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Articles by T Kobayashi
Total Records ( 13 ) for T Kobayashi
  S Togo , X Liu , X Wang , H Sugiura , K Kamio , S Kawasaki , T Kobayashi , R. F Ertl , Y Ahn , O Holz , H Magnussen , K Fredriksson , C. M Skold and S. I. Rennard

Fibrotic diseases are characterized by the accumulation of extracellular matrix together with distortion and disruption of tissue architecture. Phosphodiesterase (PDE)4 inhibitors, by preventing the breakdown of cAMP, can inhibit fibroblast functions and may be able to mitigate tissue remodeling. Transforming growth factor (TGF)-β1, a mediator of fibrosis, can potentially modulate cAMP by altering PGE2 metabolism. The present study assessed whether PDE4 inhibitors functionally antagonize the profibrotic activity of fibroblasts stimulated by TGF-β1. The PDE4 inhibitors roflumilast and rolipram both inhibited fibroblast-mediated contraction of three-dimensional collagen gels and fibroblast chemotaxis toward fibronectin in the widely studied human fetal lung fibroblast strain HFL-1 and several strains of fibroblasts from adult human lung. Roflumilast was ~10-fold more potent than rolipram. There was a trend for PDE4 inhibitors to inhibit more in the presence of TGF-β1 (0.05 < P < 0.08). The effect of the PDE4 inhibitors was mediated through cAMP-stimulated protein kinase A (PKA), although a PKA-independent effect on gel contraction was also observed. The effect of PDE4 inhibitors depended on fibroblast production of PGE2 and TGF-β1-induced PGE2 production. PDE4 inhibitors together with TGF-β1 resulted in augmented PGE2 production together with increased expression of COX mRNA and protein. The present study supports the concept that PDE4 inhibitors may attenuate fibroblast activities that can lead to fibrosis and that PDE4 inhibitors may be particularly effective in the presence of TGF-β1-induced fibroblast stimulation.

  M Koga , J Murai , H Saito , S Kasayama , A Imagawa , T Hanafusa , T Kobayashi and the Members of the Japan Diabetes Society's Committee on Research on Type 1 Diabetes

Fulminant type 1 diabetes mellitus (FT1DM), a subtype of type 1 diabetes mellitus, was first reported as a disease entity in 2000. Ketoacidosis at initial onset due to acute pancreatic cell destruction makes early diagnosis and treatment for FT1DM mandatory. In the early period of FT1DM, haemoglobin (Hb)A1C levels are not markedly elevated. This study investigated serum glycated albumin (GA), which reflects acute short-term changes in plasma glucose, as a new clinical index for FT1DM at disease onset.


Subjects comprised 35 patients with FT1DM who had undergone measurement of HbA1C and serum GA at initial visit and 42 patients with type 2 diabetes mellitus (T2DM) with HbA1C <8.5% and no history of diabetes treatment as controls.


HbA1C was significantly lower in FT1DM than in T2DM, whereas serum GA was significantly higher. GA/HbA1C ratio was thus significantly higher in FT1DM than in T2DM (3.9 ± 0.5 versus 2.8 ± 0.3; P < 0.0001). GA/HbA1C ratio was >3.2 in 41 of 42 FT1DM patients (98%), compared with only one of 32 T2DM patients (3%).


Serum GA is significantly higher in FT1DM than in T2DM, whereas HbA1C is significantly lower. FT1DM can thus be distinguished from untreated T2DM by GA/HbA1C ratio at initial visit before treatment for diabetes.

  J. e Obata , T Nakamura , Y Kitta , Y Kodama , K Sano , K. I Kawabata , Y Saitoh , D Fujioka , T Kobayashi , T Yano , Y Watanabe , K Watanabe and K. Kugiyama

Background— Sirolimus-eluting stent (SES) implantation aggravated endothelial vasomotor dysfunction in infarct-related coronary arteries.

Methods and Results— This study examined the effect of SES implantation on the duration of reperfusion-induced endothelial vasomotor dysfunction in infarct-related coronary arteries and on postinfarct left ventricular dysfunction in acute myocardial infarction (AMI). Patients with a first AMI due to occlusion of the left anterior descending coronary artery and successful reperfusion using SES (n=15) or bare metal stents (BMS; n=18) were examined. The vasomotor response of the left anterior descending coronary artery to acetylcholine and left ventriculography were examined 2 weeks and 6 months after AMI. At 6 months after AMI, the impairment of epicardial coronary artery dilation and coronary blood flow increase in response to acetylcholine was recovered from 2 weeks after AMI in BMS-treated patients, whereas the responses of SES-treated patients improved but remained impaired compared with BMS-treated patients (% increase in blood flow, 77±12% in SES versus 116±15% in BMS at 10 µg/min of acetylcholine, P<0.01). Left ventricular regional wall dysfunction in the left anterior descending coronary artery territory improved from 2 weeks to 6 months after AMI in BMS-treated patients but not in SES-treated patients (% improvement of average SD/chord, 6% in SES versus 19% in BMS, P<0.05), although left ventricular global ejection fraction was similar between the groups at any time points.

Conclusions— SES implantation may delay recovery of reperfusion-induced endothelial vasomotor dysfunction in infarct-related coronary arteries and left ventricular regional dysfunction for at least 6 months after AMI.

  Y Abe , H Wada , E Yamada , M Noda , M Ikejiri , J Nishioka , T Kobayashi , T Matsumoto , M Masuya , S Isaji , M Usui , S Uemoto , N Katayama and T. Nobori

Thrombotic microangiopathy (TMA) or thrombotic thrombocytopenic purpura (TTP) is a life-threatening syndrome characterized by increased number of fragmented red cells (FRCs) and thrombocytopenia. FRCs can be measured using the recently developed automated hematology analyzer XE-2100. The normal range for FRCs is 0% to 0.205%, as determined by the automated hematology analyzer XE-2100. The FRC count is significantly elevated in patients with TMA associated with liver transplantation, bone marrow transplantation, or TTP. In patients with TMA after liver transplantation, the FRC count is significantly higher than in those without TMA. In receiver operating characteristic analysis for the diagnosis of TMA, the area under the curve is 0.986, suggesting that FRC is a useful marker for the diagnosis of TMA. When the cutoff value of FRC for TMA is 1.2%, the sensitivity is 90% and the specificity is 96%, indicating that FRC is the most useful screening test for the diagnosis of TMA.

  T Kobayashi , H Mizuno , I Imayoshi , C Furusawa , K Shirahige and R. Kageyama

Stem cells do not all respond the same way, but the mechanisms underlying this heterogeneity are not well understood. Here, we found that expression of Hes1 and its downstream genes oscillate in mouse embryonic stem (ES) cells. Those expressing low and high levels of Hes1 tended to differentiate into neural and mesodermal cells, respectively. Furthermore, inactivation of Hes1 facilitated neural differentiation more uniformly at earlier time. Thus, Hes1-null ES cells display less heterogeneity in both the differentiation timing and fate choice, suggesting that the cyclic gene Hes1 contributes to heterogeneous responses of ES cells even under the same environmental conditions.

  T Kobayashi , T Inoue , Y Shimizu , N Terada , A Maeno , Y Kajita , T Yamasaki , T Kamba , Y Toda , Y Mikami , T Yamada , T Kamoto , O Ogawa and E. Nakamura

We and others previously showed that signaling through cSrc or atypical protein kinase C (aPKC) pathway regulates the proliferation of prostate cancer cells and is associated with their progression to castrate-resistance in vivo. However, the interrelation of these two kinases has been largely unexplored. In the present study, we show that androgen-induced activation of cSrc regulates the activity of aPKC through the small molecular weight G protein Rac1 in androgen-dependent LNCaP cells. Knockdown of cSrc in those cells reduces the phosphorylation of aPKC and the abundance of activated form of Rac1. Additionally, the treatment of those cells with Rac1 inhibitor repressed cell cycle progression at G1/S transition. In fact, forced expression of a constitutively active Rac1 mutant in LNCaP cells promoted cell proliferation under androgen-depleted conditions both in vitro and in vivo. Moreover, LNCaP C4-2 and AILNCaP cells, the syngeneic androgen-independent sublines from LNCaP cells, harbored abundant Rac1-GTP. Importantly, the inhibition of Rac1 suppressed cell proliferation and induced apoptotic cell death in all prostate cancer cell lines tested irrespective of their androgen-dependence. In immunohistochemical evaluation of tumor specimens from prostate cancer patients, Rac1 pathway appeared to be activated in the majority of castrate-resistant diseases. Collectively, our present results both in vitro and in vivo highly implicate that Rac1 can be a potential therapeutic target for patients with advanced prostate cancer, especially those with castrate-resistant status.

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