Search Results (11)

We have previously shown that the transmembrane protein ODZ1 promotes cytoskeletal remodeling of glioblastoma (GBM) cells and invasion of the surrounding parenchyma through the activation of a RhoA–ROCK pathway. We also described that GBM cells can control the expression of ODZ1 through transcriptional mechanisms triggered by the binding of IL-6 to its receptor and a hypoxic environment. Epidermal growth factor (EGF) plays a key role in the invasive capacity of GBM. However, the molecular mechanisms that enable tumor cells to acquire the morphological changes to migrate out from the tumor core have not been fully characterized. Here, we show that EGF is able to induce the expression of ODZ1 in primary GBM cells. We analyzed the levels of the EGF receptor (EGFR) in 20 GBM primary cell lines and found expression in 19 of them by flow cytometry. We selected two cell lines that do or do not express the EGFR and found that EGFR-expressing cells responded to the EGF ligand by increasing ODZ1 at the mRNA and protein levels. Moreover, blockade of EGF-EGFR binding by Cetuximab, inhibition of the p38 MAPK pathway, or Additionally, the siRNA-mediated knockdown of MAPK11 (p38β MAPK) reduced the induction of ODZ1 in response to EGF. Overall, we show that EGF may activate an EGFR-mediated signaling pathway through p38β MAPK, to upregulate the invasion factor ODZ1, which may initiate morphological changes for tumor cells to invade the surrounding parenchyma. These data identify a new candidate of the EGF–EGFR pathway for novel therapeutic approaches. Full article

The NLRP3 inflammasome serves as a host defense mechanism against various pathogens, but there is growing evidence linking its activation in sterile condition to diverse inflammatory diseases. Therefore, the identification of specific inhibitors that target NLRP3 inflammasome activation is meaningful and important for novel therapies for NLRP3 inflammasome-associated diseases. In this study, we identified a chemical compound, namely ODZ10117 (ODZ), that showed NLRP3 inflammasome-targeting anti-inflammatory effects during the screening of a chemical library for anti-inflammatory activity. Although ODZ was initially discovered as a STAT3 inhibitor, here we found it also has inhibitory activity on NLRP3 inflammasome activation. ODZ inhibited the cleavage of caspase-1 and IL-1β-induced canonical NLRP3 inflammasome triggers, but had no effect on those induced by AIM2 or NLRC4 triggers. Mechanistically, ODZ impairs NLRP3 inflammasome activation through the inhibition of NLRP3–NEK7 interaction that is required for inflammasome formation. Moreover, the results obtained from the in silico docking experiment suggested that ODZ targets NLRP3 protein, which provides evidence for the specificity of ODZ to the NLRP3 inflammasome. Furthermore, ODZ administration significantly reduced MSU-induced IL-1β release and the mortality rate of mice with LPS-induced sepsis. Collectively, these results demonstrate a novel effect of ODZ10117 in regulating NLRP3 inflammasome activation both in vitro and in vivo, making it a promising candidate for the treatment of NLRP3-inflammasome-associated immune disorders and cancer. Full article

Glioblastoma (GBM) is one of the most aggressive cancers, with dismal prognosis despite continuous efforts to improve treatment. Poor prognosis is mostly due to the invasive nature of GBM. Thus, most research has focused on studying the molecular players involved in GBM cell migration and invasion of the surrounding parenchyma, trying to identify effective therapeutic targets against this lethal cancer. Our laboratory discovered the implication of TENM1, also known as ODZ1, in GBM cell migration in vitro and in tumor invasion using different in vivo models. Moreover, we investigated the microenvironmental stimuli that promote the expression of TENM1 in GBM cells and found that macrophage-secreted IL-6 and the extracellular matrix component fibronectin upregulated TENM1 through activation of Stat3. We also described that hypoxia, a common feature of GBM tumors, was able to induce TENM1 by both an epigenetic mechanism and a HIF2α-mediated transcriptional pathway. The fact that TENM1 is a convergence point for various cancer-related signaling pathways might give us a new therapeutic opportunity for GBM treatment. Here, we briefly review the findings described so far about the mechanisms that control the expression of the GBM invasion factor TENM1. Full article

Background: Glioblastoma (GBM) remains a major clinical challenge due to its invasive capacity, resistance to treatment, and recurrence. We have previously shown that ODZ1 contributes to glioblastoma invasion and that ODZ1 mRNA levels can be upregulated by epigenetic mechanisms in response to hypoxia. Herein, we have further studied the transcriptional regulation of ODZ1 in GBM stem cells (GSCs) under hypoxic conditions and analyzed whether HIF2α has any role in this regulation. Methods: We performed the experiments in three primary GSC cell lines established from tumor specimens. GSCs were cultured under hypoxia, treated with HIF regulators (DMOG, chetomin), or transfected with specific siRNAs, and the expression levels of ODZ1 and HIF2α were analyzed. In addition, the response of the ODZ1 promoter cloned into a luciferase reporter plasmid to the activation of HIF was also studied. Results: The upregulation of both mRNA and protein levels of HIF2α under hypoxia conditions correlated with the expression of ODZ1 mRNA. Moreover, the knockdown of HIF2α by siRNAs downregulated the expression of ODZ1. We found, in the ODZ1 promoter, a HIF consensus binding site (GCGTG) 1358 bp from the transcription start site (TSS) and a HIF-like site (CCGTG) 826 bp from the TSS. Luciferase assays revealed that the stabilization of HIF by DMOG resulted in the increased activity of the ODZ1 promoter. Conclusions: Our data indicate that the HIF2α-mediated upregulation of ODZ1 helps strengthen the transcriptional control of this migration factor under hypoxia in glioblastoma stem cells. The discovery of this novel transcriptional pathway identifies new targets to develop strategies that may avoid GBM tumor invasion and recurrence. Full article

Teneurin 4 (TENM4) is a transmembrane protein that is codified by the ODZ4 gene and is involved in nervous system development, neurite outgrowth, and neuronal differentiation. In line with its involvement in the nervous system, TENM4 has also been implicated in several mental disorders such as bipolar disorder, schizophrenia, and autism. TENM4 mutations and rearrangements have recently been identified in a number of tumors. This, combined with impaired expression in tumors, suggests that it may potentially be involved in tumorigenesis. Most of the TENM4 mutations that are observed in tumors occur in breast cancer, in which TENM4 plays a role in cells’ migration and stemness. However, the functional role that TENM4 plays in breast cancer still needs to be better evaluated, and further studies are required to better understand the involvement of TENM4 in breast cancer progression. Herein, we review the currently available data for TENM4′s role in breast cancer and propose its use as both a novel target with which to ameliorate patient prognosis and as a potential biomarker. Moreover, we also report data on the tumorigenic role of miR-708 deregulation and the possible use of this miRNA as a novel therapeutic molecule, as miR-708 is spliced out from TENM4 mRNA. Full article

Mesenchymal progenitor cells (MPCs) are a promising cell source for regenerative medicine because of their immunomodulatory properties, anti-inflammatory molecule secretion, and replacement of damaged cells. Despite these advantages, heterogeneity in functional potential and limited proliferation capacity of MPCs, as well as the lack of suitable markers for product potency, hamper the development of large-scale manufacturing processes of MPCs. Therefore, there is a sustained need to develop highly proliferative and standardized MPCs in vitro and find suitable functional markers for measuring product potency. In this study, three lines of pluripotent stem cell (PSC)-derived MPCs with high proliferative ability were established and compared with bone-marrow-derived MPCs using proliferation assays and microarrays. A total of six genes were significantly overexpressed (>10-fold) in the highest proliferative MPC line (CHA-hNT5-MPCs) and validated by qRT-PCR. However, only two of the genes (MYOCD and ODZ2) demonstrated a significant correlation with MPC senescence in vitro. Our study provides new gene markers for predicting replicative senescence and the available quantity of MPCs but may also help to guide the development of new standard criteria for manufacturing. Full article

Constitutively activated STAT3 plays an essential role in the initiation, progression, maintenance, malignancy, and drug resistance of cancer, including glioblastoma, suggesting that STAT3 is a potential therapeutic target for cancer therapy. We recently identified ODZ10117 as a small molecule inhibitor of STAT3 and suggested that it may have an effective therapeutic utility for the STAT3-targeted cancer therapy. Here, we demonstrated the therapeutic efficacy of ODZ10117 in glioblastoma by targeting STAT3. ODZ10117 inhibited migration and invasion and induced apoptotic cell death by targeting STAT3 in glioblastoma cells and patient-derived primary glioblastoma cells. In addition, ODZ10117 suppressed stem cell properties in glioma stem cells (GSCs). Finally, the administration of ODZ10117 showed significant therapeutic efficacy in mouse xenograft models of GSCs and glioblastoma cells. Collectively, ODZ10117 is a promising therapeutic candidate for glioblastoma by targeting STAT3. Full article

Persistently activated STAT3 is a promising target for a new class of anticancer drug development and cancer therapy, as it is associated with tumor initiation, progression, malignancy, drug resistance, cancer stem cell properties, and recurrence. Here, we discovered 3-(2,4-dichloro-phenoxymethyl)-5-trichloromethyl-[1,2,4]oxadiazole (ODZ10117) as a small-molecule inhibitor of STAT3 to be used in STAT3-targeted cancer therapy. ODZ10117 targeted the SH2 domain of STAT3 regardless of other STAT family proteins and upstream regulators of STAT3, leading to inhibition of the tyrosine phosphorylation, dimerization, nuclear translocation, and transcriptional activity of STAT3. The inhibitory effect of ODZ10117 on STAT3 was stronger than the known STAT3 inhibitors such as S3I-201, STA-21, and nifuroxazide. ODZ10117 suppressed the migration and invasion, induced apoptosis, reduced tumor growth and lung metastasis, and extended the survival rate in both in vitro and in vivo models of breast cancer. Overall, we demonstrated that ODZ10117 is a novel STAT3 inhibitor and may be a promising agent for the development of anticancer drugs. Full article

The Yangtze River Economic Belt (YREB) is an important ecological security barrier for China. The spatial-temporal pattern of land use changes and changing characteristics of soil conservation function were analyzed based on the Major Function-Oriented Zones (MFOZs) from 2010 to 2015. Soil conservation was calculated by the Revised Universal Soil Loss Equation (RUSLE). Results were as follows: in 2015, the area ratio of built-up land in the optimal development zones (ODZs), key development zones (KDZs), agricultural production zones (APZs) and key ecological function zones (KEFZs) was 25.25%, 6.55%, 3.70% and 0.40%, respectively, which reflected the gradient of territorial development based on their functions. The average annual soil retention was 18.76 billion t/year during the study period, and the per unit soil retention was 91.54 t/hm²/year. The soil conservation function capacity was weakened in the order of KEFZs, APZs, KDZs and ODZs. Soil conservation function of the YREB showed an overall improvement from 2010 to 2015. The implementation of the MOFZs strategy has contributed significantly to improving the ecological security capability of the YREB. Full article

Titanium use is limited due to its poor tribological properties, and thermal oxidation (TO) and pack carburisation with limited oxygen diffusion (PCOD) are just two of the surface treatments that can be used to enhance the surface properties of Ti. In this study, commercially pure titanium was surface modified using thermal oxidation (TO) and pack carburisation with limited oxygen diffusion (PCOD). Samples were tribological tested in a 0.9% NaCl solution under a contact load of 20 N to investigate the mechanical and electrochemical response of the surface treatments. The tests conducted show that a clear benefit can be obtained in terms of the overall material loss rate using both TO and PCOD. The TO and PCOD treatments generate very different surface structures: TO produces a rutile TiO₂ surface film and the PCOD treatment produces a TiC network structure. Both treatments improve the load bearing capacity with the assistance of an oxygen diffusion zone (ODZ). When subjected to sliding contact in a 0.9% NaCl solution, the results show the PCOD-Ti produced the best overall results, with a material loss rate 7.5 times lower than untreated Ti and 2.4 times lower than TO-Ti. The improved wear rate of the PCOD-Ti is attributed to the TiC network structure. The TO-Ti suffers from rapid film failure and high friction. The reduced material loss rate (MLR) of the TO-Ti is attributed to the hard wearing ODZ. Full article

Thermal oxidation of Ti6Al4V was carried out at 700 °C for 5 h in air atmosphere. The characteristics of morphology and structure, micro-hardness, and tribocorrosion behavior in 0.9 wt.% NaCl solution of thermally oxidized Ti6Al4V alloys were investigated and compared with those of the untreated one. The scanning electron microscope (SEM) and glow discharge spectrometer (GDS) results reveal that the oxide layer is completely coated on the substrate, which is a bilayer structure consisted of oxide film and oxygen diffusion zone (ODZ). X-ray diffraction (XRD) and Raman measurements reveal the rutile phase as the dominant phase. The micro-hardness and surface roughness (R_a) increase about 1.63 and 4 times than those of the untreated one. Thermally oxidized sample obtains corrosion and tribocorrosion resistance property in 0.9 wt.% NaCl solution. The corrosion potential has a more than 500 mV anodic shift, the corrosion current density decreases about 80%. The total material loss volume is reduced by almost an order of magnitude under tribocorrosion behavior, which is due to the improvement of the micro-hardness of the oxide layer and ODZ that reduce the corrosion and the synergistic effect of corrosion and wear. Full article