Neuroprotection of dexmedetomidine against propofol-induced neuroapoptosis partly mediated by PI3K/Akt pathway in hippocampal neurons of fetal rat

The aim was to investigate how the PI3K/Akt pathway is involved in the protection of dexmedetomidine against propofol. The hippocampal neurons from fetal rats were separated and cultured in a neurobasal medium. Cell viability was assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay. Then neurons were pretreated with different concentrations of dexmedetomidine before 100 μmol/L propofol was added. Akt, phospho-Akt(p-Akt), Bad, phospho-Bad(p-Bad), and Bcl-x L were detected by Western blot. Also, neurons were pretreated with dexmedetomidine alone or given the inhibitor LY294002 before dexmedetomidine pretreatment, and then propofol was added for 3h. The results demonstrated that propofol decreased the cell viability and the expression of p-Akt and p-Bad proteins, increased the level of Bad, and reduced the ratio of Bcl-x L/Bad. Dexmedetomidine pretreatment could reverse these effects. The enhancement of p-Akt and p-Bad induced by dexmedetomidine was prevented by LY294002. These results showed that dexmedetomidine potently protected the developing neuron and this protection may be partly mediated by the PI3K/Akt pathway.

Identification of miR-515-3p and its targets,vimentin and MMP3,as a key regulatory mechanism in esophageal cancer metastasis:functional and clinical significance

Metastasis is the main factor of treatment failure in cancer patients,but the underlying mechanism remains to be elucidated and effective new treatment strategies are urgently needed.This study aims to explore novel key metastasis-related microRNAs(miRNAs)in esophageal squamous cell carcinoma(ESCC).By comparing miRNA profiles of the highly metastatic ESCC cell sublines,we established through serial in vivo selection with the parental cells,we found that the expression level of miR-515-3p was lower in ESCC tumor tissues than adjacent normal tissues,further decreased in metastatic tumors,and moreover,markedly associated with advanced stage,metastasis and patient survival.The in vitro and in vivo assays suggested that miR-515-3p could increase the expression of the epithelial markers as well as decrease the expression of the mesenchymal markers,and more importantly,suppress invasion and metastasis of ESCC cells.Mechanistically,we revealed that miR-515-3p directly regulated vimentin and matrix metalloproteinase-3(MMP3)expression by binding to the coding sequence and 3′untranslated region,respectively.In addition,the data from whole-genome methylation sequencing and methylation-specific PCR indicated that the CpG island within miR-515-3p promoter was markedly hypermethylated in ESCC cell lines and ESCC tumor tissues,which may lead to deregulation of miR-515-3p expression in ESCC.Furthermore,our preclinical experiment provides solid evidence that systemic delivery of miR-515-3p oligonucleotide obviously suppressed the metastasis of ESCC cells in nude mice.Taken together,this study demonstrates that miR-515-3p suppresses tumor metastasis and thus represents a promising prognostic biomarker and therapeutic strategy in ESCC.