ABSTRACT
The small molecule DAPT inhibits the Notch signaling pathway by blocking γ-secretase mediated Notch cleavage. Given the critical role of the Notch signaling axis in inflammation, we asked whether DAPT could block Notch-mediated inflammation and thus exert neuronal protection. We established a mouse model of chronic exposure to cadmium (Cd)-induced toxicity and treated it with DAPT. DAPT was effective in ameliorating Cd-induced multi-organ damage and cognitive impairment in mice, as DAPT restored abnormal performance in the Y-maze, forced swimming and Morris water maze (MWM) tests. DAPT also reversed Cd-induced neuronal loss and glial cell activation to normal as observed by immunofluorescence and immunohistochemistry of brain tissue sections. In addition, Cd-intoxicated mice showed significantly increased levels of the Notch/HES-1 signaling axis and NF-κB, as well as decreased levels of the inflammatory inhibitors C/EBPß and COP1. However, DAPT down regulated the elevated Notch/HES-1 signaling axis to normal, eliminating inflammation and thus protecting the nervous system. Thus, DAPT effectively eliminated the neurotoxicity of Cd, and blocking γ-secretase as well as Notch signaling axis may be a potential target for the development of neuronal protective drugs.
ABSTRACT
Purpose Clear cell renal cell carcinoma(ccRCC) is the most common type of renal cell carcinoma. While it is curable when detected at an early stage, some patients presented with advanced disease have poor prognosis. We aimed to identify key genes and miRNAs associated with clinical prognosis in ccRCC. Methods The microarray datasets were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs) were analyzed by using GEO2R. Then, Functional enrichment analysis was performed using the DAVID. A retrospective series of 254 ccRCC patients with complete clinical information was included in this study. Kaplan-Meier analysis and multivariate cox regression analysis were used for prognostic analysis. Wound healing assay and transwell assay were designed to evaluate the migration and invasion ability of ccRCC cell lines. Results miRNA-18a was identified to be related with prognosis of ccRCC by using Kaplan-Meier analysis and multivariate cox regression analysis demonstrated that the prognostic value of miRNA-18a was independent of clinical features. Further studies showed that up-regulation of miRNA-18a had a positive effect on migration and invasion of ccRCC cells. The target gene (HIF1A) of the miRNA-18a was predicted by using the miRPathDB database. The transcription factors of DEGs were identified by using the i-cisTarget. Luckily, HIF1A was found to be one of the transcription factors of DEGs. Among these DEGs, PVT1 may be regulated by HIF1A and be related with prognosis of ccRCC. Finally, validation of miRNA18a/HIF1A/PVT1 pathway was checked via reverse transcription-polymerase chain reaction (RT-PCR) assay in both cell lines and clinical tumor samples. Conclusion Our research revealed that miRNA18a/HIF1A/PVT1 pathway might play a crucial role in ccRCC progression, providing novel insights into understanding of ccRCC molecular mechanisms. Importantly, miRNA-18a could serve as a potential diagnostic biomarker and therapeutic targets for ccRCC patients.
ABSTRACT
PURPOSE: The purpose of this study was to investigate the dental and craniofacial morphological characteristics in patients with mild skeletal facial asymmetry, and to investigate the relationship between mild skeletal facial asymmetry and dental anomalies. METHODS: Thirty patients with mild skeletal facial asymmetry (experimental group) and 30 patients with normal faces (control group) were selected. All patients were scanned by cone-beam computed tomography (CBCT) and X-ray machine, Winceph software was used to measure the posteroanterior cephalometric radiographs, NNT software was used to measure the CBCT data. The results were analyzed by Chi-square test, paired t test and independent sample t test using SPSS 19.0 software package. RESULTS: There were significant differences between the left and right sides of faces, teeth and alveolar bone of the first molar in the experimental group. The angle of mandibular dental midline and facial midline, the inclination of the frontal mandibular plane, the inclination of the first molar, the inclination of alveolar bone of the mandibular first molar, the width of alveolar bone of the mandibular first molar showed significant differences between the experimental group and the control group (P<0.05). There are some correlations among menton deviation, inclination of the first molar and alveolar bone of the first molar. CONCLUSIONS: Patients with mild skeletal facial asymmetry showed some specific skeletal and dental characteristics. There could be some correlations between these featuresï¼.
