Glucose-Dependent Insulinotropic Polypeptide Prevents the Progression of Macrophage-Driven Atherosclerosis in Diabetic Apolipoprotein E-Null Mice

Aim: We recently reported that glucose-dependent insulinotropic polypeptide (GIP) prevents the development of atherosclerosis in apolipoprotein E-null (Apoe 2/2) mice. GIP receptors (GIPRs) are found to be severely down-regulated in diabetic animals. We examined whether GIP can exert anti-atherogenic effects in diabetes. Methods: Nondiabetic Apoe 2/2 mice, streptozotocin-induced diabetic Apoe 2/2 mice, and db/db mice were administered GIP (25 nmol/kg/day) or saline (vehicle) through osmotic mini-pumps for 4 weeks. The animals were assessed for aortic atherosclerosis and for oxidized low-density lipoprotein-induced foam cell formation in exudate peritoneal macrophages. Results: Diabetic Apoe 2/2 mice of 21 weeks of age exhibited more advanced atherosclerosis than nondiabetic Apoe 2/2 mice of the same age. GIP infusion in diabetic Apoe 2/2 mice increased plasma total GIP levels by 4-fold without improving plasma insulin, glucose, or lipid profiles. GIP infusion significantly suppressed macrophage-driven atherosclerotic lesions, but this effect was abolished by co-infusions with [Pro 3]GIP, a GIPR antagonist. Foam cell formation was stimulated by 3-fold in diabetic Apoe 2/2 mice compared with their nondiabetic counterparts, but this effect was halved by GIP infusion. GIP infusion also attenuated the foam cell formation in db/db mice. In vitro treatment with GIP (1 nM) reduced foam cell formation by 15 % in macrophages from diabetic Apoe 2/2 mice, and this attenuating effect was weaker than that attained by the same treatment of macrophages from nondiabetic counterparts (35%). While GIPR expression was reduced by onl

Glucagon-like Peptide-1 Suppresses the Proliferation and Migration of Vascular Smooth Muscle Cells: Implications for Preventive Effects on Atherosclerosis

Our group previously demonstrated the suppressive effect of glucagon-like peptide-1 (GLP-1) on macrophage-driven atherosclerosis in apolipoprotein E-deficient (apoE-/-) mice. In the present study we investigated the suppressive effect of GLP-1 on the atherogenic phenotype of vascular smooth muscle cells (VSMCs) in vivo using apoE-/- mice, and the proliferation and migration of human VSMCs in vitro. A 4-week infusion of GLP-1 in 17-week-old apoE-/- mice significantly reduced the proliferative VSMC phenotype stained with SMemb. Platelet-derived growth factor (PDGF) -BB significantly stimulated the proliferation of human aortic VSMCs by three fold. Both 0.1 and 1nmol/l GLP-1 significantly suppressed the PDGF-induced VSMC proliferation, and this suppressive effect was significantly abolished by the GLP-1 receptor antagonist exendin (9-39) (50nmol/l). The GLP-1 receptor agonists liraglutide (100nmol/l) and exendin-4 (100nmol/l) mimicked GLP-1, significantly suppressing PDGF-induced VSMC proliferation. PDGF-BB significantly stimulated the migration of human aortic VSMCs by 1.7 -fold, and this effect was significantly suppressed by 1nmol/l GLP-1. These findings suggest that GLP-1-related treatments may prevent the progression of atherosclerotic lesions by suppressing the proliferation and migration of VSMCs, which are characteristic features of atherosclerosis

Effect of Cetraxate, a Mucosal Protective Agent, on Gastric Mucosal Blood Flow and Gastric Clarithromycin Concentration in Nicotine-treated Rats

Our previous study demonstrated that combination treatment with cetraxate plus omeprazole, amoxicillin, and clarithromycin is effective for the eradication of Helicobacter pylon in smokers. To evaluate the effect of cetraxate on gastric mucosal blood flow (GMBF) and the gastric concentration of clarithromycin in nicotine-treated rats, 10 rats were divided into two groups given nicotine with or without cetraxate, and GMBF was measured by laser Doppler blood flowmetry. Another 36 rats were divided into three groups (control, nicotine, and nicotine + cetraxate). Clarithromycin was administered intraduodenally and nicotine was administered after 30 minutes, with cetraxate being given 30 minutes later. The gastric mucosal clarithromycin concentration was measured. After cetraxate administration, GMBF increased significantly in the nicotine + cetraxate group compared with the nicotine group (p<0.05). The mucosal clarithromycin concentration increased in the nicotine + cetraxate group compared with the nicotine group, but the difference was not significant. Our results indicate that cetraxate increased GMBF in nicotine-treated rats

Ultrasonographic characteristics of small hepatocellular carcinoma.

The ultrasonographic characteristics of hepatocellular carcinomas (HCC) were investigated. Four typical features of HCCs, "mosaic internal echo pattern", "halo", "lateral shadow" and "posterior echo enhancement", were not recognized in minute HCCs smaller than 2 cm in diameter. These characteristics developed as the tumors grew. Only hypoechoic space-occupying lesions can be considered as small HCCs. In differentiating small HCCs from hypoechoic non-malignant space-occupying lesions in the cirrhotic liver, the ratios of short to long dimensions of the lesions seemed to be important since the ratios of HCCs were significantly larger than those of non-malignant lesions. The fact that 3 hyperechoic small HCCs could not be diagnosed even by celiac arteriography has suggested to us that ultrasonically guided biopsies should be performed in order to differentiate from small hemangiomas. Serum alpha-fetoprotein (AFP) levels of 1/3 of the patients with HCCs were below 100 ng/ml, indicating that it is impossible to detect small HCCs only by measuring serum AFP.</p

韓国および日本における中期景気循環の推計

I はじめに / II 中期景気循環モデルの定式化 / III 韓国経済における中期景気循環の実証 / IV 日本経済における中期景気循環の実証 / Ⅴ 韓国における輸出入関数の推計 / V-1 輸出関数の推計 / V-2 輸入関数の推計 / VI むすびにかえて / 計算付

発展途上国における所得移転効果について : 異なる 2つの為替相場制度をめぐって

I はじめに / II モデルの設定 / III 所得移転効果の分析 / III-A) 固定為替相場制度モデルにおける所得移転効果 / III-B) 変動為替相場制度モデルにおける所得移転効果 / Ⅳ 諸仮定および移転効果の可能性の推計 / Ⅳ-A) 輸出関数の推計 / Ⅳ-B) 輸入関数の推計 / Ⅳ-C) マーシャル・ラーナ一条件の検証 / Ⅳ-D) 所得移転効果の推定 / Ⅴ むすびにかえて / 計算付録A / 計算付録B / 計算付録C / 計算付録D / 参考文

経済発展理論と国際収支 : 開放経済モデルへの一接近

I 序 / II 産業部門 / III 貯蓄・投資，及び市場均衡 / IV オープン・モデルヘの拡張 / 〔ステップ1 : ワルラス的3部門一般均衡体系〕 / 〔ステップ2 : S部門に擬装失業を仮定した2部門一般均衡体系〕 / 〔ステップ3 : 小国を仮定したオープン・モデル〕 / 〔ステップ4 : 資本流入を考慮したオープン・モデル〕 / V むすびにかえ

Ritonavir Blocks Hepatitis E Virus Internalization and Clears Hepatitis E Virus In Vitro with Ribavirin

Hepatitis E virus (HEV) is increasingly recognized as the leading cause of acute hepatitis. Although HEV infections are mostly self-limiting, a chronic course can develop especially in those with immunocompromised state. Ribavirin is currently used to treat such patients. According to various reports on chronic HEV infections, a sustained virological response (SVR) was achieved in approximately 80% of patients receiving ribavirin monotherapy. To increase the SVR rate, drug combination might be a viable strategy, which we attempted in the current study. Ritonavir was identified in our previous drug screening while searching for candidate novel anti-HEV drugs. It demonstrated potent inhibition of HEV growth in cultured cells. In the present study, ritonavir blocked HEV internalization as shown through time-of-addition and immunofluorescence assays. Its combination with ribavirin significantly increased the efficiency of inhibiting HEV growth compared to that shown by ribavirin monotherapy, even in PLC/PRF/5 cells with robust HEV production, and resulted in viral clearance. Similar efficiency was seen for HEV genotypes 3 and 4, the main causes of chronic infection. The present findings provide insight concerning the advantage of combination therapy using drugs blocking different steps in the HEV life cycle (internalization and RNA replication) as a potential novel treatment strategy for chronic hepatitis E