摘要: Objective To explore the effects and underlying biological mechanisms of tetrahedral DNA nanostructures (TDNs) on the proliferation and osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Materials and methods Real-time cell analysis (RTCA) and CCK8 were used to screen the best concentration of TDN for PDLSCs. Cell proliferation and osteogenic differentiation were assessed after PDLSCs were treated with TDN. Data were analysed using one-way ANOVA. Results Tetrahedral DNA nanostructures could play a crucial role in accelerating the proliferation of PDLSCs and had the strongest promotive effect on PDLSCs at a concentration of 250 nmol/L. Simultaneously, the osteogenic differentiation of PDLSCs could be promoted significantly by TDNs and the finding displayed that the Wnt/beta-catenin signalling pathway might be the underlying biological mechanisms of TDNs on promoting the osteogenic differentiation of PDLSCs. Conclusion Tetrahedral DNA nanostructure treatment facilitated the proliferation of PDLSCs, significantly promoted osteogenic differentiation by regulating the Wnt/beta-catenin signalling pathway. Therefore, TDNs could be a novel nanomaterial with great potential for application to PDLSC-based bone tissue engineering.

摘要: Objectives We aimed to elucidate the role and molecular mechanisms of FOXM1 in regulating metastasis in oesophageal squamous cell carcinoma (ESCC) as well as its clinical implications. Materials and methods The expression levels of four isoforms of FOXM1 were analysed by real-time PCR. Next, genetically modification using overexpression and RNAi systems and transwell were employed to examine FOXM1c function in invasion and migration. Dual luciferase and ChIP assays were performed to decipher the underlying mechanism for transcriptional regulation. The expression levels of FOXM1 and IRF1 were determined by immunohistochemistry staining in ESCC specimens. Results The FOXM1c was predominantly overexpressed in ESCC cell lines compared to the other FOXM1 isoforms. Ectopic expression of FOXM1c promoted invasion and migration of ESCC cells lines, whereas downregulation of FOXM1c inhibited these processes. Moreover, FOXM1c expression was positively correlated with IRF1 expression in ESCC cell lines and tumour specimens. IRF1 is, at least in part, responsible for FOXM1c-mediated invasion and migration. Mechanistically, we identified IRF1 as a transcriptional target of FOXM1c and found a FOXM1c-binding site in the IRF1 promoter region. Furthermore, high expression levels of both FOXM1c and IRF1 were positively associated with low survival rate and predicted a poor prognosis of oesophageal cancer patients. Conclusion FOXM1c promotes the metastasis by transcriptionally targeting IRF1 and may serve as a potential prognostic predictor for oesophageal cancer.

摘要: Objectives Abnormal activation of NF-kappa B signalling is a major mechanism of apoptosis resistance in glioblastoma multiforme (GBM). Therefore, better understanding of the regulation of NF-kappa B signalling has a significant impact for GBM therapy. Here, we uncovered a critical role of the small GTPase RND3 in regulating the p65 subunit of NF-kappa B and NF-kappa B signalling in GBM. Materials and methods Human GBM samples, GBM cells and a human orthotopic GBM-xenografted animal model were used. The mechanisms of RND3 in regulation of NF-kappa B signalling and GBM cell apoptosis were examined by luciferase assay, quantitative PCR, immunostaining, immunoblotting, immunofluorescence, coimmunoprecipitation, TUNEL staining, JC-1 analysis and flow cytometry. Results Overexpression of RND3 led to reduced p65 activity in GBM-cultured cells and a GBM animal model, indicating that the NF-kappa B pathway is negatively regulated by RND3 in GBM. Mechanistically, we found that RND3 bound p65 and promoted p65 ubiquitination, leading to decreased p65 protein levels. Furthermore, RND3 enhanced cleaved caspase 3 levels and promoted apoptosis in GBM cells, and RND3 expression was positively correlated with cleaved caspase 3 and IL-8 in human GBM samples. The effect of RND3 on promoting apoptosis disappeared when p65 ubiquitination was blocked by protease inhibitor carfilzomib or upon co-expression of ectopic p65. Conclusions RND3 binds p65 protein and promotes its ubiquitination, resulting in reduced p65 protein expression and inhibition of NF-kappa B signalling to induce GBM cell apoptosis.

摘要: Through loss- and gain-of-function experiments in knockout and transgenic mice, Forkhead box O (FOXO) family transcription factors have been demonstrated to play essential roles in many biological processes, including cellular proliferation, apoptosis and differentiation. Osteogenic differentiation from mesenchymal stem cells (MSCs) into osteoblasts is a well-organized process that is carefully guided and characterized by various factors, such as runt-related transcription factor 2 (Runx2), beta-catenin, osteocalcin (OCN), alkaline phosphatase (ALP) and activating transcription factor 4 (ATF4). Accumulating evidence suggests multiple interactions among FOXO members and the differentiation regulatory factors listed above, resulting in an enhancement or inhibition of osteogenesis in different stages of osteogenic differentiation. To systematically and integrally understand the role of FOXOs in osteogenic differentiation and explain the contrary phenomena observed in vitro and in vivo, we herein summarized FOXO-interacting differentiation regulatory genes/factors and following alterations in differentiation. The underlying mechanism was further discussed on the basis of binding types, sites, phases and the consequent downstream transcriptional alterations of interactions among FOXOs and differentiation regulatory factors. Interestingly, a bidirectional effect of FOXOs on balancing osteogenic differentiation was discovered in MSCs. Moreover, FOXO factors are reported to be activated or suppressed by several context-dependent signalling inputs during differentiation, and the underlying molecular basis may offer new drug development targets for treatments of bone formation defect diseases.

摘要: The evolution of chronic inflammatory diseases is thought to be due to a combination of host genetic variations and environmental factors that include the alteration of intestinal flora, termed dysbiosis. The intestinal mucosal barrier includes a chemical barrier and physical barrier that have important roles in protecting the intestine against inflammatory injury. The chemical barrier includes antimicrobial peptides (AMPs), and the physical barrier includes a mucous layer, a monolayer of intestinal epithelial cells and cell junctions. The intestinal mucosal barrier is not a static barrier, but rather, it strongly interacts with the gut microbiome and cells of the immune system. Correct expression of AMPs, together with mucus and balanced epithelial cell proliferation, prevents the occurrence of disease. NLRP6, a member of the nucleotide-binding domain, leucine-rich repeat-containing (NLR) innate immune receptor family, participates in the progression of intestinal inflammation and enteric pathogen infections. It has become apparent in recent years that NLRP6 is important in disease pathogenesis, as it responds to internal ligands that lead to the release of AMPs and mucus, thus regulating the regeneration of intestinal epithelial cells. This review summarizes the activation of NLRP6 and its protective role in the intestinal epithelial cell.