Toshio Tanaka - Academia.edu (original) (raw)
Papers by Toshio Tanaka
Journal of pharmacological sciences, 2016
Age-related macular degeneration (AMD) is a major cause of irreversible loss of central vision in... more Age-related macular degeneration (AMD) is a major cause of irreversible loss of central vision in the elderly. Zebrafish is an attractive animal model in some respects, lower cost, smaller housing facilities and easier genetic manipulation compared to rodents. The present study aimed to establish a drug evaluation method against light irradiation, as a dry AMD disease model, using adult pigmented zebrafish. Intravitreal administration of an antioxidant, N-acetylcysteine, protected against light-induced retinal degeneration in a concentration-dependent manner. We established a new drug evaluation model against light-induced retinal degeneration that can provide new knowledge about dry AMD pathology and therapy.
Journal of Visualized Experiments, 2015
Toxicological sciences : an official journal of the Society of Toxicology, 2015
Sorafenib is associated with adverse cardiac effects, including left ventricular dysfunction. How... more Sorafenib is associated with adverse cardiac effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish and human cardiomyocytes. Fluorescent cardiac imaging using pigmentless zebrafish with green fluorescent protein hearts revealed that the ventricular dimensions of the longitudinal axis with sorafenib were significantly shorter than those of the control group. Transcriptome analysis of their hearts revealed that stanniocalcin 1 (stc1) was downregulated by sorafenib. stc1 knockdown in zebrafish revealed that reduction of stc1 decreased the longitudinal dimensions of zebrafish ventricles, similar to that which occurs during sorafenib treatment. STC1 downregulation and cytotoxicity were also seen in human cardiomyocytes exposed to sorafenib. To clarify the molecular function of stc1 in sorafenib-induced cardiotoxicity, we focused on oxidative stress in cardi...
Scientific reports, 2013
Parkin, a ubiquitin E3 ligase of the ring between ring fingers family, has been implicated in mit... more Parkin, a ubiquitin E3 ligase of the ring between ring fingers family, has been implicated in mitochondrial quality control. A series of recent reports have suggested that the recruitment of parkin is regulated by phosphorylation. However, the molecular mechanism that activates parkin to induce mitochondrial degradation is not well understood. Here, and in contrast to previous reports that S-nitrosylation of parkin is exclusively inhibitory, we identify a previously unrecognized site of S-nitrosylation in parkin (Cys323) that induces mitochondrial degradation. We demonstrate that endogenous S-nitrosylation of parkin is in fact responsible for activation of its E3 ligase activity to induce aggregation and degradation. We further demonstrate that mitochondrial uncoupling agents result in denitrosylation of parkin, and that prevention of denitrosylation restores mitochondrial degradation. Our data indicates that NO both positive effects on mitochondrial quality control, and suggest tha...
The Journal of Cell Biology, 2000
Many lines of evidence indicate that neoplastic transformation of cells occurs by a multistep pro... more Many lines of evidence indicate that neoplastic transformation of cells occurs by a multistep process. For neoplastic transformation of normal human cells, they must be first immortalized and then be converted into neoplastic cells. It is well known that the immortalization is a critical step for the neoplastic transformation of cells and that the immortal phenotype is recessive. Thus, we investigated proteins downregulated in immortalized cells by two-dimensional gel electrophoresis. As a result, S100C, a Ca2+-binding protein, was dramatically downregulated in immortalized human fibroblasts compared with their normal counterparts. When the cells reached confluence, S100C was phosphorylated on threonine 10. Then the phosphorylated S100C moved to and accumulated in the nuclei of normal cells, whereas in immortalized cells it was not phosphorylated and remained in the cytoplasm. Microinjection of the anti-S100C antibody into normal confluent quiescent cells induced DNA synthesis. Furt...
Journal of Pharmacological Sciences, 2008
The most important strategies in pharmacogenomics are gene expression profiling and the network a... more The most important strategies in pharmacogenomics are gene expression profiling and the network analysis of human disease models. We have previously discovered novel drug target candidates in cardiovascular diseases through investigations of these pharmacogenomics. The significant induction of S100C mRNA and protein expression was detected in the rat pulmonary hypertension and myocardial infarction model. We also found increased taurine in hypoxia, a calcium-associated cytoprotective compound, to suppress the hypoxia-induced S100C gene expression and vascular remodeling. These results suggest that S100C may be one of the potential novel drug targets in hypoxic or ischemic diseases. Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage causes cerebral ischemia and infarction. Using a DNA microarray, a prominant upregulation of heme oxygenase-1 (HO-1) and heat shock protein (HSP) 72 mRNAs were observed in the basilar artery of a murine vasospasm model. Antisense HO-1 and HSP 72 oligodeoxynucleotide inhibited HO-1 and HSP 72 induction, respectively, and significantly aggravated cerebral vasospasm. Moreover, we have also developed a unique heart failure model in zebrafish and identified several candidate genes as novel drug targets. These results suggest that pharmacogenomic network analysis has the potential to bridge the gap between in vitro and in vivo studies and could define strategies for identifying novel drug targets in various cardiovascular diseases.
Circulation, 2004
Background— Cerebral vasospasm can be defined as delayed-onset narrowing of the cerebral arteries... more Background— Cerebral vasospasm can be defined as delayed-onset narrowing of the cerebral arteries that can occur after a spontaneous aneurysmal subarachnoid hemorrhage (SAH). Despite a large number of experimental and clinical investigations, the exact pathophysiology of vasospasm remains unknown. Using a fluorescence differential-display system, we have identified the gene encoding heat shock protein 72 (HSP72) as being highly upregulated by cerebral vasospasm. We therefore elucidated the role of the HSP72 gene in cerebral vasospasm in a rat experimental SAH model. Methods and Results— By angiography, cerebral vasospasm was detected from day 1, with maximal narrowing detected on day 2. Intracisternal injection of antisense HSP72 oligodeoxynucleotide led to specific inhibition of HSP72 gene expression and significantly aggravated cerebral vasospasm on days 2 and 3 of the angiographic studies. Oral administration of geranylgeranylacetone (GGA), an antiulcer drug, enhanced HSP72 induc...
Folia Pharmacologica Japonica, 2005
Journal of Molecular and Cellular Cardiology, 2004
Cyclic nucleotides (cAMP and cGMP) phosphodiesterase (PDE) activities and expression are altered ... more Cyclic nucleotides (cAMP and cGMP) phosphodiesterase (PDE) activities and expression are altered in the cardiac muscle of cardiomyopathic heart failure, and PDE inhibitors improve the abnormal muscle condition through changing the cyclic nucleotide concentration. These observations prompted us to investigate the role of calmodulin (CaM) in the regulation of cyclic nucleotide PDE activities, and moreover to study the modulation of the PDE isozymes in heart failure, using cardiac muscles of cardiomyopathic hamster. The CaM concentrations in the heart muscle of the normal control and cardiomyopathic hamsters (each of three to four hamsters) varied with cell fraction and with the age of the animal. The CaM concentrations in the soluble fraction obtained from cardiomyopathic hamster tissue were significantly increased at 25 and 32 weeks of age (2.02 ± 0.62 µg/mg protein (mean ± S.E.), and 3.21 ± 0.95) compared with that obtained from the control (0.60 ± 0.04) or cardiomyopathic (0.95 ± 0.12) hamsters at 8 weeks of age. The solubilized PDE isolated from the hamster heart muscle (three or four hamsters in each age) by column chromatography on diethylaminoethyl (DEAE)-cellulose revealed three peaks of activity, which may correspond to the isozymes of PDE classified recently, namely PDE I, II, and III. These three peaks of activity, particularly peak III, seen in the soluble fraction of cardiomyopathic hamster heart declined in proportion to the age of the animal compared with that of the control hamster heart. In the cGMP-PDE assay system, the concentration of CaM inhibitor W-7 required for 50% inhibition (IC 50) of PDE I, II, and III peak activities was 140, 29, and 46 µM, respectively, suggesting that PDE II is more sensitive to W-7. These results suggest that alteration in these isozyme activities accompanied with changes of CaM concentration may influence the cardiac muscle contractility in cardiomyopathic hamster via changes of cyclic nucleotide concentration.
Nihon rinsho. Japanese journal of clinical medicine, 2006
Folia Pharmacologica Japonica, 1996
Folia Pharmacologica Japonica, 2006
![Research paper thumbnail of [Pharmacogenomics: the frontiers of genome medicine]](https://attachments.academia-assets.com/94589734/thumbnails/1.jpg)
](Folia Pharmacologica Japonica
Molecular medicine reports
The analysis of genes preferentially expressed in the peripheral blood cells of atopic dermatitis... more The analysis of genes preferentially expressed in the peripheral blood cells of atopic dermatitis patients may provide information on the molecular pathogenesis of the disease. We employed differential display PCR to clone a new gene (AB100163) with 99% homology to coiled-coil domain containing 132, transcript variant 1 (CCDC132) (NM_017667) (aliases, FLJ20097, FLJ23581, KIAA1861 and MGC176659). Full-length CCDC132 of approximately 4 kbp encodes mRNA expressed in almost all tissues, in particular brain tissue and skeletal muscle. A homologous gene has also been identified in mice. Using Western blot analysis, 111 kDa CCDC132 protein was detected in two human T-cell lines, MOLT-4 and Jurkat, and in the human cervical adenocarcinoma cell line HeLa. Quantitative RT-PCR revealed transcription levels of CCDC132 in the T cells of atopic dermatitis patients to be higher than in those of normal individuals. This suggests that changes in CCDC132 expression may be involved in the course of at...
Journal of Clinical Investigation, 1999
Subarachnoid hemorrhage (SAH) is a common and often devastating occurrence; each year approximate... more Subarachnoid hemorrhage (SAH) is a common and often devastating occurrence; each year approximately 7-20 of every 100,000 people experience nontraumatic SAH (1-3). Despite considerable advances in diagnostic, surgical, and anesthetic techniques, and advances in perioperative management, the outcome for patients with SAH remains poor, with an overall mortality rate of 25% and significant morbidity among approximately 50% of survivors (1-3). Cerebral vasospasm, which is a major cause of morbidity and mortality after SAH (1-3), is the delayed narrowing of large-capacitance arteries at the base of the brain. Angiographic vasospasm typically develops 3-5 days after SAH and is most severe 7-9 days after SAH (1-3). In approximately half of all cases, a delayed neurologic ischemic deficit occurs, and despite maximal therapy, 15-20% of such patients suffer stroke or die from vasospasm (1-3). Of the patients who survive, vasospasm spontaneously resolves over the course of several days and usually disappears by the end of the second or fourth week (1-3). Recent evidence suggests that hemoglobin-induced (Hb-induced) oxidative stress plays a central role in the pathogenesis of vasospasm after SAH (4). However, the mechanism by which delayed cerebral vasospasm spontaneously resolves has not been sufficiently investigated. Clarification of the intrinsic mechanism of spasmolysis may lead to a novel therapeutic approach. In the present study, we used an improved differential display technique, fluorescent differential display (FDD) (5), to identify differentially expressed genes and to evaluate the functional significance of such genes in the basilar artery with vasospasm. Methods All protocols were evaluated and approved by the Animal Ethics Review Committee of the
Folia Pharmacologica Japonica, 2000
Gene, 2009
Beta adrenergic receptors (β-ARs) are members of the G-protein-coupled receptor superfamily and m... more Beta adrenergic receptors (β-ARs) are members of the G-protein-coupled receptor superfamily and mediate various physiological processes in many species. The expression patterns and functions of β-ARs in zebrafish are, however, largely unknown. We have identified zebrafish β-AR orthologs, which we have designated as adrb1, adrb2a, adrb2b, adrb3a and adrb3b. adrb1 was found to be expressed in the heart and brain. Expression of adrb2a predominated in the brain and skin, whereas adrb2b was found to be highly expressed in muscle, pancreas and liver. Both adrb3a and adrb3b were exclusively expressed in blood. Knock-down of these β-ARs by morpholino oligonucleotides revealed a functional importance of adrb2a in pigmentation. Expression of atp5a1 and atp5b, genes that encode subunits of F1F0-ATPase, which is known to be involved in pigmentation, was significantly increased by knock-down of adrb2a. Our data suggest that adrb2a may regulate pigmentation, partly by modulating F1F0-ATPase.
Nature Communications, 2018
Ciliogenesis is generally inhibited in dividing cells, however, it has been unclear which signali... more Ciliogenesis is generally inhibited in dividing cells, however, it has been unclear which signaling cascades regulate the phenomenon. Here, we report that epidermal growth factor receptor (EGFR) kinase suppresses ciliogenesis by directly phosphorylating the deubiquitinase USP8 on Tyr-717 and Tyr-810 in RPE1 cells. These phosphorylations elevate the deubiquitinase activity, which then stabilizes the trichoplein-Aurora A pathway, an inhibitory mechanism of ciliogenesis. EGFR knockdown and serum starvation result in ciliogenesis through downregulation of the USP8-trichoplein-Aurora A signal. Moreover, primary cilia abrogation, which is induced upon IFT20 or Cep164 depletion, ameliorates the cell cycle arrest of EGFR knockdown cells. The present data reveal that the EGFR-USP8-trichoplein-Aurora A axis is a critical signaling cascade that restricts ciliogenesis in dividing cells, and functions to facilitate cell proliferation. We further show that usp8 knockout zebrafish develops ciliopathy-related phenotypes including cystic kidney, suggesting that USP8 is a regulator of ciliogenesis in vertebrates.
Scientific reports, Jan 23, 2017
The pulsatile nature of blood flow exposes vascular smooth muscle cells (VSMCs) in the vessel wal... more The pulsatile nature of blood flow exposes vascular smooth muscle cells (VSMCs) in the vessel wall to cyclic mechanical stretch (CMS), which evokes VSMC proliferation, cell death, phenotypic switching, and migration, leading to vascular remodeling. These responses have been observed in many cardiovascular diseases; however, the underlying mechanisms remain unclear. We have revealed that CMS of rat aortic smooth muscle cells (RASMCs) causes JNK- and p38-dependent cell death and that a calcium channel blocker and angiotensin II receptor antagonist decreased the phosphorylation of JNK and p38 and subsequently decreased cell death by CMS. In the present study, we showed that the expression of Cxcl1 and Cx3cl1 was induced by CMS in a JNK-dependent manner. The expression of Cxcl1 was also induced in VSMCs by hypertension produced by abdominal aortic constriction (AAC). In addition, antagonists against the receptors for CXCL1 and CX3CL1 increased cell death, indicating that CXCL1 and CX3CL...
Journal of pharmacological sciences, 2016
Age-related macular degeneration (AMD) is a major cause of irreversible loss of central vision in... more Age-related macular degeneration (AMD) is a major cause of irreversible loss of central vision in the elderly. Zebrafish is an attractive animal model in some respects, lower cost, smaller housing facilities and easier genetic manipulation compared to rodents. The present study aimed to establish a drug evaluation method against light irradiation, as a dry AMD disease model, using adult pigmented zebrafish. Intravitreal administration of an antioxidant, N-acetylcysteine, protected against light-induced retinal degeneration in a concentration-dependent manner. We established a new drug evaluation model against light-induced retinal degeneration that can provide new knowledge about dry AMD pathology and therapy.
Journal of Visualized Experiments, 2015
Toxicological sciences : an official journal of the Society of Toxicology, 2015
Sorafenib is associated with adverse cardiac effects, including left ventricular dysfunction. How... more Sorafenib is associated with adverse cardiac effects, including left ventricular dysfunction. However, the precise mechanism remains unclear. Here, we aimed to establish the genes responsible for this cardiotoxicity using zebrafish and human cardiomyocytes. Fluorescent cardiac imaging using pigmentless zebrafish with green fluorescent protein hearts revealed that the ventricular dimensions of the longitudinal axis with sorafenib were significantly shorter than those of the control group. Transcriptome analysis of their hearts revealed that stanniocalcin 1 (stc1) was downregulated by sorafenib. stc1 knockdown in zebrafish revealed that reduction of stc1 decreased the longitudinal dimensions of zebrafish ventricles, similar to that which occurs during sorafenib treatment. STC1 downregulation and cytotoxicity were also seen in human cardiomyocytes exposed to sorafenib. To clarify the molecular function of stc1 in sorafenib-induced cardiotoxicity, we focused on oxidative stress in cardi...
Scientific reports, 2013
Parkin, a ubiquitin E3 ligase of the ring between ring fingers family, has been implicated in mit... more Parkin, a ubiquitin E3 ligase of the ring between ring fingers family, has been implicated in mitochondrial quality control. A series of recent reports have suggested that the recruitment of parkin is regulated by phosphorylation. However, the molecular mechanism that activates parkin to induce mitochondrial degradation is not well understood. Here, and in contrast to previous reports that S-nitrosylation of parkin is exclusively inhibitory, we identify a previously unrecognized site of S-nitrosylation in parkin (Cys323) that induces mitochondrial degradation. We demonstrate that endogenous S-nitrosylation of parkin is in fact responsible for activation of its E3 ligase activity to induce aggregation and degradation. We further demonstrate that mitochondrial uncoupling agents result in denitrosylation of parkin, and that prevention of denitrosylation restores mitochondrial degradation. Our data indicates that NO both positive effects on mitochondrial quality control, and suggest tha...
The Journal of Cell Biology, 2000
Many lines of evidence indicate that neoplastic transformation of cells occurs by a multistep pro... more Many lines of evidence indicate that neoplastic transformation of cells occurs by a multistep process. For neoplastic transformation of normal human cells, they must be first immortalized and then be converted into neoplastic cells. It is well known that the immortalization is a critical step for the neoplastic transformation of cells and that the immortal phenotype is recessive. Thus, we investigated proteins downregulated in immortalized cells by two-dimensional gel electrophoresis. As a result, S100C, a Ca2+-binding protein, was dramatically downregulated in immortalized human fibroblasts compared with their normal counterparts. When the cells reached confluence, S100C was phosphorylated on threonine 10. Then the phosphorylated S100C moved to and accumulated in the nuclei of normal cells, whereas in immortalized cells it was not phosphorylated and remained in the cytoplasm. Microinjection of the anti-S100C antibody into normal confluent quiescent cells induced DNA synthesis. Furt...
Journal of Pharmacological Sciences, 2008
The most important strategies in pharmacogenomics are gene expression profiling and the network a... more The most important strategies in pharmacogenomics are gene expression profiling and the network analysis of human disease models. We have previously discovered novel drug target candidates in cardiovascular diseases through investigations of these pharmacogenomics. The significant induction of S100C mRNA and protein expression was detected in the rat pulmonary hypertension and myocardial infarction model. We also found increased taurine in hypoxia, a calcium-associated cytoprotective compound, to suppress the hypoxia-induced S100C gene expression and vascular remodeling. These results suggest that S100C may be one of the potential novel drug targets in hypoxic or ischemic diseases. Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage causes cerebral ischemia and infarction. Using a DNA microarray, a prominant upregulation of heme oxygenase-1 (HO-1) and heat shock protein (HSP) 72 mRNAs were observed in the basilar artery of a murine vasospasm model. Antisense HO-1 and HSP 72 oligodeoxynucleotide inhibited HO-1 and HSP 72 induction, respectively, and significantly aggravated cerebral vasospasm. Moreover, we have also developed a unique heart failure model in zebrafish and identified several candidate genes as novel drug targets. These results suggest that pharmacogenomic network analysis has the potential to bridge the gap between in vitro and in vivo studies and could define strategies for identifying novel drug targets in various cardiovascular diseases.
Circulation, 2004
Background— Cerebral vasospasm can be defined as delayed-onset narrowing of the cerebral arteries... more Background— Cerebral vasospasm can be defined as delayed-onset narrowing of the cerebral arteries that can occur after a spontaneous aneurysmal subarachnoid hemorrhage (SAH). Despite a large number of experimental and clinical investigations, the exact pathophysiology of vasospasm remains unknown. Using a fluorescence differential-display system, we have identified the gene encoding heat shock protein 72 (HSP72) as being highly upregulated by cerebral vasospasm. We therefore elucidated the role of the HSP72 gene in cerebral vasospasm in a rat experimental SAH model. Methods and Results— By angiography, cerebral vasospasm was detected from day 1, with maximal narrowing detected on day 2. Intracisternal injection of antisense HSP72 oligodeoxynucleotide led to specific inhibition of HSP72 gene expression and significantly aggravated cerebral vasospasm on days 2 and 3 of the angiographic studies. Oral administration of geranylgeranylacetone (GGA), an antiulcer drug, enhanced HSP72 induc...
Folia Pharmacologica Japonica, 2005
Journal of Molecular and Cellular Cardiology, 2004
Cyclic nucleotides (cAMP and cGMP) phosphodiesterase (PDE) activities and expression are altered ... more Cyclic nucleotides (cAMP and cGMP) phosphodiesterase (PDE) activities and expression are altered in the cardiac muscle of cardiomyopathic heart failure, and PDE inhibitors improve the abnormal muscle condition through changing the cyclic nucleotide concentration. These observations prompted us to investigate the role of calmodulin (CaM) in the regulation of cyclic nucleotide PDE activities, and moreover to study the modulation of the PDE isozymes in heart failure, using cardiac muscles of cardiomyopathic hamster. The CaM concentrations in the heart muscle of the normal control and cardiomyopathic hamsters (each of three to four hamsters) varied with cell fraction and with the age of the animal. The CaM concentrations in the soluble fraction obtained from cardiomyopathic hamster tissue were significantly increased at 25 and 32 weeks of age (2.02 ± 0.62 µg/mg protein (mean ± S.E.), and 3.21 ± 0.95) compared with that obtained from the control (0.60 ± 0.04) or cardiomyopathic (0.95 ± 0.12) hamsters at 8 weeks of age. The solubilized PDE isolated from the hamster heart muscle (three or four hamsters in each age) by column chromatography on diethylaminoethyl (DEAE)-cellulose revealed three peaks of activity, which may correspond to the isozymes of PDE classified recently, namely PDE I, II, and III. These three peaks of activity, particularly peak III, seen in the soluble fraction of cardiomyopathic hamster heart declined in proportion to the age of the animal compared with that of the control hamster heart. In the cGMP-PDE assay system, the concentration of CaM inhibitor W-7 required for 50% inhibition (IC 50) of PDE I, II, and III peak activities was 140, 29, and 46 µM, respectively, suggesting that PDE II is more sensitive to W-7. These results suggest that alteration in these isozyme activities accompanied with changes of CaM concentration may influence the cardiac muscle contractility in cardiomyopathic hamster via changes of cyclic nucleotide concentration.
Nihon rinsho. Japanese journal of clinical medicine, 2006
Folia Pharmacologica Japonica, 1996
Folia Pharmacologica Japonica, 2006
Folia Pharmacologica Japonica
Molecular medicine reports
The analysis of genes preferentially expressed in the peripheral blood cells of atopic dermatitis... more The analysis of genes preferentially expressed in the peripheral blood cells of atopic dermatitis patients may provide information on the molecular pathogenesis of the disease. We employed differential display PCR to clone a new gene (AB100163) with 99% homology to coiled-coil domain containing 132, transcript variant 1 (CCDC132) (NM_017667) (aliases, FLJ20097, FLJ23581, KIAA1861 and MGC176659). Full-length CCDC132 of approximately 4 kbp encodes mRNA expressed in almost all tissues, in particular brain tissue and skeletal muscle. A homologous gene has also been identified in mice. Using Western blot analysis, 111 kDa CCDC132 protein was detected in two human T-cell lines, MOLT-4 and Jurkat, and in the human cervical adenocarcinoma cell line HeLa. Quantitative RT-PCR revealed transcription levels of CCDC132 in the T cells of atopic dermatitis patients to be higher than in those of normal individuals. This suggests that changes in CCDC132 expression may be involved in the course of at...
Journal of Clinical Investigation, 1999
Subarachnoid hemorrhage (SAH) is a common and often devastating occurrence; each year approximate... more Subarachnoid hemorrhage (SAH) is a common and often devastating occurrence; each year approximately 7-20 of every 100,000 people experience nontraumatic SAH (1-3). Despite considerable advances in diagnostic, surgical, and anesthetic techniques, and advances in perioperative management, the outcome for patients with SAH remains poor, with an overall mortality rate of 25% and significant morbidity among approximately 50% of survivors (1-3). Cerebral vasospasm, which is a major cause of morbidity and mortality after SAH (1-3), is the delayed narrowing of large-capacitance arteries at the base of the brain. Angiographic vasospasm typically develops 3-5 days after SAH and is most severe 7-9 days after SAH (1-3). In approximately half of all cases, a delayed neurologic ischemic deficit occurs, and despite maximal therapy, 15-20% of such patients suffer stroke or die from vasospasm (1-3). Of the patients who survive, vasospasm spontaneously resolves over the course of several days and usually disappears by the end of the second or fourth week (1-3). Recent evidence suggests that hemoglobin-induced (Hb-induced) oxidative stress plays a central role in the pathogenesis of vasospasm after SAH (4). However, the mechanism by which delayed cerebral vasospasm spontaneously resolves has not been sufficiently investigated. Clarification of the intrinsic mechanism of spasmolysis may lead to a novel therapeutic approach. In the present study, we used an improved differential display technique, fluorescent differential display (FDD) (5), to identify differentially expressed genes and to evaluate the functional significance of such genes in the basilar artery with vasospasm. Methods All protocols were evaluated and approved by the Animal Ethics Review Committee of the
Folia Pharmacologica Japonica, 2000
Gene, 2009
Beta adrenergic receptors (β-ARs) are members of the G-protein-coupled receptor superfamily and m... more Beta adrenergic receptors (β-ARs) are members of the G-protein-coupled receptor superfamily and mediate various physiological processes in many species. The expression patterns and functions of β-ARs in zebrafish are, however, largely unknown. We have identified zebrafish β-AR orthologs, which we have designated as adrb1, adrb2a, adrb2b, adrb3a and adrb3b. adrb1 was found to be expressed in the heart and brain. Expression of adrb2a predominated in the brain and skin, whereas adrb2b was found to be highly expressed in muscle, pancreas and liver. Both adrb3a and adrb3b were exclusively expressed in blood. Knock-down of these β-ARs by morpholino oligonucleotides revealed a functional importance of adrb2a in pigmentation. Expression of atp5a1 and atp5b, genes that encode subunits of F1F0-ATPase, which is known to be involved in pigmentation, was significantly increased by knock-down of adrb2a. Our data suggest that adrb2a may regulate pigmentation, partly by modulating F1F0-ATPase.
Nature Communications, 2018
Ciliogenesis is generally inhibited in dividing cells, however, it has been unclear which signali... more Ciliogenesis is generally inhibited in dividing cells, however, it has been unclear which signaling cascades regulate the phenomenon. Here, we report that epidermal growth factor receptor (EGFR) kinase suppresses ciliogenesis by directly phosphorylating the deubiquitinase USP8 on Tyr-717 and Tyr-810 in RPE1 cells. These phosphorylations elevate the deubiquitinase activity, which then stabilizes the trichoplein-Aurora A pathway, an inhibitory mechanism of ciliogenesis. EGFR knockdown and serum starvation result in ciliogenesis through downregulation of the USP8-trichoplein-Aurora A signal. Moreover, primary cilia abrogation, which is induced upon IFT20 or Cep164 depletion, ameliorates the cell cycle arrest of EGFR knockdown cells. The present data reveal that the EGFR-USP8-trichoplein-Aurora A axis is a critical signaling cascade that restricts ciliogenesis in dividing cells, and functions to facilitate cell proliferation. We further show that usp8 knockout zebrafish develops ciliopathy-related phenotypes including cystic kidney, suggesting that USP8 is a regulator of ciliogenesis in vertebrates.
Scientific reports, Jan 23, 2017
The pulsatile nature of blood flow exposes vascular smooth muscle cells (VSMCs) in the vessel wal... more The pulsatile nature of blood flow exposes vascular smooth muscle cells (VSMCs) in the vessel wall to cyclic mechanical stretch (CMS), which evokes VSMC proliferation, cell death, phenotypic switching, and migration, leading to vascular remodeling. These responses have been observed in many cardiovascular diseases; however, the underlying mechanisms remain unclear. We have revealed that CMS of rat aortic smooth muscle cells (RASMCs) causes JNK- and p38-dependent cell death and that a calcium channel blocker and angiotensin II receptor antagonist decreased the phosphorylation of JNK and p38 and subsequently decreased cell death by CMS. In the present study, we showed that the expression of Cxcl1 and Cx3cl1 was induced by CMS in a JNK-dependent manner. The expression of Cxcl1 was also induced in VSMCs by hypertension produced by abdominal aortic constriction (AAC). In addition, antagonists against the receptors for CXCL1 and CX3CL1 increased cell death, indicating that CXCL1 and CX3CL...