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A polymorphism in the promoter region of uncoupling protein 2 gene -866G/A has been associated with its expression levels in adipose tissue, the risk of obesity, and metabolic abnormalities. Our purpose was to examine the associations of -866G/A with body fat and the risk of metabolic syndrome in a random sample of 4018 Asians (1858 men and 2160 women) from three ethnic groups (Chinese, Malay, and Indian). The minor allele frequency of -866G/A polymorphism in South Asians was similar to that in whites. After adjustment for covariates including age, cigarette smoking, and physical activity, the -866A/A genotype was associated with higher waist-to-hip ratio as compared with the wild-type genotype in Chinese and Indian men (p = 0.018 and p = 0.046, respectively). Moreover, Indian men with -866A/A genotype had a significantly increased risk of metabolic syndrome as compared with those homozygous for the wild-type (odds ratio, 2.66; 95% confidence interval, 1.21 to 5.88; p = 0.015). Such a risk was mainly caused by the excess presence of hypertriglyceridemia and central obesity. Our findings indicate that the uncoupling protein 2 gene -866G/A polymorphism may increase the risks of central obesity and metabolic syndrome, with greater effects on Asian men.  相似文献   

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RAP46 is a eukaryotic cochaperone that associates with several proteins, including the heat shock protein hsp70/hsc70 and the glucocorticoid receptor (GR). Here we show a downregulation of GR-mediated transactivation by RAP46 via a mechanism independent of a cytoplasmic action of this cochaperone. We demonstrate a specific cytoplasmic-nuclear recruitment of RAP46 by the liganded GR that results in inhibition of the transactivation function of the receptor. A repeated sequence motif [EEX(4)](8) at the NH(2) terminus of RAP46 or BAG-1L, a larger isoform of RAP46, is responsible for this downregulation of GR activity. BAG-1, a shorter isoform with only a duplication of the [EEX(4)] sequence, does not inhibit GR activity. The [EEX(4)](8) motif, when linked to an otherwise unrelated protein, abrogated the inhibitory action of endogenous RAP46 on GR-mediated transactivation. The nuclear effects of RAP46 and BAG-1L are specific since GR-mediated inhibition of AP-1 activity was not affected. These studies identify the [EEX(4)](8) sequence as a signature motif for inhibition of GR-mediated transactivation and demonstrate a specific nuclear action of a eukaryotic cochaperone in the regulation of GR activity.  相似文献   

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戴红娟  胡芳 《生命科学》2011,(1):96-101
糖皮质激素受体(glucocorticoid reccptor,GR)广泛分布在脊椎动物中枢神经系统的多个组织区域中,而且结构及功能保守。在与激素结合的状态下,受体能够特异性地与靶基因的启动子结合影响基因的表达,或通过激活G蛋白偶联的信号途径引起神经递质的释放。外界环境刺激和外源糖皮质激素暴露都能改变GR在脑中的表达,并对神经的发育及功能产生影响,同时也对学习、记忆以及情感等高级神经活动和行为起到重要的作用。该文对脊椎动物糖皮质激素受体的结构和在脑中的分布,以及对神经发育和功能的影响及其中的分子机制的最新研究进展进行综述。  相似文献   

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Objective: We investigated whether the presence of concomitant coronary heart disease (CHD) in patients with peripheral arterial disease (PAD) can be explained by intra‐abdominal fat accumulation and compared different measures of adiposity as predictors of CHD in patients with PAD. Research Methods and Procedures: Data were collected from patients enrolled in the Second Manifestations of ARTerial disease (SMART) study, an ongoing prospective cohort study of patients with manifest vascular disease or vascular risk factors at the University Medical Centre Utrecht. The current analysis includes 315 patients, mean age 59 ± 10 years, who had PAD with (n = 79) or without (n = 236) CHD. Parameters of adiposity were measured, and intra‐abdominal fat and subcutaneous fat were measured ultrasonographically. Metabolic syndrome was defined according to Adult Treatment Panel III. Results: The prevalence of metabolic syndrome was higher among patients with CHD (63%) than among patients without CHD (48%). All parameters of adiposity indicated more fat in patients with CHD, except for subcutaneous fat. Waist circumference was associated with 64% higher prevalence of CHD (confidence interval, 20% to 123%) per 1 standard deviation increase in waist circumference after adjustment for age and sex. The odds ratio for waist circumference remained virtually the same after additional adjustment for the components of the metabolic syndrome and smoking. Discussion: An increased waist circumference, a crude measure of intra‐abdominal fat, is associated with an increased risk of concomitant CHD in patients with PAD.  相似文献   

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The glucocorticoid receptor (GR) is an important player in the life of a cell. This is underlined by a cohort of protein and nucleic acid structures interacting with the GR. Among many issues surrounding GR activity that are under active investigation, the role of microtubules (MTs) is still unclear. This article aims to evaluate the ayes and noes in favor of microtubule importance and then form a hypothesis on their function in GR activity.  相似文献   

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Objective: Retinol binding protein‐4 (RBP4) has been reported to impair insulin sensitivity throughout the body. We investigated the relationship between serum RBP4 levels and adiposity indices as well as metabolic risk variables. Research Methods and Procedure: We recruited a total of 102 healthy women 21 to 67 years old. We assessed body composition by computed tomography and divided the study population into four groups based on body weight and visceral fat area (non‐obese without visceral adiposity, non‐obese with visceral adiposity, obese without visceral adiposity, and obese with visceral adiposity). Serum RBP4 levels were measured by radioimmunoassay. Results: Despite similar levels of total body fat, non‐obese women had lower systolic blood pressure, total cholesterol, triglyceride (TG), low‐density lipoprotein (LDL)‐cholesterol levels, insulin resistance indices, and RBP4 levels than non‐obese women with visceral adiposity and had higher high‐density lipoprotein‐cholesterol levels. Similarly, obese women without visceral adiposity had lower blood pressure, total cholesterol, TG levels, insulin resistance indices, and RBP4 levels than obese women with visceral adiposity. In addition, despite having increased body fat, obese women without visceral adiposity had lower TGs, insulin resistance indices, and serum RBP4 levels than non‐obese women with visceral adiposity. By step‐wise multiple regression analysis, visceral fat areas and LDL‐cholesterol levels independently affected RBP4 levels. Discussion: We determined that serum RBP4 levels are independently associated with visceral fat and LDL‐cholesterol levels. These results suggest that, irrespective of body weight, visceral obesity is an independent predictor of serum RBP4 levels, and RBP4 may represent a link between visceral obesity and cardiovascular disease.  相似文献   

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There is growing evidence of the correlation between cancer and reactive oxygen species (ROS), especially superoxide. Low expression levels of the Mn‐superoxide dismutase (SOD2) enzyme have been reported in cancer patients. Genetic variation in the regulatory regions of the SOD2 gene may increase the risk of cancer. We identified a genetic variation (G1677T, rs2Y758Y339) in the vicinity of the enhancer region located in intron 2 of the SOD2 gene that creates a potential glucocorticoid responsive element, and developed an assay to screen DNA samples of 220 individuals (73 control, 59 prostate cancer survival individuals and 88 lung cancer biopsies). There were no significant differences in the genotype frequency distribution among prostate, lung cancer and control (p = 0.074 and 0.057, respectively). However, we identified an association of T allele with a decreased risk of lung cancer (OR = 0.525, p = 0.037). The use of the G1677T polymorphism of SOD2 gene as a genetic risk marker may suggest new approaches for detection, prevention, treatment, and prognosis of cancer. Copyright © 2009 John Wiley & Sons, Ltd.  相似文献   

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《Epigenetics》2013,8(6):851-859
Previous studies have found that expression of the Glucocorticoid Receptor (GR) is altered or reduced in various cancers, while the GR promoter has been shown to be methylated in gastric, lung, and colorectal cancers. Examining a small cohort of matched normal and breast cancer samples we found that GR levels were dramatically reduced in almost all tumors in relation to their normal tissue. The methylation status of the GR promoter was assessed to determine if this observed decrease of expression in breast tumors could be due to epigenetic regulation. While it was not methylated in normal tissue, the GR proximal promoter was methylated in 15% of tumor samples, particularly, but not exclusively, in Estrogen Receptor positive tumors. GR expression in these tumors was particularly low and loss of GR expression was specifically correlated with methylation of the proximal promoter GR B region. Overall, these results show that hypermethylation of the promoter in tumors is a frequent event and suggests that GR may act as a tumor suppressor in breast tissue.  相似文献   

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目的:探讨热休克蛋白90(HSP90)在糖皮质激素(GC)信号通路中的作用及其对气道黏蛋白(MUC)5AC表达的调控机制。方法:体外培养气道上皮细胞株BEAS-2B,给予HSP90特异性阻断剂格尔德霉素(GA)和地塞米松(DEX)刺激,比较各组MUC5AC的含量,糖皮质激素受体(GR)的核蛋白表达和GR结合活性。结果:与对照组相比,DEX组的MUC5AC mRNA和蛋白水平降低,伴GR核蛋白水平增高(P0.05);与DEX组相比,GA+DEX组MUC5AC mRNA和蛋白水平升高,GR核蛋白水平降低。放射配体结合实验显示,与对照组相比,GA组的受体最大结合容量(Bmax)降低,平衡解离常数(Kd)升高。结论:HSP90可参与GC及GR的抗气道黏液高分泌效应,其抑制剂可阻断上述效应,该效应是通过降低GR的结合活性来调控的。  相似文献   

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We have studied the presence and functional implications of membrane glucocorticoid receptor (mGR) in several wild type (WT) and mutant mouse lymphoid cell lines (nuclear transfer decrease, NT(-); nuclear transfer increase, NT(i); and receptorless, R(-)). Direct fluorescent antibody staining revealed large aggregates of mGR-specific fluorescing antigens in the plasma membrane of the WT and mGR-enriched (mGR(++)) S-49 cells. While R(-) cells totally lacked mGR, this receptor level was low in NT(-) and NT(i) groups. FACS analysis corroborated these results, showing a approximately 4-10-fold difference between the highest mGR levels (mGR(++)) and the R(-) and NT(i) cells. Membrane extracts were analyzed for mGR by immunoblotting. Multiple receptor forms, ranging in M(r) from 94,000 to > 200,000, were observed in the WT cells, while only smaller peptides (85,000-94,000) were found in NT(-) cells. No detectable immunoreactive bands were identified in either membrane or cytosol immunoprecipitates of NT(i) and R(-) cell groups. Within 48 h post dexamethasone exposure > 98% of WT and mGR(++) S-49 cells underwent apoptosis, compared to 0-30% in the mutant cells, albeit the total receptor number is two to three times higher in NT(i) compared to WT. These results suggest a better correlation between the quantity and quality of mGRs (rather than total cellular GRs) and the ability of glucocorticoids (GCs) to lyse lymphoid cells.  相似文献   

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目的:研究慢性束缚应激时大鼠脑内糖皮质激素受体的变化以及逍遥散、四君子汤、金匮肾气丸三种中药复方对其影响.方法:制作大鼠束缚应激模型,用特制束缚架连续束缚7 d与21 d,每天3 h用免疫组织化学方法结合图像分析检测中枢(海马CA1区、齿状回、大脑皮质)糖皮质激素受体的变化.结果:慢性束缚应激后,大鼠海马CA1区、大脑皮层和齿状回GR免疫反应阳性细胞平均总面积和阳性细胞数目在慢性应激的早期(7d模型组)明显增多(P<0.05),免疫反应强度明显增强(P<0.01).在慢性应激的后期(21 d模型组),则表现为相关脑区GR免疫反应阳性细胞平均总面积和阳性细胞数目均明显减少(P<0.05),免疫反应强度明显减弱(P<0.01).中药复方各组相关脑区神经元GR免疫反应阳性细胞平均总面积和阳性细胞数目较21 d模型组明显增高,免疫反应强度明显增强,三给药组之间并无明显差异,说明三给药组均能使GR含量保持于较高的状态,同时能保持GR免疫活性,其中又以逍遥散作用为明显.结论:逍遥散、四君子汤和金匮肾气丸明显逆转糖皮质激素受体下降趋势.  相似文献   

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