GTS-21 Promotes α7 nAChR to Alleviate Intestinal Ischemia-Reperfusion-Induced Apoptosis and Inflammation of Enterocytes.

BACKGROUND Intestinal ischemia-reperfusion injury is a serious intestinal disease, with main symptoms of inflammatory reaction and severe oxidative damage. In addition, GTS-21-induced alpha7 nAChR has been shown to exert anti-inflammatory effects and anti-oxidation effects in various organs. However, whether alpha7 nAChR can alleviate ischemia-reperfusion-induced intestinal injury is unclear. MATERIAL AND METHODS We used intestinal epithelial cells (IEC-6) to perform the experiments. Oxygen glucose deprivation/reoxygenation (OGD/R) was used to simulate the physiological environment of ischemia-reperfusion. First, the expression of alpha7 nAChR was determined in these cells which was cultured under OGD/R conditions. After that, the GTS-21 was used to treat these cells and the levels of inflammatory factors (TNF-alpha, IL-1ß, IL-6, and IL-10) were assessed by ELISA. Next, the levels of ROS, SOD, and MDA were determined in IEC-6 cells. Finally, the apoptosis rates of IEC-6 cells were measured by flow cytometry. RESULTS Results showed that the expression of TNF-alpha, IL-1ß, and IL-6 was enhanced when the IEC-6 cells were cultured under OGD/R conditions. However, after treatment with GTS-21, the levels of these proinflammatory factors were suppressed. In addition, the levels of ROS and MDA were also inhibited and the expression of SOD was promoted after GTS-21 treatment. We also found that the ratios of apoptotic cells declined after GTS-21 treatment. CONCLUSIONS GTS-21-induced alpha7 nAChR decreased the OGD/R-induced inflammatory response, oxidative damage, and apoptosis of intestinal epithelial cells.

PRISMA-compliant meta-analysis: association of metabolic syndrome and its components with the risk of chronic obstructive pulmonary disease.

A preferred reporting items for systematic reviews and meta-analyses-compliant meta-analysis was conducted to test the association of metabolic syndrome and its components with the risk of chronic obstructive pulmonary disease (COPD) based on observational studies. Literature retrieval, article selection and data extraction were done by two researchers independently. Total 16 articles (20 independent studies) were analyzed with 3915 COPD patients and 25,790 control participants. Overall analysis indicated that metabolic syndrome was significantly associated with 1.53-fold (95% confidence interval [CI]: 1.23-1.9, P<0.001) increased risk of COPD, with moderate heterogeneity (I2 = 74.3%). Of four metabolic components, hypertension was significantly associated with 1.55-fold (95% CI: 1.14-2.11, P=0.005) increased risk, and averaged levels of systolic blood pressure (weighted mean difference [WMD] = 3.626 mmHg, 95% CI: 1.537-5.714, P<0.001) and glucose (WMD = 2.976 mmol/l, 95% CI: 0.141-5.812; P=0.04) were significantly higher in COPD patients than in control participants, yet that of body mass index (WMD = -1.463 kg/m2, 95% CI: -2.716 to -0.211, P=0.022) were significantly lower. Gender, race, source of control participants, matched status and sample size were identified as accountable factors for significant heterogeneity. Altogether, the presence of metabolic syndrome, especially its component hypertension, was associated with significantly increased risk of COPD.

The mutation of Trp64Arg in ß3-adrenoreceptor-encoding gene is significantly associated with increased hypertension risk and elevated blood pressure: a meta-analysis.

This meta-analysis was implemented to test the association of a missense mutation, Trp64Arg, in ß3-adrenoreceptor-encoding gene (ADRB3) with both hypertension risk and blood pressure (BP) changes. A systematic search of three publicly-available databases was launched to look for articles published as of December 2016. Qualification appraisal and data extraction were independently done by two researchers. Pooled estimates were expressed as odds ratio (OR) or weighted mean difference (WMD), and their 95% confidence intervals (95% CIs). There were separately 21 (3750/4225 patients/controls) and 17 (6100 subjects) individual studies for hypertension risk and BP changes. Integral analyses revealed that Trp64Arg mutation was associated with the significantly increased risk of hypertension, and particularly, the 64Trp/64Arg heterozygote carriers were 1.23-times more likely to develop hypertension compared with the 64Trp/64Trp homozygote carriers (OR = 1.23, 95% CI: 1.02~1.46, P = 0.021). Publication bias was extremely low for all integral comparisons. In stratified analyses, significance was spotted in populations of Chinese descent, in retrospective studies, in hospital-based studies, in age-matched case-control studies, in studies enrolling patients with mean body mass index < 25 kg/m2 and in studies with total sample size ≥ 240. Heterogeneity was improved for most stratified comparisons. Further in hypertensive patients, the 64Trp/64Arg heterozygote carriers had significantly higher systolic (WMD = 0.87 mmHg, 95% CI: 0.39~1.35, P < 0.001) and diastolic (WMD = 0.88 mmHg, 95% CI: 0.59~1.17, P < 0.001) BP than 64Trp/64Trp homozygote carriers. Altogether, ADRB3 gene Trp64Arg mutation was significantly associated with an increased predisposition toward hypertension and elevated systolic/diastolic BP in hypertensive patients, suggesting that Trp64Arg is an important hypertension-susceptibility marker.

A meta-analytical assessment of STK39 three well-defined polymorphisms in susceptibility to hypertension.

Serine/threonine kinase 39 gene (STK39) is one of the promising hypertension-susceptibility genes identified by a genome-wide association study in 2009, whereas subsequent validation in other ethnic groups is unsatisfactory, with inconsistent and inconclusive findings. We therefore aimed to meta-analytically assess the risk prediction of STK39 three polymorphisms, rs6749447, rs35929607 and rs3754777, for primary hypertension. Literature search and data collection were independently completed by two authors. Nine articles were pooled in this study. Overall analyses failed to see any significant associations of rs6749447, rs35929607 and rs3754777 with hypertension risk (odds ratio: 1.27, 0.95 and 1.21; P = 0.270, 0.507 and 0.153, respectively), and there was evident heterogeneity for three comparisons (I(2) > 80%). Meta-regression analyses indicated that smoking was a significant risk factor for the association of rs3754777 with hypertension (P = 0.017). As reflected by the Begg's and Filled funnel plots, as well as Egger's tests, there were low probabilities of publication bias. In conclusion, our meta-analytical findings suggest that STK39 might not be a hypertension-susceptibility gene.

Sevoflurane postconditioning improves long-term learning and memory of neonatal hypoxia-ischemia brain damage rats via the PI3K/Akt-mPTP pathway.

BACKGROUND: Volatile anesthetic postconditioning has been documented to provide neuroprotection in adult animals. Our aim was to investigate whether sevoflurane postconditioning improves long-term learning and memory of neonatal hypoxia-ischemia brain damage (HIBD) rats, and whether the PI3K/Akt pathway and mitochondrial permeability transition pore (mPTP) opening participate in the effect. METHODS: Seven-day-old Sprague-Dawley rats were subjected to brain HI and randomly allocated to 10 groups (n=24 each group) and treated as follows: (1) Sham, without hypoxia-ischemia; (2) HI/Control, received cerebral hypoxia-ischemia; (3) HI+Atractyloside (Atr), (4) HI+Cyclosporin A (CsA), (5) HI+sevoflurane (Sev), (6) HI+Sev+ LY294002 (LY), (7) HI+Sev+ L-NAME (L-N), (8) HI+Sev+ SB216763 (SB), (9) HI+Sev+Atr, and (10) HI+Sev+CsA. Twelve rats in each group underwent behavioral testing and their brains were harvested for hippocampus neuron count and morphology study. Brains of the other 12 animals were harvested 24h after intervention to examine the expression of Akt, p-Akt, eNOS, p-eNOS, GSK-3ß, p-GSK-3ß by Western bolting and mPTP opening. RESULTS: Sevoflurane postconditioning significantly improved the long-term cognitive performance of the rats, increased the number of surviving neurons in CA1 and CA3 hippocampal regions, and protected the histomorphology of the left hippocampus. These effects were abolished by inhibitors of PI3K/eNOS/GSK-3ß. Although blocking mPTP opening simulated sevoflurane postconditioning-induced neuroprotection, it failed to enhance it. CONCLUSIONS: Sevoflurane postconditioning exerts a neuroprotective effect against HIBD in neonatal rats via PI3K/Akt/eNOS and PI3K/Akt/GSK-3ß pathways, and blockage of mPTP opening may be involved in attenuation of histomorphological injury.