No abstract

No abstract

Neurodegeneration in Alzheimer's disease (AD) results in microglial activation, which may participate in the inflammatory cascade accelerating tissue damage. In this study, we sought to characterize the alleviatory role of microRNA-711 (miR-711) encapsulated in microglia-derived extracellular vesicles (EVs) in a model of AD. Ultracentrifugation was employed to extract EVs from microglia (BV2 cells), which were identified using Western blot analysis of the EVs marker proteins Alix and CD63. A repetitive mild traumatic brain injury (rmTBI) mouse model was induced by controlled cortical impact. After overexpressing miR-711 or 1,4,5-trisphosphate 3-kinase B (Itpkb) in BV2 cells, we evaluated the inflammation in BV2 cells and the ratio of microglia M2/M1. Further, we injected BV2 cell-secreted EVs with overexpressed miR-711 or Itpkb into rmTBI mice through a tail vein to investigate the inflammation markers in mouse serum and, the M2/M1 phenotype ratio of microglia in brain tissues, and to evaluate neurological deficit and cognitive function. The EVs obtained by ultracentrifugation were verified by the presence of Alix and CD63 expression. Mechanistic studies suggested that miR-711 targeted and inhibited Itpkb, thereby repressing Tau phosphorylation and increasing the ratio of M2/M1. Furthermore, miR-711-containing EVs reduced the score of neurological deficits and improved cognitive function in rmTBI mice. The administration of microgliaderived EVs loaded with miR-711, which mediated the hyperphosphorylation of Tau protein in the Itpkb pathway, effectively alleviated neurodegenerative changes and cognitive dysfunction in AD.

MicroRNA (miR)-410 plays a potential role in the pathogenesis of atherosclerosis. The current study mainly focuses on the underlying mechanism of miR-410/histone deacetylase 1 (HDAC1)/KLF5/nuclear factor κB (NF-κB) inhibitor α (IKBα)/NF-κB axis in atherosclerosis. miR-410 expression was determined using quantitative real-time PCR in both mouse models of atherosclerosis and human umbilical endothelial cells (HUVECs) treated with oxidized low-density lipoprotein (ox-LDL). The study subsequently predicted regulators associated with miR-410 through bioinformatics, and their binding relation was further verified through dual luciferase reporter gene and RNA immunoprecipitation (RIP) assays, and how HDAC1 regulated KLF5 was tested through coimmunoprecipitation (coIP). In HUVECs, miR-410 and HDAC1 mRNA expression; HDAC1, KLF5, IKBα, p65, p-p65, VCAM-1, ICAM-1, and MCP-1 protein expression; and inflammatory cytokine expressions were detected using quantitative real-time PCR, western blot, and ELISA. The present study further tested cell functions by Cell Counting Kit-8 (CCK-8), flow cytometry, and the colony-formation assay. It was revealed that miR-410 could target HDAC1, whereas HDAC1 could target transcription factor KLF5, increasing IKBα expression, thus suppressing NF-κB in atherosclerosis. Furthermore, silencing miR-410 or overexpressing HDAC1 increased cell viability and suppressed apoptosis and an inflammatory reaction in HUVECs in atherosclerosis. Blocking miR-410 promotes HDAC1 expression and increases IKBα levels through KLF5 to suppress NF-κB, thus preventing development of atherosclerosis.

Nasopharyngeal carcinoma (NPC) is a common cancer found in the nasopharynx with high metastatic and invasive nature. Increasing evidences have identified the critical role of gene therapy in NPC treatment. Hence, this study was designed to identify specific gene markers that affected NPC progression through gene expression profile analysis. NPC‐related gene expression data set gene set enrichment (GSE)53819 were retrieved and analyzed to screen out differentially expressed genes (DEGs), followed by determination of their expression in noncancerous tissues and NPC specimens. Next, weighted gene co‐expression network analysis (WGCNA) was conducted on DEGs to obtain tumor‐associated gene modules. Genes in those modules were intersected with DEGs for gene ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis. Then protein‐protein interaction network of tumor‐associated genes was constructed to select genes most closely linked to NPC. Afterward, expression of chromosome 9 open reading frame 24 (c9orf24), primary ciliary dyskinesia protein 1 (PCDP1), and leucine‐rich repeat‐containing protein 46 (LRRC46) was detected in GSE53819 and further verified in GSE12452 and GSE64634. Differential analysis on GSE53819 found that 2,173 genes were aberrantly expressed in NPC, among which 917 genes are upregulated and 1,256 genes are downregulated. WGCNA showed that genes were enriched in 17 modules and 727 genes exhibited ectopic expression in NPC and enriched in cytokine‐cytokine receptor interaction, cytochrome P450, and chemical carcinogenesis signaling pathways, among which c9orf24, PCDP1, and LRRC46 were poorly expressed in NPC. Therefore, c9orf24, PCDP1, and LRRC46 might serve as prominent diagnostic markers for NPC, which presents new insights for NPC therapy.

No abstract

Tongue cancer is one of the most common and deadly types of head and neck cancer. The incidence of tongue cancer has been particularly high and remained been increasing in some countries. A main reason for poor prognosis and clinical outcome for tongue cancer was its resistance to chemotherapies, behind which the mechanisms have been not clear. In this review, we summarized literatures published in recent years and listed the proteins, biomacromolecules, and signaling pathways related to this drug resistance. We hoped that this summary could provide reference for researchers to develop new treatment strategies for tongue cancer.

(NK) cells are at the first line of defence against tumours, but their anti‐tumour mechanisms are not fully understood. We aimed to investigate the mechanism by which NK cells can mediate immunotherapy against head and neck squamous cell carcinoma (HNSCC). We collected fifty‐two pairs of HNSCC tissues and corresponding adjacent normal tissues; analysis by RT‐qPCR showed underexpression of CXCL14 in HNSCC tissues. Primary NK cells were then isolated from the peripheral blood of HNSCC patients and healthy donors. CXCL14 was found to be consistently under‐expressed in the primary NK cells from the HNSCC patients. However, CXCL14 expression was increased in IL2‐activated primary NK cells and NK‐92 cells. We next evaluated NK cell migration, IFN‐γ and TNF‐α expression, cytotoxicity and infiltration in response to CXCL14 overexpression or knockdown using gain‐ and loss‐of‐function approach. The results exhibited that CXCL14 overexpression promoted NK cell migration, cytotoxicity and infiltration. Subsequent in vivo experiments revealed that CXCL14 suppressed the growth of HNSCC cells via activation of NK cells. ChIP was applied to study the enrichment of H3K27ac, p300, H3K4me1 and CDX2 in the enhancer region of CXCL14, which showed that CDX2/p300 activated the enhancer of CXCL14 to up‐regulate its expression. Rescue experiments demonstrated that CDX2 stimulated NK cell migration, cytotoxicity and infiltration through up‐regulating CXCL14. In vivo data further revealed that CDX2 suppressed tumorigenicity of HNSCC cells through enhancement of CXCL14. To conclude, CDX2 promotes CXCL14 expression by activating its enhancer, which promotes NK cell–mediated immunotherapy against HNSCC.