Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.     

A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia

Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome. We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31-2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31-2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors.     

A potent non-steroidal anti-inflammatory agent: 2-[3-chloro-4(3-pyrrolinyl)phenyl]propionic acid

Zusammenfassung Die Synthese und biologische Prüfung von 2-[3-Chlor-4(3-pyrrolinyl)phenyl]-propionsäure als neuer entzündungshemmender Stoff wird beschrieben.     

半胱氨酸亚金铵的合成、理化性质及电镀金应用

以半胱氨酸为配体合成一种新型亚金配合物NH4Au(Cys)2,对该配合物进行元素分析、红外光谱、紫外光谱、热失重分析和导电性测量等理化性质研究;以该亚金配合物为金源开展相关的电镀金工艺探索,并通过四因素三水平的正交试验获得其最佳条件参数;采用扫描电子显微镜(SEM)和X线衍射(XRD)对镀金层的表面质量进行探讨。研究结果表明:该目标产物的分子式为NH4Au(Cys)2·2H2O,该配合物中以半胱氨酸的巯基和金配位为成健特征,在170℃以下热稳定性较好,该亚金配合物是一个典型的离子化合物。在电流密度为200~300 A/m2,p H为10.5~12.0,温度为35~45℃,金质量浓度为15~25 g/L的电镀工艺条件下,得到粒度为0.5~1.0μm的单质金,且主要沿着(111)面进行生长。     

随机纳米碳管网络及其渗流性质

数值模拟了实验上构造纳米碳管网络的溶液沉积方法.与一般的随机网络模型不同,将碳管的长度计算在内,而且考虑了不同的空间相交位形.数值模拟发现网络的度分布为高斯分布,平均集聚系数约为0.11.当网络中碳管平均面密度取值在σ0=179 200根/cm2附近时,网络系综达到渗流.在临界点附近,网络的连通概率p、两极之间电导G、...     

Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer

The autocrine hypothesis proposes that a cell produces and secretes a hormone-like substance that can interact with specific membrane receptors on its surface to induce effects such as proliferation. Thus, a cancer cell could act to stimulate its own growth. Bombesin and bombesin-like peptides (BLPs) such as gastrin-releasing peptide (GRP) cause various physiological responses in mammals, including stimulation of proliferation of 3T3 mouse fibroblasts and normal human bronchial epithelial cells in vitro and induction of gastrin cell hyperplasia and increased pancreatic DNA content in vivo in rats. Human small-cell lung cancer (SCLC) cell lines produce and secrete BLPs and can express a single class of high-affinity receptors for BLPs. Exogenously added BLPs can also stimulate the clonal growth and DNA synthesis of SCLC in vitro. These findings suggest that BLPs function as autocrine growth factors for this tumour. One way to test this hypothesis is to interrupt the function of the endogenously produced BLPs. Here, we demonstrate that a monoclonal antibody to bombesin binds to the C-terminal region of BLPs, blocks the binding of the hormone to cellular receptors and inhibits the clonal growth of SCLC in vitro and the growth of SCLC xenografts in vivo. These results demonstrate that BLPs can function as autocrine growth factors for human SCLC.     

十六位微机教学实验系统分析与改进

本文在分析CCT－88／51／98教学实验系统监控程序的基础上，对该教学实验系统监控程序中存在的问题作出了一些改进。     

用脸谱图对太子河本溪市区段河流沉积物中重金属污染进行评价的研究

本文将沉积学原理及国际上新发展的两种重金属污染评价方法与多变量的图表示法——脸谱图相结合,对太子河本溪市区段河道沉积物中重金属的污染状况及潜在生态危害进行了综合性的评价研究。从脸谱图上可以直观地看出各采样点重金属的污染情况和潜在生态危害程度。从研究结果可以看出,太子河本溪市区段河道沉积物中重金属的污染是很严重的。