A ceRNA Network Composed of Survival-Related lncRNAs, miRNAs, and mRNAs in Clear Cell Renal Carcinoma.

Clear cell renal carcinoma (ccRCC) is one of the most common renal carcinomas worldwide, which has worse prognosis compared with other subtypes of tumors. We propose a potential RNA regulatory mechanism associated with ccRCC progression. Accordingly, we screened out clinical factors and the expression of RNAs and miRNAs of ccRCC from the TCGA database. 9 lncRNAs (FGF12-AS2, WT1-AS, TRIM36-IT1, AC009093.1, LINC00443, TCL6, COL18A1-AS1, AC110619.1, HOTTIP), 2 miRNAs (mir-155 and mir-21), and 3 mRNAs (COL4A4, ERMP1, PRELID2) were selected from differential expression RNAs and built predictive survival models. The survival models performed very well in predicting prognosis and were found to be highly correlated with tumor stage. In addition, the survival-related lncRNA-miRNA-mRNA (ceRNA) network was constructed by 18 RNAs including 12 mRNAs, 2 miRNAs, and 4 lncRNAs. It is found that the "ECM-receptor interaction," "Pathways in cancer," and "Chemokine signaling pathway" as the main pathways in KEGG pathway analysis. Overall, we established predictive survival model and ceRNA network based on multivariate Cox regression analysis. It may open a new approach and potential biomarkers for clinical prognosis and treatment of ccRCC patients.

Simvastatin Inhibits Tumor Growth and Migration by Mediating Caspase-1-Dependent Pyroptosis in Glioblastoma Multiforme.

OBJECTIVES: Glioblastoma multiforme (GBM) is the most common and lethal central nervous system cancer and is associated with a poor prognosis. Simvastatin, a kind of widely used hypolipidemic agent, has been investigated for its beneficial effects on various types of cancers. The main purpose of this paper is to investigate the potential inhibitory effects of simvastatin on GBM and the underlying mechanism. METHODS: Cell viability and cell cycle of simvastatin-treated U87 and U251 cells were determined by CCK8 assay and flow cytometry, respectively. Additionally, we assessed cell migration and invasion abilities using a wound-healing assay and transwell assay. mRNA and protein expression patterns of caspase-1 and its markers nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) and IL-1ß in different conditions were detected by real-time polymerase chain reaction, immunofluorescence staining, and Western blot. RESULTS: Simvastatin decreased the viability of GBM cells and inhibited cell migration and invasion in a dose-dependent manner. Moreover, suppression of pyroptosis, as characterized by decreased expression of caspase-1, NLRP3, and IL-1ß, was observed. However, use of an miR-214 inhibitor reversed the simvastatin suppressive effect on GBM cells. CONCLUSIONS: Simvastatin inhibits GBM progression by suppressing caspase-1-dependent pyroptosis, regulated by miR-214.

IFN-γ regulates the transformation of microglia into dendritic-like cells via the ERK/c-myc signaling pathway during cerebral ischemia/reperfusion in mice.

Cerebral ischemia-reperfusion injury induces a secondary immune inflammatory reaction that exacerbates brain injury and clinical prognosis. Dendritic cells (DCs) and microglia are both important regulators of neuroinflammation. Studies have confirmed that a large number of cells express the DC surface marker CD11c in the ischemic area, and some of these cells also express microglial markers. However, the specific mechanism of transformation between microglia and DCs and their roles in the process of cerebral ischemia-reperfusion injury are still not clear. In this study, we established a mouse model and flow cytometry was used to detect the expression of mature DC surface molecules in activated microglia. IFN-γ knockout mice were used to determine the regulatory effect of IFN-γ on microglial transformation. We found that CD11c+ cells were derived from microglia after ischemia-reperfusion injury, and this group of cells highly expressed MHC-II molecules and other costimulatory molecules, such as CD80 and CD86, which were regulated by IFN-γ and its downstream signaling molecules ERK/c-myc. In summary, our results showed in cerebral ischemia-reperfusion injury, IFN-γ regulates the transformation of microglia to DC-like cells. Microglial-derived DC-like cells possess the ability to present antigens and activate naïve T cells which is regulated by the ERK/c-myc signaling pathway.

Association between hyperpolarization-activated channel in interstitial cells of Cajal and gastrointestinal dysmotility induced by malignant ascites.

Advanced malignant ascites is accompanied by gastrointestinal dysmotility, and patients often feel abdominal pain, abdominal distention, nausea and constipation. Gastrointestinal dysmotility is not only painful for the patients, but it reduces the absorption of nutrients and affects the physical recovery of patients with malignant ascites. It is reported that changes in interstitial cells of Cajal (ICCs) are responsible for the gastrointestinal dysmotility induced by malignant ascites, but the mechanism is not completely understood. The present study observed a significantly decreased expression of ion channels, including hyperpolarization-activated cyclic nucleotide-gated potassium channel 2 (HCN2) and cyclic adenosine monophosphate, in the condition of malignant ascites. Using electrophysiology, it was identified that malignant ascites led to lower amplitude and slower frequency signals in cells of the small intestine. In addition, when ICCs were cultured with malignant ascites in vitro, the expression of HCN2 of ICCs was significantly reduced, and the data of flow cytometry revealed that the Ca2+ concentration of ICCs was also decreased. The results of electron microscopy analysis demonstrated the nuclei of ICCs were pyknotic, and the processes of ICCs were reduced in malignant ascites. The present study suggests the small intestinal dysmotility caused by malignant ascites may be associated with changes in HCN2 of ICCs, which offers a potential therapeutic target for gastrointestinal dysmotility in advanced malignant ascites.

Combined effect of ligament stem cells and umbilical-cord-blood-derived CD34+ cells on ligament healing.

Transplantation of ligament-tissue-derived stem cells has become a promising approach in the repair of injured ligament. Neovascularization plays an important role in ligament healing and remodeling. Recently, human umbilical-cord-blood-derived CD34+ cells have been reported to contribute to neoangiogenesis. Therefore, we performed a series of experiments to test our hypothesis that the combination of medial collateral ligament stem cells (MCL-SCs) and umbilical-cord-blood-derived CD34+ cells has synergistic effects on tendon healing. MCL-SCs and umbilical-cord-blood-derived CD34+ cells were isolated and cultured. Rat MCL injury was treated by MCL-SCs and/or CD34+ cells. Response to the cell therapy was assessed by gross observation, histological evaluation and biomechanical testing at 2 and 4 weeks after each treatment. Although each cell therapy group induced macroscopic and morphological recovery in healing MCLs, the combined use of MCL-SCs/CD34+ cells led to further improvement in healing quality. Capillary density was significantly higher in the CD34+ cell transplantation groups than in the other groups at week 2. Biomechanical testing demonstrated that the failure load of the healing ligament was greatest in the combination therapy group. The combination of MCL-SCs and CD34+ cells as a cell therapeutic thus enhances healing and restores biomechanical function toward normal after MCL injury. The findings obtained in our study suggest that the combination of MCL-SCs and CD34+ cells transplantation represents a promising strategy for ligament injury.

pCREB is involved in neural induction of mouse embryonic stem cells by RA.

Mouse embryonic stem (ES) cells can be induced by various chemicals to differentiate into a variety of cell types in vitro. In our study, retinoic acid (RA), one of the most important inducers, used at a concentration of 5 microM, was found to induce the differentiation of ES cells into neural progenitor cells (NPCs). During embryoid body (EB) differentiation, the level of active cyclic AMP response element-binding protein (CREB) was relatively high when 5 microM RA treatment was performed. Inhibition of CREB activity committed EBs to becoming other germ layers, whereas increased expression of CREB enhanced NPC differentiation. Moreover, RA increased the expression of active CREB by enhancing the activity of JNK. Our research suggests that CREB plays a role in RA-induced NPC differentiation by increasing the expression of active JNK.