Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance

G proteins are an important class of regulatory switches in all living systems. They are activated by guanine nucleotide exchange factors (GEFs), which facilitate the exchange of GDP for GTP. This activity makes GEFs attractive targets for modulating disease-relevant G-protein-controlled signalling networks. GEF inhibitors are therefore of interest as tools for elucidating the function of these proteins and for therapeutic intervention; however, only one small molecule GEF inhibitor, brefeldin A (BFA), is currently available. Here we used an aptamer displacement screen to identify SecinH3, a small molecule antagonist of cytohesins. The cytohesins are a class of BFA-resistant small GEFs for ADP-ribosylation factors (ARFs), which regulate cytoskeletal organization, integrin activation or integrin signalling. The application of SecinH3 in human liver cells showed that insulin-receptor-complex-associated cytohesins are required for insulin signalling. SecinH3-treated mice show increased expression of gluconeogenic genes, reduced expression of glycolytic, fatty acid and ketone body metabolism genes in the liver, reduced liver glycogen stores, and a compensatory increase in plasma insulin. Thus, cytohesin inhibition results in hepatic insulin resistance. Because insulin resistance is among the earliest pathological changes in type 2 diabetes, our results show the potential of chemical biology for dissecting the molecular pathogenesis of this disease.     

在线滴定技术-连续流动滴定的应用

该文介绍了一种全新的在线滴定技术连续流动滴定,它通过一个由电子开关控制的与时间变化相连的三口双通螺旋管阀来控制和测定任何时间下（包括滴定终点时）样品与滴定剂的体积比,来代替传统滴定方法必须测定平衡点时滴定剂体积,实现了真正的在线滴定。通过优化系统设置的参数及仪器的部件,对实际样品进行分析,结果显示相对标准偏差低于1%,和传统技术相比无明显差异。仪器可以根据实验需要配置不同的检测系统,如：电位计、电导计及光度计等。同时,本仪器与自动滴定仪相比,消耗的样品和滴定剂是自动滴定仪的十分之一,滴定过程全自动、易于操作,分析速度更快,价格更低,易于广泛使用。