Association between Polymorphisms of the AKT1 Gene Promoter and Risk of the Alzheimer's Disease in a Chinese Han Population with Type 2 Diabetes.

AIMS: Alzheimer's disease (AD) is a multifactor disease that has been reported to have a close association with type 2 diabetes (T2D) where the v-akt murine thymoma viral oncogene homolog 1 (AKT1) plays an important role in the protein synthesis pathways and cell apoptosis processes. Evidence has been shown that AKT1 protein may be related to AD risk among patients with T2D. The aim of this study was to analyze the potential association between single nucleotide polymorphisms of AKT1 promoter and the risk of AD among patients with T2D. METHODS: The association between AKT1 polymorphisms and AD risk in patients with T2D was assessed among 574 consecutive unrelated subjects including 112 AD patients with T2D, 231 patients with AD, and 231 healthy controls in a case-control study. The cognitive function of all subjects was assessed using MMSE. Six single nucleotide polymorphisms with minor allele frequency >0.2 (rs2498786, rs74090038, rs2494750, rs2494751, rs5811155, and rs2494752) in AKT1 promoter were analyzed by polymerase chain reaction (PCR), and the concentration of AKT1 protein in serum was tested using enzyme-linked immunosorbent assay (ELISA). RESULTS: Overall, there was statistically significant difference in AKT1 rs2498786 polymorphism. The CC frequency of AKT1 rs2498786 polymorphism in AD with T2D group and AD control group was significantly higher than that in healthy control group (PAD+T2D vs. health < 0.0001, PAD vs. health < 0.0001). However, the difference was not found between AD with T2D group and AD control group. Compared with healthy control group, the plasma levels of AKT1 protein in AD with T2D group (PAD+T2D vs. health < 0.0001) and AD control group (PAD vs. health = 0.0003) decreased significantly. Among genotypes of AKT1 rs2498786 polymorphism, the AKT1 protein level in GG genotype was significantly higher than that in GC genotype (PGG vs. GC < 0.0001) and CC genotype (PGG vs. CC < 0.0001). CONCLUSION: The study suggests that AKT1 rs2498786 polymorphism in insulin signaling pathway may be associated with AD risk and different genotypes may affects levels of protein expression. However, the polymorphism is not shown to be exclusive in AD patients with T2D.

Spatio-temporal analysis of female breast cancer incidence in Shenzhen, 2007-2012.

INTRODUCTION: Breast cancer is a leading tumor with a high mortality in women. This study examined the spatio-temporal distribution of the incidence of female breast cancer in Shenzhen between 2007 and 2012. METHODS: The data on breast cancer incidence were obtained from the Shenzhen Cancer Registry System. To describe the temporal trend, the average annual percentage change (AAPC) was analyzed using a joinpoint regression model. Spatial autocorrelation and a retrospective spatio-temporal scan approach were used to detect the spatio-temporal cluster distribution of breast cancer cases. RESULTS: Breast cancer ranked first among different types of cancer in women in Shenzhen between 2007 and 2012 with a crude incidence of 20.0/100,000 population. The age-standardized rate according to the world standard population was 21.1/100,000 in 2012, with an AAPC of 11.3%. The spatial autocorrelation analysis showed a spatial correlation characterized by the presence of a hotspot in south-central Shenzhen, which included the eastern part of Luohu District (Donghu and Liantang Streets) and Yantian District (Shatoujiao, Haishan, and Yantian Streets). Five spatio-temporal cluster areas were detected between 2010 and 2012, one of which was a Class 1 cluster located in southwestern Shenzhen in 2010, which included Yuehai, Nantou, Shahe, Shekou, and Nanshan Streets in Nanshan District with an incidence of 54.1/100,000 and a relative risk of 2.41; the other four were Class 2 clusters located in Yantian, Luohu, Futian, and Longhua Districts with a relative risk ranging from 1.70 to 3.25. CONCLUSIONS: This study revealed the spatio-temporal cluster pattern for the incidence of female breast cancer in Shenzhen, which will be useful for a better allocation of health resources in Shenzhen.

Vascular endothelial growth factor gene promoter polymorphisms and Alzheimer's disease risk: a meta-analysis.

AIM: Conclusions on the association between polymorphisms in the vascular endothelial growth factor (VEGF) gene promoter and risk of Alzheimer's disease (AD) are ambiguous, and sufficient evaluation of the association is lacking. Therefore, we performed a meta-analysis of observational studies to explore the association between polymorphisms in the VEGF gene promoter and AD risk. METHODS: Bibliographical searches were performed in the MEDLINE, EMBASE, and China National Knowledge Infrastructure (CNKI) databases without any language limitations. Three investigators independently assessed abstracts for relevant studies and independently reviewed all eligible studies. A meta-analysis was conducted using a fixed- or random-effects model. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used to assess the strength of association. All statistical analyses were performed using Stata 11.0 software. RESULTS: The meta-analysis of 2787 AD cases and 2841 controls from eight published case-control studies on the -2578C/A polymorphism and 1422 AD cases and 1063 controls from four studies on the -1154G/A polymorphism did not show any significant associations. However, in a subgroup analysis stratified by the presence of APOE є4, associations were observed with APOE ε4 (-) for -2578C/A (A vs. C: OR = 1.22, 95% CI = 1.04-1.43, P = 0.014; A/A vs. C/C: OR = 1.59, 95% CI = 1.11-2.27, P = 0.011 and A/A vs. A/C + C/C: OR = 1.46, 95% CI = 1.08-1.99, P = 0.015) and -1154G/A (A vs. G: OR = 0.74, 95% CI = 0.62-0.89, P = 0.001; A/A vs. G/G: OR = 0.57, 95% CI = 0.37-0.87, P = 0.009; A/G vs. G/G: OR = 0.69, 95% CI = 0.53-0.89, P = 0.004 and A/A + A/G vs. G/G: OR = 0.66, 95% CI = 0.52-0.85, P = 0.001). CONCLUSION: This meta-analysis showed the risk role of the -2578 polymorphism and the protective role of the -1154 polymorphism when the APOE є4 status was negative, suggesting that the two polymorphisms in the VEGF promoter may have opposing effects on AD risk in an APOE є4-independent manner.

Genetic polymorphisms of glutathione S-transferase T1 and bladder cancer risk: a meta-analysis.

In recent years, there have been numerous papers emphasizing the relationship between Glutathione S-transferases polymorphisms and bladder cancer risk, but the findings have not reached a consensus. The relationship between glutathione S-transferase T 1 null genotype and bladder cancer susceptibility is now even more disputable. Therefore, we present a meta-analysis of (nested) case-controlled, genotype-based studies (including 37 studies, 6,986 cases and 9,166 controls) examining this association. Using a fixed-effect model, statistically significant increase was observed between glutathione S-transferase T 1 deletion and bladder cancer risk for the overall studies (OR = 1.12; 95% confidence interval (CI): 1.04-1.21; P = 0.004 for Z test; I (2) = 47.43 for heterogeneity). After adjusting the result using trim-and-fill method, the outcome still had significant difference with little downgrade (OR = 1.10, 95% CI = 1.02-1.18). Three potential sources of heterogeneity including ethnicity, source of control and smoking status were also assessed. Minor increased correlation was found only in population-based studies (OR = 1.16; 95% CI = 1.03-1.30; I (2) = 47.16). Our analysis suggests that glutathione S-transferase T 1 null status is associated with a modest increase in the risk of bladder cancer and the difference exiting in source of control has been confirmed. Due to limited sample size, various confounding variables as well as discrepancy in study design, a valid conclusion still cannot be confirmed.

Cigarette smoke extract activates PKC isoforms and down-regulates the expressions of potassium channels BK(Ca) and Kv1.5 in rat bronchial smooth muscle cells.

Large-conductance calcium-activated potassium channel (BK(Ca)) and voltage-gated potassium channel Kv1.5 play an important role in the pathogenesis of bronchial hyperresponsiveness (BHR). It is known that cigarette smoke can induce BHR, however, the role of BK(Ca) and Kv1.5 expression in it remains to be further elucidated. The purpose of the present study was to investigate the direct effects of cigarette smoke extract (CSE) on BK(Ca) and Kv1.5 expression, and the role of protein kinase C (PKC) isoforms activation in primary cultured rat bronchial smooth muscle cells (BSMCs). Primarily cultured rat BSMCs were treated with 5% CSE, the expression and translocation of PKC isoforms were measured by Western blot, and the mRNA and protein levels of BK(Ca) and Kv1.5 alpha-subunits were determined by semi-quantitative RT-PCR and Western blot, respectively. The results showed that 5% CSE induced the translocation of PKCepsilon, PKCeta, PKCtheta from soluble fraction to particulate fraction, and reduced mRNA and protein expressions of BK(Ca) and Kv1.5 alpha-subunits. The decreased expression of potassium channels was partly restored by PKC inhibitor, BIM or Goe6983. In summary, CSE may activate PKC isoforms epsilon, eta, theta, thereby down-regulate the expressions of BK(Ca) and Kv1.5 in BSMCs.

[Effect of exercise stress on cigarette smoking induced downregulation of BKca and Kv1.5 expression in pulmonary arterial smooth muscle cells of rats].

OBJECTIVE: To investigate the effect of exercise stress on chronic cigarette smoking induced downregulation of large conductance calcium-activated potassium channel (BKca) and voltage-dependent delayed rectifier potassium channel (Kv1.5) expression in pulmonary arterial smooth muscle cells of rats. METHODS: Rats were divided into three groups: the normal control group, the smoking control group and the smoking + exercise group. The plasma cortisol level, the potassium channel expression and the pathological changes in lung tissue were determined with HE staining, the immunohistochemistry and the in-situ hybridization. RESULTS: (1) In the smoking + exercise group, the plasma cortisol level was determined immediately after exercise [(1528.7 +/- 469.7) ng/L] and was higher than that determined before exercise [(672.4 +/- 235.7) ng/L] (P < 0.01); (2) The HE staining showed that the chronic pulmonary inflammatory response in the smoking control group was severe while it was mild in the smoking + exercise group; (3) The mRNA and protein expression (OD value) of BKca in the smoking control group (mRNA: 0.2206 +/- 0.0415 for big artery and 0.3935 +/- 0.1378 for small artery; protein: 0.2634 +/- 0.1219 for big artery and 0.0995 +/- 0.0851 for small artery) were less than those in the normal control group. The mRNA expression of BKca in the smoking + exercise group (OD value) (0.5022 +/- 0.1134 for big artery and 0.6408 +/- 0.2135 for small artery) was higher than that in the smoking control group; (4) The mRNA and protein expression of Kv1.5 in the smoking control group (OD value) (mRNA: 0.9354 +/- 0.3290 for big artery and 0.5012 +/- 0.1170 for small artery; protein: 1.1112 +/- 0.3310 for big artery and 0.4736 +/- 0.1250 for small artery) were less than those in the normal control group. The protein expression of Kv1.5 in the smoking + exercise group (0.7445 +/- 0.2690) in small artery was higher than that in the smoking control group. CONCLUSION: Proper exercise stress can decrease inhibition effect of the chronic smoking on the expression of potassium channel BKca and Kv1.5, which perhaps partly results from exercise induced increase of cortisol secretion.

Passive sensitization increases histamine-stimulated calcium signaling and NF-kappaB transcription activity in bronchial epithelial cells.

AIM: To find out if the two aspects of asthma (chronic airway inflammation and bronchial hyperresponsiveness) are related to hypersensitivity of calcium signaling in bronchial epithelial cells. METHODS: Porcine bronchial epithelial cells (PBEC) were divided into sensitized (S) and non-sensitized (N) groups. In group S, the cells were preincubated with serum from ovalbumin sensitized guinea pigs. In group N, the cells were preincubated with serum from nonsensitized guinea pigs. Single cell calcium imaging and ELISA-based NF-kappaB activity were used to evaluate the histamine-stimulated intracellular free calcium level and NF-kappaB activity, respectively. RESULTS: First, 0.1 micromol/L histamine could induce [Ca(2+)](i) oscillations in PBEC of group S, but not in group N. Second, 1 micromol/L histamine could induce [Ca(2+)](i) oscillations of PBEC in both group S and group N. The [Ca(2+)](i) oscillation frequency of PBEC was significantly higher in group S than in group N, though the [Ca(2+)](i) oscillation amplitude showed no difference between the two groups. Finally, when 10 micromol/L histamine was used to stimulate PBEC, a transient initial increase followed by a sustained elevation (FSE) of [Ca(2+)](i) was observed in PBEC in both groups. The amplitude of the FSE of [Ca(2+)](i) in PBEC was significantly higher in group S than in group N. The subsequent NF-kappaB activity was in accordance to the calcium oscillation frequency evoked by histamine, but not to the amplitude. CONCLUSION: It was suggested that the increased sensitivity of calcium signaling in bronchial epithelial cells might contribute to the exorbitant inflammation or increased susceptibility in asthmatic airway epithelial cells.

Effect of chronic cigarette smoking on large-conductance calcium-activated potassium channel and Kv1.5 expression in bronchial smooth muscle cells of rats.

To investigate the role of potassium channels in the pathogenesis of airway hyperresponsiveness induced by cigarette smoking, the alteration in expression of large-conductance calcium-activated potassium channel (BKca) and voltage-dependent delayed rectifier potassium channel (Kv1.5) in bronchial smooth muscle cells were investigated in chronic cigarette smoking rats. Airway responsiveness was determined, hematoxylin and eosin staining, immuno-histochemistry, in-situ hybridization and western blot techniques were used. The results showed: (1) Chronic cigarette smoking down-regulated the protein synthesis and mRNA expression of BKca and Kv1.5 in bronchial and bronchiolar smooth muscles. (2) BKca decreased more markedly than Kv1.5 in bronchi, but there was no difference between them in bronchioli. (3) No changes in the expression of these two potassium channel proteins were found in extracted cell membrane protein from lung tissue. The results suggest that chronic cigarette smoking can down-regulate the levels of BKca and Kv1.5 in rat bronchial smooth muscle cells in vivo, which might contribute to the mechanism of airway hyperresponsiveness induced by cigarette smoking.