Combined the GABA-A and GABA-B receptor agonists attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism.

Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. In this study, we employed prenatally exposed to valproic acid (VPA) to establish a validated ASD mouse model and found impaired inhibitory gamma-aminobutyric acid (GABAergic) neurotransmission through a presynaptic mechanism in these model mice, which was accompanied with decreased GABA release and GABA-A and GABA-B receptor subunits expression. And acute administration of individual GABA-A or GABA-B receptor agonists partially reversed autistic-like behaviors in the model mice. Furthermore, acute administration of the combined GABA-A and GABA-B receptor agonists palliated sociability deficits, anxiety and repetitive behaviors in the animal model of autistic-like behaviors, demonstrating the therapeutic potential of above cocktail in the treatment of ASD.

Effect of silencing S-phase kinase-associated protein 2 on chemosensitivity to temozolomide of human glioma cells U251.

OBJECTIVE: To examine the effect of silencing SKP2 on chemosensitivity of human glioma cells U251 to temozolomide (TMZ). METHODS: Adenoviruses harbouring shRNA targeting SKP2 (i.e. Ad-shSKP2) and non-targeting scrambled shRNA (i.e. Ad-shNC) were used to infect U251 cells. The transduced cells were then treated with TMZ. Cell viability after treatment was assayed using CCK8; while cell cycle and apoptosis were examined using flow cytometry. To study the effect of silencing SKP2 on autophagy in U251, we co-transduced the cells with Ad-mRFP-LC3 and Ad-shSKP2/Ad-shNC. The expression of autophagy marker LC3 after TMZ treatment was studied using microscopy and Western blotting assays. RESULTS: The cytotoxicity of TMZ (i.e. 20-100 µM) was more significantly seen in Ad-shSKP2-transduced U251 cells than in the Ad-shNC-transduced U251 cells. The IC50 values in shSKP2-U251 were significantly lower than those of the shNC-U251 (P < 0.05). Both TMZ and Ad-shSKP2 alone increased apoptosis and promoted expression of LC3 in U251. Combined treatment of Ad-shSKP2 and TMZ further elevated apoptosis and LC3 expression. CONCLUSION: Silencing SKP2 in U251 cells increased chemosensitivity to TMZ that was accompanied with enhanced apoptosis and autophagy. Targeting SKP2 may be a potential approach to potentiate TMZ treatment in patients with glioma.

Low concentration of quercetin antagonizes the invasion and angiogenesis of human glioblastoma U251 cells.

Glioblastoma is the most aggressive type of brain tumor with a very poor prognosis. Therefore, it is always of great importance to explore and develop new potential treatment for glioblastoma. Quercetin, a flavonoid present in a variety of human foods, has been shown to inhibit various tumor cell proliferation. In this study, we found that treating human glioblastoma U251 cells with 10 µg/mL quercetin for 24 hours, a concentration that was far below the IC50 (113.65 µg/mL) and at which quercetin failed to inhibit cell proliferation, inhibited cell migration (30%) and cell invasion as examined by wound scratch assay and transwell assay, respectively. We further showed that 10 µg/mL quercetin inhibited cell migration and tube formation of human umbilical vein endothelial cells induced by the conditioned medium derived from U251 cell culture. The inhibitory effect of quercetin on migration and angiogenesis is possibly mediated through the downregulation of protein levels of VEGFA, MMP9, and MMP2 as detected by Western blot. Our findings demonstrated that low concentration of quercetin antagonized glioblastoma cell invasion and angiogenesis in vitro.

Metabolic syndrome is associated with increased risk of Barrett esophagus: A meta-analysis.

BACKGROUND: Barrett esophagus (BE) is considered precursor condition of esophageal adenocarcinoma. Its incidence and prevalence are increasing in general population. Studies reported that metabolic syndrome (MS) or diabetes mellitus (DM) is related to increased risk of BE. Current study was to assess and better understand the relationship between MS /DM and BE. METHODS: Electronic search was conducted in the database Pubmed/Medline (-December, 2015), Embase (-December, 2015), Cochrane Library (-December, 2015), and Web of Knowledge (-December, 2015). Studies included were assessed with summary odds ratios (ORs) with 95% confidence intervals (CIs) and compared exposure group with control group. The heterogeneity was examined by the funnel plot and the Egger's test. Subgroup analyses and sensitive analyses were performed for the detection of possible heterogeneity and impact on stability of analysis results. RESULTS: Twelve publications met the criteria and included 355,311 subjects were analyzed. The pooled results showed MS was closely associated with increased risk of BE (OR = 1.23; 95%CI 1.03-1.47; P = 0.024), and yet DM did not significantly increase the risk of BE (OR = 1.07; 95%CI 0.82-1.38; P = 0.627). Substantial heterogeneities were detected. No significant publication bias was detected by Egger's test (P = 0.23). CONCLUSIONS: Based on the results of current meta-analysis, MS is associated with increased risk of BE. Further long-term follow-up prospective study needs to verify the current results, and definite pathophysiological mechanism needs to be further investigated and clearly elucidated.

Ultrasound-guided endoscopic biliary drainage: a useful drainage method for biliary decompression in patients with biliary obstructions.

BACKGROUND: Endoscopic retrograde cholangiopancreatography with fluoroscopy guidance is a well-established technique for providing biliary drainage in patients with biliary obstructions. However, fluoroscopic facilities may not always be available and fluoroscopy carries a risk of radiation exposure. AIM: We retrospectively compared the procedure success rate and efficacy of ultrasound-guided endoscopic biliary drainage (UG-EBD) and fluoroscopy-guided endoscopic biliary drainage (FG-EBD) in patients with biliary obstructions. METHODS: Patients who had received either UG-EBD or FG-EBD were included in the study. Main outcome measurements included the procedure success rate, procedure time, and clinical response. RESULTS: A total of 125 patients who had undergone UG-EBD (n = 63) and FG-EBD (n = 62) were identified. The total procedure success rate was 93.7 % in the UG-EBD group and 96.8 % in the FG-EBD group without statistical difference. Also, no significant difference was found in the procedure success rate of lower or upper/middle obstructions of the common bile duct (CBD) between the 2 groups. The mean procedure time was not different between the 2 groups [UG-EBD group 24.54 (9.52) min vs. FG-EBD group 21.74 (8.77) min, p = 0.09]. There were no differences in the normalization of clinical and laboratory parameters and immediate complication between the 2 groups. CONCLUSIONS: Endoscopic biliary drainage (EBD) under US-guidance and under fluoroscopy guidance is equally effective and safe for patients with lower or upper/middle obstructions of the CBD. The UG-EBD technique is especially suitable for special patients, such as critically ill patients, pregnant woman, etc.