Di Yu

Maternal lifestyle factors in pregnancy and congenital heart defects in offspring: review of the current evidence

The prognosis of children with congenital heart defects(CHDs) continues to improve with advancing surgical techniques; however, lack of information about modifiable risk factors for malformations in cardiovascular development impeded the prevention of CHDs. We investigated an association between maternal lifestyle factors and the risk of CHDs, because epidemiological studies have reported conflicting results regarding maternal lifestyle factors and the risk of CHDs recently. A review published on 2007 provided a summary of maternal exposures associated with an increased risk of CHDs. As part of noninherited risk factors, we conducted a brief overview of studies on the evidence linking common maternal lifestyle factors, specifically smoking, alcohol, illicit drugs, caffeine, body mass index and psychological factors to the development of CHDs in offspring. Women who smoke and have an excessive body mass index(BMI) during pregnancy are suspected to be associated with CHDs in offspring. Our findings could cause public health policy makers to pay more attention to women at risk and could be used in the development of population-based prevention strategies to reduce the incidence and burden of CHDs. However, more prospective studies are needed to investigate the association between maternal lifestyle factors and CHDs.

Maternal Socioeconomic Status and the Risk of Congenital Heart Defects in Offspring: A Meta-Analysis of 33 Studies

Background We conducted this meta-analysis to address the open question of a possible association between maternal socioeconomic status and congenital heart defects (CHDs). Methods We searched MEDLINE and EMBASE from their inception to January 1, 2014 for case-control and cohort studies that assessed the association between maternal socioeconomic status and the risk of CHDs. Study-specific relative risk estimates were polled according to random-effect or fixed-effect models. Results From 3343 references, a total of 31 case-control studies and 2 cohort studies were enrolled in this meta-analysis, including more than 50,000 cases. We observed that maternal educational attainment, family income and maternal occupation were negatively associated with an 11% (pooled RR = 1.11, 95% CI: 1.03, 1.21), 5% (pooled RR = 1.05, 95% CI: 1.01, 1.09) and 51% (pooled RR = 1.51, 95% CI: 1.02, 2.24) increased risk of CHDs, respectively. In a subgroup analysis by geographic region, the results were inconsistent for the European region (RR = 1.29, 95% CI: 0.99–1.69) and USA/Canada region (RR = 1.06, 95% CI: 0.97, 1.16) in maternal educational attainment. Conclusion In summary, this meta-analysis suggests that a lower degree of maternal socioeconomic status is modestly associated with an increased risk of CHDs. However, further investigations are needed to confirm the association.

The Succinate Receptor GPR91 Is Involved in Pressure Overload-Induced Ventricular Hypertrophy

Background Pulmonary arterial hypertension is characterized by increased pressure overload that leads to right ventricular hypertrophy (RVH). GPR91 is a formerly orphan G-protein-coupled receptor (GPCR) that has been characterized as a receptor for succinate; however, its role in RVH remains unknown. Methods and Results We investigated the role of succinate-GPR91 signaling in a pulmonary arterial banding (PAB) model of RVH induced by pressure overload in SD rats. GPR91 was shown to be located in cardiomyocytes. In the sham and PAB rats, succinate treatment further aggravated RVH, up-regulated RVH-associated genes and increased p-Akt/t-Akt levels in vivo. In vitro, succinate treatment up-regulated the levels of the hypertrophic gene marker anp and p-Akt/t-Akt in cardiomyocytes. All these effects were inhibited by the PI3K antagonist wortmannin both in vivo and in vitro. Finally, we noted that the GPR91-PI3K/Akt axis was also up-regulated compared to that in human RVH. Conclusions Our findings indicate that succinate-GPR91 signaling may be involved in RVH via PI3K/Akt signaling in vivo and in vitro. Therefore, GPR91 may be a novel therapeutic target for treating pressure overload-induced RVH.

Association between alcohol consumption during pregnancy and risks of congenital heart defects in offspring: meta-analysis of epidemiological observational studies

BackgroundTo explore the association between maternal alcohol consumption and/or binge drinking and congenital heart defects (CHDs), we conducted a meta-analysis for more sufficient evidence on this issue.MethodsWe searched Medline, EMBASE, and the Cochrane Library from their inceptions to December 2014 for case-control and cohort studies that assessed the association between maternal alcohol consumption and CHD risk. Study-specific relative risk estimates were calculated using random-effect or fixed-effect models.ResultsA total of 19 case-control studies and 4 cohort studies were included in the meta-analysis. We observed a null association between maternal alcohol consumption during pregnancy and the risk of CHDs. Even in the analysis of different trimesters of pregnancy, we found little association between the two.ConclusionsThis meta-analysis suggests that maternal alcohol consumption is modestly not associated with the risk of CHDs. However, further investigation is needed to confirm this conclusion.

Neuroprotective effect of nicorandil through inhibition of apoptosis by the PI3K/Akt1 pathway in a mouse model of deep hypothermic low flow

OBJECTIVE Nicorandil exerts a protective effect on ischemia-reperfusion (I/R) injury in the brain and kidney through anti-apoptotic mechanisms. However, the mechanism by which nicorandil protects against I/R injury induced by deep hypothermic low flow (DHLF) remains unclear. METHODS We used a cerebral I/R model induced by DHLF to determine the neuroprotective effects and possible mechanisms of nicorandil. RESULTS Hematoxylin-eosin (HE) staining and in situ terminal deoxynucleotidyl transferase UTP nick end labeling (TUNEL) assay were used to detect changes in cell morphology and the number of apoptotic cells in hippocampus, respectively. The apoptotic regulators including Bcl-2, Bax, Akt, and p-Akt (the active, phosphorylated form of Akt) were examined by Western blot (WB). Histopathological findings showed that nicorandil significantly alleviated morphological damage in hippocampal and reduced the number of TUNEL-positive nuclei induced by DHLF. Nicorandil also increased the expression of Bcl-2 and decreased the expression of Bax, while increasing p-Akt level. Consistent with these results, nicorandil-mediated neuroprotection was reduced in the Akt1+/- mutant mice and inhibited by LY294002, a PI3K inhibitor. CONCLUSIONS These findings showed that nicorandil provides a neuroprotective role in DHLF-induced I/R injury by inhibiting apoptosis via activation of the PI3K/Akt1 signaling pathway.

Maternal parity and the risk of congenital heart defects in offspring: a dose-response meta-analysis of epidemiological observational studies.

Background Epidemiological studies have reported conflicting results regarding maternal parity and the risk of congenital heart defects (CHDs). However, a meta-analysis of the association between maternal parity and CHDs in offspring has not been conducted. Methods We searched MEDLINE and EMBASE for articles catalogued between their inception and March 8, 2014; we identified relevant published studies that assessed the association between maternal parity and CHD risk. Two authors independently assessed the eligibility of the retrieved articles and extracted data from them. Study-specific relative risk estimates were pooled by random-effects or fixed-effects models. From the 11272 references, a total of 16 case-control studies and 3 cohort studies were enrolled in this meta-analysis. Results The overall relative risk of CHD in parous versus nulliparous women was 1.01 (95% CI, 0.97–1.06; Q = 32.34; P = 0.006; I2 = 53.6%). Furthermore, we observed a significant association between the highest versus lowest parity number, with an overall RR = 1.20 (95% CI, 1.10–1.31; (Q = 74.61, P<0.001, I2 = 82.6%). A dose–response analysis also indicated a positive effect of maternal parity on CHD risk, and the overall increase in relative risk per one live birth was 1.06 (95% CI, 1.02–1.09); Q = 68.09; P<0.001; I2 = 80.9%). We conducted stratified and meta-regression analyses to identify the origin of the heterogeneity among studies. A Galbraith plot was created to graphically assess the sources of heterogeneity. Conclusion In summary, this meta-analysis provided a robust estimate of the positive association between maternal parity and risk of CHD.

Sildenefil increases connexin 40 in smooth muscle cells through activation of BMP pathways in pulmonary arterial hypertension

C disease (CVD) is one of the leading causes of serious illness and death worldwide. Screening for the risk factors of CVD (i.e. hypertension, hyperglycemia, hypercholesteremia and obesity) allows for early prevention and decreased risk of the development of CVD. We looked at the prevalence of these risk factors among adolescents at Jacobo Z. Memorial National High School Laguna, Philippines. An analytical cross-sectional design was done using a convenience sampling of 303 adolescents aged 12-17 in Jacobo Z. Gonzales Memorial National High School. The information on dependent and independent variables were determined through questionnaires, actual measurements and blood chemistry analysis. Data was analyzed using State SE to determine the Odds Ratio for each group. The groups were divided based on diet, physical activity, familial history of disease and smoking status. The prevalence of hypertension, hyperglycemia, hypercholesterolemia, central obesity, and obesity was 36.33%, 48.51%, 38.94%, 35.31%, and 7.61%, respectively. Attributes related to hypertension included a family history of diabetes. Those related to hyperglycemia were passive smoking and a family history of heart disease. Attributes related to hypercholesterolemia were sodium consumption above the daily allowable limit. There are certain variables that increase the odds of developing different risk factors. Family history of heart disease, being a passive-smoker and low physical activity increases the odds of having hyperglycemia. Sodium consumption above allowable daily intake increases the odds of having hypercholesterolemia. Family history of diabetes mellitus is associated with increased odds of developing hypertension.BACKGROUND Pulmonary arterial hypertension (PAH) is a cardiovascular disorder associated with enhanced proliferation and suppressed apoptosis of pulmonary arterial smooth muscle cells (PASMCs). The sildenafil can regulate the Connexin (Cx) 43 in the PASMCs and thus inhibit the PASMCs proliferation and the remodeling of pulmonary arterial. However, how sildenafil exert regulation in the Cx40 in the PASMCs in PAH remains unclear. METHODS AND RESULTS Using the rat PAH model induced by the monocrotoline, we demonstrated that the Cx40 in the PASMCs is down-regulated in the PAH. The sildenafil promotes the up-regulation of Cx40 in the PASMCs via bone morphogenetic protein (BMP) signaling, accompanied by an anti-proliferative response in PASMCs. Inhibition of the BMP axis reverses the up-regulation of Cx40 and anti-proliferation of the sildenafil in these cells. In monocrotaline-induced PAH rat models, which display reduced levels of BMP signaling, this study further indicates that the BMP-Cx40 axis is activated in lungs following the sildenafil treatment. Furthermore, we also find in vitro that sildenafil increases the Cx40 expression of PASMCs isolated from MCT-PAH rats and inhibit the proliferation of these cells. These phenomenon are reversed by LDN-193189, the antagonist of type II receptor for bone morphogenetic protein (BMPR2) treatment, providing strong evidence for the protect effect of sildenafil and the BMP-Cx40 axis involvement. CONCLUSIONS Taken together, these data suggest the sildenafil activate BMP-Cx40 signaling in the PAH. This axis may be a potential therapeutic target in PAH.Objective: Microglial cells are part of endogenous defense mechanisms to prevent hypoxia-involved neonatal stroke, thus increasing microglia proliferation may provide a new therapeutic method. Methods: In this study, we used western blot, cell cycle assay, proliferation assay, RT-PCR, RNA interference, lentivirus transduction technologies to explore the role of Ligusticum wallichii on the proliferation of hypoxia-induced human microglia cells. Results: In our study, we primarily found that Ligusticum wallichii enhance the proliferation of hypoxia-stimulated human microglia cells. Furthermore, Ligusticum wallichii regulated the expression of MET gene, encoding a cell surface receptor tyrosine kinase for recognizing hepatocyte growth factor ligand, acts an important down-stream effective molecule for Ligusticum wallichii in treatment with hypoxia-induced human microglia. Moreover, Ligusticum wallichii enhances the binding of HIF-1α to the promoter of MET gene in hypoxia-treated human microglia, providing the rational explanation why hypoxia-administrated human microglia treated by ligusticum wallichii have highest MET expression. Conclusion: We have identified a potential mechanism by which MET regulated by HIF-1α contributes to Ligusticum wallichii-mediated increase of proliferation of hypoxia-induced human microglia. Thus Ligusticum wallichi and targeting MET should be considered as two potential strategies for enhancing the hypoxia-stimulated human microglia.

MTHFR A1298C polymorphisms reduce the risk of congenital heart defects: a meta-analysis from 16 case-control studies

BackgroundMethylenetetrahydrofolate reductase (MTHFR) plays a crucial role in the hyperhomocysteinemia, which is a risk factor related to the occurrence of congenital heart defect (CHD). However, the association between MTHFR polymorphism and CHD has been inconclusive.MethodsWe conducted an updated meta-analysis to provide comprehensive evidence on the role of MTHFR A1298C polymorphism in CHD. Databases were searched and a total of 16 studies containing 2207 cases and 2364 controls were included.ResultsWe detected that a significant association was found in the recessive model (CC vs. AA + AC: OR = 1.38, 95% CI: 1.10–1.73) for the overall population. Subgroup analysis showed that associations were found in patients without Down Syndrome in genetic models for CC vs. AA (OR = 1.47, 95% CI: 1.01–2.14), CC vs. AC (OR = 1.29, 95% CI: 1.00–1.66) and recessive model (OR = 1.44, 95% CI: 1.14–1.82). We conducted a meta-regression analysis, Galbraith plots and a sensitivity analysis to assess the sources of heterogeneity.ConclusionsIn summary, our present meta-analysis supports the MTHFR 1298C allele as a risk factor for CHD. However, further studies should be conducted to investigate the correlation of plasma homocysteine levels, enzyme activity, and periconceptional folic acid supplementation with the risk of CHD.

VEGF Polymorphisms do not contribute to the risk of congenital heart defect

Objective: To clarify the role of VEGF polymorphisms in CHD, we performed a meta-analysis to determine the association between these three variants and risk of CHD. Methods: Our meta-analysis included a total of 6, 4, and 6 research articles for each of the C2578A, G1154A, and G634C polymorphisms, respectively. Data extraction and study quality assessment were performed in duplicate. Summary odds ratios (ORs) and 95% confidence intervals (CIs) of allele contrast and genotype contrast were estimated using either a fixed or random effects model. The Q-statistic test was used to identify heterogeneity and a funnel plot was adopted to evaluate publication bias. Results: Six articles containing 1080 cases and 2289 controls were relevant to C2578A, 4 researches containing 528 cases and 1036 controls were relevant to G1154A, and 6 articles containing 1081 cases and 2281 controls were relevant to G634C. The results of overall meta-analysis showed that none of the VEGF C2578A, G1154A, G634C increased the susceptibility of CHD. In summary, this meta-analysis demonstrates that the three analyzed VEGF polymorphisms do not increase the risk of CHD. Conclusions: Our meta-analysis suggests that the common VEGF polymorphisms C2578A, G1154A, and G634C do not alter CHD risk.