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Articles by Y Tanaka
Total Records ( 10 ) for Y Tanaka
  M Inoue , N Kurahashi , M Iwasaki , T Shimazu , Y Tanaka , M Mizokami , S Tsugane and for the Japan Public Health Center Based Prospective Study Group

In spite of their anticarcinogenic potential, the effect of coffee and green tea consumption on the risk of liver cancer has not been clarified prospectively in consideration of hepatitis C (HCV) and B virus (HBV) infection. We examined whether coffee and green tea consumption was associated with a reduced risk of liver cancer by hepatitis virus infection status in the Japan Public Health Center-Based Prospective Study Cohort II. A total of 18,815 subjects ages 40 to 69 years participating in a questionnaire and health checkup survey in 1993 to 1994 were followed for the incidence of liver cancer through 2006. A total of 110 cases of liver cancer were newly documented. Hazard ratios for coffee and green tea consumption categories were calculated with a Cox proportional hazards model. Compared with almost never drinkers, increased coffee consumption was associated with a reduced risk of liver cancer in all subjects (hazard ratio for <1, 1-2, and ≥3 cups/d; Ptrend = 0.67, 0.49, 0.54, and 0.025). A similar risk tendency was observed in those with either or both HCV and HBV infection. In contrast, no association was observed between green tea consumption and the risk of liver cancer in all subjects. Our results suggest that coffee consumption may reduce the risk of liver cancer regardless of HCV and HBV infection status, whereas green tea may not reduce this risk.(Cancer Epidemiol Biomarkers Prev 2009;18(6):1746–53)

  H Horigome , M Nagashima , N Sumitomo , M Yoshinaga , H Ushinohama , M Iwamoto , J Shiono , K Ichihashi , S Hasegawa , T Yoshikawa , T Matsunaga , H Goto , K Waki , M Arima , H Takasugi , Y Tanaka , N Tauchi , M Ikoma , N Inamura , H Takahashi , W Shimizu and M. Horie

Background— Data on the clinical presentation and genotype-phenotype correlation of patients with congenital long-QT syndrome (LQTS) diagnosed at perinatal through infantile period are limited. A nationwide survey was conducted to characterize how LQTS detected during those periods is different from that in childhood or adolescence.

Methods and Results— Using questionnaires, 58 cases were registered from 33 institutions. Diagnosis (or suspicion) of LQTS was made during fetal life (n=18), the neonatal period (n=31, 18 of them at 0 to 2 days of life), and beyond the neonatal period (n=9). Clinical presentation of LQTS included sinus bradycardia (n=37), ventricular tachycardia/torsades de pointes (n=27), atrioventricular block (n=23), family history of LQTS (n=21), sudden cardiac death/aborted cardiac arrest (n=14), convulsion (n=5), syncope (n=5), and others. Genetic testing was available in 41 (71%) cases, and the genotype was confirmed in 29 (71%) cases, consisting of LQT1 (n=11), LQT2 (n=11), LQT3 (n=6), and LQT8 (n=1). Ventricular tachycardia/torsades de pointes and atrioventricular block were almost exclusively observed in patients with LQT2, LQT3, and LQT8, as well as in those with no known mutation. In LQT1 patients, clues to diagnosis were mostly sinus bradycardia or family history of LQTS. Sudden cardiac death/aborted cardiac arrest (n=14) was noted in 4 cases with no known mutations as well as in 4 genotyped cases, although the remaining 6 did not undergo genotyping. Their subsequent clinical course after aborted cardiac arrest was favorable with administration of β-blockers and mexiletine and with pacemaker implantation/implantable cardioverter-defibrillator.

Conclusions— Patients with LQTS who showed life-threatening arrhythmias at perinatal periods were mostly those with LQT2, LQT3, or no known mutations. Independent of the genotype, aggressive intervention resulted in effective suppression of arrhythmias, with only 7 deaths recorded.

  H Yamabe , Y Tanaka , K Morihisa , T Uemura , K Enomoto , H Kawano and H. Ogawa

Background— Calcium channel–dependent tissue has been suggested to be involved in the circuit of verapamil-sensitive atrial tachycardia originating from the atrioventricular (AV) node vicinity (V-AT), but little information exists.

Methods and Results— To examine the tachycardia circuit of V-AT, a single extrastimulus was delivered during tachycardia to 10 sites of the intraatrial septum: the earliest atrial activation site; His bundle (HB) site; 3 arbitrarily divided sites on the AV junction extending from the HB site to the coronary sinus ostium (CSOS) (sites S, M, and I); the internal-CSOS, inferior-CSOS, superior-CSOS, posterior-CSOS, and posteroinferior-CSOS in 10 patients with V-AT. The longest coupling interval that reset V-AT and subsequent return cycle were measured. The longest coupling interval at earliest atrial activation site was significantly longer than the longest coupling interval at the HB site, site S, M, and I, internal-CSOS, inferior-CSOS, superior-CSOS, posterior-CSOS, and posteroinferior-CSOS, respectively (P<0.001 for HB site and P<0.0001 for the remaining 8 sites). The return cycle at earliest atrial activation site did not differ from the tachycardia cycle length, whereas those at the remaining 9 sites were significantly longer than tachycardia cycle length (P<0.001). Furthermore, a single extrastimulus delivered from sites inferior to the HB site advanced His potential without resetting V-AT in 7 patients in whom AV block was not observed during tachycardia.

Conclusions— Atrial tissue within the Koch’s triangle extending from the HB site to posteroinferior-CSOS is not involved in the tachycardia circuit. Verapamil-sensitive atrial tissue close to the AV node but not the AV nodal conducting system forms the tachycardia circuit of V-AT.

  K Nakano , T Higashi , R Takagi , K Hashimoto , Y Tanaka and S. Matsushita

A major neurotransmitter dopamine transmits signals via five different seven transmembrane G protein-coupled receptors termed D1–D5. It is now evident that dopamine is released from leukocytes and acts as autocrine or paracrine immune modulator. However, the role of dopamine for dendritic cells (DCs) and Th differentiation remains unclear. We herein demonstrate that human monocyte-derived dendritic cells (Mo-DCs) stored dopamine in the secretary vesicles. The storage of dopamine in Mo-DCs was enhanced by forskolin and dopamine D2-like receptor antagonists via increasing cyclic adenosine 3',5'-monophosphate (cAMP) formation. Antigen-specific interaction with naive CD4+ T cells induced releasing dopamine-including vesicles from Mo-DCs. In naive CD4+ T cells, dopamine dose dependently increased cAMP levels via D1-like receptors and shifts T-cell differentiation to Th2, in response to anti-CD3 plus anti-CD28 mAb. Furthermore, we demonstrated that dopamine D2-like receptor antagonists, such as sulpiride and nemonapride, induced a significant DC-mediated Th2 differentiation, using mixed lymphocyte reaction between human Mo-DCs and allogeneic naive CD4+ T cells. When dopamine release from Mo-DCs is inhibited by colchicines (a microtubule depolymerizer), T-cell differentiation shifts toward Th1. These findings identify DCs as a new source of dopamine, which functions as a Th2-polarizing factor in DC-naive T-cell interface.

  S Yanaka , M Kudou , Y Tanaka , T Sasaki , S Takemoto , A Sakata , Y Hattori , T Koshi , S Futaki , K Tsumoto and T. Nakashima

Staphylococcal enterotoxin B (SEB), a toxin produced by Staphylococcus aureus, causes food poisoning and other fatal diseases by inducing high levels of pro-inflammatory cytokines. These cytokines are released from CD4+ T cells and major histocompatibility complex (MHC) class II antigen-presenting cells, which are activated through binding of wild-type (WT) SEB to both the MHC class II molecule and specific T-cell receptor Vβ chains. Here, we focused on a trypsin/cathepsin cleavage site of WT SEB, which is known to be cleaved in vivo between Lys97 and Lys98, located within the loop region. To know the function of the cleavage, an SEB mutant, in which both of these Lys residues have been changed to Ser, was examined. This mutant showed prolonged tolerance to protease cleavage at a different site between Thr107 and Asp108, and structural analyses revealed no major conformational differences between WT SEB and the mutant protein. However, differential scanning calorimetric analysis showed an increase in enthalpy upon thermal denaturation of the mutant protein, which correlated with the speed of cleavage between Thr107 and Asp108. The mutant protein also had slightly increased affinity for MHC. In the in vivo experiment, the SEB mutant showed lower proliferative response in peripheral blood mononuclear cells and had lower cytokine-induction activity, compared with WT SEB. These results highlight the importance of the flexible loop region for the functional, physical and chemical properties of WT SEB, thus providing insight into the nature of WT SEB that was unrevealed previously.

  T Morisugi , Y Tanaka , T Kawakami and T. Kirita

Temporomandibular joint disorders (TMD) show complex symptoms associated with inflammation, pain and degeneration of the peripheral tissues including synovium. Although it is believed that excessive mechanical stress on synovium causes development of TMD, the molecular mechanism by which mechanical stress triggers TMD has still remained unclear. In order to examine the effect of mechanical stress on synoviocytes, rabbit synovial cells were cyclically stretched in vitro. The stretch efficiently increased the gene expressions of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and NF-B responsive reporter gene constructs. The interruption of NF-B activating pathway by inhibitors resulted in the abrogation of those expressions, indicating the pivotal role of NF-B in the mechanical stretch-mediated COX-2 and iNOS expressions. In parallel, the stretch remarkably increased NO production and poly(ADP-ribose) (PAR) synthesis, suggesting that excessive amounts of NO causes DNA injury and in turn activates PAR synthesis by poly(ADP-ribose) polymerase (PARP). The inhibition of PAR synthesis by a PARP inhibitor or a radical scavenger enhanced the mechanical stretch-induced gene expressions in a NF-B-independent manner, implying an involvement of PARP in the gene expression. Taken together, these results demonstrate that mechanical stress on synovial cells not only induces gene expressions of COX-2 and iNOS but also affects PAR synthesis.

  K Gotoh , Y Tanaka , A Nishikimi , R Nakamura , H Yamada , N Maeda , T Ishikawa , K Hoshino , T Uruno , Q Cao , S Higashi , Y Kawaguchi , M Enjoji , R Takayanagi , T Kaisho , Y Yoshikai and Y. Fukui

Plasmacytoid dendritic cells (pDCs) play a key role in antiviral immunity, but also contribute to the pathogenesis of certain autoimmune diseases, by producing large amounts of type I IFNs. Although activation of pDCs is triggered by engagement of nucleotide-sensing toll-like receptors (TLR) 7 and 9, type I IFN induction additionally requires IB kinase (IKK) –dependent activation of IFN regulatory factor (IRF) 7. However, the signaling pathway mediating IKK- activation is poorly defined. We show that DOCK2, an atypical Rac activator, is essential for TLR7- and TLR9-mediated IFN- induction in pDCs. We found that the exposure of pDCs to nucleic acid ligands induces Rac activation through a TLR-independent and DOCK2-dependent mechanism. Although this Rac activation was dispensable for induction of inflammatory cytokines, phosphorylation of IKK- and nuclear translocation of IRF-7 were impaired in Dock2-deficient pDCs, resulting in selective loss of IFN- induction. Similar results were obtained when a dominant-negative Rac mutant was expressed in wild-type pDCs. Thus, the DOCK2–Rac signaling pathway acts in parallel with TLR engagement to control IKK- activation for type I IFN induction. Owing to its hematopoietic cell-specific expression, DOCK2 may serve as a therapeutic target for type I IFN–related autoimmune diseases.

  Y. J Cui , L. M Aleksunes , Y Tanaka , M. J Goedken and C. D. Klaassen

Alpha-naphthyl isothiocyanate (ANIT) is a hepatotoxicant that produces acute intrahepatic cholestasis in rodents. Farnesoid X receptor (FXR) and pregnane X receptor (PXR) are two major bile acid sensors in liver. The purpose of this study was to characterize the regulation of hepatic transporters by FXR and PXR during ANIT-induced liver injury. Wild-type, FXR-null, and PXR-null mice were administered ANIT (75 mg/kg, po) and evaluated 48 h later for hepatotoxicity and messenger RNA (mRNA) expression of basolateral uptake (sodium taurocholate–cotransporting polypeptide, organic anion transporting polypeptide [Oatp] 1a1, Oatp1a4, Oatp1b2) and efflux transporters (organic solute transporter [Ost] , Ostβ, multidrug resistance–associated protein [Mrp] 3, Mrp4), as well as canalicular transporters (bile salt export pump [Bsep], Mrp2, multidrug resistance protein 2 [Mdr2], ATPase, class I, type 8B, member 1 [Atp8b1]). Livers from wild-type and PXR-null mice had comparable multifocal necrosis 48 h after ANIT. However, ANIT-treated FXR-null mice have fewer and smaller necrotic foci than wild-type mice but had scattered single-cell hepatocyte necrosis throughout the liver. Serum alanine transaminase, alkaline phosphatase (ALP), and direct bilirubin were increased in all genotypes, with higher ALP levels in FXR-null mice. Serum and liver unconjugated bile acids were higher in ANIT-treated FXR-null mice than the other two genotypes. ANIT induced mRNA expression of Mdr2, Bsep, and Atp8b1 in wild-type and PXR-null mice but failed to upregulate these genes in FXR-null mice. mRNA expression of uptake transporters declined in livers of all genotypes following ANIT treatment. ANIT increased Ostβ and Mrp3 mRNA in livers of wild-type and PXR-null mice but did not alter Ostβ mRNA in FXR-null mice. In conclusion, FXR deficiency enhances susceptibility of mice to ANIT-induced liver injury, likely a result of impaired induction of hepatobiliary efflux transporters and subsequent hepatic accumulation of unconjugated bile acids.

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