Dezhi Mu

Involvement of the Akt/GSK-3β/CRMP-2 pathway in axonal injury after hypoxic–ischemic brain damage in neonatal rat

Akt has been demonstrated as a survival kinase in brain after hypoxia-ischemia (HI). Previous studies have shown that glycogen synthase kinase-3β (GSK-3β)/collapsin response mediator protein 2 (CRMP-2) signaling pathway could be regulated by Akt for axonal-dendritic polarity. CRMP-2 is associated also with microtubule-mediated trafficking. However, whether Akt could regulate GSK-3β/CRMP-2 pathway and the possible effects of this regulation is unclear in developing brain after HI. In this study, we detected the expression of total and phosphorylated Akt, GSK-3β, and CRMP-2, as well as the axonal injury marker amyloid precursor protein (APP) by utilizing an HI model in postnatal 10-day rats. Axonal loss was determined by Bielschowsky silver impregnation, and histological injury was evaluated by hematoxylin and eosin (H&E) staining. We found that the phosphorylation of Akt was accompanied by phosphorylation of GSK-3β and dephosphorylation of CRMP-2 after HI. Furthermore, Akt inhibition significantly decreased the phosphorylation of GSK-3β and dephosphorylation of CRMP-2. Moreover, the down-regulation of dephosphorylated CRMP-2 was associated with increased axonal injury (increased APP expression and axonal loss). Our findings suggest that the Akt/GSK-3β/CRMP-2 pathway mediates axonal injury in neonatal rat brain after HI.

Performance of Different Scan Protocols of Fetal Echocardiography in the Diagnosis of Fetal Congenital Heart Disease: A Systematic Review and Meta-Analysis

Objective The rapid progress in fetal echocardiography has lead to early detection of congenital heart diseases. Increasing evidences have shown that prenatal diagnosis could be life saving in certain cases. However, there is no agreement on which protocol is most adaptive diagnostic one. Thus, we use meta-analysis to conduct a pooled performance test on 5 diagnostic protocols. Methods We searched PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials and WHO clinical trails registry center to identify relevant studies up to August, 2012. We performed meta-analysis in a fixed/random-effect model using Meta-disc 1.4. We used STATA 11.0 to estimate the publication bias and SPSS 17.0 to evaluate variance. Results We use results from 81 studies in 63 articles to analyze the pooled accuracy. The overall performance of pooled sensitivities of spatiotemporal image correlation (STIC), extend cardiac echography examination (ECEE) and 4 chambers view + outflow tract view + 3 vessels and trachea view (4 CV+OTV+3 VTV) were around 0.90, which was significant higher than that of 4 chambers view + outflow tract view or 3 vessels and trachea view (4 CV+OTV/3 VTV) and 4 chambers view (4 CV). Unfortunately the pooled specificity of STIC was 0.92, which was significant lower than that of other 4 protocols which reached at 1.00. The area under the summary receiver operating characteristic curves value of STIC, ECEE, 4 CV+OTV+3 VTV, 4 CV+OTV/3 VTV and 4 CV were 0.9700, 0.9971, 0.9983, 0.9929 and 0.9928 respectively. Conclusion These results suggest a great diagnostic potential for fetal echocardiography detection as a reliable method of fetal congenital heart disease. But at least 3 sections view (4 CV, OTV and 3 VTV) should be included in scan protocol, while the STIC can be used to provide more information for local details of defects, and can not be used to make a definite diagnosis alone with its low specificity.

miR-199a-3p Inhibits Aurora Kinase A and Attenuates Prostate Cancer Growth: New Avenue for Prostate Cancer Treatment

Prostate cancer (PCa) is the most common solid tumor malignancy in men that severely influences quality of life. Surgery is most often the recommended treatment for PCa, but radical prostatectomy can cause significant urinary adverse effects. Therefore, finding effective biochemical treatments for PCa remains a necessity. Aurora kinase A has been shown to be involved in PCa progression, thus making it a good target for PCa therapy. miRNAs are important regulators of gene expression, with some miRNAs specifically involved in carcinogenesis. Therefore, herein, we identified miRNAs targeted to aurora kinase A and examined their effects on the growth of PCa. We used primary samples from PCa patients and PCa cell lines as research subjects. We demonstrate that miR-199a-3p is down-regulated in PCa tissues compared with normal prostate tissues, with the expression pattern inversely correlated with the expression pattern of aurora kinase A. We find that miR-199a-3p agomir inhibits aurora kinase A and attenuates xenograft tumor growth of PCa. Moreover, we demonstrate that down-regulation of miR-199a-3p results from enhancement of the methylation of miR-199a gene in PCa. Furthermore, we find that the expression level of miR-199a-3p is inversely correlated to tumor stage and Gleason score of PCa. Revealing novel mechanisms for oncogene inhibition by miRNA-mediated pathways offers new avenues for PCa treatment.

The neuroprotective role and mechanisms of TERT in neurons with oxygen-glucose deprivation.

Telomerase reverse transcriptase (TERT) is reported to protect neurons from apoptosis induced by various stresses including hypoxia-ischemia (HI). However, the mechanisms by which TERT exerts its anti-apoptotic role in neurons with HI injury remain unclear. In this study, we examined the protective role and explored the possible mechanisms of TERT in neurons with HI injury in vitro. Primary cultured neurons were exposed to oxygen and glucose deprivation (OGD) for 3h followed by reperfusion to mimic HI injury in vivo. Plasmids containing TERT antisense, sense nucleotides, or mock were transduced into neurons at 48h before OGD. Expression and distribution of TERT were measured by immunofluorescence labeling and western blot. The expression of cleaved caspase 3 (CC3), Bcl-2 and Bax were detected by western blot. Neuronal apoptosis was measured with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL). The mitochondrial reactive oxygen species (ROS) were measured by MitoSOX Red staining. Fluorescent probe JC-1 was used to measure the mitochondrial membrane potential (ΔΨm). We found that TERT expression increased at 8h and peaked at 24h in neurons after OGD. CC3 expression and neuronal apoptosis were induced and peaked at 24h after OGD. TERT inhibition significantly increased CC3 expression and neuronal apoptosis after OGD treatment. Additionally, TERT inhibition decreased the expression ratio of Bcl-2/Bax, and enhanced ROS production and ΔΨm dissipation after OGD. These data suggest that TERT plays a neuroprotective role via anti-apoptosis in neurons after OGD. The underlying mechanisms may be associated with regulating Bcl-2/Bax expression ratio, attenuating ROS generation, and increasing mitochondrial membrane potential.

Enhanced migration and CXCR4 over-expression in fibroblasts with telomerase reconstitution

Telomerase reconstitution shows great potential for cell treatment and tissue engineering. Although the effects of telomerase on cell lifespan are well documented, the effects of telomerase on cellular biological characteristics, such as cellular migration, are relatively unknown. In this study, we tried to investigate if telomerase is involved in the regulation of fibroblast migration and the mechanism behind it. We found that when stimulated with a chemokine, CXCL12, the rate of migration was significantly higher in fibroblasts with telomerase reconstitution than that in fibroblasts without. Furthermore, the CXCL12 receptor, CXCR4, and multiple down-stream factors (Rho family members), were upregulated in the telomerase reconstituted fibroblasts. We concluded for the first time that telomerase reconstitution increased fibroblast migration through activation of CXCL12/CXCR4 axis and Rho family. The finding that fibroblasts with telomerase reconstitution have enhanced migration may have broad implications for cell therapy.

Parental Occupational Exposures to Endocrine Disruptors and the Risk of Simple Isolated Congenital Heart Defects

This study aims to explore the associations between parental occupational exposures to endocrine disruptors (EDs) and simple isolated congenital heart defects (CHDs). A case–control study with standardized data collection involving 761 children with isolated CHDs and 609 children without any congenital malformations was conducted in Sichuan Province of China from March in 2012 to August in 2013. An adjusted job exposure matrix was used for occupational EDs exposure assessment. Logistic regression analysis was performed to assess the associations between parental occupational EDs exposures and CHDs. Maternal age at births, maternal education level, gravity, parity, induced abortion, folic acid use, medication use, drinking capacity and area of residence periconceptionally were selected as confounding factors for mothers. For fathers, we selected the following confounding factors: paternal education level, smoking, drinking frequencies and drinking capacity periconceptionally. Maternal occupational exposures to phthalates are associated with perimembranous ventricular septal defect (PmVSD) (Pxa0=xa00.001, adjusted OR 3.7, 95xa0% CI 1.7–8.0), patent ductus arteriosus (PDA) (Pxa0=xa00.002, adjusted OR 3.8, 95xa0% CI 1.6–8.9), secundum atrial septal defect (s-ASD) (Pxa0=xa00.008, adjusted OR 3.5, 95xa0% CI 1.4–8.7) and pulmonary valve stenosis (PS) (Pxa0=xa00.035, adjusted OR 4.2, 95xa0% CI 1.1–16.0), to alkylphenolic compounds and PmVSD (Pxa0=xa00.003, adjusted OR 2.2, 95xa0% CI 1.3–3.6), PDA (Pxa0=xa00.005, adjusted OR 2.0, 95xa0% CI 1.1–3.5) and PS (Pxa0=xa00.004, adjusted OR 3.8, 95xa0% CI 1.5–9.4), to heavy metals with PmVSD (Pxa0=xa00.003, adjusted OR 7.3, 95xa0% CI 2.0–27.6) and s-ASD (Pxa0=xa00.034, adjusted OR 6.5, 95xa0% CI 1.1–36.7). Paternal occupational exposures to phthalates are associated with PmVSD (Pxa0=xa00.035, adjusted OR 1.6, 95xa0% CI 1.0–2.4) and PS (Pxa0=xa00.026, adjusted OR 2.4, 95xa0% CI 1.1–5.2), to alkylphenolic compounds (Pxa0=xa00.027, adjusted OR 1.5, 95xa0% CI 1.0–2.2) with PmVSD. In conclusion, parental occupational exposures to some specific EDs, in particular phthalates and alkylphenolic compounds, are associated with an increased risk of some CHD phenotypes. However, the findings need to be considered more circumspectly regarding a crude measure of exposure probabilities and small numbers.

Neurodevelopmental delay with critical congenital heart disease is mainly from prenatal injury not infant cardiac surgery: current evidence based on a meta‐analysis of functional magnetic resonance imaging

No consensus has been reached regarding whether brain injury related to congenital heart disease (CHD) is caused by infant cardiac surgery and/or prenatal injury resulting from the CHD. We performed this meta‐analysis to identify the likely cause of neurodevelopmental delay in CHD patients.

Evaluation of therapeutic effect and cytokine change during transplacental Digoxin treatment for fetal heart failure associated with fetal tachycardia, a case–control study

a Dept. of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu 610041, PR China b Dept. of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, PR China c Dept. of Ultrasound Cardiography, West China Second University Hospital, Sichuan University, Chengdu 610041, PR China d Dept. of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, PR China e Key Laboratory of Ob&G and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, PR China f Program for Yangtze River Scholars and Innovative Research Team in University, West China Medical Center, West China Second University Hospital, Sichuan University, Chengdu 610041, PR China

The effect of maternal obesity on the expression and functionality of placental P-glycoprotein: Implications in the individualized transplacental digoxin treatment for fetal heart failure

INTRODUCTIONSnPlacental P-glycoprotein (P-gp) plays a significant role in controlling digoxin transplacental rate. Investigations on P-gp regulation in placenta of women with different pregnant pathology are of great significance to the individualized transplacental digoxin treatment for fetal heart failure (FHF). This study aimed to explore the effect of maternal obesity on the expression and functionality of placental P-gp both in human and in mice.nnnMETHODSnPlacenta tissues from obese and lean women were collected. Female C57BL mice were fed with either a normal chow diet or a high-fat diet for 12 weeks before mating and throughout pregnancy. Maternal plasma glucose, HDL-C, LDL-C, TC, TGs, insulin, IL-1β, IL-6 and TNF-α concentrations was detected. Placental ABCB1/Abcb1a/Abcb1b/IL-1β/IL-6/TNF-α mRNA and P-gp/IL-1β/IL-6/TNF-α protein expression were determined by real-time quantitative PCR and western-blot, respectively. Maternal plasma and fetal-unit digoxin concentrations were detected by a commercial kit assay.nnnRESULTSnBoth ABCB1 gene mRNA and protein expression of obesity group was significantly lower than that of control group in human. The high-fat dietary intervention resulted in an overweight phenotype, a significant increased Lees index, higher levels of plasma glucose, HDL-C, LDL-C, insulin and TGs, increased peri-renal and peri-reproductive gland adipose tissue weight, and larger size of adipose cell. Compared with control group at the same gestational day (E12.5, E15.5, E17.5), placental Abcb1a mRNA and P-gp expression of obese group were significantly decreased in mice, while digoxin transplacental rates were significantly increased. Higher maternal plasma IL-1β/TNF-α concentrations and placental IL-1β/TNF-α expression were observed in obesity groups in comparison with control group at the same gestational age.nnnCONCLUSIONSnMaternal obesity could inhibit placental P-gp expression and its functionality both in human and in mice, which might be resulted from a heightened inflammatory response.

Risk factors and prognosis of atrioventricular block after atrial septum defect closure using the Amplatzer device.

Amplatzer septal occluder (ASO)-induced complications have been observed. However, little attention is paid to the atrioventricular block (AVB) induced by atrial septum defect (ASD) closure using the Amplatzer device. This study aimed to analyze the risk factors and prognosis of AVB after catheter closure and to reduce the incidence of adverse events. In this study, 706 ASD patients who received closure in our division were investigated retrospectively for the relationship between AVB and factors such as age, size of the ASD (Dd), diameter of the occluder (Do), diameter of the septum (Ds), Do/Dd ratio, and Do/Ds ratio. Data distribution was evaluated with the Kolmogorov–Smirnov normality test. The Wilcoxon rank sum test was used to compare non-normal distribution data. A p value lower than 0.05 was considered significant. Of the 706 patients, six had experienced the development of AVB, giving an incidence of 0.85xa0%. The risk factors included younger age, larger size of the ASD, larger size of the device, and the Do/Ds ratio (≥0.45). The milder AVB is, the better the prognosis. An AVB of III° and an unchanged electrocardiogram (ECG) within 3xa0days after the procedure are poor prognostic indicators. More attention should be paid to AVB induced by ASD closure. Younger age, size of the ASD, size of the device, and a Do/Ds ratio of 0.45 or higher are the risk factors associated with AVB after closure. A timely retrieval of the device should be considered for a good prognosis.