薬理と治療
2009, 37巻Suppl 1
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特集 【肝病態生理研究のあゆみ 第17回肝病態生理研究会報告 於:神戸 】
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2 .Organic Anion Transporting Polypeptide 1B1 (OATP1B1),Organic Anion Transporting Polypeptide 1B3(OATP1B3)の基質を用いたファーマコフォア解析,三次元定量的構造活性相関
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4 .Bile Salt Export Pump(BSEP)の内在化過程におけるクラスリンアダプター蛋白質Adaptor Protein Complex 2(AP2)の関与の検討
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5 .Lipopolysaccharide により低下したタウロコール酸の胆汁中排泄に及ぼす4-フェニルブチレートの影響
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6 .Investigation of Canalicular Efflux Mechanisms of SC-62807, a Major Metabolite of Celecoxib
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7.有機カチオンの胆汁排泄におけるMultidrug and Toxin Extrusion 1 の寄与の解析
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8 .Sandwich 培養肝細胞を用いた薬物の胆汁排泄に関与するトランスポーターの寄与率の算定
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10.15R-[11C]TIC を用いた Positron Emission Tomography(PET)による肝胆系輸送の機能評価
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11.PET プローブ 15R-[11C]TIC の肝胆系輸送に関与するトランスポーターの同定ならびにヒト相互作用試験時の血漿・肝臓内濃度変動およびin vitro 試験からの予測
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15.非代償性肝硬変で出現する血漿アミノ酸 Imbalance は樹状細胞成熟化を抑制し,分岐鎖アミノ酸(BCAA)により改善する
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19.肝線維化進展・肝発癌過程におけるインスリン抵抗性の関与
37巻Suppl 1(2009);View Description Hide DescriptionBackground Recent studies have revealed a close relationship between insulin resistance (IR)and the progression of chronic liver diseases. The aim of this study was to elucidate the possible mechanisms of IR on the liver fibrosis development and hepatocarcinogenesis using obese diabetic Otsuka Long-Evans Tokushima Fatty(OLETF)rats. Methods Liver fibrosis and hepatocarcinogenesis were induced in OLETF and non-diabetic control Long-Evans Tokushima Otsuka(LETO)by pig-serum and diethylnitrosamine(DEN),respectively. Results The liver fibrosis development and glutathione-S-transferase placental form (GST-P)-positive pre-neoplastic lesions were both markedly accelerated in OLETF. In the fibrosis experiment, α-smooth muscle actin(α-SMA)-positive activated hepatic stellate cells(HSC)also increased in OLETF along with augmentation of the hepatic collagen contentand transforming growth factor-β1(TGF-β1). In the DEN model, the neovascularization was up-regulated in OLETF almost in parallel with the pre-neoplastic lesions development and a potent angiogenic factor, the vascular endothelial growth factor(VEGF). Our in vitro study showed that both glucose and insulin stimulated the proliferation of the activated HSC and augmented the neovascularization. Conclusion These results indicated that the IR status directly accelerated the liver fibrosis development and hepatocarcinogenesis at least partly through the stimulation of activated HSC proliferation and hepatic neovascularization, respectively, in the rat. -
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20.Repeat Biopsy を施行した NASH 症例の検討
37巻Suppl 1(2009);View Description Hide DescriptionThe histological course of nonalcoholic steatohepatitis(NASH)remains undescribed. Therefore, we examined the liver histology of NASH patients who had undergone repeat liver biopsies. Twenty-five patients(age, 64.7±14.4;17 women), who were mostly treated with antioxidative therapies(phlebotomy, vitamin E), ursodeoxycholic acid, and/or lipid-lowering agents, underwent a second liver biopsy 31.1±6.8 mo after the first. Fibrosis stage progressed in 16%, remained stable in 36% and regressed in 48%. Variables were compared between patients with(group I)and without(group NI)fibrosis improvement. Dyslipidemia was significantly more prevalent in group I than in group NI. Other clinical characteristics were similar between two groups. Levels of AST, ALT, and type IV collagen 7s improved significantly between biopsies, especially in group I. Insulin resistance evaluated by HOMA-IR was significantly improved only in group I, but not in group NI. In conclusion, inflammation and insulin resistance should be relieved by intensive pharmacological therapies to obtain fibrosis improvement in NASH. -
21.非アルコール性脂肪性肝炎の進展と治療効果予測に関わる因子―AGE,sRAGE との関連について―
37巻Suppl 1(2009);View Description Hide DescriptionBackground We have reported the elevation of serum advanced glycation endproducts(AGEs)in nonalcoholic steatohepatitis(NASH), and have elucidated the importance of AGEs for the liver fibrogenesis in vitro. In this study, we explored the clinical usefulness of serum AGEs and soluble receptor for AGEs(sRAGE)in NASH. Methods Sixty-seven patients with biopsy proven NASH were enrolled. Clinical parameters and follow-up biopsies were examined before and after therapies(Therapies were carried out based upon the metabolic factors). Serum AGEs and sRAGE were examined before therapies. Patients were divided into two groups based upon the changes of nonalcoholic fatty liver disease activity score(NAS)or fibrosis stage, respectively. Deteriorated groups were defined as NAS or fibrosis stage increased, and others not. The clinical parameters were compared between these groups. Results Follow-up biopsies were obtained in thirty-eight patients. sRAGE levels before therapies were significantly lower in deteriorated group of NAS compared with the other group. In deteriorated group of fibrosis stage, ferritin levels were significantly higher before and after therapies and further, post-therapy ALT levels were significantly higher than the other group. Changes of NAS were correlated with sRAGE before therapies, changes of ALT, and of BMI. Changes of fibrosis stage were correlated with AGEs and ferritin before therapies, and changes of BMI. Lower levels of sRAGE with higher levels of AGEs were the determinant of fibrosis deterioration. Conclusions AGEs and sRAGE levels might be useful parameters in determining the histological outcome in NASH. -
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