Sho-Ichi Yamagishi

Publications (243)805.68 Total impact

• Article: Telmisartan inhibits AGE-induced podocyte damage and detachment.

  Kei Fukami, Sho-Ichi Yamagishi, Kumiko Kaifu, Takanori Matsui, Yusuke Kaida, Seiji Ueda, Masayoshi Takeuchi, Katsuhiko Asanuma, Seiya Okuda
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  ABSTRACT: Advanced glycation end products (AGE) formed at an accelerated rate under diabetes, could cause podocyte apoptosis, thereby being involved in the development and progression of diabetic nephropathy. Renin-angiotensin system (RAS) plays a role in diabetic nephropathy as well. However, it remains unknown whether there exists a pathophysiological crosstalk between the RAS and AGE in podocyte damage in diabetic nephropathy. Therefore, this study investigated the effects of telmisartan, an angiotensin II (Ang II) type 1 receptor (AT1R) blocker on AGE or Ang II-induced podocyte damage in vitro. We further examined here the effects of AGE on AT1R expression levels in podocytes. AGE or Ang II not only increased DNA damage of podocytes which was evaluated by comet assay, but also induced cell detachment, both of which were significantly blocked by the treatment with telmisartan. AGE significantly increased AT1R levels in podocytes, whereas podocyte Ang II production was modestly stimulated by AGE. Telmisartan alone did not affect the release of lactate dehydrogenase from podocytes. Our present study suggests that AGE could induce podocyte DNA damage and detachment partly via stimulation of the Ang II-AT1R axis, thus providing a novel beneficial aspect of telmisartan in diabetic nephropathy.
  Microvascular Research 05/2013; · 2.83 Impact Factor
• Article: DNA aptamer raised against AGEs blocks the progression of experimental diabetic nephropathy.

  Yusuke Kaida, Kei Fukami, Takanori Matsui, Yuichiro Higashimoto, Yuri Nishino, Nana Obara, Yosuke Nakayama, Ryotaro Ando, Maki Toyonaga, Seiji Ueda, Masayoshi Takeuchi, Hiroyoshi Inoue, Seiya Okuda, Sho-Ichi Yamagishi
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  ABSTRACT: Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. We screened DNA aptamer directed against AGEs (AGEs-aptamer) in vitro, and examined its effects on renal injury in KKAy/Ta mice, an animal model of type 2 diabetes. Eight week-old male KKAy/Ta or C57BL/6J mice received continuous intraperitoneal infusion of AGEs- or control-aptamer for 8 weeks. AGEs-aptamer was detected and its level was increased in the kidney for at least 7 days. The elimination half-lives of AGEs-aptamer in the kidney were about 7 days. Compared with C57BL/6J mice, glomerular AGEs levels were significantly increased in KKAy/Ta mice, which were blocked by AGEs-aptamer. Urinary albumin and 8-hydroxy-2'-deoxy-guanosine levels were increased, and glomerular hypertrophy and enhanced extracellular matrix accumulation were observed in KKAy/Ta mice, all of which were prevented by AGEs-aptamer. Moreover, AGEs-aptamer significantly reduced gene expression of RAGE, monocyte chemoattractant protein-1, connective tissue growth factor or type-IV collagen both in the kidney of KKAy/Ta mice and in AGEs-exposed human cultured mesangial cells. Our present data suggest that continuous administration of AGEs-aptamer could protect against experimental diabetic nephropathy by blocking the AGEs-RAGE axis and may be a feasible and promising therapeutic strategy for the treatment of diabetic nephropathy.
  Diabetes 04/2013; · 8.29 Impact Factor
• Article: Sodium-glucose cotransporter 2-mediated oxidative stress augments advanced glycation end products (AGEs)-induced tubular cell apoptosis.

  Sayaka Maeda, Takanori Matsui, Masayoshi Takeuchi, Sho-Ichi Yamagishi
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  ABSTRACT: BACKGROUNDS: Ninety percent of glucose filtered by the glomerulus is reabsorbed by a sodium-glucose cotransporter 2 (SGLT2), which is expressed mainly on the apical membrane of renal proximal tubules. Since blockade of SGLT2 promotes urinary glucose excretion and resultantly improves hyperglycemia, selective inhibition of SGLT2 has been proposed as a potential therapeutic target for the treatment of patients with diabetes. Moreover, advanced glycation end products (AGEs)-receptor (RAGE) system induces apoptosis of tubular cells, thereby playing a role in diabetic nephropathy as well. However, the pathophysiological crosstalk of SGLT2 with AGEs-RAGE axis and its role in diabetic nephropathy remains unknown. METHODS: This study investigated whether and how blockade of SGLT2 could prevent AGEs-elicited apoptosis of high glucose-exposed proximal tubular cells in vitro. RESULTS: SGLT2 was expressed in tubular cells. Tubular SGLT2 expression and glucose entry into the cells were completely blocked by the treatment with small interfering RNAs (siRNAs) raised against SGLT2. High glucose increased reactive oxygen species generation and RAGE expression levels in tubular cells, both of which were partly suppressed by SGLT2 siRNAs or an anti-oxidant, N-acetylcysteine. Further, high glucose was found to augment the AGEs-induced tubular cell apoptosis, which was also inhibited by SGLT2 siRNAs. CONCLUSIONS: Our present data suggest that SGLT2-mediated, high glucose-induced ROS generation could augment the AGEs-induced apoptotic cell death of tubular cells via RAGE induction. SGLT2 may play some role in tubular apoptosis in diabetic nephropathy. Copyright © 2013 John Wiley & Sons, Ltd.
  Diabetes/Metabolism Research and Reviews 03/2013; · 3.37 Impact Factor
• Article: Evidence for a positive association between serum carnitine and free testosterone levels in uremic men with hemodialysis.

  Kazuko Sakai, Kei Fukami, Sho-Ichi Yamagishi, Yusuke Kaida, Takeki Adachi, Ryotaro Ando, Rie Manabe, Aki Otsuka, Kenzo Sugi, Seiji Ueda, Seiya Okuda
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  ABSTRACT: Background and Aims: Low free testosterone levels are associated with sexual dysfunction and an increased risk of cardiovascular disease in male hemodialysis patients. Carnitine deficiency is frequently observed in hemodialysis patients as well. However, relationship between carnitine and testosterone levels remains unknown. In this study, we examined whether carnitine deficiency was independently associated with low free testosterone levels in male hemodialysis patients. Methods: Nineteen male hemodialysis patients underwent determinations of blood chemistries, including serum levels of free testosterone, carnitine and pentosidine, one of the well-characterized advanced glycation end products. Results: Mean free testosterone levels in hemodialysis patients were significantly lower than those in healthy controls (4.67 ± 2.69 vs 9.50 ± 3.67 pg/ml, p<0.001). Univariate analysis revealed that carnitine (p=0.023), pentosidine (inversely, p=0.027), blood glucose (inversely, p=0.032), creatinine (p=0.026) levels and statin use (inversely, p=0.034) were correlated with free testosterone values. Multiple stepwise regression analysis revealed that carnitine (p=0.001) and statin use (inversely, p=0.002) were the independent determinants of age-adjusted free testosterone levels in hemodialysis patients (r2=0.612). Conclusions: The present study gives the first evidence that decreased carnitine levels were independently associated with low free testosterone values in male hemodialysis patients. Our study suggests that decreased carnitine levels may be a novel therapeutic target for uremic men with hemodialysis.
  Rejuvenation Research 03/2013; · 3.83 Impact Factor
• Article: Pigment epithelium-derived factor (PEDF) inhibits survival and proliferation of VEGF-exposed multiple myeloma cells through its anti-oxidative properties.

  Ritsuko Seki, Sho-Ichi Yamagishi, Takanori Matsui, Takafumi Yoshida, Takuji Torimura, Takato Ueno, Michio Sata, Takashi Okamura
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  ABSTRACT: Vascular endothelial growth factor (VEGF) has been reported not only to induce angiogenesis within the bone marrow, but also directly stimulate the proliferation and survival of multiple myeloma cells, thus being involved in the development and progression of this second most common hematological malignancy. We, along with others, have found that pigment epithelium-derived factor (PEDF) has anti-angiogenic and anti-vasopermeability properties both in cell culture and animal models by counteracting the biological actions of VEGF. However, effects of PEDF on VEGF-exposed myeloma cells remain unknown. In this study, we examined whether and how PEDF could inhibit the VEGF-induced proliferation and survival of myeloma cells. PEDF, a glutathione peroxidase mimetic, ebselen, or an inhibitor of NADPH oxidase, diphenylene iodonium significantly inhibited the VEGF-induced reactive oxygen species (ROS) generation, increase in anti-apoptotic and growth-promoting factor, myeloid cell leukemia 1 (Mcl-1) expression, and proliferation in U266 myeloma cells. VEGF blocked apoptosis of multiple myeloma cells isolated from patients, which was prevented by PEDF. PEDF also reduced p22phox levels in VEGF-exposed U266 cells. Furthermore, overexpression of dominant-negative human Rac-1 mutant mimicked the effects of PEDF on ROS generation and Mcl-1 expression in U266 cells. Our present study suggests that PEDF could block the VEGF-induced proliferation and survival of multiple myeloma U266 cells through its anti-oxidative properties via suppression of p22phox, one of the membrane components of NADPH oxidase. Suppression of VEGF signaling by PEDF may be a novel therapeutic target for multiple myeloma.
  Biochemical and Biophysical Research Communications 01/2013; · 2.48 Impact Factor
• Article: Serum levels of advanced glycation end products (AGEs) are independently correlated with circulating levels of dipeptidyl peptidase-4 (DPP-4) in humans.

  Nobuhiro Tahara, Sho-Ichi Yamagishi, Masayoshi Takeuchi, Atsuko Tahara, Kumiko Kaifu, Seiji Ueda, Seiya Okuda, Tsutomu Imaizumi
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  ABSTRACT: OBJECTIVES: Inhibition of dipeptidyl peptidase-4 (DPP-4) has been proposed as a potential therapeutic target for type 2 diabetes. Although soluble DPP-4 has been identified in human serum and could be associated with DPP-4 activity, the kinetics and regulation of circulating DPP-4 levels remain unknown. In this study, we examined which anthropometric and metabolic variables, including serum levels of advanced glycation end products (AGEs), were independently associated with serum DPP-4 levels. Further, we investigated the effects of AGEs on DPP-4 expression in, and soluble DPP-4 release from human cultured proximal tubular epithelial cells. DESIGN AND METHODS: The study involved 432 consecutive outpatients (301 male and 131 female; mean ages 61.8±8.8) who underwent complete history and physical examinations, and determinations of blood chemistry and anthropometric variables. Serum DPP-4 and AGE levels were examined by enzyme-linked immunosorbent assay. Protein expression levels of DPP-4 and its release from the cells were analyzed with western blot analysis. RESULTS: Mean serum levels of DPP-4 and AGEs were 520.2±39.9 ng/mL and 8.96±2.57 U/mL, respectively. In multiple regression analysis, female (p<0.001), HDL-cholesterol (p<0.001), glycated hemoglobin (p<0.001), AGEs (p<0.03), and the absence of hypertension medication (p<0.05) are independently associated with DPP-4 levels (R(2)=0.167). Western blot analysis revealed that AGEs significantly increased DPP-4 expression in, and soluble DPP-4 release from tubular cells. CONCLUSIONS: The present study reveals that serum levels of DPP-4 are independently associated with various metabolic parameters in a general population. AGEs may up-regulate cellular DPP-4 expression and subsequently increase circulating levels of DPP-4 in humans.
  Clinical biochemistry 12/2012; · 2.02 Impact Factor
• Article: Asymmetrical dimethylarginine level is independently associated with circulating levels of RAGE and PEDF.

  Nobuhiro Tahara, Sho-Ichi Yamagishi, Atsuko Tahara, Masayoshi Takeuchi, Tsutomu Imaizumi
  International journal of cardiology 12/2012; · 7.08 Impact Factor
• Article: Serum asymmetric dimethylarginine levels are independently associated with procollagen III N-terminal peptide in nonalcoholic fatty liver disease patients.

  Hideyuki Hyogo, Sho-Ichi Yamagishi, Sayaka Maeda, Kei Fukami, Seiji Ueda, Seiya Okuda, Takashi Nakahara, Yuki Kimura, Tomokazu Ishitobi, Kazuaki Chayama
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  ABSTRACT: Although impaired synthesis and/or bioavailability of nitric oxide are considered to contribute to insulin resistance and the progression of liver disease in nonalcoholic fatty liver disease, role of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, has not been examined. We examined retrospectively which anthropometric and metabolic parameters were independently associated with serum levels of asymmetric dimethylarginine in nonalcoholic fatty liver disease. A total of 194 consecutive biopsy-proven nonalcoholic fatty liver disease patients with or without type 2 diabetes were enrolled. Serum asymmetric dimethylarginine levels in nonalcoholic fatty liver disease patients were significantly higher, irrespective of the presence or absence of diabetes, than those in healthy control. Multiple stepwise regression analysis showed that decreased total protein and procollagen N-terminal peptide levels, markers of advanced liver disease and hepatic fibrosis, respectively, were independently associated with asymmetric dimethylarginine levels in nonalcoholic fatty liver disease subjects without diabetes, whereas soluble form of receptor for advanced glycation end products and density ratio of liver to spleen in computed tomography were independent correlates of asymmetric dimethylarginine in diabetic patients. The present study suggests that asymmetric dimethylarginine may be associated with nonalcoholic fatty liver disease, especially subjects without diabetes.
  Clinical and Experimental Medicine 11/2012; · 1.58 Impact Factor
• Article: Glucagon-like Peptide-1 Receptor Agonist Inhibits Asymmetric Dimethylarginine Generation in the Kidney of Streptozotocin-Induced Diabetic Rats by Blocking Advanced Glycation End Product-Induced Protein Arginine Methyltranferase-1 Expression.

  Ayako Ojima, Yuji Ishibashi, Takanori Matsui, Sayaka Maeda, Yuri Nishino, Masayoshi Takeuchi, Kei Fukami, Sho-Ichi Yamagishi
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  ABSTRACT: Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, contributes to diabetic nephropathy. We have found that glucagon-like peptide-1 (GLP-1) inhibits the AGE-induced inflammatory reactions in endothelial cells. However, effects of GLP-1 on the AGE-RAGE-ADMA axis are unknown. This study examined the effects of GLP-1 on reactive oxygen species (ROS) generation, gene expression of protein arginine methyltransfetase-1 (PRMT-1), an enzyme that mainly generates ADMA, and ADMA levels in human proximal tubular cells. Streptozotocin-induced diabetic rats received continuous i.p. infusion of 0.3 μg of vehicle or 1.5 μg of the GLP-1 analog exendin-4 per kilogram of body weight for 2 weeks. We further investigated whether and how exendin-4 treatment reduced ADMA levels and renal damage in streptozotocin-induced diabetic rats. GLP-1 inhibited the AGE-induced RAGE and PRMT-1 gene expression, ROS, and ADMA generation in tubular cells, which were blocked by small-interfering RNAs raised against GLP-1 receptor. Exendin-4 treatment decreased gene expression of RAGE, PRMT-1, ICAM-1, and MCP-1 and ADMA level; reduced urinary excretions of 8-hydroxy-2'-deoxyguanosine and albumin; and improved histopathologic changes of the kidney in diabetic rats. Our present study suggests that GLP-1 receptor agonist may inhibit the AGE-RAGE-mediated ADMA generation by suppressing PRMT-1 expression via inhibition of ROS generation, thereby protecting against the development and progression of diabetic nephropathy.
  American Journal Of Pathology 11/2012; · 4.89 Impact Factor
• Article: PEDF inhibits AGE-induced podocyte apoptosis via PPAR-gamma activation.

  Yuji Ishibashi, Takanori Matsui, Keisuke Ohta, Ryuichiro Tanoue, Masayoshi Takeuchi, Katsuhiko Asanuma, Kei Fukami, Seiya Okuda, Kei-Ichiro Nakamura, Sho-Ichi Yamagishi
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  ABSTRACT: Advanced glycation end products (AGEs) formed at an accelerated rate under diabetes, elicit oxidative and pro-apoptotic reactions in various types of cells, including podocytes, thus being involved in the development and progression of diabetic nephropathy. Recently, we, along with others, have found that pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, inhibits AGE-elicited mesangial and tubular cell damage through its anti-oxidative properties. However, the effects of PEDF on podocyte loss, one of the characteristic features of diabetic nephropathy remain unknown. In this study, we investigated whether and how PEDF could protect against AGE-elicited podocyte apoptosis in vitro. AGEs decreased PEDF mRNA level in podocytes, which was blocked by neutralizing antibody raised against receptor for AGEs (RAGE-Ab). PEDF or RAGE-Ab was found to inhibit the AGE-induced up-regulation of RAGE mRNA level, oxidative stress generation and resultant apoptosis in podocytes. All of the beneficial effects of PEDF on AGE-exposed podocytes were blocked by the treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPARγ). Further, although PEDF did not affect protein expression levels of PPARγ, it significantly restored the PPARγ transcriptional activity in AGE-exposed podocytes. The present results demonstrated for the first time that PEDF could block the AGE-induced apoptotic cell death of podocytes by suppressing RAGE expression and subsequent ROS generation partly via PPARγ activation. Our present study suggests that substitution of PEDF proteins may be a promising strategy for preventing the podocyte loss in diabetic nephropathy.
  Microvascular Research 10/2012; · 2.83 Impact Factor
• Article: Author reply: Comment to "Atorvastatin improves disease activity of nonalcoholic steatohepatitis partly through its tumour necrosis factor-α-lowering property"

  Sho-Ichi Yamagishi, Sayaka Maeda, Hideyuki Hyogo
  Digestive and Liver Disease 10/2012; · 3.05 Impact Factor
• Article: First reported case of collagenofibrotic glomerulopathy with a full-house pattern of immune deposits.

  Kei Fukami, Sho-Ichi Yamagishi, Tomohisa Minezaki, Shinichi Nishi, Satoshi Hisano, Seiya Okuda
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  ABSTRACT: Collagenofibrotic glomerulopathy is a very rare glomerular disease characterized by the deposition of Type III collagen fibrils within the subendothelial and mesangial areas, and by elevated serum levels of pro-collagen Type III peptide. We reported here an elderly patient representing the first case of collagenofibrotic glomerulopathy with a "full-house" pattern of glomerular immunoglobulin and complement deposits by immunofluorescence. A 79-year-old Japanese woman was admitted to our hospital for clinical examinations of leg edema. A renal biopsy specimen showed a remarkable enlargement of the glomerular tufts due to the deposition of periodic acid-Schiff- and Masson's trichrome-positive material. All three immunoglobulins, complements, and light chains were detected in the subendothelial space and capillary walls of the glomeruli. Electron microscopy of tannic acid staining showed spiraled and frayed fibers in the subendothelial areas, which were positive for Type III collagen staining. Serum levels of pro-collagen Type III peptide were increased. Therefore, even in cases where the renal biopsy sample displays a "full-house" immunofluorescence pattern of glomerulopathy, as in systemic lupus erythematosus, we may not always rule out the diagnosis of collagenofibrotic glomerulopathy.
  Clinical nephrology 10/2012; · 1.17 Impact Factor
• Article: Experimental diabetic nephropathy is accelerated in matrix metalloproteinase-2 knockout mice.

  Yoshimi Takamiya, Kei Fukami, Sho-Ichi Yamagishi, Yusuke Kaida, Yosuke Nakayama, Nana Obara, Ryuji Iwatani, Ryotaro Ando, Kiyomi Koike, Takanori Matsui, Yuri Nishino, Seiji Ueda, Mark E Cooper, Seiya Okuda
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  ABSTRACT: Background Matrix metalloproteinase-2 (MMP-2) is responsible for the degradation of various types of extracellular matrix (ECM) proteins such as type IV collagen. Decreased MMP-2 expression and activity has been generally thought to contribute to increased accumulation of ECM at the advanced stage of diabetic nephropathy. However, the kinetics and role of MMP-2 in the early phase of diabetic nephropathy remain unclear. To address this issue, we examined whether streptozotocin (STZ)-induced early diabetic nephropathy was accelerated in MMP-2 knockout (KO) mice.Methods Diabetes was induced by the injection of STZ in 6-week-old control and MMP-2 KO mice. Animals were killed after 16 weeks of diabetes of after observation alone.ResultsCompared with non-diabetic control mice, renal MMP-2 expression and activity were increased in 16-week old diabetic mice. Serum levels of blood urea nitrogen and creatinine and urinary excretion levels of albumin and N-acetyl-β-d-glucosaminidase were significantly elevated in diabetic MMP-2 KO mice when compared with wild-type diabetic littermates. Further, accumulation of ECM in the glomeruli and atrophy and fibrosis in the tubulointerstitium were exacerbated, and renal α-smooth muscle actin expression was enhanced in diabetic MMP-2 KO mice.Conclusions Our present study suggests that renal expression and activity of MMP-2 are increased as a compensatory mechanism in the early phase of diabetic nephropathy. Since MMP-2 could play a protective role against the progression of diabetic nephropathy, further enhancement of MMP-2 expression and/or activity in the kidney may be a therapeutic target for the treatment of early diabetic nephropathy.
  Nephrology Dialysis Transplantation 09/2012; · 3.40 Impact Factor
• Article: Positive Association Between Serum Level of Glyceraldehyde-Derived Advanced Glycation End Products and Vascular Inflammation Evaluated by [18F]Fluorodeoxyglucose Positron Emission Tomography.

  Nobuhiro Tahara, Sho-Ichi Yamagishi, Masayoshi Takeuchi, Akihiro Honda, Atsuko Tahara, Yoshikazu Nitta, Norihiro Kodama, Minori Mizoguchi, Hayato Kaida, Masatoshi Ishibashi, Naofumi Hayabuchi, Takanori Matsui, Tsutomu Imaizumi
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  ABSTRACT: OBJECTIVE Advanced glycation end products (AGEs) evoke inflammatory reactions, contributing to the development and progression of atherosclerosis. We investigated the relationship between serum AGE level and vascular inflammation.RESEARCH DESIGN AND METHODS The study involved 275 outpatients at Kurume University, Japan (189 males and 86 females; mean age 61.2 ± 8.8 years) who underwent complete history and physical examinations and determinations of blood chemistry and anthropometric variables, including AGEs. Serum AGE level was examined by enzyme-linked immunosorbent assay. Vascular [(18)F]fluorodeoxyglucose (FDG) uptake, an index of vascular inflammation, was measured as blood-normalized standardized uptake value, known as the target-to-background ratio (TBR), by FDG-positron emission tomography (FDG-PET). Furthermore, we examined whether the changes in serum AGE level after treatment with oral hypoglycemia agents (OHAs) were correlated with those of TBR in another 18 subjects whose AGE value was >14.2 units/mL (mean ± 2 SD).RESULTSMean serum AGE level and carotid TBR values were 9.15 ± 2.53 and 1.43 ± 0.22 units/mL, respectively. Multiple stepwise regression analysis revealed that TBR was independently correlated with AGEs (P < 0.001), carotid intima-media thickness (P < 0.01), and BMI (P < 0.02). When age- and sex-adjusted AGE values stratified by TBR tertiles were compared using ANCOVA, a significant trend was observed (P < 0.01). In addition, the changes in AGEs after OHA treatment were positively (r = 0.50, P < 0.05) correlated with those in TBR value.CONCLUSIONS The current study reveals that serum AGE level is independently associated with vascular inflammation evaluated by FDG-PET, suggesting that circulating AGE value may be a biomarker that could reflect vascular inflammation within an area of atherosclerosis.
  Diabetes care 08/2012; · 8.09 Impact Factor
• Article: Serum levels of pigment epithelium-derived factor (PEDF) are independently associated with procollagen III N-terminal peptide levels in patients with nonalcoholic fatty liver disease.

  Hideyuki Hyogo, Sho-Ichi Yamagishi, Sayaka Maeda, Yuki Kimura, Tomokazu Ishitobi, Kazuaki Chayama
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  ABSTRACT: OBJECTIVES: Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors with complex anti-oxidative, anti-fibrotic, and anti-inflammatory properties, thus being involved in cardiometabolic disorders. Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the metabolic syndrome as well. However, the pathophysiological role of PEDF in NAFLD remains largely unknown. We studied here the relationship between serum PEDF levels and various clinical markers of NAFLD in humans. DESIGN AND METHODS: The study involved 194 biopsy-proven NAFLD patients (102 male and 92 female) with a mean age of 51.3±13.8years. We examined which anthropometric, metabolic and inflammatory variables, and liver steatosis and fibrosis markers are independently associated with serum levels of PEDF. RESULTS: Mean serum levels of PEDF were 16.4±5.7μg/mL. Univariate analysis revealed that age (inversely), male, body mass index, waist circumference, numbers of white blood cells and platelets, aspartate aminotransferase, alanine aminotransferase, fasting plasma glucose, glycated hemoglobin, uric acid, procollagen type III N-terminal peptide (P-III-P), subcutaneous fat areas, visceral fat areas and liver to spleen density ratio in computed tomography, the presence of diabetes and medication for hyperlipidemia were significantly associated with serum levels of PEDF. In multiple stepwise regression analysis, age (p<0.01, inversely), male (p<0.05), waist circumference (p<0.01), white blood cell number (p<0.05), P-III-P (p<0.05), and the presence of diabetes (p<0.05) and medication for hyperlipidemia (p<0.01), were independently correlated to serum levels of PEDF (R(2)=0.285). CONCLUSIONS: The present study reveals that serum levels of PEDF are independently associated with P-III-P levels, suggesting that PEDF level is a novel biomarker of liver fibrosis in patients with NAFLD.
  Clinical biochemistry 08/2012; · 2.02 Impact Factor
• Article: Serum levels of pigment epithelium-derived factor, a novel marker of insulin resistance, are independently associated with fasting apolipoprotein B48 levels in humans.

  Nobuhiro Tahara, Sho-Ichi Yamagishi, Atsuko Tahara, Masayoshi Takeuchi, Tsutomu Imaizumi
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  ABSTRACT: OBJECTIVES: Fasting apolipoprotein B48 (apoB48) levels are associated with postprandial hyperlipidemia and carotid artery intima-media thickness (IMT), one of the markers of metabolic derangements and atherosclerosis, respectively. However, it remains unknown whether fasting serum levels of apoB48 are independently correlated with insulin resistance and vascular inflammation in humans. DESIGN AND METHODS: The study involved 315 consecutive outpatients in our hospital (218 males and 97 females) with a mean age of 62.0±9.2. We examined which anthropometric, metabolic and inflammatory variables, including serum levels of pigment epithelium-derived factor (PEDF), a novel marker of insulin resistance were independently associated with fasting apoB48. Moreover, we investigated whether fasting apoB48 levels were correlated with atherosclerotic plaque inflammation evaluated by [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET). Carotid [(18)F]-FDG uptake, an index of vascular inflammation within the atherosclerotic plaques, was measured as blood-normalized standardized uptake value, known as the target-to-background ratio (TBR). RESULTS: Mean serum levels of apoB48, PEDF, carotid IMT and TBR values were 2.77±0.21μg/mL, 13.45±1.03μg/mL, 0.71±0.15mm, and 1.43±0.21, respectively. Univariate analysis revealed that apoB48 levels were weakly, but not significantly associated with TBR (p=0.057). In multiple stepwise regression analysis, triglycerides (p<0.001), male (p=0.039), age (inversely, p=0.010), uric acid (p=0.007), medication for diabetes (p=0.029), and PEDF (p=0.049) were independently correlated to fasting apoB48 levels (R(2)=0.371). CONCLUSIONS: The present study reveals that serum levels of PEDF are independently associated with fasting apoB48 levels, suggesting that PEDF level is a novel biomarker that could reflect postprandial hyperlipidemia in humans.
  Clinical biochemistry 07/2012; · 2.02 Impact Factor
• Article: Increased insulinogenic index is an independent determinant of nonalcoholic fatty liver disease activity score in patients with normal glucose tolerance.

  Hideyuki Hyogo, Sho-Ichi Yamagishi, Sayaka Maeda, Yuki Kimura, Tomokazu Ishitobi, Kazuaki Chayama
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  ABSTRACT: Although insulin resistance is involved in nonalcoholic fatty liver disease, role of abnormalities in early phase of insulin secretion has not been examined. We examined which anthropometric and metabolic parameters, including insulinogenic index during oral glucose tolerant test, were independently associated with the disease activity of nonalcoholic fatty liver disease. A total of 114 consecutive biopsy-proven nonalcoholic fatty liver disease patients without type 2 diabetes were enrolled. Age, aspartate aminotransferase, free fatty acid, ferritin type IV collagen, hyaluronic acid, procollagen N-terminal peptide, fasting plasma glucose and 2-h insulin after glucose loading were significantly higher in patients with impaired glucose tolerance than those with normal glucose tolerance. Multiple stepwise regression analysis revealed that glycated haemoglobin, decreased density ratio of liver to spleen in computed tomography and increased insulinogenic index were independently associated with nonalcoholic fatty liver disease activity score in normal glucose tolerance patients, whereas aspartate aminotransferase and 2-h insulin in impaired glucose tolerance subjects. However, there were no significant independent correlations between insulinogenic index and steatosis grade/fibrosis stage in normal glucose tolerance patients. The present study suggests that increased early phase of insulin secretion may contribute to nonalcoholic fatty liver disease activity score in patients with normal glucose tolerance.
  Digestive and Liver Disease 07/2012; 44(11):935-9. · 3.05 Impact Factor
• Article: Decreased serum carnitine is independently correlated with increased tissue accumulation levels of advanced glycation end products in hemodialysis patients.

  Takeki Adachi, Kei Fukami, Sho-Ichi Yamagishi, Yusuke Kaida, Ryotaro Ando, Kazuko Sakai, Hisashi Adachi, Aki Otsuka, Seiji Ueda, Kenzo Sugi, Seiya Okuda
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  ABSTRACT: SUMMARY AT A GLANCE: This study demonstrated decreased serum carnitine levels and elevated skin AGEs in hemodialysis patients, and provides a possible novel marker of cardiovascular outcomes in this group of patients. ABSTRACT: Background and Aims:   There is accumulating evidence that advanced glycation end products (AGEs) play a role in cardiovascular disease (CVD) in patients with hemodialysis (HD). Carnitine deficiency is frequently observed in HD patients, which may also contribute to CVD. In this study, we examined whether carnitine deficiency was independently associated with increased tissue accumulation levels of AGEs in HD patients. Methods:   One hundred twenty nine HD patients underwent determinations of blood chemistries including serum level of carnitine. Tissue AGE levels were evaluated by measuring skin autofluorescence with an AGE-reader. Results:   Serum carnitine levels were significantly lower, while skin AGE levels were significantly higher in HD patients compared with healthy control (p<0.001). In univariate analysis, β(2) -microglobulin (β(2) -MG) and carnitine (inversely) were correlated with skin AGE levels. Multiple stepwise regression analysis revealed that carnitine levels were one of the independent determinants of skin AGE levels (p=0.024). When β(2) -MG-adjusted skin AGE levels were stratified by serum carnitine levels, a statistical significance and dose-response relationship were observed (p=0.043). Furthermore, skin AGE levels were one of the independent determinants of serum carnitine levels as well (p=0.012). Conclusions:   The present study demonstrated that decreased carnitine levels were independently associated with increased skin AGE levels in HD patients. Since carnitine is reported to inhibit the formation of AGEs in vitro, our study suggests that supplementation of carnitine may be a therapeutic target for preventing the accumulation of tissue AGEs and subsequently reducing the risk of CVD in HD patients. © 2012 The Authors. Nephrology © 2012 Asian Pacific Society of Nephrology.
  Nephrology 07/2012; · 1.31 Impact Factor
• Article: Glucagon-like peptide-1 inhibits angiotensin II-induced mesangial cell damage via protein kinase A.

  Yuji Ishibashi, Takanori Matsui, Ayako Ojima, Yuri Nishino, Sae Nakashima, Sayaka Maeda, Sho-Ichi Yamagishi
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  ABSTRACT: There is a growing body of evidence that renin-angiotensin system plays a role in diabetic nephropathy. Recently, we have found that glucagon-like peptide-1 (GLP-1), one of the incretins, a gut hormone secreted from L cells in the intestine in response to food intake, inhibits advanced glycation end product-induced monocyte chemoattractant protein-1 gene expression in mesangial cells thorugh the interaction with the receptor of GLP-1. However, effects of GLP-1 on angiotensin II-exposed mesangial cells are unknown. This study investigated whether and how GLP-1 blocked the angiotensin II-induced mesangial cell damage in vitro. GLP-1 completely blocked the angiotensin II-induced superoxide generation, NF-κB activation, up-regulation of mRNA levels of intercellular adhesion molecule-1 and plasminogen activator inhibitor-1 in mesangial cells, all of which were prevented by the treatments with H-89, an inhibitor of protein kinase A. The present results demonstrated for the first time that GLP-1 blocked the angiotensin II-induced mesangial cell injury by inhibiting superoxide-mediated NF-κB activation via protein kinase C pathway. Our present study suggests that strategies to enhance the biological actions of GLP-1 may be a promising strategy for the treatment of diabetic nephropathy.
  Microvascular Research 06/2012; · 2.83 Impact Factor
• Article: Proteinuria elevates asymmetric dimethylarginine levels via protein arginine methyltransferase-1 overexpression in a rat model of nephrotic syndrome.

  Yusuke Kaida, Seiji Ueda, Sho-Ichi Yamagishi, Yosuke Nakayama, Ryotaro Ando, Ryuji Iwatani, Kei Fukami, Seiya Okuda
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  ABSTRACT: Proteinuria is an independent risk factor for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Asymmetric dimethylarginine (ADMA) is a mediator of endothelial dysfunction and is associated with proteinuria in CKD patients. Thus, ADMA can partially account for the increased risk of CVD in CKD patients presenting proteinuria. However, a causal relationship between proteinuria and ADMA remains to be demonstrated. We first investigated whether and how proteinuria might increase ADMA levels in adriamycin (ADR)-treated rats. Next, we examined the effects of human serum albumin (HSA) on ADMA production by human renal proximal tubular epithelial cells (RPTECs) cultured in vitro. Proteinuria was associated with ADMA levels in ADR treated rats. Although ADR treatment did not affect the expression levels of the dimethylarginine dimethylaminohydrolase (DDAH)-1 or -2 enzymes that degrade ADMA, it significantly increased the expression levels of protein arginine methyltransferase-1 (PRMT-1) that facilitates the production of ADMA. HSA increased the generation of reactive oxygen species in RPTECs, which was blocked by the anti-oxidant N-acetylcysteine (NAC) or an inhibitor of NADPH oxidase. Furthermore, HSA increased ADMA generation by RPTECs in a dose- and time-dependent manner and induced gene expression of PRMT-1 but not DDAHs, which were also suppressed by NAC. Our data suggest that proteinuria might enhance ADMA generation in tubular cells, at least in part via the overexpression of PRMT-1 triggered by oxidative stress. Our findings thereby propose a mechanistic link between proteinuria and ADMA levels in CKD patients.
  Life sciences 06/2012; 91(9-10):301-5. · 2.56 Impact Factor