through plasma membrane potential-dependent coupling with PTEN.

DOI： 10.1096/fj.201802811R

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

TRPC channels in exercise-mimetic therapy.
Physical exercise yields beneficial effects on all types of muscle cells, which are essential for the maintenance of cardiovascular homeostasis and good blood circulation. Daily moderate exercise increases systemic antioxidative capacity, which can lead to the prevention of the onset and progression of oxidative stress-related diseases. Therefore, exercise is now widely accepted as one of the best therapeutic strategies for the treatment of ischemic (hypoxic) diseases. Canonical transient receptor potential (TRPC) proteins are non-selective cation channels activated by mechanical stress and/or stimulation of phospholipase C-coupled surface receptors. TRPC channels, especially diacylglycerol-activated TRPC channels (TRPC3 and TRPC6; TRPC3/6), play a key role in the development of cardiovascular remodeling. We have recently found that physical interaction between TRPC3 and NADPH oxidase (Nox) 2 under hypoxic stress promotes Nox2-dependent reactive oxygen species (ROS) production and mediates rodent cardiac plasticity, and inhibition of the TRPC3-Nox2 protein complex results in enhancement of myocardial compliance and flexibility similar to that observed in exercise-treated hearts. In this review, we describe current understanding of the roles of TRPC channels in striated muscle (patho)physiology and propose that targeting TRPC-based protein complexes could be a new strategy to imitate exercise therapy.

DOI： 10.1007/s00424-018-2211-3

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

Mitochondrial dynamics in exercise physiology.
A growing body of evidence suggests that exercise shows pleiotropic effects on the maintenance of systemic homeostasis through mitochondria. Dysregulation of mitochondrial dynamism is associated with metabolic inflexibility, resulting in many of the metabolic diseases and aging. Studies have suggested that exercise prevents and delays the progression of mitochondrial dysfunction by improving mitochondrial metabolism, biogenesis, and quality control. Exercise modulates functions of mitochondrial dynamics-regulating proteins through post-translational modification mechanisms. In this review, we discuss the putative mechanisms underlying maintenance of mitochondrial homeostasis by exercise, especially focusing on the post-translational modifications of several signaling proteins contributing to mitochondrial biogenesis, autophagy or mitophagy flux, and fission/fusion cycle. We also introduce novel small molecules that can potentially mimic exercise therapy through preserving mitochondrial dynamism. These recent advancements in the field of mitochondrial biology may lead to a greater understanding of exercise signaling.

DOI： 10.1007/s00424-019-02258-3

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

DOI： 10.1074/jbc.RA118.006111

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

Language：English   Publishing type：Research paper (conference, symposium, etc.)  

Mitochondria-specific SQR deficiency in mice causes lethal impairment of sulfur respiration

DOI： 10.1016/j.freeradbiomed.2018.10.209

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

DOI： 10.3389/fphar.2018.00523

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

DOI： 10.1016/j.bbrc.2017.12.088

Language：English   Publishing type：Research paper (conference, symposium, etc.)  

DOI： 10.1016/bs.ampbs.2018.01.002

Language：English   Publishing type：Research paper (conference, symposium, etc.)  

DOI： 10.1248/yakushi.18-00091-1

Language：English   Publishing type：Research paper (conference, symposium, etc.)  

DOI： 10.1248/yakushi.18-00091-F

Authorship：Last author,　Corresponding author   Language：English  

DOI： 10.1016/j.pharmthera.2017.06.010

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

Role of TRPC3 and TRPC6 channels in the myocardial response to stretch: Linking physiology and pathophysiology.

DOI： 10.1016/j.pbiomolbio.2017.06.010

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

DOI： 10.1038/s41467-017-01311-y

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

DOI： 10.1016/j.jphs.2017.09.002

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

DOI： 10.1021/acs.chemrestox.7b00120

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

DOI： 10.3389/fcvm.2017.00056

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

TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy
Myocardial atrophy is a wasting of cardiac muscle due to hemodynamic unloading. Doxorubicin is a highly effective anticancer agent but also induces myocardial atrophy through a largely unknown mechanism. Here, we demonstrate that inhibiting transient receptor potential canonical 3 (TRPC3) channels abolishes doxorubicin-induced myocardial atrophy in mice. Doxorubicin increased production of ROS in rodent cardiomyocytes through hypoxic stress-mediated upregulation of NADPH oxidase 2 (Nox2), which formed a stable complex with TRPC3. Cardiomyocyte-specific expression of TRPC3 C-terminal minipeptide inhibited TRPC3-Nox2 coupling and suppressed doxorubicin-induced reduction of myocardial cell size and left ventricular (LV) dysfunction, along with its upregulation of Nox2 and oxidative stress, without reducing hypoxic stress. Voluntary exercise, an effective treatment to prevent doxorubicin-induced cardiotoxicity, also downregulated the TRPC3-Nox2 complex and promoted volume load-induced LV compliance, as demonstrated in TRPC3-deficient hearts. These results illustrate the impact of TRPC3 on LV compliance and flexibility and, focusing on the TRPC3-Nox2 complex, provide a strategy for prevention of doxorubicin-induced cardiomyopathy.

DOI： 10.1172/jci.insight.93358

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

DOI： 10.1016/j.freeradbiomed.2017.01.024

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

DOI： 10.1038/s41598-017-07903-4

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

DOI： 10.1016/j.phrs.2017.03.013

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

DOI： 10.3389/fphar.2017.00428

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

DOI： 10.1161/JAHA.116.003601

Language：English   Publishing type：Research paper (conference, symposium, etc.)  

DOI： 10.1254/fpj.149.84

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

TRPC3 participates in angiotensin II type 1 receptor-dependent stress-induced slow increase in intracellular Ca2+ concentration in mouse cardiomyocytes

Language：English   Publishing type：Research paper (conference, symposium, etc.)  

DOI： 10.1254/fpj.149.269

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

DOI： 10.1038/srep39383

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

DOI： 10.1038/srep37001

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

DOI： 10.1038/srep28944

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

DOI： 10.1016/j.abb.2015.11.008

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

DOI： 10.3164/jcbn.15-111

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

DOI： 10.1124/mol.115.102863

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

DOI： 10.1210/me.2015-1201

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

DOI： 10.1042/BJ20150596

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

DOI： 10.1039/c6md00023a

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

DOI： 10.1074/jbc.M115.656710

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

DOI： 10.1021/tx500416y

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

DOI： 10.1093/cvr/cvu185

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

DOI： 10.1016/j.yjmcc.2014.02.003

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

DOI： 10.1161/ATVBAHA.113.001974

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

Beta-arrestins (β-arrestin1 and β-arrestin2) are known as cytosolic proteins that mediate desensitization and internalization of activated G protein-coupled receptors. In addition to these functions, β-arrestins have been found to work as adaptor proteins for intracellular signaling pathways. β-arrestin1 and β-arrestin2 are expressed in the heart and are reported to participate in normal cardiac function. However, the physiological and pathological roles of β-arrestin1/2 in myocardial infarction (MI) have not been examined. Here, we demonstrate that β-arrestin2 negatively regulates inflammatory responses of macrophages recruited to the infarct area. β-arrestin2 knockout (KO) mice have higher mortality than wild-type (WT) mice after MI. In infarcted hearts, β-arrestin2 was strongly expressed in infiltrated macrophages. The production of inflammatory cytokines was enhanced in β-arrestin2 KO mice. In addition, p65 phosphorylation in the macrophages from the infarcted hearts of β-arrestin2 KO mice was increased in comparison to that of WT mice. These results suggest that the infiltrated macrophages of β-arrestin2 KO mice induce excessive inflammation at the infarct area. Furthermore, the inflammation in WT mice transplanted with bone marrow cells of β-arrestin2 KO mice is enhanced by MI, which is similar to that in β-arrestin2 KO mice. In contrast, the inflammation after MI in β-arrestin2 KO mice transplanted with bone marrow cells of WT mice is comparable to that in WT mice transplanted with bone marrow cells of WT mice. In summary, our present study demonstrates that β-arrestin2 of infiltrated macrophages negatively regulates inflammation in infarcted hearts, thereby enhancing inflammation when the β-arrestin2 gene is knocked out. β-arrestin2 plays a protective role in MI-induced inflammation.

DOI： 10.1371/journal.pone.0068351

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

Voltage-dependent N-type Ca2+ channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by angiotensin II in mice
N-type voltage-dependent Ca2+channels (VDCCs), expressed predominantly in the nervous system, play pivotal roles in sympathetic regulation of the circulatory system. Although N-type VDCCs are also reportedly expressed in the vasculature, their pathophysiological role is obscure. We demonstrated that oxidative stress-related endothelial dysfunction induced by angiotensin (Ang) II is suppressed in mice lacking the N-type VDCC α1B subunit (Cav 2.2). Impairment of endothelium-dependent relaxation of the thoracic aorta observed following Ang II treatment in wild-type (WT) mice was significantly attenuated in the Ang II-treated Cav 2.2-deficient mice, despite the comparable increase of the blood pressure in the two groups of mice. The thoracic aorta of the Cav 2.2-deficient mice showed a smaller positive area of oxidative stress markers as compared to the WT mice. The Ang II-induced endothelial dysfunction was also suppressed by cilnidipine, an L/N-type VDCC blocker, but not by amlodipine, an L-type VDCC blocker; however, this unique effect of cilnidipine was completely abolished in the Cav 2.2-deficient mice. Furthermore, selective inhibition of N-type VDCCs by ω-conotoxin GVIA dramatically suppressed the production of reactive oxygen species (ROS) as well as agonist-induced Ca2+ influx in the vascular endothelial cells. These results suggest that N-type VDCCs expressed in the vascular endothelial cells contribute to ROS production and endothelial dysfunction observed in Ang II-treated hypertensive mice. © 2013 Elsevier Inc.

DOI： 10.1016/j.bbrc.2013.03.040

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

DOI： 10.1038/ncomms2540

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

DOI： 10.1093/jb/mvs145

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

DOI： 10.1074/jbc.M112.357871

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

DOI： 10.1242/bio.20121370

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

Recombinant mitochondrial transcription factor A protein inhibits nuclear factor of activated T cells signaling and attenuates pathological hypertrophy of cardiac myocytes.
The overexpression of mitochondrial transcription factor A (TFAM) attenuates the decrease in mtDNA copy number after myocardial infarction, ameliorates pathological hypertrophy, and markedly improves survival. However, non-transgenic strategy to increase mtDNA for the treatment of pathological hypertrophy remains unknown. We produced recombinant human TFAM protein (rhTFAM). rhTFAM rapidly entered into mitochondria of cultured cardiac myocytes. rhTFAM increased mtDNA and abolished the activation of nuclear factor of activated T cells (NFAT), which is well known to activate pathological hypertrophy. rhTFAM attenuated subsequent morphological hypertrophy of myocytes as well. rhTFAM would be an attractive molecule in attenuating cardiac pathological hypertrophy. (C) 2012 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

DOI： 10.1016/j.mito.2012.06.002

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

DOI： 10.1161/ATVBAHA.110.221010

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

DOI： 10.1254/jphs.11R05CP

Language：English  

DOI： 10.1016/j.niox.2010.10.003

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

DOI： 10.1016/j.bbrc.2011.04.124

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

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

DOI： 10.1254/jphs.10279FP

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

Dual Signaling Pathways of Arterial Constriction by Extracellular Uridine 5 '-Triphosphate in the Rat
We investigated actions of uridine 5'-triphosphate (UTP) in rat aorta, cerebral and mesenteric arteries, and their single myocytes. UTP (≥10 µM) elicited an inward-rectifying current strongly reminiscent of activation of P2X(1) receptor, and a similar current was also induced by α,β-methylene adenosine 5'-triphosphate (ATP) (≥100 nM). UTP desensitized α,β-methylene ATP-evoked current, and vice versa. The UTP-activated current was insensitive to G-protein modulators, TRPC3 inhibitors, or TRPC3 antibody, but was sensitive to P2-receptor inhibitors or P2X(1)-receptor antibody. Both UTP (1 mM) and α,β-methylene ATP (10 µM) elicited similar conductance single channel activities. UTP (≥10 µM) provoked a dose-dependent contraction of de-endothelialized aortic ring preparation consisting of phasic and tonic components. Removal of extracellular Ca(2+) or bath-applied 2',3'-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP) (30 µM) or nifedipine (10 µM) completely inhibited the phasic contraction while only partially reducing the tonic one. The tonic contraction was almost completely abolished by additional application of thapsigargin (2 µM). Similar biphasic rises in [Ca(2+)](i) were also evoked by UTP in rat aortic myocytes. In contrast to the low expression of TRPC3, significant expression of P2X(1) receptor was detected in all arteries by RT-PCR and immunoblotting, and its localization was limited to plasma membrane of myocytes as indicated by immunohistochemistry. These results suggest that UTP dually activates P2X(1)-like and P2Y receptors, but not TRPC3.

DOI： 10.1254/jphs.10281fp

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

DOI： 10.1007/978-1-61779-126-0_17

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

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

DOI： 10.1074/jbc.M109.076232

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

DOI： 10.1074/jbc.M109.074104

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

Ca2+ influx and protein scaffolding via TRPC3 sustain PKC beta and ERK activation in B cells

DOI： 10.1242/jcs.061051

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

Amphotericin B-induced renal tubular cell injury is mediated by Na+ Influx through ion-permeable pores and subsequent activation of mitogen-activated protein kinasesand elevation of intracellular Ca2+ concentration.
Amphotericin B (AMB) is one of the most effective antifungal agents; however, its use is often limited by the occurrence of adverse events, especially nephrotoxicity. The present study was designed to determine the possible mechanisms underlying the nephrotoxic action of AMB. The exposure of a porcine proximal renal tubular cell line (LLC-PK1 cells) to AMB caused cell injury, as assessed by mitochondrial enzyme activity, the leakage of lactate dehydrogenase, and tissue ATP depletion. Propidium iodide uptake was enhanced, while terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was not affected by AMB, suggesting a lack of involvement of apoptosis in AMB-induced cell injury. The cell injury was inhibited by the depletion of membrane cholesterol with methyl-beta-cyclodextrin, which lowered the extracellular Na(+) concentration or the chelation of intracellular Ca(2+). The rise in the intracellular Ca(2+) concentration may be mediated through the activation of the ryanodine receptor (RyR) on the endoplasmic reticulum and the mitochondrial Na(+)-Ca(2+) exchanger, since cell injury was attenuated by dantrolene (an RyR antagonist) and CGP37157 (an Na(+)-Ca(2+) exchange

DOI： 10.1128/AAC.01137-08

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

DOI： 10.1073/pnas.0808793106

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

A food-derived synergist of NGF signaling: identification of protein tyrosine phosphatase 1B as a key regulator of NGF receptor-initiated signal transduction

DOI： 10.1111/j.1471-4159.2008.05686.x

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

DOI： 10.1007/s00210-008-0321-8

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

DOI： 10.1021/bi800199z

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

DOI： 10.1074/jbc.M611780200

Language：English  

DOI： 10.1016/j.bbadis.2007.03.006

Language：English  

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

TRP channels: Molecular diversity and physiological function

DOI： 10.1080/10739680600885111

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

DOI： 10.1074/jbc.M602832200

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

Blocker-resistant presynaptic voltage-dependent Ca2+ channels underlying glutamate release in mice nucleus tractus solitarii

DOI： 10.1016/j.brainres.2006.05.077

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

DOI： 10.1161/01.RES.0000233356.10630.8a

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

DOI： 10.1254/jphs.FP0051036

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

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

DOI： 10.1016/j.cellsig.2004.12.014

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

Comprehensive analysis of the ascidian genome reveals novel insights into the molecular evolution of ion channel genes.

DOI： 10.1152/physiolgenomics.00229.2004

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

DOI： 10.1074/jcb.M409397200

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

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

DOI： 10.1074/jbc.M409710200

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

DOI： 10.1038/ng1393

Language：English  

Language：English  

Language：English  

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

DOI： 10.1016/S0891-5849(03)00172-2

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

DOI： 10.1161/01.RES.0000043282.39776.7C

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

DOI： 10.1006/bbrc.2002.6553

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

DOI： 10.1074/jbc.M107392200

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

DOI： 10.1084/jem.20011758

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

DOI： 10.1016/S1097-2765(01)00438-5

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

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

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

Event date： 2012.3

Presentation type：Symposium, workshop panel (public)  

Venue：京都   Country：Japan  

Event date： 2012.3

Presentation type：Oral presentation (invited, special)  

Venue：京都   Country：Japan  

Event date： 2011.11

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2011.11

Presentation type：Oral presentation (general)  

Venue：大阪   Country：Japan  

Event date： 2011.7

Presentation type：Oral presentation (general)  

Venue：北海道（小樽）   Country：Japan  

Event date： 2011.3

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2010.12

Presentation type：Symposium, workshop panel (public)  

Venue：神戸   Country：Japan  

Event date： 2010.6

Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2010.5

Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2010.3

Presentation type：Symposium, workshop panel (public)  

Venue：岡山   Country：Japan  

Event date： 2010.3

Presentation type：Symposium, workshop panel (public)  

Venue：大阪   Country：Japan  

Event date： 2010.3

Presentation type：Symposium, workshop panel (public)  

Venue：大阪   Country：Japan  

Event date： 2010.3

Presentation type：Oral presentation (general)  

Venue：京都大学桂キャンパス   Country：Japan  

Event date： 2010.2

Presentation type：Symposium, workshop panel (public)  

Country：Korea, Republic of  

Event date： 2009.11

Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2009.9

Presentation type：Symposium, workshop panel (public)  

Venue：Joetsu Kokusai Ski Resort, Nagano   Country：Japan  

Event date： 2009.7

Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Country：Japan  

Event date： 2009.7

Presentation type：Symposium, workshop panel (public)  

Venue：福岡   Country：Japan  

Event date： 2009.3

Presentation type：Symposium, workshop panel (public)  

Venue：京都   Country：Japan  

Event date： 2009.3

Presentation type：Symposium, workshop panel (public)  

Venue：横浜   Country：Japan  

Event date： 2008.12

Presentation type：Symposium, workshop panel (public)  

Venue：神戸   Country：Japan  

Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2024.7

Language：Japanese  

Venue：イギリス   Country：Japan  

Event date： 2024.4

Language：Japanese  

Country：Japan  

Event date： 2023.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：神戸国際会議場・神戸国際展示場2号館（神戸市）   Country：Japan  

Event date： 2023.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2023.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：神戸国際会議場・神戸国際展示場2号館   Country：Japan  

Event date： 2023.12

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：神戸国際会議場・神戸国際展示場2号館（神戸市）   Country：Japan  

Event date： 2023.12

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2023.11

Language：Japanese  

Venue：第一薬科大学（福岡市南区）   Country：Japan  

Event date： 2023.10 - 2023.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡国際会議場・マリンメッセ福岡B館   Country：Japan  

Event date： 2023.10 - 2023.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡国際会議場・マリンメッセ福岡B館   Country：Japan  

Event date： 2023.10 - 2023.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡国際会議場・マリンメッセー福岡B館   Country：Japan  

Event date： 2023.10 - 2023.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡国際会議場・マリンメッセ福岡B館   Country：Japan  

Event date： 2023.10

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2023.10

Language：Japanese  

Country：Japan  

Event date： 2023.10

Language：Japanese  

Venue：沖縄   Country：Japan  

Event date： 2023.10

Language：Japanese  

Venue：岡崎   Country：Japan  

Event date： 2023.10

Language：Japanese  

Venue：岡崎   Country：Japan  

Event date： 2023.10

Language：Japanese  

Venue：岡崎   Country：Japan  

Event date： 2023.9

Language：Japanese  

Country：Japan  

Event date： 2023.9

Language：Japanese  

Country：Japan  

Event date： 2023.9

Language：Japanese  

Venue：福岡   Country：Japan  

Event date： 2023.9

Language：Japanese  

Venue：福岡   Country：Japan  

Event date： 2023.9

Language：Japanese  

Venue：秋田   Country：Japan  

Event date： 2023.9

Language：Japanese  

Venue：岡山   Country：Japan  

Event date： 2023.8 - 2023.9

Language：Japanese  

Venue：秋田   Country：Japan  

Event date： 2023.7

Language：Japanese  

Country：Japan  

Event date： 2023.7

Language：Japanese  

Country：Japan  

Event date： 2023.7

Language：Japanese  

Venue：山形   Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：English  

Country：Japan  

Event date： 2023.6

Language：English  

Country：Korea, Republic of  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：English  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：English   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Venue：熊本   Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Venue：静岡   Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Venue：福岡   Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Country：Japan  

Event date： 2023.6

Language：Japanese  

Venue：静岡   Country：Japan  

Event date： 2023.5

Language：Japanese  

Venue：岡崎   Country：Japan  

Event date： 2023.5

Language：Japanese  

Country：Japan  

Event date： 2023.5

Language：Japanese  

Country：Japan  

Event date： 2023.4

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2023.3

Language：Japanese  

Country：Japan  

Event date： 2023.3

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2023.3

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2023.2

Language：Japanese  

Country：Japan  

Event date： 2023.2

Language：Japanese  

Country：Japan  

Event date： 2023.2

Language：Japanese  

Country：Japan  

Event date： 2023.2

Language：Japanese  

Country：Japan  

Event date： 2023.2

Language：Japanese  

Country：Japan  

Event date： 2023.2

Language：Japanese  

Country：Japan  

Event date： 2023.2

Language：Japanese  

Country：Japan  

Event date： 2023.2

Language：Japanese  

Country：Japan  

Event date： 2023.2

Language：Japanese  

Country：Japan  

Event date： 2023.2

Language：Japanese  

Country：Japan  

Event date： 2023.1

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2023.1

Language：Japanese  

Country：Japan  

Event date： 2023.1

Language：Japanese  

Country：Japan  

Event date： 2022.12

Language：Japanese  

Country：Japan  

Event date： 2022.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：名古屋   Country：Japan  

Event date： 2022.10

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：東京   Country：Japan  

Event date： 2022.9

Language：Japanese  

Venue：淡路島   Country：Japan  

Event date： 2022.8

Language：Japanese  

Venue：静岡   Country：Japan  

Event date： 2022.7

Language：Japanese  

Venue：札幌   Country：Japan  

Event date： 2022.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌   Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Venue：熊本市   Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：English  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：English  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.6

Language：Japanese  

Country：Japan  

Event date： 2022.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：WEB   Country：Japan  

Event date： 2022.4

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：岡山   Country：Japan  

Event date： 2022.1 - 2023.1

Language：Japanese  

Country：Japan  

Event date： 2021.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：オンライン開催   Country：Japan  

Event date： 2021.3

Language：English  

Country：Japan  

Event date： 2021.1

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪   Country：Japan  

Event date： 2021.1

Language：Japanese  

Country：Japan  

Event date： 2021.1

Language：Japanese  

Country：Japan  

Event date： 2021.1

Language：Japanese  

Country：Japan  

Event date： 2021.1

Language：Japanese  

Country：Japan  

Event date： 2021.1

Language：Japanese  

Country：Japan  

Event date： 2021.1

Language：Japanese  

Venue：大阪   Country：Japan  

Event date： 2021.1

Language：Japanese  

Venue：愛知   Country：Japan  

Event date： 2021.1

Language：Japanese  

Venue：香川   Country：Japan  

Event date： 2021.1

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2021.1

Language：English   Presentation type：Oral presentation (general)  

Country：United States  

Event date： 2021.1

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Korea, Republic of  

Event date： 2021.1

Language：English   Presentation type：Oral presentation (general)  

Country：Korea, Republic of  

Event date： 2020.12

Language：English  

Country：Japan  

Event date： 2020.12

Language：Japanese  

Country：Japan  

Event date： 2020.12

Language：Japanese  

Venue：福岡   Country：Japan  

Event date： 2020.12

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2020.12

Language：Japanese  

Country：Japan  

Event date： 2020.11

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2020.11

Language：Japanese  

Venue：大阪   Country：Japan  

Event date： 2020.10

Language：Japanese  

Country：Japan  

Event date： 2020.10

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2020.10

Language：Japanese  

Country：Japan  

Event date： 2020.9

Language：Japanese  

Country：Japan  

Event date： 2020.9 - 2020.4

Language：English  

Country：Japan  

Event date： 2020.9

Language：Japanese  

Country：Japan  

Event date： 2020.8

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：仙台   Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：京都   Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：札幌   Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：徳島   Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：横浜   Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：九重   Country：Japan  

Event date： 2020.7

Language：English  

Country：Japan  

Event date： 2020.7

Language：English  

Country：Japan  

Event date： 2020.7

Language：English  

Country：Japan  

Event date： 2020.7

Language：English  

Country：Taiwan, Province of China  

Event date： 2020.7

Language：Japanese  

Venue：横浜   Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：横浜   Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：福岡   Country：Japan  

Event date： 2020.7

Language：English  

Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：高松   Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：高松   Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：沖縄   Country：Japan  

Event date： 2020.7

Language：English  

Country：Japan  

Event date： 2020.7

Language：English  

Country：Japan  

Event date： 2020.7

Language：English  

Country：Japan  

Event date： 2020.7

Language：English  

Country：Japan  

Event date： 2020.7

Language：English  

Country：Japan  

Event date： 2020.7

Language：English  

Country：Japan  

Event date： 2020.7

Language：English  

Country：Japan  

Event date： 2020.7

Language：English  

Country：Japan  

Event date： 2020.7

Language：English  

Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：久留米   Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：旭川   Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：横浜   Country：Japan  

Event date： 2020.7

Language：Japanese  

Venue：山口   Country：Japan  

Event date： 2020.4

Language：English  

Country：Japan  

Event date： 2020.4

Language：English  

Country：Japan  

Event date： 2020.4

Language：English  

Country：Japan  

Event date： 2020.4

Language：English  

Country：Japan  

Event date： 2020.4

Language：English  

Country：Japan  

Event date： 2020.4

Language：English  

Country：Japan  

Event date： 2020.3 - 2021.3

Language：Japanese  

Country：Japan  

Event date： 2020.3