1.

論文

論文
Iwata, Yasunori ; Wada, Takashi ; Yokoyama, Hitoshi ; Toyama, Tadashi ; Kitajima, Shinji ; Okumura, Toshiya ; Hara, Akinori ; Yamahana, Junya ; Nakaya, Izaya ; Kobayashi, Motoo ; Kitagawa, Kiyoki ; Kokubo, Satoshi ; Yoshimoto, Keiichi ; Shimizu, Kazuaki ; Sakai, Norihiko ; Furuichi, Kengo ; Koshino, Yoshitaka ; Takaeda, Chikako ; Takeda, Shinichi ; Takasawa, Kazuya ; Ohta, Satoshi ; Takaeda, Masayoshi ; Kaneko, Shuichi
出版情報: Internal Medicine.  46  pp.447-452,  2007-04-08.  日本内科学会
URL: http://hdl.handle.net/2297/6249
概要: 金沢大学保健管理センター<br />金沢大学大学院医学系研究科<br />金沢大学附属病院<br />Background: In hemodialysis patients, adynamic bone disease has been reported to be closely associated with low levels of parathyroid hormone (PTH) due to exposure to high levels of serum calcium following the administration of calcium carbonate (CaCO3) or vitamin D agents. This study was conducted to clarify the therapeutic effect of a non-calcemic phosphate binder, sevelamer hydrochloride (sevelamer), for hypoparathyroidism in hemodialysis patients with or without diabetes mellitus. Methods: Based on entry criteria, 40 Japanese chronic hemodialysis patients (22 males and 18 females with a mean age of 60.6, 14 diabetic patients and 26 non-diabetic patients) were switched from CaCO3 to sevelamer for 48 weeks. Serum calcium, phosphate, intact (i) PTH and PTH-(1-84) were analyzed. Bone remodeling activity was evaluated by determining intact osteocalcine (iOC), bone-specific alkaline phosphatase (BAP). Results: The switch from CaCO3 to sevelamer significantly decreased the serum levels of calcium, resulting in the elevation of iPTH levels from 31±18 pg/mL to 95±96 pg/mL by 48 weeks. In contrast, serum phosphate levels remained similar to those in patients with CaCO3 treatment. Concomitantly, the levels of BAP and iOC were elevated. Further, these beneficial effects on bone turnover were observed in both diabetic and non-diabetic patients. Conclusion: Sevelamer reduced the calcium concentration and thereby increased PTH levels, resulting in the improvement of markers of bone turnover. The administration of sevelamer is of therapeutic benefit for the improvement of bone remodeling activity even in hemodialysis patients with diabetes. © 2007 The Japanese Society of Internal Medicine. 続きを見る
2.

その他

その他
金沢大学フロンティアサイエンス機構 ; 金子, 周一 ; 荒井, 章司 ; Kaneko, Shuichi ; Arai, Shoji
出版情報: FSO Newsletter = Frontier Science Organization Newsletter.  3  pp.2-2,  2008-03-07.  金沢大学フロンティアサイエンス機構 = Frontier Science Organization Kanazawa University
URL: http://hdl.handle.net/2297/30121
3.

論文

論文
Nakamura, Seiji ; Takamura, Toshinari ; Matsuzawa-Nagata, Naoto ; Takayama, Hiroaki ; Misu, Hirofumi ; Noda, Hiroyo ; Nabemoto, Satoko ; Kurita, Seiichiro ; Ota, Tsuguhito ; Ando, Hitoshi ; Miyamoto, Kenichi ; Kaneko, Shuichi
出版情報: The Journal of biological chemistry.  284  pp.14809-14818,  2009-05-29.  American Society for Biochemistry and Molecular Biology
URL: http://hdl.handle.net/2297/18986
概要: Visceral adiposity in obesity causes excessive free fatty acid (FFA) flux into the liver via the portal vein and may cau se fatty liver disease and hepatic insulin resistance. However, because animal models of insulin resistance induced by lipid infusion or a high fat diet are complex and may be accompanied by alterations not restricted to the liver, it is difficult to determine the contribution of FFAs to hepatic insulin resistance. Therefore, we treated H4IIEC3 cells, a rat hepatocyte cell line, with a monounsaturated fatty acid (oleate) and a saturated fatty acid (palmitate) to investigate the direct and initial effects of FFAs on hepatocytes. We show that palmitate, but not oleate, inhibited insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 2 and serine phosphorylation of Akt, through c-Jun NH2-terminal kinase (JNK) activation. Among the well established stimuli for JNK activation, reactive oxygen species (ROS) played a causal role in palmitate-induced JNK activation. In addition, etomoxir, an inhibitor of carnitine palmitoyltransferase-1, which is the rate-limiting enzyme in mitochondrial fatty acid β-oxidation, as well as inhibitors of the mitochondrial respiratory chain complex (thenoyltrifluoroacetone and carbonyl cyanide m-chlorophenylhydrazone) decreased palmitate-induced ROS production. Together, our findings in hepatocytes indicate that palmitate inhibited insulin signal transduction through JNK activation and that accelerated β-oxidation of palmitate caused excess electron flux in the mitochondrial respiratory chain, resulting in increased ROS generation. Thus, mitochondria-derived ROS induced by palmitate may be major contributors to JNK activation and cellular insulin resistance. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc. 続きを見る
4.

論文

論文
Saito, Shigeru ; Honda, Masao ; Kaneko, Shuichi ; Horimoto, Katsuhisa
出版情報: Proceedings of the IEEE Conference on Decision and Control.  pp.5624-5630,  2009-01-01.  IEEE = Institute of Electrical and Electronics Engineers
URL: http://hdl.handle.net/2297/24279
概要: One of the most characteristic features of biological molecular networks is that the network structure itself changes, d epending on the cellular environment. Indeed, activated molecules show a variety of responses to distinctive cell conditions, and subsequently the network structures of active molecules also change. Here we present an approach to trace the network structure changes by using the graphical chain model developed from the gene expression data. The previous procedure for applying the graphical chain model to the expression profiles of a limited number of genes has been improved to analyze the entire set of genes. Furthermore, the chain model has been rearranged according to the association strength, and was scrutinized to identify the candidates of essential gene-gene relationships for the network changes, by using the path consistency algorithm. The improved procedure was applied to the expression profiles of 8,427 genes, which were measured in two distinctive stages of liver cancer progression. As a result, the chain model of the 18 gene cluster relationships with strong associations was inferred, in which the coordination of clusters was described in the cell stage progression, and the gene-gene relationships between known cancer-related genes causing the progression were further refined. Thus, the present procedure is a useful method to model the network structure changes in the cell stage progression, and to clarify the gene candidates for the progression. ©2009 IEEE. 続きを見る
5.

論文

論文
Kurita, Seiichiro ; Ando, Hitoshi ; Kaneko, Shuichi ; Takamura, Toshinari
出版情報: Internal medicine (Tokyo, Japan).  47  pp.1065-1066,  2008-01-01.  日本内科学会
URL: http://hdl.handle.net/2297/11571
概要: 金沢大学医薬保健研究域医学系
6.

論文

論文
Uno, Masafumi ; Kurita, Seiichiro ; Misu, Hirofumi ; Ando, Hitoshi ; Ota, Tsuguhito ; Matsuzawa-Nagata, Naoto ; Kita, Yuki ; Nabemoto, Satoko ; Akahori, Hiroshi ; Zen, Yoh ; Nakanuma, Yasuni ; Kaneko, Shuichi ; Takamura, Toshinari
出版情報: Hepatology.  48  pp.109-118,  2008-07-01.  John Wiley & Sons
URL: http://hdl.handle.net/2297/11569
概要: 金沢大学医薬保健研究域医学系<br />Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease and is one of the most common liver diseases in the developed world. The histological findings of NASH are characterized by hepatic steatosis, inflammation, and fibrosis. However, an optimal treatment for NASH has not been established. Tranilast, N-(3′,4′-dimedioxycinnamoyl)- anthranilic acid, is an antifibrogenic agent that inhibits the action of transforming growth factor beta (TGF-β). This drug is used clinically for fibrogenesis-associated skin disorders including hypertrophic scars and scleroderma. TGF-β plays a central role in the development of hepatic fibrosis, and tranilast may thus ameliorate the pathogenesis of NASH. We investigated the effects of tranilast using an established dietary animal model of NASH, obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and nondiabetic control Long-Evans Tokushima Otsuka (LETO) rats fed a methionine-deficient and choline-deficient diet. Treatment with 2% tranilast (420 mg/kg/day) for 8 weeks prevented the development of hepatic fibrosis and the activation of stellate cells, and down-regulated the expression of genes for TGF-β and TGF-β-target molecules, including α1 procollagen and plasminogen activator-1. In addition, tranilast attenuated hepatic inflammation and Kupffer cell recruitment, and down-regulated the expression of tumor necrosis factor alpha. Unexpectedly, tranilast ameliorated hepatic steatosis and up-regulated the expression of genes involved in beta-oxidation, such as peroxisome proliferator-activated receptor α and carnitine O-palmitoyltransferase-1. Most of these effects were observed in LETO rats and OLETF rats, which suggest that the action of tranilast is mediated through the insulin resistance-independent pathway. Conclusion: Our findings suggest that targeting TGF-β with tranilast represents a new mode of therapy for NASH. Copyright © 2008 by the American Association for the Study of Liver Diseases. 続きを見る
7.

論文

論文
Ando, Hitoshi ; Takamura, Toshinari ; Matsuzawa-Nagata, Naoto ; Shima, Kosuke R. ; Nakamura, Seiji ; Kumazaki, Masafumi ; Kurita, Seiichiro ; Misu, Hirofumi ; Togawa, Naoyuki ; Fukushima, Tatsunobu ; Fujimura, Akio ; Kaneko, Shuichi
出版情報: Biochemical and Biophysical Research Communications.  380  pp.684-688,  2009-03-13.  Elsevier
URL: http://hdl.handle.net/2297/17062
概要: 金沢大学医薬保健研究域医学系<br />Recent studies have correlated metabolic diseases, such as metabolic syndrome and non-alcoholic fatt y liver disease, with the circadian clock. However, whether such metabolic changes per se affect the circadian clock remains controversial. To address this, we investigated the daily mRNA expression profiles of clock genes in the liver of a dietary mouse model of non-alcoholic steatohepatitis (NASH) using a custom-made, high-precision DNA chip. C57BL/6J mice fed an atherogenic diet for 5 weeks developed hypercholesterolemia, oxidative stress, and NASH. DNA chip analyses revealed that the atherogenic diet had a great influence on the mRNA expression of a wide range of genes linked to mitochondrial energy production, redox regulation, and carbohydrate and lipid metabolism. However, the rhythmic mRNA expression of the clock genes in the liver remained intact. Most of the circadianly expressed genes also showed 24-h rhythmicity. These findings suggest that the biological clock is protected against such a metabolic derangement as NASH. © 2009 Elsevier Inc. All rights reserved. 続きを見る
8.

論文

論文
Takamura, Toshinari ; Shimizu, Akiko ; Komura, Takuya ; Ando, Hitoshi ; Zen, Yoh ; Minato, Hiroshi ; Matsushita, Eiki ; Kaneko, Shuichi
出版情報: Internal Medicine.  46  pp.579-581,  2007-05-01.  日本内科学会
URL: http://hdl.handle.net/2297/6609
概要: 金沢大学大学院医学系研究科環境社会医学<br />A 53-year-old postmenopausal woman, who had a family history of cryptogenic liver cirrhosis, wa s diagnosed with osteoporosis, and started on the selective estrogen receptor modulator (SERM) raloxifene 60 mg/day orally. She developed marked liver dysfunction. Her body mass index (BNU) was 26.5. Her blood chemistry indicated AST 342 IU/L, ALT 356 IU/L, and hyaluronic acid 255 ng/mL. An oral glucose tolerance test showed impaired glucose tolerance with marked insulin resistance. Histologically, we diagnosed this case as having pre-cirrhotic nonalcoholic steatohepatitis (NASH). This is the first histologically confirmed case of NASH that was aggravated by raloxifene. © 2007 The Japanese Society of Internal Medicine. 続きを見る
9.

論文

論文
Koike, Nobuhiko ; Takamura, Toshinari ; Kaneko, Shuichi
出版情報: Life Sciences.  80  pp.1721-1728,  2007-04-01.  Elsevier
URL: http://hdl.handle.net/2297/3863
概要: 大学院医学系研究科環境社会医学<br />Diabetic nephropathy is a major complication of diabetes leading to end-stage renal disease, which requires hemodialysis. Although the mechanism by which it progresses is largely unknown, the role of hyperglycemia-derived oxidative stress has recently been the focus of attention as the cause of diabetic complications. Constituent cells of the renal glomeruli have the capacity to release reactive oxygen species (ROS) upon stimulation of NADPH oxidase activated by protein kinase C (PKC). Hyperglycemia and insulin resistance in the diabetic state are often associated with activation of PKC and tumor necrosis factor (TNF)-α, respectively. The aim of this study is to clarify the signaling pathway leading to ROS production by PKC and TNF-α in rat glomeruli. Isolated rat glomeruli were stimulated with phorbol 12-myristate 13-acetate (PMA) and TNF-α, and the amount of ROS was measured using a chemiluminescence method. Stimulation with PMA (10 ng/ml) generated ROS with a peak value of 136 ± 1.2 cpm/mg protein (mean ± SEM). The PKC inhibitor H-7, the NADPH oxidase inhibitor diphenylene iodonium and the phosphatidylinositol-3 (PI-3) kinase inhibitor wortmannin inhibited PMA-induced ROS production by 100%, 100% and 80%, respectively. In addition, TNF-α stimulated ROS production (283 ± 5.8/mg protein/20 min). The phosphodiesterase inhibitor cilostazol activates protein kinase A and is reported to improve albuminuria in diabetic rats. Cilostazol (100 μg/ml) inhibited PMA, and TNF-α-induced ROS production by 78 ± 1.8, and 19 ± 2.7%, respectively. The effects of cilostazol were not additive with wortmannin. Cilostazol arrests oxidative stress induced by PKC activation by inhibiting the PI-3 kinase-dependent pathway, and may thus prevent the development of diabetic nephropathy. © 2007 Elsevier Inc. All rights reserved. 続きを見る
10.

論文

論文
Ota, Tsuguhito ; Takamura, Toshinari ; Kaneko, Shuichi
出版情報: New England Journal of Medicine.  356  pp.1067-1069,  2007-03-08.  Massachusetts Medical Society
URL: http://hdl.handle.net/2297/9927
概要: 金沢大学医薬保健研究域医学系