摘要: Intervertebral disc degeneration (IDD) is a common cause of low back pain, which inflicts more global disability than any other condition. Although IDD was deemed to be a natural process that comes with ageing, a growing body of evidence suggested that both genetic and environmental factors could modify the development of IDD. In this connection, aberrant function of nucleus pulposus cells has been implicated in IDD pathogenesis. Circular RNAs are a novel class of endogenous non-coding RNAs that play crucial regulatory roles in diverse cellular processes. Recently, deregulation of circRNAs in nucleus pulposus cells was found to functionally participate in IDD development. In this review, we summarize the current knowledge regarding the deregulation of circRNAs in IDD in relation to their actions on nucleus pulposus cell functions, including cell proliferation, apoptosis and extracellular matrix synthesis/degradation. The potential clinical utilities of circRNAs as therapeutic targets for the management of IDD are also discussed.

摘要: Objectives Osteogenesis is coupled with angiogenesis during bone remodelling. G-protein-coupled receptor (GPCR) kinase 2-interacting protein-1 (GIT1) is an important protein that participates in fracture healing by regulating angiogenesis. This study investigated whether GIT1 could affect bone mesenchymal stem cells (BMSCs) to secrete angiogenic factors to enhance fracture healing by promoting angiogenesis and its possible mechanism. Materials and methods The angiogenesis of mice post-fracture was detected by micro-CT and immunofluorescence. Subsequently, vascular endothelial growth factor (VEGF) level in mouse and human BMSCs (hBMSCs) under TNF-alpha stimulation was detected. The hBMSCs were transfected with GIT1 shRNAs to further explore the relationship between GIT1 and VEGF and angiogenesis in vitro. Furthermore, based on previous research on GIT1, possible signal pathways were investigated. Results GIT1 knockout mice exhibited impaired angiogenesis and delayed fracture healing. And GIT1 deficiency remarkably reduced the expression of VEGF mRNA in BMSCs, which affected the proliferation and migration of human umbilical vein endothelial cells. GIT1 knockdown inhibited the activation of Notch and NF-kappa B signals by decreasing nuclear transportation of NICD and P65/P50, respectively. Overexpression of the canonical NF-kappa B subunits P65 and P50 markedly increased NICD-dependent activation of recombination signal-binding protein-j kappa reporter. Finally, GIT1 enhanced the affinity of NF-kappa B essential modulator (NEMO) for K63-linked ubiquitin chains via interaction with NEMO coiled-coil 2 domains. Conclusion These data revealed a positive role for GIT1 by modulating the Notch/NF-kappa B signals which promoting paracrine of BMSCs to enhance angiogenesis and fracture healing.

摘要: Objective Inflammatory bowel disease (IBD) is a disorder intestinal inflammation and impaired barrier function, associated with increased epithelial expression of monocarboxylate transporter 4 (MCT4). However, the specific non-metabolic function and clinical relevance of MCT4 in IBD remain to be fully elucidated. Methods Lentivirus-mediated overexpression of MCT4 was used to assess the role of MCT4 in transcriptionally regulating ZO-1 and IL-6 expression by luciferase assays, WB and ChIP. IP was used to analyse the effect of MCT4 on the interaction NF-kappa B-CBP or CREB-CBP, and these MCT4-mediated effects were confirmed in vivo assay. Results We showed that ectopic expression of MCT4 inhibited ZO-1 expression, while increased pro-inflammatory factors expression, leading to destroy intestinal epithelial barrier function in vitro and in vivo. Mechanistically, MCT4 contributed NF-kappa B p65 nuclear translocation and increased the binding of NF-kappa B p65 to the promoter of IL-6, which is attributed to MCT4 enhanced NF-kappa B-CBP interaction and dissolved CREB-CBP complex, resulting in reduction of CREB activity and CREB-mediated ZO-1 expression. In addition, treatment of experimental colitis with MCT4 inhibitor alpha-cyano-4-hydroxycinnamate (CHC) ameliorated mucosal intestinal barrier function, which was due to attenuation of pro-inflammation factors expression and enhancement of ZO-1 expression. Conclusion These findings suggested a novel role of MCT4 in controlling development of IBD and provided evidence for potential targets of IBD.

摘要: Objectives To investigate the function and regulatory mechanism of Kruppel-like factor 3 (KLF3) in lung cancer. Materials and Methods KLF3 expression was analysed by qRT-PCR and Western blot assays. The proliferation, migration, invasion, cycle and apoptosis were measured by CCK-8 and EdU, wound-healing and Transwell, and flow cytometry assays. The tumour growth was detected by nude mouse tumorigenesis assay. In addition, the interaction between KLF3 and Sp1 was accessed by luciferase reporter, EMSA and ChIP assay. JAK2, STAT3, PI3K and p-AKT levels were evaluated by Western blot and IHC assays. Results The results indicated that KLF3 expression was elevated in lung cancer tissues. Knockdown of KLF3 inhibited lung cancer cell proliferation, migration and invasion, and induced cell cycle arrest and apoptosis. In addition, the downregulation of KLF3 suppressed tumour growth in vivo. KLF3 was transcriptionally activated by Sp1. miR-326 could bind to 3 ' UTR of Sp1 but not KLF3 and decreased the accumulation of Sp1, which further indirectly reduced KLF3 expression and inactivated JAK2/STAT3 and PI3K/AKT signaling pathways in vitro and in vivo. Conclusions Our data demonstrate that miR-326/Sp1/KLF3 regulatory axis is involved in the development of lung cancer, which hints the potential target for the further therapeutic strategy against lung cancer.

摘要: Objectives The chemotherapy drug resistance is a major challenge for non-small-cell lung cancer (NSCLC) treatment. Combination of immunotherapy and chemotherapy has shown promise for cancer. The goal of this study was to evaluate the anti-tumour efficacy of interleukin-7 (IL-7) combining cisplatin against NSCLC. Materials and Methods Cell proliferation was analysed using CCK-8 assay, EdU proliferation assay and colony-forming assay. Cell apoptosis was evaluated using HOECHST 33342 assay and flow cytometry. The protein expression levels were analysed by Western blot. The blocking antibody against the IL-7 receptor and the inhibitors of STAT5 and JAK3 were used to investigate the pathway involved. A xenograft model was established to assess the anti-tumour efficacy of IL-7 combining cisplatin in vivo. Results Here we found IL-7R was increased in A549/DDP cells compared with A549 cells. The block of IL-7R reversed the inhibitory effects of IL-7 combined with cisplatin and decreased the numbers of apoptosis cells induced by treatment of IL-7 combined with cisplatin. The JAK3 inhibitor and STAT5 inhibitor were used to identify the pathway involved. The results showed that JAK3/STAT5 pathway was involved in enhancing role of cisplatin sensitivity of NSCLC cells by IL-7. In vivo, cisplatin significantly inhibited tumour growth and IL-7 combined with cisplatin achieved the best therapeutic effect. Conclusion Together, IL-7 promoted the sensitivity of NSCLC cells to cisplatin via IL-7R-JAK3/STAT5 signalling pathway.