Planar Cell Polarity Signaling Pathway in Congenital Heart Diseases

Congenital heart disease (CHD) is a common cardiac disorder in humans. Despite many advances in the understanding of CHD and the identification of many associated genes, the fundamental etiology for the majority of cases remains unclear. The planar cell polarity (PCP) signaling pathway, responsible for tissue polarity in Drosophila and gastrulation movements and cardiogenesis in vertebrates, has been shown to play multiple roles during cardiac differentiation and development. The disrupted function of PCP signaling is connected to some CHDs. Here, we summarize our current understanding of how PCP factors affect the pathogenesis of CHD

Involvement of the JNK/FOXO3a/Bim Pathway in Neuronal Apoptosis after Hypoxic-Ischemic Brain Damage in Neonatal Rats.

c-Jun N-terminal kinase (JNK) plays a key role in the regulation of neuronal apoptosis. Previous studies have revealed that forkhead transcription factor (FOXO3a) is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether the JNK/FOXO3a pathway is involved in neuronal apoptosis in the developing rat brain after hypoxia-ischemia (HI). In this study, we generated an HI model using postnatal day 7 rats. Fluorescence immunolabeling and Western blot assays were used to detect the distribution and expression of total and phosphorylated JNK and FOXO3a and the pro-apoptotic proteins Bim and CC3. We found that JNK phosphorylation was accompanied by FOXO3a dephosphorylation, which induced FOXO3a translocation into the nucleus, resulting in the upregulation of levels of Bim and CC3 proteins. Furthermore, we found that JNK inhibition by AS601245, a specific JNK inhibitor, significantly increased FOXO3a phosphorylation, which attenuated FOXO3a translocation into the nucleus after HI. Moreover, JNK inhibition downregulated levels of Bim and CC3 proteins, attenuated neuronal apoptosis and reduced brain infarct volume in the developing rat brain. Our findings suggest that the JNK/FOXO3a/Bim pathway is involved in neuronal apoptosis in the developing rat brain after HI. Agents targeting JNK may offer promise for rescuing neurons from HI-induced damage

Research Progress on the Role and Mechanism of Action of Activin A in Brain Injury

Activin A belongs to the transforming growth factor superfamily and has a variety of biological functions. Studies have revealed that activin A can regulate the body's immune and inflammatory responses and participate in the regulation of cell death. In addition, activin A also has neurotrophic function and plays an important role in the repair of brain damage. This article summarizes recent advances in understanding the role and mechanism of action of activin A in brain injury and provides new hints into the application of activin A in the treatment of brain injury

Dose and formulation of azithromycin in mass drug administration studies: a systematic review protocol

Introduction: Azithromycin has been given for tropical infectious diseases such as trachoma and yaws by mass drug administration (MDA). As well as controlling the infectious disease in question, MDA may have a beneficial effect in reducing mortality in young children. However, the dose, formulation, frequency and duration of azithromycin used in certain infectious diseases may vary in different studies, and these differences may have impacts on the effectiveness of azithromycin MDA. Furthermore, whether the dose, formulation, frequency and duration are associated with the effectiveness of azithromycin for reducing child mortality—if indeed this effect can be confirmed—remain unknown. In this study, we will investigate whether different strategies such as different dose, formulation, frequency and duration affect the effectiveness of azithromycin MDA on the prevalence of certain infectious diseases or child mortality.Methods and analysis: A narrative systematic review will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform will be searched. No language restrictions will be applied. All randomised/quasi-controlled trials, observational studies (cross-sectional studies, cohort studies and case–control studies), case series and registered protocols will be considered. Dose, duration, frequency, rounds and formulations of azithromycin used in MDA will be collected and reviewed. The outcomes will be disease prevalence/control in children and child mortality. Data from the individual studies will not be pooled

Rapamycin sensitizes T-ALL cells to dexamethasone-induced apoptosis

<p>Abstract</p> <p>Background</p> <p>Glucocorticoid (GC) resistance is frequently seen in acute lymphoblastic leukemia of T-cell lineage (T-ALL). In this study we investigate the potential and mechanism of using rapamycin to restore the sensitivity of GC-resistant T-ALL cells to dexamethasone (Dex) treatment.</p> <p>Methods</p> <p>Cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay. Fluorescence-activated cell sorting (FACS) analysis was used to analyze apoptosis and cell cycles. Western blot analysis was performed to test the expression of the downstream effector proteins of mammalian target of rapamycin (mTOR), the cell cycle regulatory proteins, and apoptosis associated proteins.</p> <p>Results</p> <p>10 nM rapamycin markedly increased GC sensitivity in GC-resistant T-ALL cells and this effect was mediated, at least in part, by inhibition of mTOR signaling pathway. Cell cycle arrest was associated with modulation of G₁-S phase regulators. Both rapamycin and Dex can induce up-regulation of cyclin-dependent kinase (CDK) inhibitors of p21 and p27 and co-treatment of rapamycin with Dex resulted in a synergistic induction of their expressions. Rapamycin did not obviously affect the expression of cyclin A, whereas Dex induced cyclin A expression. Rapamycin prevented Dex-induced expression of cyclin A. Rapamycin had a stronger inhibition of cyclin D1 expression than Dex. Rapamycin enhanced GC-induced apoptosis and this was not achieved by modulation of glucocorticoid receptor (GR) expression, but synergistically up-regulation of pro-apoptotic proteins like caspase-3, Bax, and Bim, and down-regulation of anti-apoptotic protein of Mcl-1.</p> <p>Conclusion</p> <p>Our data suggests that rapamycin can effectively reverse GC resistance in T-ALL and this effect is achieved by inducing cell cycles arrested at G₀/G₁phase and activating the intrinsic apoptotic program. Therefore, combination of mTOR inhibitor rapamycin with GC containing protocol might be an attracting new therapeutic approach for GC resistant T-ALL patients.</p

Cumulative Evidence for Relationships Between 8q24 Variants and Prostate Cancer

Multiple independent cancer susceptibility loci at chromosome 8q24 have been identified by GWAS (Genome-wide association studies). Forty six articles including 60,293 cases and 62,971 controls were collected to conduct a meta-analysis to evaluate the associations between 21 variants in 8q24 and prostate cancer risk. Of the 21 variants located in 8q2\5 were significantly associated with the risk of prostate cancer. In particular, both homozygous AA and heterozygous CA genotypes of rs16901979, as well as the AA and CA genotypes of rs1447295, were associated with the risk of prostate cancer. Our study showed that variants in the 8q24 region are associated with prostate cancer risk in this large-scale research synopsis and meta-analysis. Further studies are needed to explore the role of the 8q24 variants involved in the etiology of prostate cancer

The integrin αvβ8 mediates epithelial homeostasis through MT1-MMP–dependent activation of TGF-β1

Întegrins, matrix metalloproteases (MMPs), and the cytokine TGF-β have each been implicated in homeostatic cell behaviors such as cell growth and matrix remodeling. TGF-β exists mainly in a latent state, and a major point of homeostatic control is the activation of TGF-β. Because the latent domain of TGF-β1 possesses an integrin binding motif (RGD), integrins have the potential to sequester latent TGF-β (SLC) to the cell surface where TGF-β activation could be locally controlled. Here, we show that SLC binds to αvβ8, an integrin expressed by normal epithelial and neuronal cells in vivo. This binding results in the membrane type 1 (MT1)-MMP–dependent release of active TGF-β, which leads to autocrine and paracrine effects on cell growth and matrix production. These data elucidate a novel mechanism of cellular homeostasis achieved through the coordination of the activities of members of three major gene families involved in cell–matrix interactions

Corticosteroids for the prevention of bronchopulmonary dysplasia in preterm infants: a network meta-analysis

Objective: To determine the comparative efficacy and safety of corticosteroids in the prevention of bronchopulmonary dysplasia (BPD) in preterm infants.  Study design: We systematically searched PubMed, EMBASE and the Cochrane Library. Two reviewers independently selected randomised controlled trials (RCTs) of postnatal corticosteroids in preterm infants. A Bayesian network meta-analysis and subgroup analyses were performed.  Results: We included 47 RCTs with 6747 participants. The use of dexamethasone at either high dose or low dose decreased the risk of BPD (OR 0.29, 95% credible interval (CrI) 0.14 to 0.52; OR 0.58, 95% CrI 0.39 to 0.76, respectively). High-dose dexamethasone was more effective than hydrocortisone, beclomethasone and low-dose dexamethasone. Early and long-term dexamethasone at either high dose or low dose decreased the risk of BPD (OR 0.11, 95% CrI 0.02 to 0.4; OR 0.37, 95% CrI 0.16 to 0.67, respectively). There were no statistically significant differences in the risk of cerebral palsy (CP) between different corticosteroids. However, high-dose and long-term dexamethasone ranked lower than placebo and other regimens in terms of CP. Subgroup analyses indicated budesonide was associated with a decreased risk of BPD in extremely preterm and extremely low birthweight infants (OR 0.60, 95% CrI 0.36 to 0.93).  Conclusions: Dexamethasone can reduce the risk of BPD in preterm infants. Of the different dexamethasone regimens, aggressive initiation seems beneficial, while a combination of high-dose and long-term use should be avoided because of the possible adverse neurodevelopmental outcome. Dexamethasone and inhaled corticosteroids need to be further evaluated in large-scale RCTs with long-term follow-ups