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論文

論文
Watanabe, Toshifumi ; Tajima, Hidehiro ; Hayashi, Hironori ; Nakagawara, Hisatoshi ; Ohnishi, Ichiro ; Takamura, Hiroyuki ; Ninomiya, Itasu ; Kitagawa, Hirohisa ; Fushida, Sachio ; Tani, Takashi ; Fujimura, Takashi ; Ohta, Tetsuo ; Wakayama, Tomohiko ; Iseki, Shoichi ; Harada, Shinichi ; 田島, 秀浩 ; 林, 泰寛 ; 中川原, 寿俊 ; 高村, 博之 ; 二宮, 致 ; 北川, 裕久 ; 伏田, 幸夫 ; 谷, 卓 ; 藤村, 隆 ; 太田, 哲生 ; 若山, 友彦 ; 井関, 尚一 ; 原田, 真市
出版情報: International Journal of Molecular Medicine.  28  pp.919-925,  2011-12.  Spandidos Publications
URL: http://hdl.handle.net/2297/00049836
概要: 金沢大学医薬保健研究域医学系<br />Histone acetylation and deacetylation have been thought to be related to gene expression, and there are many reports indicating that histone deacetylase inhibitors (HDACis) exert antifibrogenic effects in several organs. In injured livers, hepatic stellate cells (HSCs) are activated in response to profibrogenic mediators and produce large amounts of extracellular matrix. In particular, transforming growth factor-β1 (TGF-β1) is considered as a key factor in accelerating hepatic fibrosis because it is released from activated HSCs and further stimulates them. The present study aimed to clarify whether sodium valproate (VPA) has suppressive effects on cultured human HSCs (LI90). We showed that treatment with VPA had no significantly suppressive effect on cell proliferation at a concentration of 1 mM, which corresponded approximately to the serum concentration obtained by the administration of a clinical dose. However, VPA prevented the morphological changes characteristic for activation and inhibited the expression of collagen type 1 α1 (COL1A1) and TGF-β1 in activated LI90 cells at the mRNA and protein levels. Our results support the hypothesis that VPA exerts antifibrogenic activity with little cytotoxicity at 1 mM, and HDACis are expected to be used in clinical practice for the treatment of fibrotic diseases.<br />Embargo Period 6 months 続きを見る
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論文

論文
Khemawoot, Phisit ; Maruyama, Chiharu ; Tsukada, Hirotaka ; Noda, Hiroyo ; Ishizaki, Junko ; Yokogawa, Koichi ; Miyamoto, Kenichi
出版情報: Biopharmaceutics and Drug Disposition.  28  pp.331-338,  2007-09-01.  John Wiley & Sons
URL: http://hdl.handle.net/2297/7119
概要: The influence of chronic hepatic failure on the disposition kinetics of valproate (VPA) excretion via a phase II reactio n was examined in rats treated with carbon tetrachloride (1.0 mg/kg, s.c., 3 times a week) for 2 or 3 months. There was no significant difference in the plasma concentration-time courses of VPA among the control and two treated groups up to 120 min after i.v. administration of VPA (75 mg/kg), but subsequently the plasma concentrations of the treated groups declined significantly below the control levels. Expression of Mrp2 mRNA in the liver of the treated groups was significantly lower than in the control group; conversely that in the kidney was significantly higher. The enzyme activity of UGTs in the liver of the treated groups decreased significantly, but UGT1A8 mRNA expression in the duodenum was increased about 3-fold. Cumulative excretion of VPA glucuronide (VPA-G) in bile of the treated groups was reduced significantly, while that in urine was markedly increased. In conclusion, the area under the VPA plasma concentration-time curve was decreased significantly in rats with chronic hepatic failure owing to increased excretion of VPA-G via the kidney as a result of induction of Mrp2, and inhibition of enterohepatic circulation of VPA-G. Copyright © 2007 John Wiley & Sons, Ltd. 続きを見る