HucMSC-Ex carrying miR-203a-3p.2 ameliorates colitis through the suppression of caspase11/4-induced macrophage pyroptosis.

BACKGROUND: Inflammatory bowel disease (IBD) is a kind of chronic, idiopathic, and recurrent inflammation, associated with dysregulated intestinal mucosal immunity. Caspase (casp) 11/4-induced macrophage pyroptosis contributes to the development of inflammation, while human umbilical cord mesenchymal stem cell-secreted exosomes (hucMSC-Ex) play a reparative role in IBD. OBJECTIVE: The present study focused on the treatment of IBD with hucMSC-Ex and its regulatory mechanism via the casp11/4 pathway. METHODS: BALB/c mice were used to establish a dextran sulfate sodium (DSS)-induced colitis model, and hucMSC-Ex was administered intravenously to estimate its therapeutic effect. In vitro, RAW264.7 cells line, THP-1 cells line, and mouse peritoneal macrophages (MPMs) were stimulated with lipopolysaccharides (LPS) to activate an inflammatory environment of pyroptosis, followed by repairing with hucMSC-Ex. MicroRNA mimics and inhibitors were provided to verify the role of miR-203a-3p.2 from hucMSC-Ex in inflammation. The results were analyzed by Western blot, RT-qPCR、ELISA, and LDH secretion. RESULTS: HucMSC-Ex inhibited the activation of casp11 and reduced the secretion of interleukin (IL)-1ß, IL-6, and casp11, which relieved macrophage pyroptosis to alleviate murine colitis. A consistent outcome was revealed in the cell experiments, where hucMSC-Ex contributed to a decreased casp11/4 expression, and lactate dehydrogenase (LDH) release, as a marker of cell damage. Moreover, miR-203a-3p.2 from hucMSC-Ex functioned as an effective mediator in the interaction with casp4 in THP-1 macrophage pyroptosis. CONCLUSION: HucMSC-Ex ameliorates colitis through the suppression of casp11/4-induced macrophage pyroptosis, and hucMSC-Ex carrying miR-203a-3p.2 inhibits casp4-induced macrophage pyroptosis in an inflammatory environment.

hucMSC-Derived Exosomes Alleviate the Deterioration of Colitis via the miR-146a/SUMO1 Axis.

Human umbilical cord mesenchymal stem cell-derived exosome (hucMSC-Ex) plays an important role in tissue repair and immunomodulation, leading to the mitigation of inflammatory bowel disease. However, the preventive function of hucMSC-Ex in the onset and progression of colitis-associated colon cancer (CAC) is poorly understood. In the current study, dextran sodium sulfate/azoxymethane-induced colitis mouse model was established, and the mice disease activity index, body weight, colon length, tumor counts, survival curve, tissue H&E/immunohistochemistry, and cytokines expression were analyzed to evaluate the effects of hucMSC-Ex on CAC. In addition, miR-146a mimics were transfected into colonic epithelial cells (fetal human cells) to evaluate their role in the hucMSC-Ex-mediated regulation of SUMO1. The results showed that hucMSC-Ex inhibits the expression of SUMO1 to reduce the process of CAC progression. Further analysis indicated that miR-146a targets and inhibits SUMO1 expression and its binding to ß-catenin. In conclusion, our findings showed that hucMSC-Ex is effective in alleviating the deterioration of colitis via the miR-146a-mediated inhibition of SUMO1, which is crucial in this disease process.

Selective downregulation of distinct circRNAs in the tissues and plasma of patients with primary hepatic carcinoma.

Multiple studies have indicated that circular RNAs (circRNAs) are closely associated with malignant tumor development and metastasis. However, the significance of circRNAs in primary hepatic carcinoma (PHC), particularly in the plasma, remains largely undetermined. In the current study, circRNA expression profiles in three pairs of tumor and adjacent normal samples from patients with PHC, were examined using circRNA chip screening. A total of 80 circRNAs were upregulated, while 75 circRNAs were downregulated in PHC tissues, relative to para-tumor tissues (fold change, ≥1.5). A total of two upregulated circRNAs and three downregulated circRNAs were selected as candidates for further validation of their differential expression. This was performed using reverse transcription-quantitative PCR with 11 pairs of PHC tissues and para-tumor tissues. The results indicated that hsa_circ_0003056 exhibited reduced expression in PHC tissues. Moreover, hsa_circ_0003056 and hsa_circ_0067127 were quantified in the plasma samples of 35 PHC patients and 32 healthy donors. The results revealed that hsa_circ_0067127 was significantly downregulated in the patients' plasma. Finally, a competing endogenous RNA network was constructed, which consisted of one circRNA (hsa_circ_0003056 or has_circ_0067127), five miRNAs and miRNA-targeted genes (mRNAs). Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that differentially expressed (DE) genes were significantly enriched in the pathway associated with 'regulation of the pluripotency of stem cells' for hsa_circ_0003056, and 'ubiquitin-mediated proteolysis' and 'prostate cancer' for hsa_circ_0067127. Gene ontology analysis revealed that DE genes were primarily associated with the 'modulation of kinase activity' and 'intracellular and transmembrane-ephrin receptor activity' for hsa_circ_0003056, 'artery morphogenesis activity', 'HOPS complex and transferase activity' and in 'transferring acyl groups' for hsa_circ_0067127. This approach indicated that hsa_circ_0003056 in PHC tissue, and hsa_circ_0067127 in PHC plasma, are downregulated and may be implicated in the tumorigenesis of PHC.

[Increased serum IL-6 and soluble IL-6 receptor in breast cancer patients after radiotherapy are correlated with proportions of immune cells].

Objective To investigate the value of serum interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R) levels of breast cancer patients in evaluating immune function after radiotherapy. Methods We randomly selected 55 cases of breast cancer patients who had received radiotherapy as an observation group, and 55 cases of normal healthy adults as a control group. ELISA was used to detect serum IL-6 and sIL-6R levels. Flow cytometry was used to detect CD45+CD19+ B lymphocytes, CD45+CD3+CD4+ T lymphocytes, CD45+CD3+CD8+ T lymphocytes and CD45+CD16+CD56+ NK cells in peripheral blood. The correlation of lymphocyte subsets with IL-6 or sIL-6R levels was analyzed. Results Serum IL-6 and sIL-6R levels of the observation group patients after radiotherapy were significantly higher than those before radiotherapy and in the control group, and the IL-6 and sIL-6R levels of patients of III or IV stage breast cancer increased significantly. Flow cytometry showed that the ratios of total T lymphocytes and NK cells in the observation group after radiotherapy were significantly reduced, while the ratio of B lymphocytes was significantly elevated. In addition, the levels of IL-6 and sIL-6R were positively correlated with the ratio of NK cells and negatively correlated with the ratio of B lymphocytes. Conclusion Serum IL-6 and sIL-6R levels in patients with breast cancer can be used as references for assessing the course of breast cancer and immune function after radiotherapy.

Circulating miRNAs as novel diagnostic biomarkers in hepatocellular carcinoma detection: a meta-analysis based on 24 articles.

The diagnostic value and suitability of circulating miRNAs for the detection of hepatocellular carcinoma have been inconsistent in the literature. A meta-analysis is used to systematically evaluate the diagnostic value of circulating miRNAs. Eligible studies were selected and the heterogeneity was assessed by subgroup analysis, meta-regression, and publication bias. After strictly and comprehensive screening, the source methods, internal reference and the cut-off values of the included miRNAs were first listed. Circulating miRNAs demonstrated a relatively good diagnostic value in hepatocellular carcinoma, In the subgroup analysis, diagnosis odds ratio showed a higher accuracy with multiple miRNAs than with a single miRNA as well as with serum types than plasma types. In addition, although miRNAs have many expression patterns, the high frequency expression miRNAs (miR-21, miR-199 and miR-122) might be more specific for the diagnosis of hepatocellular carcinoma.The sources of heterogeneity might be related to the number of miRNAs and the specimen types in meta-regression. Furthermore, it's surprised that the pooled studies were first demonstrated publication bias (P < 0.05). In conclusion, multiple miRNAs in serum have a better diagnostic value, and the publication bias was stable. To validate the potential applicability of miRNAs in the diagnosis of hepatocellular carcinoma, more rigorous studies are needed to confirm these conclusions.

EpCAM Inhibition Sensitizes Chemoresistant Leukemia to Immune Surveillance.

The lack of effective tumor-associated antigens restricts the development of targeted therapies against myeloid leukemia. In this study, we compared gene expression patterns of acute myeloid leukemia (AML) and normal bone marrow samples and found that epithelial cell adhesion molecule (EpCAM) is frequently overexpressed in patients with AML, with EpCAM+ leukemic cells exhibiting enhanced chemoresistance and oncogenesis. The chemotherapeutic resistance of EpCAM-positive leukemic cells is a consequence of increased WNT5B signaling. Furthermore, we generated EpCAM antibodies that enabled phagocytosis or cytotoxicity of AML cells by macrophage or natural killer cells, respectively. Finally, EpCAM antibody treatment depleted AML in subcutaneous, disseminated, and intramedullary engrafted mice. In summary, EpCAM exhibits promise as a novel target for the treatment of leukemia. Cancer Res; 77(2); 482-93. ©2016 AACR.