Connexin 43 reverses malignant phenotypes of glioma stem cells by modulating E-cadherin.

Malfunctioned gap junctional intercellular communication (GJIC) has been thought associated with malignant transformation of normal cells. However, the role of GJIC-related proteins such as connexins in sustaining the malignant behavior of cancer stem cells remains unclear. In this study, we obtained tumorspheres formed by glioma stem cells (GSCs) and adherent GSCs and then examined their GJIC. All GSCs showed reduced GJIC, and differentiated glioma cells had more gap junction-like structures than GSCs. GSCs expressed very low level of connexins, Cx43 in particular, which are key components of gap junction. We observed hypermethylation in the promoter of gap junction protein α1, which encodes Cx43 in GSCs. Reconstitution of Cx43 in GSCs inhibited their capacity of self-renewal, invasiveness, and tumorigenicity via influencing E-cadherin and its coding protein, which leads to changes in the expression of Wnt/ß-catenin targeting genes. Our results suggest that GSCs require the low expression of Cx43 for maintaining their malignant phenotype, and upregulation of Cx43 might be a potential strategy for treatment of malignant glioma.

The chemokine CXCL12 and its receptor CXCR4 promote glioma stem cell-mediated VEGF production and tumour angiogenesis via PI3K/AKT signalling.

Chemokines and their receptors are actively involved in inflammation, immune responses, and cancer development. Here we report the detection of CD133(+) glioma stem-like cells (GSCs) co-expressing a chemokine receptor CXCR4 in human primary glioma tissues. These GSCs were located in areas adjacent to tumour vascular capillaries, suggesting an association between GSCs and tumour angiogenesis. To test this hypothesis, we isolated CD133(+) GSCs from surgical specimens of human primary gliomas and glioma cell lines. As compared to CD133(-) cells, CD133(+) GSCs expressed significantly higher levels of CXCR4 mRNA and protein, and migrated more efficiently in response to the CXCR4 ligand CXCL12. In addition, CXCL12 induced vascular endothelial growth factor (VEGF) production by CD133(+) GSCs via activation of the PI3K/AKT signalling pathway. Furthermore, knocking down of CXCR4 using RNA interference or inhibition of CXCR4 function by an antagonist AMD3100 not only reduced VEGF production by CD133(+) GSCs in vitro, but also attenuated the growth and angiogenesis of tumour xenografts in vivo formed by CD133(+) GSCs in SCID mice. These results indicate that CXCL12 and its receptor CXCR4 promote GSC-initiated glioma growth and angiogenesis by stimulating VEGF production.

Nanocatalyst-Assisted Fine Tailoring of Pore Structure in Holey-Graphene for Enhanced Performance in Energy Storage.

Nanoporous holey-graphene (HG) shows potential versatility in several technological fields, especially in biomedical, water filtration, and energy storage applications. Particularly, for ultrahigh electrochemical energy storage applications, HG has shown promise in addressing the issue of low gravimetric and volumetric energy densities by boosting of the ion-transport efficiency in a high-mass-loaded graphene electrode. However, there are no studies showing complete control over the entire pore architecture and density of HG and their effect on high-rate energy storage. Here, we report a unique and cost-effective method for obtaining well-controlled HG, where a copper nanocatalyst assists the predefined porosity tailoring of the HG and leads to an extraordinary high pore density that exceeds 1 × 103 µm-2. The pore architectures of the hierarchical and homogenous pores of HG were realized through a rationally designed nanocatalyst and the annealing procedure in this method. The HG electrode with a high mass loading results in improved supercapacitor performance that is at least 1 order of magnitude higher than conventional graphene flakes (reduced electrochemically exfoliated graphene (rECG)) in areal capacitance (∼100% retention of capacitance until 15 000 cycles), energy density, and power density. The diffusion coefficient of the HG electrode is 1.5-fold higher than that of rECG at a mass loading of 15 mg cm-2, indicating excellent ion-transport efficiency. The excellent ion-transport efficiency of HG is further proved by nearly 4-fold magnitude lowering of its Rion (the ionic resistance in the electrolyte-filled pores) value as compared with rECG when estimated for equivalent high-mass-loaded electrodes. Furthermore, the HG exhibits a packing density that is 2 orders of magnitude higher than rECG, revealing the utility of the maximum electrode mass and possessing higher volumetric capacitance. The perfect tailoring of HG with optimized porosity allows the achievement of high areal capacitance and excellent cycling stability due to the facile ion- and charge-transport at high-mass-loaded electrodes, which could open a new avenue for addressing the long-existing issue of practical application of graphene-based energy storage devices.

Phase-field modeling and machine learning of electric-thermal-mechanical breakdown of polymer-based dielectrics.

Understanding the breakdown mechanisms of polymer-based dielectrics is critical to achieving high-density energy storage. Here a comprehensive phase-field model is developed to investigate the electric, thermal, and mechanical effects in the breakdown process of polymer-based dielectrics. High-throughput simulations are performed for the P(VDF-HFP)-based nanocomposites filled with nanoparticles of different properties. Machine learning is conducted on the database from the high-throughput simulations to produce an analytical expression for the breakdown strength, which is verified by targeted experimental measurements and can be used to semiquantitatively predict the breakdown strength of the P(VDF-HFP)-based nanocomposites. The present work provides fundamental insights to the breakdown mechanisms of polymer nanocomposite dielectrics and establishes a powerful theoretical framework of materials design for optimizing their breakdown strength and thus maximizing their energy storage by screening suitable nanofillers. It can potentially be extended to optimize the performances of other types of materials such as thermoelectrics and solid electrolytes.

An inhibitor of arachidonate 5-lipoxygenase, Nordy, induces differentiation and inhibits self-renewal of glioma stem-like cells.

Recent progress in cancer biology indicates that eradication of cancer stem cells (CSCs) is essential for more effective cancer therapy. Unfortunately, cancer stem cells such as glioma stem-like cells (GSLCs) are often resistant to either radio- or chemotherapy. Therefore, screening and development for novel therapeutic modalities against CSCs has been an important emerging field in cancer research. In this study, we report that a synthetic dl-nordihydroguaiaretic acid compound (dl-NDGA or "Nordy"), inhibited self-renewal and induced differentiation of GSLCs in vitro and in vivo. We found that Nordy inhibited an enzyme known to be involved in leukemia stem cell and leukemia progression, Alox-5, and attenuated the growth of GSLCs in vitro. Nordy reduced the GSLC pool through a decrease in the CD133(+) population and abrogated clonogenicity. Nordy appeared to exert its effect via astrocytic differentiation by up-regulation of GFAP and down-regulation of stemness related genes, rather than by inducing apoptosis of GSLCs. The growth inhibition of xenografted glioma by Nordy was more long-lasting compared with that of the akylating agent BCNU, which exhibited significant relapse on drug discontinuation resulting from an enrichment of GSLCs. Meanwhile, transient exposure to Nordy reduced tumorigenecity of GSLCs and induced differentiation of the xenografts. Taken together, we have identified Alox-5 as a novel target in GSLCs and its inhibition with Nordy exhibits therapeutic implications through inducing GSLC differentiation.