Laminar shear stress alleviates monocyte adhesion and atherosclerosis development via miR-29b-3p/CX3CL1 axis regulation.

Laminar shear stress (Lss) is an important anti-atherosclerosis (anti-AS) factor, but its mechanism network is not clear. Therefore, this study aimed to identify how Lss acts against AS formation from a new perspective. In this study, we analyzed high-throughput sequencing data from static and Lss-treated human aortic and human umbilical vein endothelial cells (HAECs and HUVECs, respectively) and found that the expression of CX3CL1, which is a target gene closely related to AS development, was lower in the Lss group. Lss alleviated the inflammatory response in TNF-α (also known as TNF)-activated HAECs by regulating the miR-29b-3p/CX3CL1 axis, and this was achieved by blocking nuclear factor (NF)-κB signaling. In complementary in vivo experiments, a high-fat diet (HFD) induced inflammatory infiltration and plaque formation in the aorta, both of which were significantly reduced after injection of agomir-miRNA-29b-3p via the tail vein into HFD-fed ApoE-/- mice. In conclusion, this study reveals that the Lss-sensitive miR-29b-3p/CX3CL1 axis is an important regulatory target that affects vascular endothelial inflammation and AS development. Our study provides new insights into the prevention and treatment of AS.

Alterations and Mechanism of Gut Microbiota in Graves' Disease and Hashimoto's Thyroiditis.

To explore the role of gut microbiota in Graves' disease (GD) and Hashimoto's thyroiditis (HT). Seventy fecal samples were collected, including 27 patients with GD, 27 with HT, and 16 samples from healthy volunteers. Chemiluminescence was used to detect thyroid function and autoantibodies (FT3, FT4, TSH, TRAb, TGAb, and TPOAb); thyroid ultrasound and 16S sequencing were used to analyze the bacteria in fecal samples; KEGG (Kyoto Encyclopedia of Genes and Genomes) and COG (Clusters of Orthologous Groups) were used to analyze the functional prediction and pathogenesis. The overall structure of gut microbiota in the GD and HT groups was significantly different from the healthy control group. Proteobacteria and Actinobacteria contents were the highest in the HT group. Compared to the control group, the GD and HT groups had a higher abundance of Erysipelotrichia, Cyanobacteria, and Ruminococcus_2 and lower levels of Bacillaceae and Megamonas. Further analysis of KEGG found that the "ABC transporter" metabolic pathway was highly correlated with the occurrence of GD and HT. COG analysis showed that the GD and HT groups were enriched in carbohydrate transport and metabolism compared to the healthy control group but not in amino acid transport and metabolism. Our data suggested that Bacillus, Blautia, and Ornithinimicrobium could be used as potential markers to distinguish GD and HT from the healthy population and that "ABC transporter" metabolic pathway may be involved in the pathogenesis of GD and HT.

Laminar shear stress inhibits inflammation by activating autophagy in human aortic endothelial cells through HMGB1 nuclear translocation.

Prevention and treatment of atherosclerosis (AS) by targeting the inflammatory response in vascular endothelial cells has attracted much attention in recent years. Laminar shear stress (LSS) has well-recognized anti-AS properties, however, the exact molecular mechanism remains unclear. In this study, we found that LSS could inhibit the increased expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), cyclooxygenase-2 (COX-2), and matrix metallopeptidase-9 (MMP-9) caused by TNF-α in an autophagy-dependent pathway in human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs). Whole-transcriptome sequencing analysis revealed that erythropoietin-producing hepatocyte receptor B2 (EPHB2) was a key gene in response to LSS. Moreover, co-immunoprecipitation assay indicated that LSS could enhance the EPHB2-mediated nuclear translocation of high mobility group box-1 (HMGB1), which interacts with Beclin-1 (BECN1) and finally leads to autophagy. Simultaneously, we identified an LSS-sensitive long non-coding RNA (lncRNA), LOC10798635, and constructed an LSS-related LOC107986345/miR-128-3p/EPHB2 regulatory axis. Further research revealed the anti-inflammatory effect of LSS depends on autophagy activation resulting from the nuclear translocation of HMGB1 via the LOC107986345/miR-128-3p/EPHB2 axis. Our study demonstrates that LSS could regulate the expression of EPHB2 in HAECs, and the LOC107986345/miR-128-3p/EPHB2 axis plays a vital role in AS development.

A predictive analysis approach for paediatric and adult high-grade glioma: miRNAs and network insight.

BACKGROUND: Brain tumours are the most common solid tumour in children and are a cause of mortality in adults. Most cases of brain tumour-related death are attributed to glioblastoma (GBM), with an elevated rate for high-grade glioma (HGG). Showing strong heterogeneity, the lesion location, molecule expression and type of HGG differ between adults and children. However, with regard to pathogenesis, brain tumours are expected to have the same underlying molecular processes. METHODS: In this study, we obtained data from the Gene Expression Omnibus (GEO) database to analyse molecular expression in HGG between adults and children. The same and different mutations were identified in these groups, and the genes involved were compared using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Molecular analysis revealed the same trend of differences between children and adults, which was verified in The Cancer Genome Atlas (TCGA). RESULTS: A total of 12 microarrays including 455 HGG patients were screened. Through a rigorous intersecting process, we identified miR-10a, miR-10b, and miR-139 as having common differences, as well as 6 target genes, such as CDK6, SOX4 and VEGFA, etc. And 12 long noncoding RNAs (lncRNAs). CONCLUSIONS: We identified that these key molecules are involved in development and progression of HGG between adults and children. The findings provide a comprehensive description of the similarities in advanced diseases between adults and children and molecular diagnostic directions for precision small-molecule medicine to treat HGG in different age populations.

Serum miR-515-3p, a potential new RNA biomarker, is involved in gastric carcinoma.

OBJECTIVES: microRNAs (miRNAs) have provided a new opportunity for developing diagnostic biomarkers and effective therapeutic targets in gastric cancer (GC). In this study, we aimed to investigate the relationship between miR-515-3p and GC development. EXPERIMENTAL DESIGN: The Gene Expression Omnibus (GEO) database was used for screening genes and miRNA and for 2R analysis. miRNA prediction target genes and screening key genes were analyzed using protein interactions (PPI) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. A network of miRNA-mRNA interactions was predicated by Cytoscape (v.3.5.1), Institute of Systems Biology & University of California, San Diego & Pasteur institute & University of California, San Francisco. Finally, miR-515-3p levels were detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in gastric cells and plasma levels. Then, the association between the expression level of miR-515-3p and the clinicopathological features of patients with GC was further analyzed. OBSERVATIONS AND CONCLUSIONS: We found that miR-515-3p was markedly overexpressed in individuals with GC compared with that in normal gastric cells (NCs) and the surgery group (P < 0.0001). In addition, receiver operating characteristic (ROC) analysis yielded an area under the curve (AUC) value of 0.8555 for miR-515-3p. SIGNIFICANCE: Our results present new information to the field of gastric cancer and has done a good job of creating an initial hypothesis using the database as well as validate their initial results. These results suggest that serum miR-515-3p is a novel potential biomarker for the detection of GC.

Combining multi-dimensional data to identify a key signature (gene and miRNA) of cisplatin-resistant gastric cancer.

Gastric cancer (GC) is one of the most lethal malignant tumors; the resistance of this type of tumor is the main source of GC treatment failure. In this study, we used bioinformatics analysis to verify differences in resistant GCs and identify an effective method for reversing drug resistance in GC. Microarray data [gene and microRNA (miRNA)] were analyzed using GEO2R software, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied to further enrich the genetic data. miRNA-gene interactions were determined using Cytoscape (v.3.5.1). Online software was used to analyze protein interactions and predict network structure. The Cancer Genome Atlas (TCGA) database was used to verify the expression levels of genes in GC resistance. miR-604 expression levels were verified by real-time PCR in GC cell lines. We screened 3981 GC resistance-associated genes and 244 miRNAs using bioinformatics methods. Six hub genes were identified and verified in the TCGA database, including five up-regulated genes, POLR2L, POLR2C, POLR2F, APRT, and LMAN2, and a down-regulated gene, NFKB2. The up-regulated genes POLR2L, POLR2C, APRT, and LMAN2 interact with miR-604; therefore, we focused on miR-604, which has low expression in drug-resistant GC. The results of this study indicate that through bioinformatics technologies, we have determined the hub genes and hub miRNAs related to drug resistance in GC. Among them, miR-604 could become a new indicator in the diagnosis of drug-resistant GC and may be used to investigate the pathogenesis of resistance in GC.

Apoptin-derived peptide reverses cisplatin resistance in gastric cancer through the PI3K-AKT signaling pathway.

The prognosis of gastric cancer (GC) remains poor due to clinical drug resistance, and novel drugs are urgently needed. Apoptin-derived peptide (AdP) is an antitumor polypeptide constructed in our laboratory that has been used to combat cisplatin (CDDP) resistance in GC cells. MTT and colony-formation assays and Hoechst 33342 staining were used to measure the cytotoxicity of CDDP and AdP in GC cells. Cell apoptosis was measured using an Annexin-V-FITC/PI dual staining assay. Western blot analysis was conducted to detect the expression of proteins in the PI3K/AKT signaling pathway and resistance-related markers. AdP exerted a specific cytotoxic effect on GC cells and CDDP-resistant GC cells in a concentration- and time-dependent manner. AdP also suppressed cell invasion and migration. Additionally, AdP inhibited the expression of p85, AKT, p-p85, p-AKT, multidrug resistance 1 (MDR1), and aryl hydrocarbon nuclear translocator (ARNT) in the PI3K/AKT/ARNT signaling pathway, which promoted apoptosis and necrosis in GC cells. AdP promoted apoptosis in CDDP-resistant GC cells by suppressing the PI3K/AKT/ARNT signaling pathway and might be considered a candidate agent for the clinical treatment of cisplatin-resistant GC.

A peptide derived from apoptin inhibits glioma growth.

Glioblastoma (GBM) is associated with poor prognosis due to its resistance to surgery, irradiation, and conventional chemotherapy. Thus, efficient therapeutic approaches for the treatment of GBM are urgently needed. HSP70 is an antiapoptotic protein that participates in the inhibition of both mitochondrial and membrane receptor apoptosis pathways and is highly expressed in glioma tissues. Here, we investigated a derivative of apoptin; specifically, a chicken anemia viral protein with selective toxicity toward cancer cells that can inhibit hyperactive molecules, including HSP70. Our earlier studies demonstrated that apoptin directly binds to the promoter of HSP70 and inhibits HSP70 transcription, which contributes to HSP70 downregulation. This study provides the first demonstration of the therapeutic potential of an apoptin-derived peptide for the treatment of GBM by identifying the minimal region of the apoptin domain required for interaction with the heat-shock element (HSE). This apoptin-derived peptide (ADP) inhibits glioma cell proliferation and tumor growth as well as exhibits an increased ability to promote apoptosis in GBM cells compared with rapamycin and temozolomide. ADP treatment inhibited xenograft tumor growth and increased the overall health and survival of nude mice implanted with GBM cells. These effects were measured in tumors obtained from cell lines and were observed in both intracranial and subcutaneous xenografts. In conclusion, we provide the first demonstration that ADP has therapeutic potential for the treatment of human GBM. Specifically, this study suggests that ADP is a potent candidate for drug development based on its favorable toxicity and pharmacokinetic profiles as well as its time- and cost-saving benefits.