摘要: Objectives The study aimed to determine whether dental pulp stem cell-derived exosomes (DPSC-Exos) exert protective effects against cerebral ischaemia-reperfusion (I/R) injury and explore its underlying mechanism. Materials and Methods Exosomes were isolated from the culture medium of human DPSC. Adult male C57BL/6 mice were subjected to 2 hours transient middle cerebral artery occlusion (tMCAO) injury followed by 2 hours reperfusion, after which singular injection of DPSC-Exos via tail vein was administrated. Brain oedema, cerebral infarction and neurological impairment were measured on day 7 after exosomes injection. Then, oxygen-glucose deprivation-reperfusion (OGD/R) induced BV2 cells were studied to analyse the therapeutic effects of DPSC-Exos on I/R injury in vitro. Protein levels of TLR4, MyD88, NF-kappa B p65, HMGB1, IL-6, IL-1 beta and TNF-alpha were determined by western blot or enzyme-linked immunosorbent assay. The cytoplasmic translocation of HMGB1 was detected by immunofluorescence staining. Results DPSC-Exos alleviated brain oedema, cerebral infarction and neurological impairment in I/R mice. DPSC-Exos inhibited the I/R-mediated expression of TLR4, MyD88 and NF-kappa B significantly. DPSC-Exos also reduced the protein expression of IL-6, IL-1 beta and TNF-alpha compared with those of the control both in vitro and in vivo. Meanwhile, DPSC-Exos markedly decreased the HMGB1 cytoplasmic translocation induced by I/R damage. Conclusions DPSC-Exos can ameliorate I/R-induced cerebral injury in mice. Its anti-inflammatory mechanism might be related with the inhibition of the HMGB1/TLR4/MyD88/NF-kappa B pathway.

摘要: Neuropathic pain is a major type of chronic pain caused by the disease or injury of the somatosensory nervous system. It afflicts about 10% of the general population with a significant proportion of patients' refractory to conventional medical treatment. This highlights the importance of a better understanding of the molecular pathogenesis of neuropathic pain so as to drive the development of novel mechanism-driven therapy. Circular RNAs (circRNAs) are a type of non-coding, regulatory RNAs that exhibit tissue- and disease-specific expression. An increasing number of studies reported that circRNAs may play pivotal roles in the development of neuropathic pain. In this review, we first summarize circRNA expression profiling studies on neuropathic pain. We also highlight the molecular mechanisms of specific circRNAs (circHIPK3, circAnks1a, ciRS-7, cZRANB1, circZNF609 and circ_0005075) that play key functional roles in the pathogenesis of neuropathic pain and discuss their potential diagnostic, prognostic, and therapeutic utilization in the clinical management of neuropathic pain.

摘要: Objectives NLRP3 inflammasome is a critical part of the innate immune system and plays an important role in a variety of inflammatory diseases. However, the effects of NLRP3 inflammasome on periodontitis have not been fully studied. Materials and methods We used ligature-induced periodontitis models of NLRP3 knockout mice (NLRP3(KO)) and their wildtype (WT) littermates to compare their alveolar bone phenotypes. We further used Lysm-Cre/Rosa(nTnG) mouse to trace the changes of Lysm-Cre(+) osteoclast precursors in ligature-induced periodontitis with or without MCC950 treatment. At last, we explored MCC950 as a potential drug for the treatment of periodontitis in vivo and in vitro. Results Here, we showed that the number of osteoclast precursors, osteoclast differentiation and alveolar bone loss were reduced in NLRP3(KO) mice compared with WT littermates, by using ligature-induced periodontitis model. Next, MCC950, a specific inhibitor of the NLRP3 inflammasome, was used to inhibit osteoclast precursors differentiation into osteoclast. Further, we used Lysm-Cre/Rosa(nTnG) mice to demonstrate that MCC950 decreases the number of Lysm-Cre(+) osteoclast precursors in ligature-induced periodontitis. At last, treatment with MCC950 significantly suppressed alveolar bone loss with reduced IL-1 beta activation and osteoclast differentiation in ligature-induced periodontitis. Conclusion Our findings reveal that NLRP3 regulates alveolar bone loss in ligature-induced periodontitis by promoting osteoclastic differentiation.

摘要: Objectives: Cancer cell migration to secondary organs remains an essential cause of death among breast cancer (BrCa) patients. Cell motility mainly relies on actin dynamics. Our previous reports verified that dishevelled-associated activator of morphogenesis 1 (Daam1) regulates invadopodia extension and BrCa cell motility. However, how Daam1 is involved in actin filament assembly and promotes pseudopodia formation in BrCa cells remains unclear. Materials and methods: One hundred human BrCa samples were collected at Women's Hospital of Nanjing Medical University. Immunohistochemistry (IHC) was used to examine Daam1 and Fascin expression. Wound healing and Boyden chamber assays were used to explore cell migration and pseudopodia extension of BrCa cells. Co-IP/pull down and Western blotting were performed to study the physical interaction between Daam1 and Fascin. Immunofluorescence assays were performed to observe whether Daam1 and Fascin were colocalized and mediated actin filament assembly. Results: Fascin was upregulated in BrCa tissues compared with that in paracarcinoma tissues. The downregulation of Fascin caused a decline in pseudopodia formation and cell motility. Moreover, we found that Daam1 interacted with Fascin via formin homology (FH) domains, especially the FH2 domain. Immunofluorescence assays showed that Daam1 and Fascin partially colocalized to actin filaments, and the knockdown of Daam1 or Fascin failed to colocalize to short and curved actin filaments. Conclusions: Daam1 specifically binds to Fascin via FH domains and cooperatively facilitates pseudopodia formation and cell migration by promoting actin filament assembly in BrCa.

摘要: Objectives: Circadian rhythm controls complicated physiological activities in organisms. Circadian clock genes have been related to tumour progression, but its role in glioma is unknown. Therefore, we explored the relationship between dysregulated circadian clock genes and glioma progression. Materials and Methods: Samples were divided into different groups based on circadian clock gene expression in training dataset (n = 672) and we verified the results in other four validating datasets (n = 1570). The GO and GSEA enrichment analysis were conducted to explore potential mechanism of how circadian clock genes affected glioma progression. The single-cell RNA-Seq analysis was conducted to verified previous results. The immune landscape was evaluated by the ssGSEA and CIBERSORT algorithm. Cell proliferation and viability were confirmed by the CCK8 assay, colony-forming assay and flow cytometry. Results: The cluster and risk model based on circadian clock gene expression can predict survival outcome. Samples were scoring by the least absolute shrinkage and selection operator regression analysis, and high scoring tumour was associated with worse survival outcome. Samples in high-risk group manifested higher activation of immune pathway and cell cycle. Tumour immune landscape suggested high-risk tumour infiltrated more immunocytes and more sensitivity to immunotherapy. Interfering TIMELESS expression affected circadian clock gene expression, inhibited tumour cell proliferation and arrested cell cycle at the G0/G1 phase. Conclusions: Dysregulated circadian clock gene expression can affect glioma progression by affecting tumour immune landscape and cell cycle. The risk model can predict glioma survival outcome, and this model can also be applied to pan-cancer.