Search

Summary Inhibitor of differentiation 1 (ID1) is highly expressed in glioblastoma stem cells (GSCs). However, the regulatory mechanism responsible for its role in GSCs is poorly understood. Here, we report that ID1 activates GSC proliferation, self-renewal, and tumorigenicity by suppressing CULLIN3 ubiquitin ligase. ID1 induces cell proliferation through increase of CYCLIN E, a target molecule of CULLIN3. ID1 overexpression or CULLIN3 knockdown confers GSC features and tumorigenicity to murine Ink4a/Arf -deficient astrocytes. Proteomics analysis revealed that CULLIN3 interacts with GLI2 and DVL2 and induces their degradation via ubiquitination. Consistent with ID1 knockdown or CULLIN3 overexpression in human GSCs, pharmacologically combined control of GLI2 and β-CATENIN effectively diminishes GSC properties. A ID1-high/CULLIN3-low expression signature correlates with a poor patient prognosis, supporting the clinical relevance of this signaling axis. Taken together, a loss of CULLIN3 represents a common signaling node for controlling the activity of intracellular WNT and SHH signaling pathways mediated by ID1. [ABSTRACT FROM AUTHOR]

Glioma stem cells (GSCs) are known to be maintained within a 'vascular niche'; thereby, disruption of this microenvironment using antiangiogenesis agents is a promising therapeutic modality. However, this regimen leads to treatment failure and tumor recurrence in patients with glioblastoma multiforme (GBM). Therefore, more effective therapeutic approaches that can eradicate GSCs and the bulk tumors are needed. Toward this goal, we examined the antitumor effects of an antiangiogenesis approach combined with conventional chemotherapy on suppressing glioma xenograft growth. We established three genetically engineered mesenchymal stem cell (MSC) lines (GE-AF-MSCs) by stably transducing the gene encoding endostatin (an antiangiogenesis factor), the gene encoding secretable form of carboxylesterase 2 (sCE2, a prodrug-activating enzyme), or a mixture of both genes. Among the three GE-AF-MSC cell lines, injection of amniotic fluid (AF)-MSCs-endostatin-sCE2 cells into U87MG-EGFRvIII-driven orthotopic brain tumor and postsurgery tumor recurrence models, and subsequent CPT11 treatment yielded the strongest antitumor responses, including diminished angiogenesis, increased cell death, and a reduced Nestin-positive GSC population. Therefore, our antitumor strategy provides a novel basis for designing stem cell-mediated therapeutic approaches to target and eradicate GSCs and the bulk tumors. [ABSTRACT FROM AUTHOR]

Abstract: Glioma stem cells (GSCs) are presumably major culprits for brain tumor initiation, progression, and recurrence after conventional therapies. Thus, selective targeting and eradication of GSCs may provide a promising and effective therapeutic approach. Here, we isolated a GSC-targeting (GSCT) peptide that demonstrated selective binding affinity for many undifferentiated GSCs using in vitro phage display technology. This GSCT peptide binds to isotypes of Nestin proteins specifically expressed in GSCs, enabling it to target Nestin-positive cells in human glioblastoma tissues. In human glioblastoma tissue specimens, the fluorescence-conjugated GSCT peptide could visualize putative GSC populations, showing its possible use as a diagnostic agent. GSCT peptide is also internalized into undifferentiated GSCs specifically in vitro, and moreover, intravenously injected GSCT peptide effectively penetrated into tissues, specifically accumulated in gliomas that arise from subcutaneous and orthotopic implantation, and predominantly targeted Nestin-positive cells in these tumors. Thus, our GSCT peptide may be useful for the development of more promising therapeutic and diagnostic modalities that target GSCs in brain tumors. [Copyright &y& Elsevier]

Cation identity in the electrolyte is known to have a critical influence on electrocatalytic CO 2 reduction reaction (CO 2 RR). However, the impact of cation aggregation state at the electrode/electrolyte interface, particularly for organic cations, remains unclear for CO 2 RR. In this study, we investigated the effect of the organic cation aggregation state, by examining the CO 2 RR behaviors over a copper (Cu) electrode, before and after the surface modification of a polyelectrolyte (i.e. , quaternary ammonia poly (N-methyl-piperidine-co-p-terphenyl) with grafted piperidinium cations), in an aqueous electrolyte with free-moving piperidinium (Pip+) cations. Immobilizing the Pip+ cations on Cu surface was found to effectively promote the CO 2 RR selectivity. The underlying cause was further explored by in-situ attenuated total reflectance surface-enhanced infrared absorption spectroscopy and electrochemical double-layer capacitance measurements, illustrating that the enhanced CO 2 RR performance was due to the change in electrode/electrolyte interface properties. These findings would contribute to further optimization of the electrode/electrolyte interface for efficient CO 2 RR. [ABSTRACT FROM AUTHOR]

The invasiveness of glioblastoma is a major cause of poor prognosis and relapse. However, the molecular mechanism controlling glioma cell invasion is poorly understood. Here, we report that receptor activator of nuclear factor kappa-B (NFκB) ligand (RANKL) promotes glioma cell invasion in vivo , but not in vitro . Unlike the invasiveness under in vitro culture conditions, in vivo xenograft studies revealed that LN229 cells expressing high endogenous RANKL generated more invasive tumors than U87MG cells expressing relatively low endogenous RANKL. Consistently, RANKL-overexpressing U87MG resulted in invasive tumors, whereas RANKL-depleted LN229 generated rarely invasive tumors. We found that the number of activated astrocytes was markedly increased in the periphery of RANKL-high invasive tumors. RANKL activated astrocytes through NFκB signaling and these astrocytes in turn secreted various factors which regulate glioma cell invasion. Among them, transforming growth factor β (TGF-β) signaling was markedly increased in glioblastoma specimens and xenograft tumors expressing high levels of RANKL. These results indicate that RANKL contributes to glioma invasion by modulating the peripheral microenvironment of the tumor, and that targeting RANKL signaling has important implications for the prevention of highly invasive glioblastoma. [ABSTRACT FROM AUTHOR]

Abstract: Aberrant epidermal growth factor receptor (EGFR) signaling is a typical oncogenic signature in glioblastoma. Here, we show that EGFR inhibition in primary glioma stem cells (GSCs) with oncogenic EGFRvIII and EGFRvIII-transduced glioma stem-like cells promotes invasion by decreasing ID3 levels. ID3 suppresses GSC invasiveness by inhibiting p27KIP1-RhoA-dependent migration and MMP3 expression. Xenograft and human glioblastoma specimens show that ID3 localizes within glioblastoma cores, whereas p27KIP1 and MMP3 are predominantly expressed in glioma cells in invasive fronts. Together, our findings show that EGFR inhibition induces GSC invasiveness by abolishing ID3-mediated inhibition of p27KIP1 and MMP3 expression. [Copyright &y& Elsevier]

Abstract: The objective of this study was to identify the proteins involved in bovine intramuscular fat (IMF) development. Global proteins were monitored in bovine skeletal muscle at muscle-developing versus IMF-increasing stages and with higher versus lower IMF scores, respectively. We identified two differentially expressed (two-fold or more) proteins at the IMF-increasing stage, up-regulated heat shock protein beta 1 (HSPB1) and down-regulated ATP synthase D chain (ATP5H), and two down-regulated proteins with higher IMF scores, carbonic anhydrase 2 (CA2) and myosin light chain 3 (MYL3). In vitro, after adipogenic differentiation, the mRNA expression of HSPB1 and ATP5H did not be changed, but that of CA2 and MYL3 decreased significantly (P <0.05). After myogenic differentiation, the mRNA expression of HSPB1 increased significantly (P <0.05), but expression of other genes did not vary. We suggested that CA2 and MYL3, which expressed down during adipogenic differentiation, could be indicative markers for negative regulation of IMF development. [Copyright &y& Elsevier]

Glioblastoma (GBM) is the most common and fatal form of malignant brain tumor. Despite intensive effort, there is still no effective GBM treatment. Therefore, novel and more effective GBM therapeutic approaches are highly desired. In this study, we combined polymeric nanotechnology with microRNA (miRNA) regulation technology to develop a targeted polymeric nanoparticle to co-deliver anti-miR-21 and miR-124 into the brain to effectively treat GBM. The polymeric nanoparticle decorated with Angiopep-2 peptide not only can encapsulate miRNA via triple-interaction (electrostatic, hydrogen bond and hydrophobic bonding) to protect miRNA against enzyme degradation in the blood, but also is capable of crossing blood brain barrier (BBB) and allowing targeted delivery of miRNAs to GBM tissue due to the dual-targeting function of Angiopep-2. Moreover, the co-delivered anti-miR-21 and miR-124 simultaneously regulated the mutant RAS/PI3K/PTEN/AKT signaling pathway in tumor cells, consequently achieving combinatorial GBM therapy. This combinatorial effect was confirmed by our results showing that these miRNA nanomedicines can effectively reduce tumor cell proliferation, migration and invasion as well as reducing tumor angiogenesis. Consequently, effective suppression of tumor growth and significantly improved medium survival time are observed when these miRNA nanomedicines were assessed in an orthotopic GBM xenograft model. This work indicated that our new polymeric nanoparticles successfully mediate inhibition of miR-21 and miR-124 supplementation to significantly reduce tumorigenesis, and may have strong potential in GBM therapy. [ABSTRACT FROM AUTHOR]

Hydrogen oxidation reaction (HOR), as the anode reaction in alkaline polymer electrolyte fuel cells (APEFCs), is kinetically much more sluggish than that in the proton exchange membrane fuel cell (PEMFC). Therefore, developing efficient non-platinum or even non-noble metal HOR electro-catalysts is of great significance. Herein, the carbon support (Meso C) with mesoporous ravine-like channel and corresponding Ru-loaded catalyst (Ru/Meso C) is deliberately designed to explore the effect of porous microstructure on the HOR electro-catalysis. Both the electrochemical and fuel cell tests manifests that the Ru/Meso C achieves a superior electro-catalytic performance toward the HOR with a peak power density of 1.02 W cm−2. The Cu-UPD and CO-stripping methods are creatively coupled to probe the underlying mechanism of Ru/Meso C. It is proposed that the holey microstructure is relatively hydrophobic to favor H 2 access, and the mesoporous channel can provide a confined environment to protect the Ru NPs from oxidation, both facilitating the adsorption and dissociation of H 2 and synergistically boosting the HOR. Therefore, to engineer porous microstructure is proved to be a feasible pathway to design efficient HOR electro-catalysts. Meanwhile, the electrochemical techniques (Cu-UPD & CO-stripping) may act as a potential tool to probe the hydrophilic-hydrophobic properties. Image 1 • The porous microstructure is engineered to study the effect on the HOR catalysis. • The Ru/Meso C shows extraordinary HOR activity and APEFC performance. • The Cu UPD and CO stripping techniques are employed to probe the possible mechanism. [ABSTRACT FROM AUTHOR]

• Stiffness of hbPGs is the main factor for antifouling property. • Young's modulus and adhesion force of hbPGs is the intrinsic properties to drive antifouling phenomena. • Oleic acid-modified hbPGs is the excellent cell membrane engineering block. Owing to the excellent biocompatibility, hyperbranched polyglycerols (hbPGs) are one of the most promising polymers and widely employed in drug delivery. Presented as an excellent bioinert coating material, hbPGs can significantly improve the biosafety of biomedical nanomaterials. However, it is still unclear what specific properties of hbPGs are the key effectors to bioinertness. Here, atomic force microscopy was employed to test the Young's modulus and adhesion of hbPGs, spin-coated onto mica substrate. High Young's modulus indicated that the hbPGs cannot be further compressed and low adhesion implied that it is not easy to form hbPGs aggregators. This could owe to the intramolecular hydrogen bond. Morphology characterization of hbPGs self-assembled monolayer onto Si(100) substrate, confirmed the lower adhesion among different hbPGs and indicated their biofouling properties. Further confocal laser microscopy of cell membrane modified with alkyl chain (C18)-modified hbPGs and hbPGs-NH 2 , confirmed that the antifouling properties of hbPGs are determined by terminal glycerol units. Our findings demonstrated that only hbPGs with entire terminal surface can be used as perspective cell membrane modification skeleton. [ABSTRACT FROM AUTHOR]