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  2. Mitsuyasu Itoh

Mitsuyasu Itoh

  (伊藤 光泰)

Profile Information

Affiliation
Professor of Medicine, School of Medicine, Faculty of Medicine, Fujita Health University
Degree
(BLANK)
J-GLOBAL ID
200901010157792273
researchmap Member ID
1000049261

Research Interests

 6

Research Areas

 1

Education

 4

Awards

 1

Papers

 49
  • Sakura Yamamoto, Atsushi Suzuki, Hitomi Sasaki, Sahoko Sekiguchi-Ueda, Shogo Asano, Megumi Shibata, Nobuki Hayakawa, Shuji Hashimoto, Kiyotaka Hoshinaga, Mitsuyasu Itoh
    JOURNAL OF BONE AND MINERAL METABOLISM, 31(1) 116-122, Jan, 2013  Peer-reviewed
    Post-transplantation bone diseases negatively affect the quality of life of solid organ recipients. Secondary or tertiary hyperparathyroidism is a frequent complication in kidney transplantation (KTx) recipients. Treatment with immunosuppressive agents including glucocorticoids can lead to deterioration in bone metabolism in these patients. In the present study, we explored the effects of a three-year treatment period with oral alendronate (ALN) in long-term KTx recipients. Post-KTx recipients were recruited (n = 24, M/F = 12/12, mean age 52.0 +/- A 7.8 years) into this study. All patients were prescribed methylprednisolone (4.07 +/- A 0.86 mg/day) with various immunosuppressive agents. Before treatment with oral ALN (35 mg/week), the mean concentrations of intact parathyroid hormone (iPTH) and 25-hydroxyvitamin D were 139.2 +/- A 71.4 pg/mL and 20.8 +/- A 4.1 ng/mL, respectively. After 36 months of ALN treatment, mean iPTH levels increased slightly (+20.9 %). Treatment with ALN reduced bone-specific alkaline phosphatase (-35.4 %), serum type I collagen N-terminal telopeptide (-31.2 %) and osteocalcin (-55.6 %) levels. ALN did not increase bone mass after 24 months. Four patients with the highest baseline iPTH levels suffered a clinical osteoporotic fracture during the 36-month ALN treatment period. Higher iPTH levels with chronic kidney disease (CKD) at baseline were associated with the incidence of new clinical fractures during ALN treatment. In conclusion, anti-resorptive therapy with ALN can suppress bone turnover even when iPTH concentration is elevated in long-term KTx recipients. However, hyperparathyroidism with CKD seems to be associated with new clinical fractures during ALN treatment.
  • Akira Ota, Akira Nakashima, Yoko S. Kaneko, Keiji Mori, Hiroshi Nagasaki, Takeshi Takayanagi, Mitsuyasu Itoh, Kazunao Kondo, Toshiharu Nagatsu, Miyuki Ota
    JOURNAL OF NEURAL TRANSMISSION, 119(11) 1327-1342, Nov, 2012  Peer-reviewed
    Aripiprazole is the only atypical antipsychotic drug known to cause the phosphorylation of AMP-activated protein kinase (AMPK) in PC12 cells. However, the molecular mechanisms underlying this phosphorylation in aripiprazole-treated PC12 cells have not yet been clarified. Here, using PC12 cells, we show that these cells incubated for 24 h with aripiprazole at 50 mu M and 25 mM glucose underwent a decrease in their NAD(+)/NADH ratio. Aripiprazole suppressed cytochrome c oxidase (COX) activity but enhanced the activities of pyruvate dehydrogenase (PDH), citrate synthase and Complex I. The changes in enzyme activities coincided well with those in NADH, NAD(+), and NAD(+)/NADH ratio. However, the bioenergetic peril judged by the lowered COX activity might not be accompanied by excessive occurrence of apoptotic cell death in aripiprazole-treated cells, because the mitochondrial membrane potential was not decreased, but rather increased. On the other hand, when PC12 cells were incubated for 24 h with clozapine at 50 mu M and 25 mM glucose, the NAD(+)/NADH ratio did not change. Also, the COX activity was decreased; and the PDH activity was enhanced. These results suggest that aripiprazole-treated PC12 cells responded to the bioenergetic peril more effectively than the clozapine-treated ones to return the ATP biosynthesis back toward its ordinary level. This finding might be related to the fact that aripiprazole alone causes phosphorylation of AMPK in PC12 cells.
  • Atsushi Yokoyama, Ryuji Nomura, Masafumi Kurosumi, Atsushi Shimomura, Takanori Onouchi, Akiko Iizuka-Kogo, Ron Smits, Riccardo Fodde, Mitsuyasu Itoh, Takao Senda
    MEDICAL MOLECULAR MORPHOLOGY, 45(3) 161-167, Sep, 2012  Peer-reviewed
    Adenomatous polyposis coli (Apc) is a multifunctional protein as well as a tumor suppressor. To determine the functions of the C-terminal domain of Apc, we examined Apc (1638T/1638T) mice that express a truncated Apc lacking the C-terminal domain. The Apc (1638T/1638T) mice were tumor free and exhibited growth retardation. We recently reported abnormalities in thyroid morphology and functions of Apc (1638T/1638T) mice, although the mechanisms underlying these abnormalities are not known. In the present study, we further compared thyroid gland morphology in Apc (1638T/1638T) and Apc (+/+) mice. The diameters of thyroid follicles in the left and right lobes of the same thyroid gland of Apc (1638T/1638T) mice were significantly different whereas the Apc (+/+) mice showed no significant differences in thyroid follicle diameter between these lobes. To assess the secretory activities of thyroid follicular cells, we performed double-immunostaining of thyroglobulin, a major secretory protein of these cells, and the rough endoplasmic reticulum (rER) marker calreticulin. In the Apc (1638T/1638T) follicular epithelial cells, thyroglobulin was mostly colocalized with calreticulin whereas in the Apc (+/+) follicular epithelial cells, a significant amount of the cytoplasmic thyroglobulin did not colocalize with calreticulin. In addition, in thyroid-stimulating hormone (TSH)-treated Apc (1638T/1638T) mice, electron microscopic analysis indicated less frequent pseudopod formation at the apical surface of the thyroid follicular cells than in Apc (+/+) mice, indicating that reuptake of colloid droplets containing iodized thyroglobulin is less active. These results imply defects in intracellular thyroglobulin transport and in pseudopod formation in the follicular epithelial cells of Apc (1638T/1638T) mice and suggest suppressed secretory activities of these cells.
  • Keiko Yamamoto, Mitsuyasu Itoh, Tomoko Okamura, Maiko Kimura, Atsushi Yokoyama, Yasumasa Yoshino, Masaki Makino, Nobuki Hayakawa, Atsushi Suzuki
    THYROID, 22(5) 516-521, May, 2012  Peer-reviewed
    Background: Interactions between CD40 and its ligand (CD40L) have important roles in T-cell-dependent activation of B cells, which may be related to the thyrotoxic activity of Graves' disease (GD). Soluble forms of CD40 ligand (sCD40L) are released from activated T cells and platelets, and several types of inflammatory cytokines are increased in patients with hyperthyroid GD. The aim of this study was to assess sCD40L and other cytokines as clinical indicators of disease activity or as possible markers of remission in GD. Methods: Serum levels of sCD40L, interleukin 18 (IL-18), tumor necrosis factor-alpha (TNF alpha), and TNF alpha receptors 1 and 2 (TNFR1 and TNFR2) were investigated in patients with active GD (GD-A), intractable GD (GD-IT), inactive GD (GD-IA), GD in remission (GD-R), and Hashimoto's thyroiditis (HT), and in control subjects (CON). Results: Serum concentrations of sCD40L were higher in the GD-A and GD-IT groups than in the HT and CON groups. Similarly, serum concentrations of IL-18, which induces Th1 cytokines, such as interferon-gamma, were higher in the GD-A and GD-IT groups than in all other groups. Serum levels of TNFR1 and TNFR2 were also significantly higher in the GD-A than in all other groups. The mean serum concentration of TNF alpha was higher in the GD-R compared with the GD-A and GD-IT groups, although the difference was not significant. Serum sCD40L concentrations in the GD-R group were lower than in the GD-A and GD-IT groups. Finally, the ratio of serum TNF alpha to sCD40L was higher in the GD-R group than in the GD-A and GD-IT groups. This is the first report that serum sCD40L is increased in active GD, and that the serum TNF alpha:sCD40L ratio is a marker for remission in GD. Conclusions: Our results suggest that not only thyrotoxicosis, but also the activity of the immunoreaction presenting as anti-thyrotropin receptor antibodies (TRAb) titer in GD, affects inflammatory cytokine serum profiles. Serum profiles of cytokines vary in patients with GD depending on disease activity. An elevated serum TNF alpha:sCD40L ratio indicates declining disease activity and reflects a shift from Th2 to Th1 dominance, suggesting that suppression of sCD40L or increased production of TNF alpha is required to initiate or maintain remission of GD.
  • Shogo Asano, Atsushi Suzuki, Junnichi Ishii, Sahoko Sekiguchi-Ueda, Megumi Shibata, Yasumasa Yoshino, Kazuhiro Nakamura, Yasukazu Akiyama, Fumihiko Kitagawa, Toshiaki Sakuishi, Takashi Fujita, Mitsuyasu Itoh
    Diabetology International, 3(1) 29-36, Mar, 2012  Peer-reviewed
    Background: Chronic elevation of cardiac troponin T (TnT) levels as measured by conventional assays is strongly associated with structural heart disease and cardiovascular events. A new high-sensitivity assay for TnT makes it possible to measure concentrations more than a factor of 5 lower than the limits of detection of conventional assays. We evaluated the utility of serum TnT as a risk marker of cardiovascular disease in 409 outpatients with type-2 diabetes mellitus (T2DM). Results: TnT was detectable (&gt 0. 002 ng/mL) in 80% of patients, and elevation in TnT levels (&gt 0. 014 ng/mL) was found in 19. 3%, suggesting a higher prevalence of structural heart diseases in T2DM patients. A history of cardiovascular disease was noted in 89 (22%) patients. Patients with diabetic microvascular complications and those with abnormal electrocardiogram including left ventricular hypertrophy had higher TnT levels. Patients with increased levels of TnT (&gt 0. 014 ng/mL) were older, had higher values of N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein, cystatin C, and urinary albumin/creatinine ratio, had lower values of hemoglobin and estimated glomerular filtration rate, and had a higher prevalence of cardiovascular disease compared with those without increased TnT levels. In stepwise logistic analysis, NT-proBNP (odds ratio 7. 40 per 10-fold increase, P &lt 0. 0001) and cystatin C (18. 0 per 1. 0 mg/L, P &lt 0. 0001) were independently associated with elevation of TnT levels. HsTnT level, cystatin C, and HDL-cholesterol were also independent risk factors for history of major cardiovascular diseases in T2DM patients. Conclusion: This new high-sensitivity TnT assay may be useful for stratifying cardiovascular risk in outpatients with T2DM. © 2011 The Japan Diabetes Society.
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Misc.

 75
  • R Masunaga, A Nagasaka, Y Sawai, N Hayakawa, A Nakai, K Hotta, Y Kato, H Hishida, H Takahashi, M Naka, Y Shimada, T Tanaka, H Hidaka, M Itoh
    JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 37(3) 767-774, Sep, 2004  
    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 mug/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 111, 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 (IC50) of PDE 1, 11, and III peak activities was 140, 29, and 46 muM respectively, suggesting that PDE 11 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. (C) 2004 Elsevier Ltd. All rights reserved.
  • K Fujiwara, A Nagasaka, M Nagata, K Yamamoto, S Imamura, N Oda, Y Sawai, N Hayakawa, A Suzuki, M Itoh
    EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES, 112(7) 390-394, Jul, 2004  
    Aims: To confirm whether a prostacyclin (prostaglandin 12) affects the increased TNF-alpha concentration in sera of diabetic patients, we measured serum TNF-alpha concentration and treated these patients with oral administration of the stable prostacyclin analogue (Beraprost). Twelve of 20 type 11 diabetic patients were investigated for follow up-study and 6 of those patients were for therapy with Beraprost for diabetic neuropathy. Subjects and Methods: Serum TNF-alpha concentration was quantified by EASIA using monoclonal antibodies directed against distinct epitopes of TNF-alpha. Results: In diabetic patients, serum TNF-alpha concentration was significantly increased compared with that of healthy subjects. The augmented TNF-alpha concentration in these patients was not decreased by diabetic control using antihyperglycemic agents for 8 weeks but was reduced with oral administration of a stable prostacyclin (prostaglandin 12) analogue for 5 weeks without any changes of blood glucose levels. Conclusions: Stable prostacyclin analogue administration for a short term period reduced increased TNF-alpha levels in diabetic patients, not through the improved hyperglycemic condition but another pathway, probably a cAMP system. These results imply that treatment with the prostacyclin analogue may contribute to the prevention of progression in diabetic complications.
  • A Kakita, A Suzuki, Y Ono, Y Miura, M Itoh, Y Oiso
    PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS, 70(5) 469-474, May, 2004  
    Prostaglandins are now recognized to be important regulators for both bone formation and resorption. Among them, prostaglandin E-1 (PGE(1)) has been reported to stimulate cAMP accumulation and to induce alkaline phosphatase (ALP) activity, a marker of differentiation, in osteoblast-like cells. Recently, we have shown that p38 mitogen-activated protein (MAP) kinase pathway regulates ALP activity in response to activation of Gi protein-coupled receptors in mouse osteoblast-like MC3T3-E1 cells (Suzuki et al., Endocrinology 140 (1999) 3177). In the present study, we investigated whether p38 MAP kinase is involved in ALP activation by PGE(1) in MC3T3-E1 osteoblast-like cells. PGE(1) dose-dependently enhanced ALP activities in the concentration range between 1 nM and 1 muM in MC3T3-E1 cells. SB203580, a specific inhibitor of p38 MAP kinase, blocked the increase in ALP activity induced by PGE(1). Further analysis with western blotting suggested that PGE(1) induced an increase in tyrosine (Tyr) phosphorylation of p38 MAP kinase. Both Bt(2)cAMP, a permeable analogue of cAMP, and forskolin, which directly activates adenylate cyclase, also induced an increase in Tyr phosphorylation of p38 MAP kinase. H-89, a potent inhibitor of protein kinase A (PKA), significantly suppressed PGE(1)-induced Tyr phosphorylation of p38 MAP kinase. The results of this study suggest that PGE(1) stimulates p38 MAP kinase through the activation of PKA, resulting in the enhancement of ALP activity. (C) 2003 Elsevier Ltd. All rights reserved.
  • A Kakita, A Suzuki, K Nishiwaki, Y Ono, M Kotake, Y Ariyoshi, Y Miura, M Itoh, Y Oiso
    ATHEROSCLEROSIS, 174(1) 17-24, May, 2004  
    We investigated the effect of platelet-derived growth factor B homodimer (PDGF-BB) on inorganic phosphate (Pi) transport activity, which has been reported to be involved in the mechanism of atherosclerosis, in A-10 rat aortic vascular smooth muscle cells (VSMCs). PDGF-BB time- and dose-dependently stimulated Pi transport in A-10 cells. Using northern blot analysis, the PDGF-BB-enhanced Pi transporter (PiT) in A-10 cells was identified as Pit-1 (Glvr-1), a member of the type III Na-dependent PiT. An inhibitor of PDGF P-receptor tyrosine kinase suppressed PDGF-BB-induced Pi transport. Both a protein kinase C (PKC) inhibitor calphostin C and PKC down regulation suppressed the stimulatory effect of PDGF-BB on Pi transport. On the other hand, inhibition of mitogen-activated protein (MAP) kinases by selective inhibitors did Dot affect Pi transport. Ly294002, a phosphatidylinositol (PI) 3-kinase inhibitor, partially attenuated PDGF-BB-induced Pi transport. A selective inhibitor Of S-6 kinase, rapamycin, reduced this effect of PDGF-BB, while Akt kinase inhibitor did not. In summary, these results indicated that PDGF-BB is a potent and selective stimulator of Pi transport in VSMCs. The mechanism responsible for this effect is not mediated by MAP kinase, but involves activation of PKC, PI 3-kinase and S-6 kinase. (C) 2004 Published by Elsevier Ireland Ltd.
  • K Fujiwara, K Mori, YS Kaneko, A Nakashima, A Nagasaka, M Itoh, A Ota
    BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 1670(3) 181-198, Feb, 2004  
    Tetrahydrobiopterin is an essential cofactor for nitric oxide synthase (NOS). This study was undertaken to examine the effects of intraperitoneally injected lipopolysaccharide on tetrahydrobiopterin biosynthesis in murine white and brown adipose tissues. Tetrahydrobiopterin content, catalytic activity and mRNA expression level of GTP cyclohydrolase I (GCH), rate-controlling enzyme in de novo biosynthesis of tetrahydrobiopterin, in both adipose tissues were up-regulated by 500-gg lipopolysaccharide at 6 h after the injection. On the contrary, treatment of 3T3-L1 adipocytes with lipopolysaccharide alone did not affect GCH mRNA expression level, whereas the combination of lipopolysaccharide, tumor necrosis factor (TNF)-alpha, and interferon gamma induced the increase in expression levels of GCH mRNA and CD14 mRNA. Collectively, our results showed that tetrahydrobiopterin biosynthesis can be augmented by increased GCH activity caused by a synergistic effect of lipopolysaccharide and cytokines in white and brown adipose tissues. These observations support the view that tetrahydrobiopterin biosynthesis in the adipose tissues is a target of inflammatory events triggered by peripheral LPS injection. (C) 2004 Elsevier B.V All rights reserved.
  • Journal of Endocrinology, 181, 429-435, 2004  
  • Hormone and Metabolic Research, 36, 453-457, 2004  
  • Biochimica et Biophysica Acta, 1673, 194-200, 2004  
  • Metabolism, 53(5), 550-555, 2004  
  • Nakano, I, T Tsugawa, R Shinohara, F Watanabe, T Fujita, M Nagata, T Kato, Y Himeno, T Kobayashi, K Fujiwara, M Nagata, M Itoh, A Nagasaka
    JOURNAL OF DIABETES AND ITS COMPLICATIONS, 17(6) 337-342, Nov, 2003  
    The amounts of sorbitol (SOR) excreted in 24-h urine were determined on two groups, i.e., diabetic and nondiabetic patients, using an improved method in which ion exchange resin column processing was applied, and these levels were compared with SOR levels in whole blood. Urinary SOR concentration was also determined in diabetic and normal rats in the same manner and its relationship to aldose reductase (AR) activity in whole blood was investigated. Changes in SOR levels in urine and whole blood were compared in diabetic rats after administration of an AR inhibitor (ARI). Whole blood SOR levels and urinary SOR excretion were significantly higher in diabetic patients than in nondiabetic patients. The same results were obtained in the animal models. In diabetic rats, the urinary SOR excretion was about five times higher than that in control rats, and the AR activity in whole blood was also significantly higher. The increase in urinary SOR excretion and whole blood SOR levels, as well as AR activity, in blood in the diabetic state was inhibited by ARI administration. The influence of the diabetic state and the efficacy of the ARI were more marked in urinary SOR excretion than in whole blood SOR levels. These data indicate that determinations of urinary SOR excretion and AR activity are easily measurable and of benefit to assessing the diabetic condition. (C) 2003 Elsevier Inc. All rights reserved.
  • Sato, I, A Suzuki, A Kakita, Y Ono, Y Miura, M Itoh, Y Oiso
    PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS, 68(5) 311-315, May, 2003  
    Prostaglandin F-2alpha (PGF(2alpha)) has been reported to activate protein kinase C (PKC) through both phospholipase (PL) C and D, resulting in the proliferation of ostcoblast-like cells. In addition, it has also been reported that Erk mitogen-activated protein kinase is also involved in the mechanism of PGF(2alpha)-induced proliferation of these cells. Recently, we have reported that several growth factors stimulate Na-dependent phosphate transport (Pi transport) activity of osteoblast-like cells, which has been recognized to play an important role in their mineralization. In the present study, we investigated the effect of PGF(2alpha) on Pi transport in MC3T3E- E1 osteoblast-like cells. PGF(2alpha) stimulated Na-dependent Pi transport dose dependently in the range between 1 nM and 10 muM in MC3T3-E1 cells. The effect was time dependent up to 24h. Kinetic analysis revealed that PGF(2alpha) induces newly synthesized Pi transporter. Pretreatment with actinomycin D and cycloheximide suppressed PGF(2alpha)-induced enhancement of Pi transport. Combined effect of PMA and PGF(2alpha) was not additive in Pi transport. Calphostin C, a PKC inhibitor, dose-dependently suppressed Pi transport induced by PGF(2alpha). On the contrary, U0126, which inhibits an upstream kinase of Erk (MEK), did not affect PGF(2alpha)-induced enhancement of Pi transport. In conclusion, PGF(2alpha) stimulates Pi transport through activation of PKC in osteoblast-like cells. (C) 2003 Elsevier Science Ltd. All rights reserved.
  • Journal of Pharmacological Sciences, 93, 265-271, 2003  
  • Y Horikawa, N Oda, L Yu, S Imamura, K Fujiwara, M Makino, Y Seino, M Itoh, J Takeda
    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 88(1) 244-247, Jan, 2003  
    The 112/121 haplotype combination defined by the UCSNP-43, -19, and -63 alleles in the calpain-10 gene is associated with type 2 diabetes in Mexican Americans. To determine whether this genetic variation constitutes risk of type 2 diabetes in Japanese, we investigated its frequency in 177 patients with type 2 diabetes and 172 controls. Though this variation occurs in Japanese more frequently than in Mexican Americans, there is no significant difference in frequency between diabetic (29.9%) and control (31.9%) subjects. We also screened all exons and the putative promoter of the calpain-10 gene for mutations in 96 of the genotyped patients, resulting in the identification of 7 coding variants, including 3 missense mutations and 5 nucleotide alterations in the promoter. However, their frequencies all are similar in patients and controls, suggesting that these genetic variations are not a major factor in the occurrence of type 2 diabetes in Japanese, although they could yet. be associated with various phenotypes of the disease.
  • M Itoh, K Uchimura, K Yamamoto, M Makino, S Imamura, T Kobayashi, K Fujiwara, T Kato, N Hayakawa, Y Sawai, A Nagasaka, K Iwase, T Nomura, Y Hagino
    CYTOKINE, 19(3) 107-114, Aug, 2002  
    The possible role of abnormal T cell-dependent B-cell activation in Graves' disease was investigated by comparing lymphocyte subset distribution and the production of soluble CD8 (sCD8), sCD23, IL-10 and IL-12 by peripheral blood cells (PBMC) and thyroid-infiltrating lymphocytes (TL) in vitro. In TL, the percentage of CD8(+) cells was slightly higher and the sCD8 concentration was significantly higher than in PBMC. The ratio CD23(+) cells to CD20(+) cells (activated B/pan B cells) was increased in TL compared to PBMC from Graves' or normal controls, although the percentage of CD20(+) cells was decreased. Compared to PBMC in Graves' disease, the relative ratio of IL-10 to IL-12 release (IL-10/IL-12) by unstimulated TL was increased, despite a lack of significant difference between PBMC and TL in mean values for either IL-10 or IL-12 secretion. Incubating PBMC with a combination of anti-CD40 monoclonal antibodies and interleukin-4 (IL-4) resulted in B cell activation, reflected in an increase in the sCD23 level in both controls and Graves' patients, but especially prominent in the latter. Stimulation with anti-CD40 antibody and IL-4 also decreased the percentage of CD8+ cells in PBMC but not TL from both Graves' disease and normal controls, and the percentage of CD8(+) cells in TL was higher than PBMC after the stimulation. The sCD23 concentration in TL was decreased compared to PBMC both in patients with Graves' disease and normal controls. However, in contrast to the increased responses observed in Graves' PBMC or normal controls after stimulation, sCD23 levels remained the same in stimulated TL from Graves' patients. This combination of B cell stimulants increased production of IL-10 in PBMC but not in TL obtained from patients with Graves' disease, and the increased IL-10/IL-12 ratio declined to a value no different from that in PBMC group after stimulation. Thus, T cell-dependent B-cell activation via a CD40 pathway may cause a shift in the Th-1/Th-2 balance to Th-2 dominance in Graves' disease, while increased CD8(+) cells in TL may suppress sCD23 production and IL-10-producing Th2 cells. (C) 2002 Elsevier Science Ltd. All rights reserved.
  • Clinical & Experimental Pharmacology & Physiology, 29(11), 980-989, 2002  
  • Journal of endocrinology, 175(1), 233-239, 2002  
  • Metabolism, 51(10), 1230-1234, 2002  
  • Molecular and Cellular Endocrinology, 192, 127-132, 2002  
  • Metabolism, 51(7), 871-875, 2002  
  • Clinical & Experimental Immunology, 128, 308-312, 2002  
  • Life Sciences, 70, 2187-2198, 2002  
  • Hormone Research, 56, 165-171, 2001  
  • Journal of Endocrinology, 171, 259-265, 2001  
  • Prostaglandins & Other Lipid Mediators, 66, 221-234, 2001  
  • Metabolism, 50(6), 631-634, 2001  
  • Cytokine, 12(6) 688-693, 2000  
  • Toshiki Mano, Rikio Shinohara, Akio Nagasaka, Hifumi Nakagawa, Keiko Uchimura, Ritsuko Hayashi, Itsuko Nakano, Toru Tsugawa, Fumiko Watanabe, Takako Kobayashi, Kentaro Fujiwara, Akira Nakai, Mitsuyasu Itoh
    Metabolism: Clinical and Experimental, 49(4) 427-431, 2000  
    Free radicals and lipid peroxide (LPO), easily formed in the diabetic state, play an important role in the development of diabetic complications. Potentially, nicorandil may reduce the production of free radicals and LPO in various organs. In fact, increased LPO levels in the serum, kidney, and cardiac muscle of diabetic (DM) rats were reduced by nicorandil treatment (N treatment). Xanthine oxidase (XOD), which produces free radicals, was decreased in the liver and increased in the kidney of DM rats compared with control rats, and these changes were prevented by N treatment. The concentration of Cu, Zn-superoxide dismutase (SOD) decreased in the cardiac muscle and increased in the kidney of DM rats, and these changes returned to normal after N treatment. The decreased concentration of Mn-SOD in the liver, kidney, and cardiac muscle from DM rats was also reversed by N treatment. The changes in catalase and glutathione peroxidase (GSH-PX) activities in DM rats were not improved effectively by N treatment. Another K-adenosine triphosphate (K-ATP) channel opener, tilisolol hydrochloride, had an effect similar to that of nicorandil. The effects of nicorandil and tilisolol were studied only in DM rats. These data imply that N treatment, as an antioxidative therapy, may be beneficial in preventing diabetic complications due to lipoperoxidation and free radicals in DM rats. Copyright (C) 2000 by W. B. Saunders Company.
  • Journal of Endocrinology, 164 97-102, 2000  
  • K Uchimura, A Nagasaka, R Hayashi, M Makino, M Nagata, H Kakizawa, T Kobayashi, K Fujiwara, T Kato, K Iwase, R Shinohara, K Kato, M Itoh
    JOURNAL OF DIABETES AND ITS COMPLICATIONS, 13(5-6) 264-270, Sep, 1999  
    To investigate whether the two free-radical scavengers, Cu, Zn- and Mn-superoxide dismutase (SOD), are changed in leukocytes of diabetic patients, and the alteration of these enzymes correlates with the diabetic state, we measured the activity and concentration of these enzymes in leukocytes from diabetic patients. Both Cu, Zn-SOD and Mn-SOD activities in neutrophils and lymphocytes were significantly lower in patients with non-insulin-depend ent diabetes mellitus than in healthy controls. The concentrations of these enzymes in leukocytes from diabetic patients, however, did not differ from those in controls. Cu, Zn-SOD and Mn-SOD activities in neutrophils inversely correlated with HbA(1c) concentrations. Myeloperoxidase activity in leukocytes was significantly reduced in NIDDM patients. These findings suggest that changes in these enzymes may affect the susceptibility to infection and immunocompetence of patients with diabetes. (C) 2000 Elsevier Science Inc.
  • T Mokuno, K Uchimura, R Hayashi, N Hayakawa, M Makino, M Nagata, H Kakizawa, Y Sawai, M Kotake, N Oda, A Nakai, A Nagasaka, M Itoh
    JOURNAL OF ENDOCRINOLOGY, 160(2) 285-289, Feb, 1999  
    The deterioration of glucose metabolism frequently observed in hyperthyroidism may be due in part to increased gluconeogenesis in the liver and glucose efflux through hepatocyte plasma membranes. Glucose transporter 2 (GLUT 2), a facilitative glucose transporter localized to the liver and pancreas, may play a role in this distorted glucose metabolism. We examined changes in the levels of GLUT 2 in livers from rats with L-thyroxine-induced hyperthyroidism or methimazole-induced hypothyroidism by using Western blotting to detect GLUT 2. An oral glucose tolerance test revealed an oxyhyperglycemic curve (impaired glucose tolerance) in hyperthyroid rats (n=7) and a flattened curve in hypothyroid rats (n=7). GLUT 2 levels in hepatocyte plasma membranes were significantly increased in hyperthyroid rats and were not decreased in hypothyroid rats compared with euthyroid rats. The same results were obtained with a densitometric assay. These findings suggest that changes in the liver GLUT 2 concentration may contribute to abnormal glucose metabolism in thyroid disorders.
  • T Mano, K Mori, Y Sawai, N Oda, T Tugawa, Nakano, I, F Watanabe, M Hamada, P Nakai, H Yamamoto, N Harada, A Nagasaka, M Itoh
    ENDOCRINE RESEARCH, 25(3-4) 371-380, 1999  
    About 28% of patients with the Crow-Fukase syndrome exhibit glucose intolerance which may be induced by low serum levels of dehydroepiandrosterone (DHEA). We report a patient with the Crow-Fukase syndrome who exhibited non-insulin dependent diabetes mellitus (NIDDM) worsened prior to admission. He received the DHEA sulfate (DHEA-S) infusion test to evaluate aromatase activity. This patient exhibited an increase in aromatase activity measured by the conversion of the intravenously loaded DHEA-S to estrogen, and low serum levels of DHEA and DHEA-S, These abnormalities returned to nearly normal during the administration of prednisolone, 60 mg per day. No adverse effect on his diabetes was observed during the corticosteroid treatment. Five control patients with diabetes but without the Crow-Fukase syndrome showed no increase in the conversion of DHEA-S to estrogen, which suggests that aromatase activity is normal in diabetes. The increase in aromatase activity in our patient may have led to a low serum concentration of DHEA that in turn caused glucose intolerance and a deterioration of the diabetes prior to admission. Glucocorticoid therapy may be beneficial in Crow-Fukase syndrome to improve the distorted metabolism of DHEA with no adverse effect on the diabetes.
  • Hormone and Metabolic Research, 31 602-605, 1999  
  • Diabetes Care, 22(7) 1221-1224, 1999  
  • R Shinohara, T Mano, A Nagasaka, Y Sawai, K Uchimura, R Hayashi, N Hayakawa, M Nagata, M Makino, H Kakizawa, Y Itoh, A Nakai, M Itoh
    BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 1425(3) 577-586, Nov, 1998  
    Sorbitol accumulation plays an important role in diabetic complications involving the kidney, nerves, retina, lens and cardiac muscle. To investigate the influence of thyroid hormone on the sorbitol pathway, we studied the effects of thyroid hormone on polyol metabolism in normal and diabetic rats. Rats were divided into three groups: controls, streptozotocin (STZ)-induced diabetic euthyroid rats (DM) and STZ-induced diabetic hyperthyroid (thyroxine-injected) rats (DM+HT). The sorbitol (Sor) concentrations in the kidney, liver and sciatic nerve (2.53 +/- 0.74, 0.97 +/- 0.16 and 24.0 +/- 5.1 nmol/mg protein, respectively) of the DM rats were significantly higher than those (1.48 +/- 0.31, 0.58 +/- 0.13 and 3.1 +/- 0.6 nmol/mg protein) of the control rats. The Sor concentrations in the kidney and sciatic nerve of the DM+HT rats (1.26 +/- 0.29 and 9.40 +/- 1.2 nmol/mg protein) were significantly lower than those in the DM rats. These values were reduced in the liver, unchanged in the kidney, and increased in the sciatic nerve from the hyperthyroid rats without diabetes. Thyroid hormone reduced the aldose reductase (AR) activities in the kidney, liver and sciatic nerve of the DM rats, and similarly reduced AR in the kidney and liver, but not in the sciatic nerve, of the non-diabetic rats. The sorbitol dehydrogenase (SDH) activities were decreased by thyroid hormone in the kidney and liver but not the sciatic nerve of DM rats. In the non-diabetic rats, this enzyme activity was decreased in liver, but not in kidney or sciatic nerve. A positive correlation between the Sor concentration and AR activity was observed in the kidney and liver but not in the sciatic nerve from control, DM and DM+HT rats. A negative correlation was observed between the Sor concentration and SDH activities in the same organs. These data suggest that thyroid hormone affects the sorbitol pathway, but the detailed mechanism whereby this hormone reduces the sorbitol content (especially in diabetic rats) remains to be clarified. (C) 1998 Published by Elsevier Science B.V. All rights reserved.
  • M Itoh, K Uchimura, N Hayakawa, M Makino, R Hayashi, M Nagata, H Kakizawa, A Nagasaka, H Sakamoto, H Kuzuya
    CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 113(2) 309-314, Aug, 1998  
    We investigated the effect of T cell-dependent B cell activation on the surface expression and release of the soluble forms of CD8 and CD23 by peripheral blood mononuclear cells (PBMC) obtained from patients with GD, versus patients with Hashimoto's thyroiditis, and normal controls. Incubating the PBMC with anti-CD40 MoAbs and IL-4 increased the soluble CD23 levels in cells from all three groups. An increase in the number of CD23(+) cells was observed in the PBMC from the patients with GD, but not in PBMC from Hashimoto's thyroiditis or controls. Less soluble CD8 was released from anti-CD40 antibody and IL-4-stimulated PBMC obtained from patients with GD relative to those from the controls. In addition, the number of CD8(+) cells was significantly reduced in stimulated PBMC from the GD patients relative to those from controls. Incubation of PBMC with anti-CD40 antibody plus IL-4 did not affect the proportions of CD4(+), CD20(+), Fas(+)CD4(+), and Fas(+)CD8(+) cells. The addition of T-3 to cultured PBMC from controls did not reproduce the changes in CD23(+) and CD8(+) cells noted in the samples from GD patients. Thus, T cell-dependent B cell activation, mediated by a CD40 pathway, may reduce the number of CD8(+) cells, causing exacerbation of GD.
  • T Mano, K Iwase, R Hayashi, N Hayakawa, K Uchimura, M Makino, M Nagata, Y Sawai, N Oda, M Hamada, T Aono, A Nakai, A Nagasaka, M Itoh
    AMERICAN JOURNAL OF THE MEDICAL SCIENCES, 315(4) 230-232, Apr, 1998  
    To clarify the different roles of free radical scavenging systems in various thyroid disorders, we measured the levels of alpha-, beta-, and gamma-tocopherols and coenzyme Q in the thyroid tissues of patients with thyroid tumors and Graves' disease using high-performance liquid chromatography. The levels of alpha-tocopherols and gamma-tocopherols in the thyroid tissue of patients with papillary carcinoma and the level of gamma-tocopherol in the thyroid tissue of patients with malignant lymphoma were elevated compared with those in normal thyroid tissues. The level of coenzyme Q was reduced in the thyroid tissue of patients with Graves' disease and follicular and papillary thyroid carcinomas. These findings imply that vitamin E and coenzyme Q as scavengers play some role in thyroid follicular cell hyperfunction or dysfunction.
  • T Mano, H Sakamoto, K Fujita, M Makino, H Kakizawa, M Nagata, M Kotake, M Hamada, K Uchimura, N Hayakawa, R Hayashi, A Nakai, M Itoh, H Kuzuya, A Nagasaka
    THYROID, 8(4) 353-358, Apr, 1998  
    Clinical and experimental data suggest that thyroid hormone affects the actions of catecholamine (CA). However, the serum or tissue levels of CA during thyroid disorders have not been well defined. Accordingly, we investigated the levels of CA and their metabolites in the cardiac muscle, the cerebral cortex, and the plasma of rats with hyperthyroidism and hypothyroidism vel sus euthyroid animals. The Neurochem analyzer system (ESA, Inc., Bedford, MA) was used in such determinations. The cardiac muscles of hyperthyroid rats exhibited a 16% decrease in the levels of 1-dopa, 3-methoxytyramine (3-MT) and homovanillic acid (HVA) as compared with those in euthyroid rats. The levels of norepinephrine (NE) in cardiac muscle of these rats increased significantly (5.2-fold) relative to the levels in euthyroid rats. ME was undetectable in the cardiac muscles of the hypothyroid rats. Epinephrine (E) and dopamine (DA) were nor detected in the cardiac muscles of the rats with either thyroid disorder. Levels of E and 3,4-dihydroxymandelic acid (DOPEG) were detected only in the cerebral cortex of hyperthyroid rats. The cerebral cortex levels of 3-methyoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC), metanephrine (MN), and homovanillic acid (HVA) were all significantly increased in the hyperthyroid versus the euthyroid rats. The cerebral cortex levels of DA, NE, normetanephrine (NMN), and VMA in the hyperthyroid rats all showed a significant decrease. Levels of NE, NMN, and DOPAC in the cerebral cortex increased significantly in the hypothyroid rats. The level of VMA was undetectable in cerebral cortex of such animals. Data from studies on cardiac muscle and cerebral cortex indicate that the changes in CA and CA metabolites are responsible in part for the cardiovascular and the central nervous system symptoms observed in hyperthyroidism and hypothyroidism.
  • R Hayashi, N Hayakawa, M Makino, M Nagata, H Kakizawa, K Uchimura, M Hamada, T Aono, T Fujita, R Shinohara, A Nagasaka, M Itoh
    DIABETES CARE, 21(4) 672-673, Apr, 1998  
  • European Journal of Endocrinology, 139(3) 323-329, 1998  
  • Diabetic Medicine, 15(8) 668-671, 1998  
  • M Itoh, Y Goto, Y Ohta, Y Goto, H Ohashi
    CLINICAL RHEUMATOLOGY, 17(1) 26-30, 1998  
    The relationship between surface expression of the interleukin-2 receptor (n-2R) and release of the soluble form of the receptor (sn-2R alpha or sCD25) was investigated with peripheral blood mononuclear cells (PBMCs) from individuals with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). The spontaneous release of sCD25 was significantly increased in PBMCs from RA patients and decreased in cells from SLE patients, compared with normal controls. However, the extent of sCD25 release from phytohaemaggulutinin (PHA)-stimulated PBMCs did not differ between RA or SLE patients and normal controls. The serum concentration of sCD25 was significantly increased in SLE or RA patients compared with the normal controls. Whereas the surface expression of CD25 by unstimulated PBMCs did not differ among the three groups of subjects, this parameter was significantly reduced for PHA-stimulated PBMCs from RA patients relative to those from normal controls. The surface expression of CD25 showed a positive correlation with sCD25 release for PBMCs from SLE patients under either basal or stimulated conditions. No such relation was apparent for cells from RA patients. The surface expression of LL-2R beta (CD122) under basal or stimulated conditions was significantly reduced in PBMCs from RA or SLE patients, compared with cells from normal controls. Thus, the increased concentration of sCD25 in the serum of individuals with these autoimmune rheumatic diseases may result from two different mechanisms: an increase in the spontaneous release of sCD25 in RA, and reduced clearance of this protein in SLE.
  • A Nakai, Y Sawai, K Miura, N Oda, T Mokuno, K Shimazaki, R Kato, N Hayakawa, M Itoh, Y Kurosawa, A Nagasaka
    CLINICA CHIMICA ACTA, 263(1) 15-23, Jul, 1997  
    We expressed the extracellular domain (20-408 aa, (T)) of human TSH receptor (TSHR) in E. coli to detect TSHR autoantibodies (TRAb) and, moreover, we expressed the two portions (20-218 aa (5') and 217-408 aa (3')) of the extracellular domain thought to distinguish thyroid stimulating antibodies (TSAb) from blocking antibodies (TSBAb), using pGEX.3X as the expression vector. Using Western blotting analysis of the sera from patients with autoimmune thyroid disease, sera from Graves' patients and patients with idiopathic myxedema who had TSBAb reacted with the fusion protein (T), but none of the control sera reacted with it. We further evaluated whether or not the positive sera for T recognized fusion proteins (5') or (3'). The sera from Graves' patients reacted with both fusion proteins (5') and (3'). The sera from patients with idiopathic myxedema did not react with either of fusion proteins (5') or (3'). These findings suggest that these recombinant TSHR proteins could be used as antigens to detect TRAb, and differentiate TSBAb from patients with idiopathic myxedema. (C) 1997 Elsevier Science B.V.
  • THYROID, 7(4) 567-573, 1997  
  • Japanese Journal of Rheumatology, 7(2) 115-121, 1997  
  • T Mokuno, Y Sawai, N Oda, T Mano, N Hayakawa, R Kato, Y Itoh, K Shimazaki, M Kotake, A Nakai, S Hiramitsu, M Itoh, S Morimoto, A Nagasaka
    DIABETES CARE, 19(4) 375-378, Apr, 1996  
    We report a case of diabetic ketoacidosis (DKA) complicated by acute myocarditis, which was confirmed by cardiac biopsy. ii 26-year-old man was hospitalized with severe DKA. On admission, nonspecific ST-T change was noted on the electrocardiogram (EGG). The patient's levels of creatine phosphokinase (CPK) and glutamic oxaloacetic transaminase were slightly elevated, but he did not complain of chest discomfort or symptoms of heart disease. On the first day after admission, ST-T elevation was noted on ECG during treatment of DKA. By cardiac angiography and cardiac biopsy, coronary heart disease was ruled out and postmyocarditic change was histologically confirmed. An episode of upper respiratory viral infection before the onset of acute diabetes suggested that the patient suffered from viral-induced myocarditis and consequent development of IDDM. This possibility was confirmed by the clinical course of ECG change, with elevated CPK and lactate dehydrogenase and a slightly elevated antibody titer for echovirus.
  • Hormone and Metabolic Research, 28(10) 565-569, 1996  
  • Journal of Autoimmunity, 9(4) 545-550, 1996  
  • M Hakamata, M Itoh, Y Sudo, E Katada, N Miyata
    EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES, 104(1) 85-88, 1996  
    A 56-year-old female with Graves' disease who presented with decreased secretion of gonadotropins is described. She was admitted to hospital because of her being in a state of confusion. One month before admission she had been diagnosed as having Graves' disease and was treated with methimazole since then. Plasma LH and FSH levels were undetectable, and their responses to LH-RH were extremely decreased in spite of undetectable levels of plasma estradiol and estriol. One year after treatment, both basal and stimulated values of LH and FSH reverted to normal as did those of TSH. Reversible suppression of gonadotropins as described herein has never been reported in cases of Graves' disease.
  • N ODA, A NAKAI, T MOKUNO, Y SAWAI, Y NISHIDA, T MANO, K ASANO, Y ITOH, M KOTAKE, S KATO, R MASUNAGA, K IWASE, T TSUJIMURA, M ITOH, T KAWABE, A NAGASAKA
    EUROPEAN JOURNAL OF ENDOCRINOLOGY, 133(1) 121-126, Jul, 1995  
    To clarify the effect of glucocorticoid on glucose transporters (GLUT) in adipocytes and muscle, we examined the changes of GLUT4 in rat heart muscle, skeletal muscle and adipocytes during long-term administration of dexamethasone and the translocation of GLUT4. The levels of GLUT4 in the plasma membrane and the low-density microsome fraction were measured by Western blotting using anti-GLUT4 peptide antibody. The levels of GLUT4 in the heart and skeletal muscles of rat were unchanged by treatment of dexamethasone. In the adipocytes the level of GLUT4 in plasma membrane was changed, but it was decreased in the low-density microsome fraction. Although adipocytes are less involved in blood sugar regulation than skeletal muscle, this finding suggests that glucose metabolism in Cushing's syndrome is affected partly by a decrease of GLUT4 in the adipocytes.
  • T OKUGAWA, M ITOH, Y MURATA, H SEO
    EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES, 103(2) 88-93, 1995  
    To investigate whether partial inhibition of DNA synthesis affects the growth of thyroid cells, human thyroid cells were cultured in the presence of aphidicolin for 24 h. After removal of aphidicolin, the growth of thyroid cells was evaluated by [H-3] thymidine uptake and analysis of cell cycle by flow cytometry. In Graves' thyroid cells, [H-3] thymidine uptake and the percentage of cells in S+G(2)/M phase increased during 24 hours after washout of aphidicolin, whereas those were not augmented in normal thyroid cells. Thus, the acceleration of DNA synthesis occurred after the partial inhibition of it by aphidicolin in Graves' thyroid cells, but not in the normal thyroid cells. This phenomenon might, at least in part, explain the difference of growth regulation between Graves' and normal thyroid cells.

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