circ_0008285 Regulates Glioma Progression via the miR-384/HMGB1 Axis.

Background: Recent studies indicate that circular RNAs (circRNAs) have been implicated in the initiation or progression of a wide spectrum of diseases. In the current study, we explored the potential engagement of circ_0008285 in glioma and investigated the downstream regulators. Methods: The detection of circ_0008285 level in glioma specimens and cell lines was conducted by quantitative real-time polymerase chain reaction. The chi-squared test was employed to evaluate the relationship between the circ_0008285 level and the clinical features of glioma patients. The roles of circ_0008285 on the proliferation and apoptosis of glioma cells were studied by knockdown experiment. Meanwhile, the regulatory relationship of circ_0008285, miR-384, and high mobility group protein B1 (HMGB1) was explored in glioma cells, and we explored the effects of circ_0008285/miR-384/HMGB1 pathway on glioma cells. Results: In glioma specimens and cell lines, the expression of circ_0008285 was significantly increased, and a high circ_0008285 level was associated with a larger tumor size and more advanced grading in glioma patients. Furthermore, downregulating circ_0008285 suppressed proliferation and triggered apoptosis of glioma cells, which was associated with a cell cycle arrest at the G1/G0 phase. Mechanism studies indicated that circ_0008285 regulated HMGB1 by sponging miR-384. Functional experiments demonstrated that circ_0008285 promoted the malignant phenotype of glioma cells by miR-384/HMGB1 axis. Conclusion: Our study revealed circ_0008285 as a novel oncogenic factor in glioma through modulating the miR-384/HMGB1 pathway, suggesting that targeting circ_0008285 could serve as a strategy for glioma management.

DC-CTL targeting carbonic anhydrase IX gene combined with iAPA therapy in the treatment of renal cell carcinoma.

INTRODUCTION: To deliver specific antigens in tumor immunotherapy, tumor cell lysates are commonly used to sensitize dendritic cells (DCs). However, the lysates possess low immunogenicity and contain many types of non-tumor-related antigens, which may induce autoimmune diseases. Tumor antigen peptides can provide high specificity but are expensive and their short half-lives limit their clinical application. METHODS: In this study, we used adenovirus to transfer the carbonic anhydrase IX (CA9) gene into DCs to generate specificity to renal cell carcinoma (RCC) which is the most common space-occupying lesion in humans. Inhibition of antigen presentation attenuators (iAPA) technology was also used to enhance the DC delivery capacity. Finally, DCs were co-cultured with cytotoxic T-lymphocytes (CTLs) and the anti-tumor effects were evaluated. RESULTS: The results showed that the CA9-DC-CTLs possessed a high specificity to CA9-positive cells and showed stronger anti-tumor activity than GFP-DC-CTLs both in vitro and in vivo. DISCUSSION: These findings may suggest a novel treatment option for RCC.

A novel therapeutic approach for inflammatory bowel disease by exosomes derived from human umbilical cord mesenchymal stem cells to repair intestinal barrier via TSG-6.

BACKGROUND: Exosomes as the main therapeutic vectors of mesenchymal stem cells (MSC) for inflammatory bowel disease (IBD) treatment and its mechanism remain unexplored. Tumor necrosis factor-α stimulated gene 6 (TSG-6) is a glycoprotein secreted by MSC with the capacities of tissue repair and immune regulation. This study aimed to explore whether TSG-6 is a potential molecular target of exosomes derived from MSCs (MSCs-Exo) exerting its therapeutic effect against colon inflammation and repairing mucosal tissue. METHODS: Two separate dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced IBD mouse models were intraperitoneally administered MSCs-Exo extracted from human umbilical cord MSC (hUC-MSC) culture supernatant. Effects of MSCs-Exo on intestinal inflammation, colon barrier function, and proportion of T cells were investigated. We explored the effects of MSCs-Exo on the intestinal barrier and immune response with TSG-6 knockdown. Moreover, recombinant human TSG-6 (rhTSG-6) was administered exogenously and colon inflammation severity in mice was evaluated. RESULTS: Intraperitoneal injection of MSCs-Exo significantly ameliorated IBD symptoms and reduced mortality rate. The protective effect of MSCs-Exo on intestinal barrier was demonstrated evidenced by the loss of goblet cells and intestinal mucosa permeability, thereby improving the destruction of tight junctions (TJ) structures and microvilli, as well as increasing the expression of TJ proteins. Microarray analysis revealed that MSCs-Exo administration downregulated the level of pro-inflammatory cytokines and upregulated the anti-inflammatory cytokine in colon tissue. MSCs-Exo also modulated the response of Th2 and Th17 cells in the mesenteric lymph nodes (MLN). Reversely, knockdown of TSG-6 abrogated the therapeutic effect of MSCs-Exo on mucosal barrier maintenance and immune regulation, whereas rhTSG-6 administration showed similar efficacy to that of MSCs-Exo. CONCLUSIONS: Our findings suggested that MSCs-Exo protected against IBD through restoring mucosal barrier repair and intestinal immune homeostasis via TSG-6 in mice.

Therapeutic mechanism of human neural stem cell-derived extracellular vesicles against hypoxia-reperfusion injury in vitro.

AIMS: This study aimed to explore that the human neural stem cell derived extracellular vesicles (hNSC-EVs) have therapeutic effect on neuronal hypoxia-reperfusion (H/R) injured neurons in vitro by mediating the nuclear translocation of NF-E2-related factor 2 (Nrf2) to regulate the expression of downstream oxidative kinases. MAIN METHODS: The neuroprotective effects of hNSC-EVs were evaluated in an in vitro neuronal H/R model. Three parameters of hNSC-EVs, structure, phenotype and particle size, were characterized. At the cellular level, a human neuron cerebral ischemic reperfusion (CIR) injury model was constructed. Cell viability, apoptosis, and the amount of reactive oxygen species (ROS) were detected using real-time cell analysis (RTCA), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and dichloro-dihydro-fluorescein diacetate (DCFH-DA), respectively. The neuronal axonal elongation was assessed by Opera Phenix™ screening system. The angiogenesis of human umbilical vein endothelial cells (HUVECs) was evaluated by co-culturing HUVECs with hNSC-EVs in Matrigel. The expression of apoptosis and oxidative stress-related proteins in cells and the nuclear transfer of Nrf2 following hypoxia-reperfusion (H/R) was verified by Western-blotting. KEY FINDINGS: We found that the hNSC-EVs can promote the survival of post-H/R injury neurons, inhibit neuronal apoptosis, and enhance nuclear transfer of Nrf2, in response to oxidative stress. We also found the hNSC-EVs can promote the elongation of neuronal axons and the angiogenesis of HUVECs. SIGNIFICANCE: At present, there is no effective therapy for CIR injury. We suggest that the hNSC-EVs could be considered a new strategy to achieve nerve repair for the treatment of neurological diseases, especially stroke.

l-Arginine Enhances Resistance against Oxidative Stress and Heat Stress in Caenorhabditis elegans.

The antioxidant properties of l-arginine (l-Arg) in vivo, and its effect on enhancing resistance to oxidative stress and heat stress in Caenorhabditis elegans were investigated. C. elegans, a worm model popularly used in molecular and developmental biology, was used in the present study. Here, we report that l-Arg, at a concentration of 1 mM, prolonged C. elegans life by 26.98% and 37.02% under oxidative and heat stress, respectively. Further experiments indicated that the longevity-extending effects of l-Arg may be exerted by its free radical scavenging capacity and the upregulation of aging-associated gene expression in worms. This work is important in the context of numerous recent studies that concluded that environment stresses are associated with an increased population death rate.

A Novel Peptide from Soybean Protein Isolate Significantly Enhances Resistance of the Organism under Oxidative Stress.

Recent studies have indicated that protein hydrolysates have broad biological effects. In the current study we describe a novel antioxidative peptide, FDPAL, from soybean protein isolate (SPI). The aim of this study was to purify and characterize an antioxidative peptide from SPI and determine its antioxidative mechanism. LC-MS/MS was used to isolate and identify the peptide from SPI. The sequence of the peptide was determined to be Phe-Asp-Pro-Ala-Leu (FDPAL, 561 Da). FDPAL can cause significant enhancement of resistance to oxidative stress both in cells as well as simple organisms. In Caenorhabditis elegans (C. elegans), FDPAL can up-regulate the expression of certain genes associated with resistance. The antioxidant activity of this peptide can be attributed to the presence of a specific amino acid sequence. Results from our work suggest that FDPAL can facilitate potential applications of proteins carrying this sequence in the nutraceutical, bioactive material and clinical medicine areas, as well as in cosmetics and health care products.

Yolk-shell hybrid nanoparticles with magnetic and pH-sensitive properties for controlled anticancer drug delivery.

A facile and effective way for the preparation of nano-sized Fe3O4@graphene yolk-shell nanoparticles via a hydrothermal method is developed. Moreover, the targeting properties of the materials for anticancer drug (doxorubicin hydrochloride) delivery are investigated. Excitingly, these hybrid materials possess favorable dispersibility, good superparamagnetism (the magnetic saturation value is 45.740 emu g(-1)), high saturated loading capacity (2.65 mg mg(-1)), and effective loading (88.3%). More importantly, the composites exhibit strong pH-triggered drug release response (at the pH value of 5.6 and 7.4, the release rate was 24.86% and 10.28%, respectively) and good biocompatibility over a broad concentration range of 0.25-100 µg mL(-1) (the cell viability was 98.52% even at a high concentration of 100 µg mL(-1)) which sheds light on their potentially bright future for bio-related applications.