K Kato

Aichi Medical University, Okazaki, Aichi, Japan

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Publications (139)298.77 Total impact

  • Annals of Oncology 11/2013; 24(suppl 9):ix95-ix95. DOI:10.1093/annonc/mdt460.144 · 6.58 Impact Factor
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    ABSTRACT: Introduction Standard chemotherapy is increasingly discontinued after successful “induction” in patients (pts) undergoing 1st line treatment for mCRC. MGN1703 is a synthetic DNA-based immunomodulator acting as an agonist of TLR-9 that has shown preclinical activity in mCRC. This study has been conducted to assess clinical efficacy, immunogenicity, and safety of MGN1703 as maintenance vs. placebo.
    Annals of Oncology 09/2012; 23(suppl 9):ix178-ix223. DOI:10.1093/annonc/mds397 · 6.58 Impact Factor
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    ABSTRACT: Background TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G + T to standard dose G as first-line therapy of PAC.
    Annals of Oncology 09/2012; 23(suppl 9):ix224-ix257. DOI:10.1093/annonc/mds398 · 6.58 Impact Factor
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    ABSTRACT: Proinsulin C-peptide is involved in several biological activities. However, the role of C-peptide in vascular smooth muscle cells is unclear. We therefore investigated its effects, in vascular smooth muscle cells in high-glucose conditions. Rat aortic smooth muscle cells were cultured with 5.5 or 20 mmol/l glucose with or without C-peptide (1 to 100 nmol/l) for 3 weeks. Proliferation activities, the protein expression of platelet-derived growth factor (PDGF)-beta receptor, the phosphorylation of p42/p44 mitogen-activated protein (MAP) kinases, and glucose uptake were measured. The proliferation activities increased approximately three-fold under high-glucose conditions (p<0.05). C-peptide suppressed hyperproliferation activities that were induced by high glucose. This happened in a dose-dependent manner from 1 to 100 nmol/l of C-peptide. C-peptide (10 and 100 nmol/l) inhibited the increased protein expression of PDGF-beta receptor and the phosphorylation of p42/p44 MAP kinases that had been induced by high glucose (p<0.05). Furthermore, 100 nmol/l of C-peptide augmented the impaired glucose uptake in the high-glucose conditions. These observations suggest that C-peptide could prevent diabetic macroangiopathy by inhibiting smooth muscle cell growth and ameliorating glucose utilisation in smooth muscle cells. C-peptide may thus be a novel agent for treating diabetic macroangiopathy in patients with type 1 and type 2 diabetes.
    Diabetologia 12/2005; 48(11):2396-401. DOI:10.1007/s00125-005-1942-9 · 6.88 Impact Factor
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    ABSTRACT: Background Although cholesterol management reportedly reduces fatal and non-fatal coronary heart disease (CHD) events in subjects with or without evident atherosclerotic disease, it is still uncertain whether these benefits extend to Japanese. Methods and Results The study group comprised 8,009 subjects with mildly elevated total cholesterol who were randomized to treatment with 10-20 mg pravastatin plus diet (2,691 women, 1,267 men) or diet alone (2,758 women, 1,293 men). The groups were extremely well balanced with respect to baseline demographics and risk factors such as blood pressure and plasma lipids. Over a 5-year period of follow-up, the primary end-points will be a composite of fatal and non-fatal coronary events. Secondary end-points will include stroke and transient ischemic attack, all cardiovascular events and total mortality. Conclusions The 2 groups will be followed up until the end of March 2004 and end-points will be analyzed by full analysis set.
    Circulation Journal 09/2004; 68(9):860-867. · 3.69 Impact Factor
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    ABSTRACT: The protein kinase C (PKC), platelet-derived growth factor (PDGF) and polyol pathway play important parts in the hyperproliferation of smooth muscle cells, a characteristic feature of diabetic macroangiopathy. The precise mechanism, however, remains unclear. This study investigated the relation between polyol pathway, protein kinase C and platelet-derived growth factor in the development of diabetic macroangiopathy. Smooth muscle cells were cultured with 5.5 or 20 mmol/l glucose with or without an aldose reductase inhibitor, epalrestat, or a PKC-beta specific inhibitor, LY333531. Protein kinase C activities, the expression of PKC-beta II isoform and PDGF-beta receptor protein, free cytosolic NAD+:NADH ratio, the contents of reduced glutathione, and proliferation activities were measured. Smooth muscle cells cultured with 20 mmol/l glucose showed statistically significant increases in protein kinase C activities, the expression of PKC-beta II isoform and PDGF-beta receptor protein, and proliferation activities, compared with smooth muscle cells cultured with 5.5 mmol/l glucose. Although epalrestat and LY333531 inhibited protein kinase C activation induced by glucose to the same degree, the effects of epalrestat on proliferation activities and expression of the PDGF-beta receptor were more prominent than those of LY333531. Epalrestat improved the glucose-induced decrease in free cytosolic NAD+:NADH ratio and reduced glutathione content, but LY333531 did not. The increased expression of membranous PKC-beta II isoform was normalized by epalrestat. These observations suggest that polyol pathway hyperactivity contributes to the development of diabetic macroangiopathy through protein kinase C, PDGF-beta receptor, and oxidative stress, and that an aldose reductase inhibitor has a therapeutic value for this complication.
    Diabetologia 05/2001; 44(4):480-7. DOI:10.1007/s001250051646 · 6.88 Impact Factor
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    ABSTRACT: To clarify the role of the polyol pathway in the intracellular formation of advanced glycation end products in human tissues, we examined the effects of epalrestat, an aldose reductase inhibitor, on the level of Nepsilon-(carboxymethyl)lysine (CML) along with 3-deoxyglucosone (3-DG) and triosephosphates in erythrocytes from diabetic patients. Plasma thiobarbituric acid-reactive substances (TBARS) were also determined as indicators of oxidative stress. Blood samples were collected from 12 nondiabetic volunteers, 38 untreated type 2 diabetic patients, and 16 type 2 diabetic patients who had been treated with 150 mg epalrestat/day. Blood samples were also collected from 14 of the untreated type 2 diabetic patients before and after the administration of epalrestat for 2 months. The amount of erythrocyte CML was determined by a competitive enzyme-linked immunosorbent assay, and 3-DG was measured by high-performance liquid chromatography In diabetic patients not treated with epalrestat, the erythrocyte CML level was significantly elevated above levels seen in nondiabetic individuals (49.9 +/- 5.0 vs. 31.0 +/- 5.2 U/g protein, P < 0.05) and was significantly lower in patients receiving epalrestat (33.1 +/- 3.8 U/g protein, P < 0.05). Similar results were observed with 3-DG. The treatment of patients with epalrestat for 2 months significantly lowered the level of erythrocyte CML (46.2 +/- 5.6 at baseline vs. 34.4 +/- 5.0 U/g protein, P < 0.01) along with erythrocyte 3-DG (P < 0.05), triosephosphates (P < 0.05), fructose (P < 0.05), sorbitol (P < 0.05), and plasma TBARS (P < 0.05) without changes in plasma glucose and HbA(1c) levels. A positive correlation was evident between the erythrocyte CML and sorbitol (r = 0.49, P < 0.01) or fructose (r = 0.40, P < 0.05) levels in diabetic patients. The results indicate that epalrestat administration lowers CML and associated variables and that polyol metabolites are correlated with CML in the erythrocytes of diabetic patients. The observed results suggest that aldose reductase activity may play a substantial role in the intracellular formation of CML in the mediation of reactive intermediate metabolites and oxidative stress.
    Diabetes Care 11/2000; 23(10):1539-44. DOI:10.2337/diacare.23.10.1539 · 8.57 Impact Factor
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    ABSTRACT: The pathogenesis of pericyte loss, an initial deficit in the early stage of diabetic retinopathy, remains unclear. Polyol pathway hyperactivity has been implicated in the pathogenesis of diabetic retinopathy, and recent studies have suggested that apoptosis may be involved in pericyte loss. The present study was conducted to investigate whether high glucose induces apoptosis in cultured bovine retinal pericytes. The effect of an aldose reductase inhibitor, SNK-860, was also examined. After a 5 day incubation with various concentrations of glucose (5.5-40 m M) in the presence or absence of SNK-860, the cell viability and the percentages of dead cells were measured, and staining with the TUNEL method and Hoechst 33342, and DNA electrophoresis were performed. High glucose reduced the viability and increased the percentages of dead cells. TUNEL-positive cells were observed in pericytes under high glucose, but not in those under 5.5 m M glucose. In the staining of nuclei with Hoechst 33342, the percentage of apoptotic cells in total cells counted under high glucose was higher than that under 5.5 m M glucose. DNA electrophoresis of pericytes cultured with high glucose demonstrated a 'ladder pattern'. Hyperosmolarity also induced apoptosis in pericytes, but less than that by high glucose. SNK-860 inhibited the glucose-induced apoptosis in pericytes. These observations suggest that the pericyte loss in diabetic retinopathy involves an apoptotic process, and that the polyol pathway hyperactivity plays an important role in inducing apoptosis in pericytes by high glucose.
    Experimental Eye Research 10/2000; 71(3):309-15. DOI:10.1006/exer.2000.0882 · 3.02 Impact Factor
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    ABSTRACT: Although increased protein kinase C (PKC) activity has been invoked in the pathogenesis of diabetic retinopathy, nephropathy and macroangiopathy, the role of PKC in neuropathy remains unclear. We reported that total PKC activity in sciatic nerves of STZ-induced diabetic rats was not altered compared with that of normal rats, and that PKC-β inhibitor, LY-333531 (LY) ameliorated neural dysfunction and reduced endoneurial blood flow without affecting PKC activity, suggesting that this effect of LY would be mediated through its action on endoneurial microvasculature. In this study, effect of LY on diabetic neuropathy was investigated in Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of type 2 diabetes. Three-month-old male OLETF rats and Long-Evans Tokushima Otsuka (LETO) rats as normal control rats were divided into 5 groups as follows: 1) LETO control, 2) OLETF control, 3) LY (1 mg/kg/day)-treated OLETF, 4) sucrose-fed OLETF, and 5) sucrose-fed OLETF treated with LY. After 21-month treatment, motor nerve conduction velocity (MNCV) in tail nerves, sciatic nerve blood flow (SNBF) and protein expression of phosphorylated PKC in sciatic nerves were measured. 1) MNCV: OLETF rats demonstrated a significant delay in MNCV, which was enhanced by sucrose feeding, and these deficits were prevented by LY. 2) SNBF: reduced SNBF in OLETF and sucrose-fed OLETF rats was ameliorated by LY. 3) PKC: phosphorylated PKC expression was decreased in OLETF rats, which was more prominent in sucrose-fed OLETF rats. Treatment with LY increased phosphorylated PKC expression in both groups of OLETF rats. These observations suggest that diabetes with long duration and poor glycemic control decreases phosphorylated PKC in nerve tissues, which would contribute to the development of diabetic neuropathy, and that PKC-β inhibition would be beneficial for the prevention of this neuropathy.
    Journal of the Peripheral Nervous System 09/2000; 5(3):181-181. DOI:10.1046/j.1529-8027.2000.005003181.x · 2.50 Impact Factor
  • Diabetes Research and Clinical Practice 09/2000; 50:362-362. DOI:10.1016/S0168-8227(00)81235-8 · 2.54 Impact Factor
  • Diabetes Research and Clinical Practice 09/2000; 50:373-373. DOI:10.1016/S0168-8227(00)81273-5 · 2.54 Impact Factor
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    Diabetes Care 03/2000; 23(2):253-4. DOI:10.2337/diacare.23.2.253 · 8.57 Impact Factor
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    ABSTRACT: Although increased polyol pathway activity has been implicated in the pathogenesis of diabetic microangiopathy, the relation with diabetic macroangiopathy remains unclear. Galactose feeding is known to stimulate the polyol pathway and to develop abnormalities similar to those in diabetic microangiopathy. Our study was conducted to investigate whether an activation of polyol pathway by long-term treatment with galactose produced morphological changes in coronary arteries of dogs and the effect of an aldose reductase inhibitor, epalrestat, was also studied. Dogs received either normal chow or chow containing 30% galactose with or without epalrestat given orally (20 or 50 mg x kg(-1)). After 44 months, morphometric analyses of coronary arteries were carried out and the galactitol contents in aortas were measured. The ratio of areas of the intimal layer to those of the medial layer, an indicator of intimal thickening, was statistically significantly increased in galactose-fed dogs compared with control dogs. Galactose-fed dogs had a remarkable accumulation of galactitol in their aortas. These morphological and biochemical deficits were reduced by treatment with epalrestat. This report morphologically shows diabetes-like macrovascular abnormalities in galactosaemic animals, suggesting that polyol pathway hyperactivity is closely related to the development of diabetic macroangiopathy, which could be prevented by aldose reductase inhibition.
    Diabetologia 01/2000; 42(12):1404-9. DOI:10.1007/s001250051310 · 6.88 Impact Factor
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    ABSTRACT: Increased protein kinase C (PKC) activity has been implicated in the pathogenesis of diabetic retinopathy and nephropathy. However, the role of PKC in diabetic neuropathy remains unclear. The present study was conducted to compare the effect of PKC inhibition by a PKC-beta-selective inhibitor, LY333531 (LY), on diabetic nerve dysfunction with that of an aldose reductase inhibitor, NZ-314 (NZ). Streptozotocin-induced diabetic rats were treated with or without LY and/or NZ for 4 weeks, and motor nerve conduction velocity (MNCV), coefficient of variation of R-R interval (CVR-R), sciatic nerve blood flow (SNBF), peak latencies of oscillatory potentials on electroretinogram, PKC activities in membranous and cytosolic fractions of sciatic nerves, and polyol contents in the tail nerves were measured. Untreated diabetic rats demonstrated delayed MNCV, decreased CVR-R, reduced SNBF, and prolonged peak latencies of oscillatory potentials. Treatment with LY as well as NZ prevented all these deficits in diabetic rats. There were no significant differences in PKC activities in membranous or cytosolic fractions of sciatic nerves between normal and diabetic rats. Treatment with neither LY nor NZ altered PKC activities. Nerve myo-inositol depletion in diabetic rats was ameliorated not only by NZ, but also by LY. These observations suggest that inhibition of PKC-beta by LY may have a beneficial effect in preventing the development of diabetic nerve dysfunction, and that this effect may be mediated through its action on the endoneurial micro-vasculature.
    Diabetes 11/1999; 48(10):2090-5. DOI:10.2337/diabetes.48.10.2090 · 8.47 Impact Factor
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    ABSTRACT: To investigate the relationship between polyol pathway hyperactivity and altered carnitine metabolism in the pathogenesis of diabetic neuropathy, the effects of an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl]acetic acid (TAT), and a carnitine analog, acetyl-L-carnitine (ALC), on neural functions and biochemistry and hemodynamic factors were compared in streptozotocin-diabetic rats. Significantly delayed motor nerve conduction velocity, decreased R-R interval variation, reduced sciatic nerve blood flow and decreased erythrocyte 2, 3-diphosphoglycerate concentrations in diabetic rats were all ameliorated by treatment with TAT (administered with rat chow containing 0.05% TAT, approximately 50 mg/kg/day) or ALC (by gavage, 300 mg/kg/day) for 4 weeks. Platelet hyperaggregation activity in diabetic rats was diminished by TAT but not by ALC. TAT decreased sorbitol accumulation and prevented not only myo-inositol depletion but also free-carnitine deficiency in diabetic nerves. On the other hand, ALC also increased the myo-inositol as well as the free-carnitine content without affecting the sorbitol content. These observations suggest that there is a close relationship between increased polyol pathway activity and carnitine deficiency in the development of diabetic neuropathy and that an aldose reductase inhibitor, TAT, and a carnitine analog, ALC, have therapeutic potential for the treatment of diabetic neuropathy.
    Journal of Pharmacology and Experimental Therapeutics 01/1999; 287(3):897-902. · 3.86 Impact Factor
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    ABSTRACT: Hepatocyte transplantation is a potential therapeutic modality for overcoming the shortage of liver donors, and the clinical application of allogeneic hepatocyte transplantation has been considered. However, there are two major problems with allogeneic hepatocyte transplantation: protection of transplanted hepatocytes from rejection and stimulation of the rapid proliferation of surviving cells. Without immunosuppression, allogeneic hepatocytes are rapidly rejected within a few days after transplantation, even though it is relatively easy to induce immunotolerance after allogeneic whole liver transplantation. Accordingly, different rejection mechanisms seem to operate after allogeneic hepatocyte transplantation and whole liver transplantation. To overcome the rejection of transplanted hepatocytes, induction of donor-specific unresponsiveness to graft without compromising the host immune system would be ideal. We previously reported that the Fas-Fas ligand system plays a critical role in the CD28-independent pathway of hepatocyte rejection. Therefore, blockade of rejection using CTLA4 immunoglobulin (CTLA4Ig) or anti-CD80/86 monoclonal antibodies and anti-FasL monoclonal antibody may prolong the survival of transplanted allogeneic hepatocytes. Furthermore, administration of hepatocyte growth factor (HGF) can promote the proliferation of allogeneic hepatocytes and this may lead to the development of a functioning liver substitute.
    Journal of Gastroenterology and Hepatology 10/1998; 13 Suppl:S119-23. · 3.63 Impact Factor
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    ABSTRACT: The expression and enzymatic activity of the cytochrome P450 LAomega within intrasplenically transplanted hepatocytes was investigated. Fetal hepatocytes were harvested from spontaneously hypertensive rats and transplanted into recipient adult spontaneously hypertensive rat spleens. Microscopic examination revealed masses of hepatocytes in the red pulp. Immunochemical studies detected cytochrome P450 LAomega in transplanted hepatocytes by 6 and 10 weeks after transplantation. Cytochrome P450 LAomega mRNA accumulates at 6 weeks after transplantation. Cytochrome P450-arachidonic acid omega/omega-1 hydroxylase activity (formation of 20/19-hydroxyeicosatetraenoic acid) was detected at 10 weeks after transplantation. These results demonstrated that fetal hepatocytes grow in the spleen and function similarly to adult hepatocytes.
    Transplantation 09/1998; 66(4):441-5. · 3.78 Impact Factor
  • Transplantation Proceedings 03/1998; 30(1):13-5. DOI:10.1016/S0041-1345(97)01164-0 · 0.95 Impact Factor
  • Transplantation Proceedings 03/1998; 30(1):16-8. DOI:10.1016/S0041-1345(97)01165-2 · 0.95 Impact Factor
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    ABSTRACT: Mitral valve aneurysm is defined as a localized protrusion of the valve with a different radius from that of the remaining portion of the valve. The medical records and pathological findings of seven patients with mitral valve aneurysm [aged 48-69 years (mean 64), 4 males] and the pathological findings of other 29 Japanese cases were reviewed. All seven patients were diagnosed pathologically as infective endocarditis, but two patients had no documentation of clinical symptoms suggestive of infective endocarditis (latent infective endocarditis). The underlying lesion of the heart was aortic valve disease and/or fibrosal degeneration of the mitral valve. Only 29 of 36 Japanese case reports stated a precise description of the valve pathology. Of these 29 cases, 23 were associated with infective endocarditis, two with rheumatic valvular disease with fusion and/or shrinkage of the chordae tendineae, three with mitral valve prolapse or myxomatous degeneration of the mitral valve, and one with aortitis syndrome. Neovascularization was described in eight cases. Neovascularization with thick wall should be considered as post-inflammatory vascularization. This review indicates that patients with latent infective endocarditis and mitral valve aneurysm should be considered as potential candidates for valve surgery.
    Journal of Cardiology 02/1998; 31 Suppl 1:19-33; discussion 34-6. · 2.57 Impact Factor

Publication Stats

1k Citations
298.77 Total Impact Points

Institutions

  • 2005
    • Aichi Medical University
      • Division of Internal Medicine
      Okazaki, Aichi, Japan
  • 1970–2000
    • Nagoya University
      • Division of of Internal Medicine
      Nagoya-shi, Aichi-ken, Japan
  • 1991–1998
    • Juntendo University
      • • Second Department of Surgery
      • • Department of Immunology
      Edo, Tōkyō, Japan
  • 1994–1997
    • New York Medical College
      • • Department of Surgery
      • • Department of Medicine
      New York, New York, United States
  • 1991–1996
    • The Cardiovascular Institute
      Tōkyō, Japan
  • 1993
    • Tsukuba Research Institute
      Edo, Tōkyō, Japan