Institute of Bio Response Informatics

Kyoto, Japan

Institute of Bio Response Informatics

Kyoto, Japan
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Kadoya M.,Kyoto Prefectural University of Medicine | Yamamoto A.,Kyoto Prefectural University of Medicine | Hamaguchi M.,Kyoto Prefectural University of Medicine | Obayashi H.,Institute of Bio Response Informatics | And 7 more authors.
Biochemical and Biophysical Research Communications | Year: 2014

Allograft inflammatory factor-1 (AIF-1) is expressed by macrophages, fibroblasts, endothelial cells and smooth muscle cells in immune-inflammatory disorders such as systemic sclerosis, rheumatoid arthritis and several vasculopathies. However, its molecular function is not fully understood. In this study, we examined gene expression profiles and induction of chemokines in monocytes treated with recombinant human AIF (rhAIF-1). Using the high-density oligonucleotide microarray technique, we compared mRNA expression profiles of rhAIF-1-stimulated CD14+ peripheral blood mononuclear cells (CD14+ PBMCs) derived from healthy volunteers. We demonstrated upregulation of genes for several CC chemokines such as CCL1, CCL2, CCL3, CCL7, and CCL20. Next, using ELISAs, we confirmed that rhAIF-1 promoted the secretion of CCL3/MIP-1α and IL-6 by CD14+ PBMCs, whereas only small amounts of CCL1, CCL2/MCP-1, CCL7/MCP-3 and CCL20/MIP-3α were secreted. Conditioned media from rhAIF-1stimulated CD14+ PBMCs resulted in migration of PBMCs. These findings suggest that AIF-1, which induced chemokines and enhanced chemotaxis of monocytes, may represent a molecular target for the therapy of immune-inflammatory disorders. © 2014 Elsevier Inc. All rights reserved.


Imai S.,Osaka Prefecture University | Matsuda M.,Kajiyama Clinic | Hasegawa G.,Kyoto Prefectural University of Medicine | Fukui M.,Kyoto Prefectural University of Medicine | And 4 more authors.
Asia Pacific Journal of Clinical Nutrition | Year: 2011

This study aimed to determine whether educating diabetic patients to 'eat vegetables before carbohydrate' was as effective on long-term glycemic control as a traditional exchange-based meal plan. To test this hypothesis, we carried out a randomized, controlled trial in patients with type 2 diabetes that compared changes in HbA1c as the primary outcome. A total of 101 patients were stratified according to sex, age, BMI, duration of diabetes, and HbA1c, and then randomized to receive instructions to eat either vegetables before carbohydrate (VBC, n=69) or an exchange-based meal plan (EXB, n=32). The impact of the two plans on glycemic control was compared over 24 months of follow-up. Significant improvements in HbA1c over 24 months were observed in both groups (VBC, 8.3 to 6.8% vs EXB, 8.2 to 7.3%). HbA1c levels were significantly lower in the VBC group than in the EXB group after 6, 9, 12 and 24 months of the study. Both groups exhibited similar improvements in dietary practices with respect to intake of carbohydrate, fats and sweets, while the VBC group had a significant increase in consumption of green vegetables and a significant decrease in fruit consumption. A simple meal plan of 'eating vegetables before carbohydrate' achieved better glycemic control than an exchange-based meal plan in Japanese patients with type 2 diabetes over a 24-month period.


Hasegawa G.,Kyoto Prefectural University of Medicine | Yamasaki M.,Kyoto Prefectural University of Medicine | Kadono M.,Kyoto Prefectural University of Medicine | Tanaka M.,Kyoto Prefectural University of Medicine | And 8 more authors.
Endocrinology | Year: 2010

Senescence marker protein-30 (SMP30) is an androgen-independent factor that decreases with age. We recently identified SMP30 as the lactone-hydrolyzing enzyme gluconolactonase (GNL), which is involved in vitamin C biosynthesis in animal species. To examine whether the age-related decrease in SMP30/GNL has effects on glucose homeostasis, we used SMP30/GNL knockout (KO) mice treated with L-ascorbic acid. In an ip glucose tolerance test at 15 wk of age, blood glucose levels in SMP30/GNL KO mice were significantly increased by 25% at 30 min after glucose administration compared with wildtype( WT)mice.Insulin levels inSMP30/GNLKOmiceweresignificantlydecreasedby37%at30minafter glucose compared with WT mice. Interestingly, an insulin tolerance test showed a greater glucoselowering effect in SMP30/GNL KO mice. High-fat diet feeding severely worsened glucose tolerance in both WT and SMP30/GNL KO mice. Morphometric analysis revealed no differences in the degree of high-fat diet-induced compensatory increase in β-cell mass and proliferation. In the static incubation study of islets, insulin secretion in response to 20 mM glucose or KCl was significantly decreased in SMP30/GNLKOmice.Onthe other hand, islet ATP content at 20mMin SMP30/GNLKOmice was similar to that in WT mice. Collectively, these data indicate that impairment of the early phase of insulin secretion due to dysfunction of the distal portion of the secretion pathway underlies glucose intolerance in SMP30/GNL KO mice. Decreased SMP30/GNL may contribute to the worsening of glucose tolerance that occurs in normal aging. Copyright © 2010 by The Endocrine Society.


Okada H.,Kyoto Prefectural University of Medicine | Senmaru T.,Kyoto Prefectural University of Medicine | Fukui M.,Kyoto Prefectural University of Medicine | Kondo Y.,Tokyo Metropolitan University | And 6 more authors.
Journal of Diabetes Investigation | Year: 2015

Aims/Introduction: Senescence marker protein-30 (SMP30) is abundantly expressed in renal proximal tubule cells, but its expression decreases with age. Previous studies have shown that reduced SMP30 expression could contribute to aging-associated deterioration of cellular function and tissue injury. In the present study, we investigated the effects of SMP30 deficiency on the pathogenesis of diabetic nephropathy. Materials and Methods: Diabetes was induced using streptozotocin in male SMP30 knockout mice (KO) and wild-type mice at 7 weeks-of-age. Vitamin C was added to the drinking water to prevent vitamin C deficiency in KO mice. The mice were killed 12 weeks after the induction of diabetes. Results: Urinary biomarkers for proximal tubule damage were significantly increased in non-diabetic KO mice compared with wild-type mice. Furthermore, diabetes-induced tubular damage was significantly exacerbated by SMP30 deletion. Morphological analysis showed a link between cortical tubulointerstitial fibrosis area and the degree of tubular damage. However, SMP30 deletion did not affect mesangial expansion. Tubular injury was associated with accumulation of hypoxia-inducible factor-1α and increased hypoxia-inducible factor-1α targeted gene expression. SMP30 deletion initiated oxidative stress; however, it did not exacerbate the oxidative stress seen in diabetic mice. In contrast, tubular inflammation was associated with SMP30 deletion only in diabetic mice. Conclusions: Based on this evidence, we concluded that SMP30 deficiency exacerbates proximal tubule injury in diabetic mice. Decreased SMP30 could contribute to the increased incidence of various chronic kidney diseases, including diabetic nephropathy, with age. Decreased SMP30 may contribute to the increased incidence of various chronic kidney diseases, including diabetic nephropathy, with age. © 2014 The Authors. Journal of Diabetes Investigation published by Asian Association of the Study of Diabetes (AASD) and Wiley Publishing Asia Pty Ltd.


Mitsuhashi K.,Kyoto Prefectural University of Medicine | Senmaru T.,Kyoto Prefectural University of Medicine | Fukuda T.,Kyoto Prefectural University of Medicine | Yamazaki M.,Kyoto Prefectural University of Medicine | And 9 more authors.
Endocrine | Year: 2016

Decreases in serum testosterone concentrations in aging men are associated with metabolic disorders. Testosterone has been reported to increase GLUT4-dependent glucose uptake in skeletal muscle cells and cardiomyocytes. However, studies on glucose uptake occurring in response to testosterone stimulation in adipocytes are currently not available. This study was designed to determine the effects of testosterone on glucose uptake in adipocytes. Glucose uptake was assessed with 2-[3H] deoxyglucose in 3T3-L1 adipocytes. GLUT4 translocation was evaluated in plasma membrane (PM) sheets and PM fractions by immunofluorescence and immunoblotting, respectively. Activation of GLUT4 translocation-related protein kinases, including Akt, AMPK, LKB1, CaMKI, CaMKII, and Cbl was followed by immunoblotting. Expression levels of androgen receptor (AR) mRNA and AR translocation to the PM were assessed by real-time RT-PCR and immunoblotting, respectively. The results showed that both high-dose (100 nM) testosterone and testosterone-BSA increased glucose uptake and GLUT4 translocation to the PM, independently of the intracellular AR. Testosterone and testosterone-BSA stimulated the phosphorylation of AMPK, LKB1, and CaMKII. The knockdown of LKB1 by siRNA attenuated testosterone- and testosterone-BSA-stimulated AMPK phosphorylation and glucose uptake. These results indicate that high-dose testosterone and testosterone-BSA increase GLUT4-dependent glucose uptake in 3T3-L1 adipocytes by inducing the LKB1/AMPK signaling pathway. © 2015, Springer Science+Business Media New York.


Yamamoto A.,Kyoto Prefectural University of Medicine | Ashihara E.,Kyoto University | Nakagawa Y.,Kyoto University | Obayashi H.,Institute of Bio Response Informatics | And 10 more authors.
Immunology Letters | Year: 2011

Allograft inflammatory factor (AIF)-1 has been identified in chronic rejection of rat cardiac allografts and is thought to be involved in the immune response. We previously showed that AIF-1 was strongly expressed in synovial tissues in rheumatoid arthritis and that rAIF-1 increased the IL-6 production of synoviocytes and peripheral blood mononuclear cells. Recently, the expression of AIF-1 has been reported in systemic sclerosis (SSc) tissues, whose clinical features and histopathology are similar to those of chronic graft-vs-host disease (GVHD). To clarify the pathogenic mechanism of fibrosis, we examined the expression and function of AIF in sclerodermatous (Scl) GVHD mice. We demonstrated that immunoreactive AIF-1 and IL-6 were significantly expressed in infiltrating mononuclear cells and fibroblasts in thickened skin of Scl GVHD mice compared with control. The immunohistochemical findings were confirmed by Western blot analysis. Wound healing assay also revealed that rAIF-1 increased the migration of normal human dermal fibroblasts (NHDF) directly, but cell growth assay did not show that rAIF-1 increased the proliferation of them. These findings suggest that AIF-1, which can induce the migration of fibroblasts and the production of IL-6 in affected skin tissues, is an important molecule promoting fibrosis in GVHD. Although the biological function of AIF-1 has not been completely elucidated, AIF-1 can induce IL-6 secretion on mononuclear cells and fibroblast chemotaxis. AIF-1 may accordingly provide an attractive new target for antifibrotic therapy in SSc as well as Scl GVHD. © 2010 Elsevier B.V.


Senmaru T.,Kyoto Prefectural University of Medicine | Fukui M.,Kyoto Prefectural University of Medicine | Okada H.,Kyoto Prefectural University of Medicine | Mineoka Y.,Kyoto Prefectural University of Medicine | And 7 more authors.
Metabolism: Clinical and Experimental | Year: 2013

Objective Although low serum testosterone (T) is associated with metabolic disorders, the mechanism of this association is unclear. The objective of the present study was to investigate the combined effects of T deficiency and a high-fat diet (HFD) on hepatic lipid homeostasis in mice. Materials/Methods Orchiectomized (ORX) mice and sham-operated (SHAM) mice were randomly divided into five groups: SHAM mice fed a standard diet (SD), SHAM mice fed HFD, ORX mice fed SD, ORX mice fed HFD, and ORX mice fed HFD with T supplementation. After 4 weeks of treatment, we investigated the synthesis and secretion of lipids in the liver and detailed serum lipoprotein profiles in each group. Results ORX mice fed HFD showed increased hepatic steatosis, markedly decreased serum triglyceride (TG) and TG-VLDL content, and increased serum very small-LDL content. Gene expression analysis revealed that ORX mice fed HFD showed significantly decreased expression of microsomal triglyceride transfer protein, lipin-1, peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ coactivator 1-α, and significantly increased sterol regulatory element-binding protein-1, diacylglycerol acyltransferase-2 and fatty acid synthase. Reduction of hepatic AMPK phosphorylation was observed in ORX mice fed HFD. These perturbations in ORX mice fed HFD were normalized to the levels of SHAM mice fed HFD by T supplementation. Conclusion T deficiency is associated with failure of lipid homeostasis mediated by altered expression of genes involved in hepatic assembly and secretion of lipids. © 2013 Elsevier Inc.


Park H.,Saiseikai Suita Hospital | Park H.,Kyoto Prefectural University of Medicine | Shima T.,Saiseikai Suita Hospital | Yamaguchi K.,Kyoto Prefectural University of Medicine | And 12 more authors.
Journal of Gastroenterology | Year: 2011

Background: Hyperlipidemia, insulin resistance, and oxidative stress can heavily contribute to the initiation and progression of nonalcoholic fatty liver disease (NAFLD). Currently, there is no established treatment for this disease. Recently, several studies have shown that ezetimibe (EZ), a lipid-lowering drug, attenuates liver steatosis in an experimental NAFLD model. This study was designed to assess the efficacy of long-term EZ monotherapy in patients with NAFLD. Methods: A total of 45 patients with newly diagnosed liver biopsy-proven NAFLD were treated with EZ (10 mg/day) for 24 months. NAFLD-related biochemical parameters, imaging by computerized tomography, and liver biopsy were studied before and after treatment. Results: Ezetimibe therapy significantly improved NAFLD-related metabolic parameters including visceral fat area, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-R), triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-Ch), oxidative-LDL, the net electronegative charge modified-LDL, profiles of lipoprotein particle size and fatty acids component, and estimated desaturase activity. EZ therapy also significantly lowered serum alanine aminotransferase and high-sensitivity C-reactive protein levels, whereas no significant changes were found in serum type IV collagen 7S, adiponectin, leptin, and resistin levels. Histological features of steatosis grade (P = 0.0003), necroinflammatory grade (P = 0.0456), ballooning score (P = 0.0253), and NAFLD activity score (NAS) (P = 0.0007) were significantly improved from baseline. However, the fibrosis stage was not significantly (P = 0.6547) changed. Conclusion: The results in this study suggest that the long-term EZ therapy can lead to improvement in metabolic, biochemical, and histological abnormalities of NAFLD. Therefore, EZ may be a promising agent for treatment of NAFLD. © 2010 Springer.


PubMed | Institute of Bio Response Informatics and Kyoto Prefectural University of Medicine
Type: Journal Article | Journal: Endocrine | Year: 2016

Decreases in serum testosterone concentrations in aging men are associated with metabolic disorders. Testosterone has been reported to increase GLUT4-dependent glucose uptake in skeletal muscle cells and cardiomyocytes. However, studies on glucose uptake occurring in response to testosterone stimulation in adipocytes are currently not available. This study was designed to determine the effects of testosterone on glucose uptake in adipocytes. Glucose uptake was assessed with 2-[(3)H] deoxyglucose in 3T3-L1 adipocytes. GLUT4 translocation was evaluated in plasma membrane (PM) sheets and PM fractions by immunofluorescence and immunoblotting, respectively. Activation of GLUT4 translocation-related protein kinases, including Akt, AMPK, LKB1, CaMKI, CaMKII, and Cbl was followed by immunoblotting. Expression levels of androgen receptor (AR) mRNA and AR translocation to the PM were assessed by real-time RT-PCR and immunoblotting, respectively. The results showed that both high-dose (100nM) testosterone and testosterone-BSA increased glucose uptake and GLUT4 translocation to the PM, independently of the intracellular AR. Testosterone and testosterone-BSA stimulated the phosphorylation of AMPK, LKB1, and CaMKII. The knockdown of LKB1 by siRNA attenuated testosterone- and testosterone-BSA-stimulated AMPK phosphorylation and glucose uptake. These results indicate that high-dose testosterone and testosterone-BSA increase GLUT4-dependent glucose uptake in 3T3-L1 adipocytes by inducing the LKB1/AMPK signaling pathway.


PubMed | Japan Bio Science Laboratory, Kobe Pharmaceutical University, Tokyo Metropolitan University, Institute of Bio Response Informatics and 2 more.
Type: Journal Article | Journal: Nutrition research (New York, N.Y.) | Year: 2015

4-Hydroxyderricin (4HD) and xanthoangelol (XAG) are major components of n-hexane/ethyl acetate (5:1) extract of the yellow-colored stem juice of Angelica keiskei. 4-Hydroxyderricin and XAG have been reported to increase glucose transporter 4 (GLUT4)-dependent glucose uptake in 3T3-L1 adipocytes, but the detailed mechanism of this phenomenon remains unknown. This present study was aimed at clarifying the detailed mechanism by which 4HD and XAG increase GLUT4-dependent glucose uptake in 3T3-L1 adipocytes. Both 4HD and XAG increased glucose uptake and GLUT4 translocation to the plasma membrane. 4-Hydroxyderricin and XAG also stimulated the phosphorylation of 5 adenosine monophosphate-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase. In addition, phosphorylation of liver kinase B1 (LKB1), which acts upstream of AMPK, was also increased by 4HD and XAG treatment. Small interfering RNA knockdown of LKB1 attenuated 4HD- and XAG-stimulated AMPK phosphorylation and suppressed glucose uptake. These findings demonstrate that 4HD and XAG can increase GLUT4-dependent glucose uptake through the LKB1/AMPK signaling pathway in 3T3-L1 adipocytes.

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