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Y Funakoshi

Publications and source records attributed to Y Funakoshi.

At least 19 recordsLinked to original sources
PubMed2004

Evidence for direct CP violation in B0-->K+pi- decays.

We report evidence for direct CP violation in the decay B0-->K+pi(-) with 253 fb(-1) of data collected with the Belle detector at the KEKB e(+)e(-) collider. Using 275x10(6) BB pairs we observe a B-->K+/-pi(-/+) signal with 2140+/-53 events. The measured CP violating asymmetry is A(CP)(K+pi(-))=-0.101+/-0.025(stat)+/-0.005(syst), corresponding to a significance of 3.9sigma including systematics. We also search for CP violation in the decays B+-->K+pi(0) and B+-->pi(+)pi(0). The measured CP violating asymmetries are A(CP)(K+pi(0))=0.04+/-0.05(stat)+/-0.02(syst) and A(CP)(pi(+)pi(0))=-0.02+/-0.10(stat)+/-0.01(syst), corresponding to the intervals -0.05<A(CP)(K+pi(0))<0.13 and -0.18<A(CP)(pi(+)pi(0))<0.14 at 90% confidence level.

Journal Article↗
PubMed2003

Observation of B-->K*l+l-.

We report the observation of the flavor-changing neutral current decay B-->K(*)l(+)l(-) and an im-proved measurement of the decay B-->Kl(+)l(-), where l represents an electron or a muon, with a data sample of 140 fb(-1) accumulated at the Upsilon(4S) resonance with the Belle detector at KEKB. The results for the branching fractions are B(B-->K(*)l(+)l(-))=(11.5(+2.6)(-2.4)+/-0.8+/-0.2)x10(-7) and B(B-->Kl(+)l(-))=(4.8(+1.0)(-0.9)+/-0.3+/-0.1)x10(-7), where the first error is statistical, the second is systematic and the third is from model dependence.

Journal Article↗
PubMed2001

Reactive oxygen species-mediated homologous downregulation of angiotensin II type 1 receptor mRNA by angiotensin II.

Recent studies suggest a crucial role of reactive oxygen species (ROS) for the signaling of angiotensin (Ang) II through Ang II type 1 receptor (AT(1)-R). However, the role of ROS in the regulation of AT(1)-R expression has not been explored. In this study, we examined the effect of an antioxidant on the homologous downregulation of AT(1)-R by Ang II. Ang II (10(-6) mol/L) decreased AT(1)-R mRNA with a peak suppression at 6 hours of stimulation in rat aortic vascular smooth muscle cells. Preincubation of vascular smooth muscle cells with N:-acetylcysteine (NAC), a potent antioxidant, almost completely inhibited the Ang II-induced downregulation of AT(1)-R mRNA. The effect of NAC was due to stabilization of the AT(1)-R mRNA that was destabilized by Ang II. The Ang II-induced AT(1)-R mRNA downregulation was also blocked by PD98059, an extracellular signal-regulated protein kinase (ERK) kinase inhibitor. Ang II-induced ERK activation was inhibited by NAC as well as by PD98059. Exogenous H(2)O(2) also suppressed AT(1)-R mRNA. These results suggest that the production of ROS and the activation of ERK are critical for the downregulation of AT(1)-R mRNA. The generation of ROS through stimulation of AT(1)-R not only mediates signaling of Ang II but also may play a crucial role in the adaptation process of AT(1)-R to the sustained stimulation of Ang II.

Acetylcysteine↗
PubMed2001

Rho-kinase mediates angiotensin II-induced monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells.

Recently, it was shown that Rho-kinase plays an important role in blood pressure regulation. However, it is not known whether Rho-kinase is involved in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine that regulates monocyte recruitment and atherogenesis. Therefore, we examined the role of Rho and Rho-kinase in the angiotensin (Ang) II-induced expression of MCP-1. Ang II dose- and time-dependently enhanced the expression of MCP-1 mRNA and the protein production in vascular smooth muscle cells. CV11974, an Ang II type 1 receptor (AT(1)-R) specific antagonist inhibited the enhancement of MCP-1 expression by Ang II, suggesting that the effect of Ang II is mediated by the AT(1)-R. Botulinum C3 exotoxin, a specific inhibitor of Rho, suppressed Ang II-induced MCP-1 production. To examine the role of Rho-kinase in Ang II-induced MCP-1 expression, we used adenovirus-mediated overexpression of the dominant negative mutant of Rho-kinase (AdDNRhoK) or Y-27632, a specific inhibitor of Rho-kinase. Both AdDNRhoK and Y-27632 strongly inhibited Ang II-induced MCP-1 expression. Although inhibition of extracellular signal-regulated protein kinase (ERK) by PD 098,059 also inhibited Ang II-induced MCP-1 expression, Y-27632 did not affect Ang II-induced activation of ERK. These results indicate that Rho-kinase plays a critical role in Ang II-induced MCP-1 production independent of ERK. The Rho-Rho-kinase pathway may be a novel target for the inhibition of Ang II signaling and the treatment of atherosclerosis.

Amides↗
PubMed2001

Thrombin induces interleukin-6 expression through the cAMP response element in vascular smooth muscle cells.

The plasma level of interleukin-6 (IL-6) is elevated in patients with acute coronary syndromes and has prognostic value. Thrombin is a potent mitogen for vascular smooth muscle cells (VSMCs) and plays an important role in the progression of atherosclerosis. We examined the mechanism of thrombin-induced IL-6 expression in VSMCs. Thrombin induced IL-6 mRNA and protein expression in a dose-dependent manner. Pharmacological inhibition of extracellular signal-regulated protein kinase (ERK), p38 mitogen-activated protein kinase (MAPK), or epidermal growth factor receptor (EGF-R) suppressed the thrombin-induced IL-6 expression. Deletion and mutation analysis of the promoter region of the IL-6 gene by using luciferase as a reporter showed that the DNA segment between -228 and -150 bp containing the cAMP response element (CRE) site played a critical role. Thrombin also induced phosphorylation of CRE binding protein (CREB) in an ERK- and a p38 MAPK-dependent manner. Overexpression of the dominant-negative form of CREB inhibited thrombin-induced IL-6 mRNA expression. These results suggest that the CRE site and CREB play an important role in thrombin-induced IL-6 gene expression in VSMCs. Transactivation of EGF-R and activation of ERK and p38 MAPK are involved in this process. CREB may be a novel transcription factor that regulates thrombin-induced gene expression.

Animals↗
PubMed2001

cAMP response element-binding protein mediates thrombin-induced proliferation of vascular smooth muscle cells.

Thrombin is a potent mitogen for vascular smooth muscle cells (VSMCs) and plays an important role in the progression of atherosclerosis. Although recent reports have suggested that cAMP response element-binding protein (CREB) is necessary for the survival of neuronal cells, the role of CREB in VSMC proliferation is not determined. We examined the role of CREB in thrombin-induced VSMC proliferation and the effect of thrombin on phosphorylation of CREB at Ser133, which is a critical marker for activation by Western blot analysis. Thrombin induced phosphorylation of CREB in a dose-dependent manner. An oligopeptide, SFLLRN, which activates the thrombin receptor, also induced the phosphorylation of CREB. Inhibition of extracellular signal-regulated protein kinase or inhibition of p38 mitogen-activated protein kinase suppressed the thrombin-induced CREB phosphorylation. Inhibition of the epidermal growth factor receptor by AG1478 also inhibited the thrombin-induced CREB phosphorylation. Overexpression of the dominant-negative form of CREB inhibited thrombin-induced c-fos mRNA expression and incorporation of [(3)H]thymidine and [(3)H]leucine. These results suggest that CREB-dependent gene transcription plays a critical role in thrombin-induced proliferation and hypertrophy of VSMCs. Transactivation of the epidermal growth factor receptor and 2 mitogen-activated protein kinase pathways are involved in this process. CREB may be a novel transcription factor mediating the vascular remodeling process induced by thrombin.

Adenoviridae↗
PubMed2001

mtv shapes the activity gradient of the Dpp morphogen through regulation of thickveins.

Drosophila wings are patterned by a morphogen, Decapentaplegic (Dpp), a member of the TGFbeta superfamily, which is expressed along the anterior and posterior compartment boundary. The distribution and activity of Dpp signaling is controlled in part by the level of expression of its major type I receptor, thickveins (tkv). The level of tkv is dynamically regulated by En and Hh. We have identified a novel gene, master of thickveins (mtv), which downregulates expression of tkv in response to Hh and En. mtv expression is controlled by En and Hh, and is complementary to tkv expression. In this report, we demonstrate that mtv integrates the activities of En and Hh that shape tkv expression pattern. Thus, mtv plays a key part of regulatory mechanism that makes the activity gradient of the Dpp morphogen.

Animals↗
PubMed2001

[A clinical study of resected bronchopulmonary carcinoids].

19 surgically treated cases with bronchopulmonary carcinoid in our hospital were studied clinically, and we discussed the criteria of limited operation for typical carcinoid. 11 cases had typical carcinoid and 8 had atypical. All patients of typical type were alive with no recurrence. No lymph node metastasis was revealed in all cases of typical type. On the contrary, in cases of atypical type, 1 had n 2 disease and 1 had distant metastasis. The five survival rates of patients with typical carcinoid was 100%, and significantly better than that of patients with atypical, 27%. Therefore, patients with typical carcinoid can be cured by limited operation, but radical operation should be indicated for atypical carcinoid.

Adult↗
PubMed2000

Peroxisome proliferator-activated receptor gamma activators downregulate angiotensin II type 1 receptor in vascular smooth muscle cells.

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) activators, such as troglitazone (Tro), not only improve insulin resistance but also suppress the neointimal formation after balloon injury. However, the precise mechanisms have not been determined. Angiotensin II (Ang II) plays crucial roles in the pathogenesis of atherosclerosis, hypertension, and neointimal formation after angioplasty. We examined the effect of PPARgamma activators on the expression of Ang II type 1 receptor (AT(1)-R) in cultured vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: AT(1)-R mRNA and AT(1)-R protein levels were determined by Northern blot analysis and radioligand binding assay, respectively. Natural PPARgamma ligand 15-deoxy-Delta(12,14)-prostaglandin J(2), as well as Tro, reduced the AT(1)-R mRNA expression and the AT(1)-R protein level. The PPARgamma activators also reduced the calcium response of VSMCs to Ang II. PPARgamma activators suppressed the AT(1)-R promoter activity measured by luciferase assay but did not affect the AT(1)-R mRNA stability, suggesting that the suppression occurs at the transcriptional level. CONCLUSIONS: PPARgamma activators reduced the AT(1)-R expression and calcium response to Ang II in VSMCs. Downregulation of AT(1)-R may contribute to the inhibition of neointimal formation by PPARgamma activators.

Angiotensin II↗
PubMed2000

Expression of monocyte chemoattractant protein-1 by nonenzymatically glycated albumin (Amadori adducts) in vascular smooth muscle cells.

The biological effects of Amadori adducts that are early nonenzymatically glycated protein on vascular cells were poorly defined. We examined the effect of glycated serum albumin (GA) on the expression of monocyte chemoattractant protein-1(MCP-1) that is an important chemokine recruiting monocyte to blood vessel. GA increased MCP-1 mRNA expression with a peak after 3 h of stimulation. The induction of MCP-1 by GA was dose-dependent. The MCP-1 mRNA expression by GA was completely inhibited by PD98059 and genistein that inhibit mitogen activated protein (MAP) kinase kinase and tyrosine kinase, respectively. N-Acetylcysteine, a potent antioxidant, also suppressed the GA-induced MCP-1 expression. These results suggest that GA induces production of reactive oxygen species and activates tyrosine kinase and MAP kinase in VSMC. Activation of these signals results in MCP-1 expression. GA-induced MCP-1 expression may be one of the mechanisms by which the diabetic patients suffer from accelerated atherosclerosis.

Animals↗
PubMed2000

Downregulation of angiotensin II type 1 receptor by all-trans retinoic acid in vascular smooth muscle cells.

All-trans retinoic acid (atRA) is a biologically active metabolite of vitamin A that plays an important role in cell differentiation and proliferation. Although neointimal formation after balloon injury of rat carotid artery is inhibited by atRA, the mechanisms are not clearly understood. Because the renin-angiotensin system is one of the crucial components of atherosclerosis, we examined the effects of atRA on the expression of angiotensin II type 1 receptor (AT(1)-R) in vascular smooth muscle cells. atRA (1 micromol/L) decreased the AT(1)-R mRNA level by 50% after 24 hours; AT(1)-R number was also reduced to the same extent after 48 hours. atRA markedly suppressed promoter activity of the AT(1)-R promoter-luciferase construct, but AT(1)-R mRNA stability was not affected. Cycloheximide blocked the atRA-induced decrease in AT(1)-R mRNA expression, suggesting that this process requires de novo protein synthesis. Simultaneous treatment with an agonist (Ro40-6055) specific for retinoic acid receptor (RAR) and an agonist (Ro25-7836) specific for retinoid X receptor (RXR) suppressed the AT(1)-R mRNA expression comparable to that with treatment with atRA, suggesting that the RAR/RXR heterodimer mediates the effect of atRA in AT(1)-R downregulation. These results suggest that atRA suppressed AT(1)-R mRNA transcription through new protein synthesis induced by RAR/RXR-dependent transcription. This study provides novel insight into a role of atRA as an important molecule that regulates AT(1)-R gene expression and provides possible mechanisms for the suppression of neointimal formation by atRA.

Animals↗
PubMed2000

Cellular proliferative and telomerase activity in canine mammary gland tumors.

In canine mammary tumors, we examined the telomerase activity, proliferative activity by proliferative cell nuclear antigen (PCNA) immunohistochemistry, and percentage of apoptotic cells by the deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method. The relationship between these measures and histopathologic malignancy was also investigated. PCNA index was highest in malignant tumors (adenocarcinoma: 27.0%; malignant mixed tumor: 15.7%), followed by benign tumors (adenoma: 4.4%; benign mixed tumor: 5.3%), hyperplasia (2.1%), and normal mammary gland (0.9%). In adenoma and adenocarcinoma, papillary and solid types showing higher cellularity tended to have higher PCNA indices than did cystic and tubular types. Although the TUNEL index was <1% in all cases, the relationship between this measure and histopathologic diagnosis showed the same tendency as observed in PCNA immunostaining. Telomerase activity was detectable in all adenomas, benign mixed tumors, and adenocarcinomas examined. In contrast, all normal mammary glands, hyperplasias, and malignant mixed tumors were negative for telomerase. Relative telomerase activity (RTA) of adenocarcinoma (56.5) was significantly higher than that of adenoma (27.8) and benign mixed tumor (33.9), and a significant positive correlation (P < 0.001) was noted between RTA and PCNA index. No significant correlations were noted between either PCNA or TUNEL index and clinical features such as metastasis and tumor diameter. PCNA index and telomerase activity may be useful markers for judging malignancy of canine mammary tumors.

Adenocarcinoma↗
PubMed1999

Induction of interleukin-6 expression by angiotensin II in rat vascular smooth muscle cells.

Recent studies suggest that atherosclerosis is a kind of inflammatory process and that cytokine plays important roles in this process. Although it is generally accepted that angiotensin II (Ang II) plays an important role in atherogenesis, the role of Ang II in cytokine production has not been explored. In this report, we investigated the effect of Ang II on the production of interleukin-6 (IL-6), which is a multifunctional proinflammatory cytokine in rat vascular smooth muscle cells. Ang II significantly increased the expression of IL-6 mRNA and protein in a dose-dependent manner (10(-10) to 10(-6) mol/L). The expression of IL-6 mRNA induced by Ang II showed 2 peaks at 30 minutes and 12 to 24 hours after stimulation. The effect of Ang II on IL-6 release and mRNA expression was completely blocked by an Ang II type 1 receptor antagonist, CV11974; however, an Ang II type 2 receptor antagonist, PD123319, showed no effect. Chelating of intracellular Ca(2+) with BAPTA-AM, inhibition of tyrosine kinase with genistein, and inhibition of mitogen-activated protein kinase kinase with PD98059 completely abolished the effect of Ang II. However, downregulation of protein kinase C by pretreatment with a phorbol ester for 24 hours or a specific protein kinase C inhibitor, calphostin C, did not affect the Ang II-induced expression of IL-6 mRNA. Deletion and mutational analysis of IL-6 gene promoter showed that cAMP-responsive element was important for Ang II-induced IL-6 gene expression. Gel mobility shift assay showed an increase of cAMP-responsive element binding protein by Ang II. These results provide new insights into Ang II signaling and the role of Ang II in the progression of inflammatory changes of blood vessels.

Angiotensin II↗
PubMed1999

Novel function of the eukaryotic polypeptide-chain releasing factor 3 (eRF3/GSPT) in the mRNA degradation pathway.

The mammalian GTP-binding protein GSPT, whose carboxy-terminal sequence is homologous to the eukaryotic elongation factor EF1alpha, binds to the polypeptide chain releasing factor eRF1 to function as eRF3 in translation termination. However, the amino-terminal domain of GSPT, which contains a prion-like sequence, is not required for the binding. Instead, the amino-terminal domain is capable of binding to the carboxy-terminal domain of polyadenylate-binding protein (PABP), whose amino terminus is associating with the poly(A) tail of mRNAs, presumably for their stabilization. Interestingly, multimerization of PABP with poly(A), which is ascribed to the action of its carboxy-terminal domain, was completely inhibited by the interaction with the amino-terminal domain of GSPT. This may facilitate shortening of the poly(A) tail of mRNAs by an RNase. Thus, GSPT/eRF3 appears to function not only as a stimulator of eRF1 in the translation termination but also as an initiator of the mRNA degradation machinery. Further physiological and cell biological approaches will be necessary to show whether our current in vitro findings on GSPT/eRF3 indeed reflect its bifunctional properties in living cells.

Animals↗
PubMed1998

Structural study of the O-linked sugar chains of human leukocyte tyrosine phosphatase CD45.

The O-linked sugar chains of the human leukocyte cell surface glycoprotein CD45 were released as tritium-labeled oligosaccharides by beta-elimination in the presence of NaB3H4. Mono Q column chromatography revealed that they comprise neutral (64%) and acidic (36%) oligosaccharides, the latter of which were converted to neutral ones by Arthrobacter ureafaciens sialidase treatment. Structural studies of each oligosaccharide fractionated on a Bio-Gel P-4 column by sequential exoglycosidase digestion and by methylation analysis revealed that human leukocyte CD45 contains mainly core 1 and core 2 oligosaccharides, 15% of which are modified with poly (N-acetyllactosamine) chains in different extensions. CD45 consists of several isoforms which were isolated after cell surface sialic acid residues were labeled by periodate/NaB3H4 treatment. Bio-Gel P-6 column chromatography of a mixture of the tritium-labeled glycopeptide/oligosaccharides obtained by pronase-digestion followed by mild alkaline borohydride treatment showed that distribution of the sialylated core 2 oligosaccharides is different among CD45 isoforms.

Carbohydrate Sequence↗
PubMed1998

Downregulation of angiotensin II type 1 receptor gene transcription by nitric oxide.

Nitric oxide (NO) plays an important role not only in the regulation of blood vessel tone, but also in the growth of vascular smooth muscle cells (VSMC). The precise mechanism involved in the inhibition of VSMC growth by NO is not known. To further explore the effect of NO on VSMC growth, we examined the effect of NO on the expression of angiotensin II type 1 receptor (AT1-R) that is important for hypertrophy and hyperplasia of VSMC. S-nitroso acetyl DL-penicillamine (SNAP; 200 micromol/L), a potent NO donor, suppressed expression level of AT1-R mRNA by 90% and AT1-R number by 60% after 24 hours of stimulation. The suppressive effect was dose-dependent. Actinomycin D, which is an inhibitor of gene transcription, did not affect the decrease of AT1-R mRNA by NO. Cyclic guanosine monophosphate (cGMP) analogue, 8 bromo-cGMP, did not affect AT1-R mRNA level. Deletion mutants of the promoter region of rat AT1a-R gene were fused to luciferase reporter gene and introduced to VSMC. Transfected cells were stimulated with SNAP, and luciferase activity was measured. Inhibitory effect of NO was still observed in the shortest deletion mutant that contained 61 bp upstream from transcription start site. In this DNA segment, two DNA binding protein were observed by gel mobility shift assay, and one of these binding proteins was decreased on stimulation by NO. NO downregulates AT1-R gene expression independently of cGMP. A DNA binding protein that binds to the proximal promoter region of AT1-R gene may be responsible for this inhibitory effect. The inhibition of AT1-R gene expression may be implicated in the anti-atherogenic property of NO.

Angiotensin II↗
PubMed1998

Effects of rebamipide on production of several cytokines by human peripheral blood mononuclear cells.

Recently, the relative contributions of local T helper cell responses of the Th1-type and Th2-type to the pathogenesis of gastritis and peptic ulcers associated with Helicobacter pylori infection have been examined. However, the results were controversial with respect to whether cellular immunity (Th1-type) or humoral immunity (Th2-type) responses predominate in H. pylori infection and with respect to how these responses may contribute to disease pathogenesis. In this study, we investigated the characteristics of the production of various cytokines induced by H. pylori or lipopolysaccharide (LPS), which was derived from H. pylori or Escherichia coli, in human peripheral blood mononuclear cells (PBMC). Live H. pylori induced production of many cytokines, such as IL-1beta, IL-10, IL-8, IFN-gamma, and TNF-alpha, whereas we could not detect IL-2 or IL-4. Moreover, we evaluated the effect of rebamipide on the production of several cytokines from PBMC induced by various stimuli. Rebamipide suppressed the production of IL-8, IL-10, TNF-alpha, and IL-1beta induced by H. pylori in a dose-dependent manner. On the other hand, the production of IL-12 induced by H. pylori showed a tendency to increase as a result of treatment of the cells with rebamipide. These results suggested that rebamipide might be effective in regulating cytokine responses in the H. pylori-infected host and maintaining host immunity. Moreover, it might contribute positively to disease progression and bacterial eradication.

Alanine↗