1,720,983 research outputs found
integrin linked kinase (ILK) is a prognostic factor in human gliomas implicated in tumor resistance to therapy
No full textThe neuropeptide PACAP38 induces dendritic spine remodeling through ADAM10-N-cadherin signaling pathway
No full textThe neuropeptide pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) has been implicated in the induction of synaptic plasticity at the excitatory glutamatergic synapse. In particular, recent studies have shown that it is involved in the regulation of Nmethyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activation. Here we demonstrate the effect of PACAP38 on the modulation of dendritic spine morphology through a disintegrin and metalloproteinase 10 (ADAM10)-N-cadherin-AMPA receptor signaling pathway. Treatment of primary hippocampal neurons with PACAP38 induced an accumulation of ADAM10 at the postsynaptic membrane. This event led to a significant decrease of dendritic spine head width and to a concomitant reduction of GluR1 colocalization with postsynaptic markers. The PACAP38-induced effect on dendritic spine head width was prevented by either treatment with the ADAM10-specific inhibitor or transfection of a cleavage-defective N-cadherin construct mutated in the ADAM10 cleavage site. Overall, our findings reveal that PACAP38 is involved in the modulation of dendritic spine morphology in hippocampal neurons, and assign to the ADAM10-N-cadherin signaling pathway a crucial role in this modification of the excitatory glutamatergic synaps
antiangiogenic treatment reduces tumor vaculature and tumor cell infiltration in a glioma cancer stem cell model in nude mice A
No full textCombined targeting of interleukin-6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness
No full textInterleukin-6 (IL6) and vascular endothelial growth factor (VEGFA) are abundantly produced by glioma cells and contribute to malignancy by promoting angiogenesis, cell proliferation and resistance to apoptosis. We compared the effect of inhibiting IL6 and VEGF on U87-derived experimental glioma grown on the chick chorio-allantoic membrane (CAM) or in the brain of xenografted mice. Tumor growth was monitored by biomicroscopy and immunohistology. In vitro, IL6 knockdown had no effect on proliferation but substantially enhanced invasion. In the CAM experimental glioma, IL6 or VEGF knockdown reduced growth and vascularization of the tumors with a comparable efficiency, but increased invasion of residual tumor cells. In contrast, combined IL6/VEGF knockdown not only showed enhanced reduction of tumor growth and angiogenesis but also significantly prevented invasion of residual tumor cells. In mice, combining IL6 knockdown and Avastin treatment completely abrogated tumor development and infiltration. Molecular response of tumor cells to single or combined treatment was studied by transcriptomic profiling. Many cell cycle promoting genes and chromatin components were silenced in the double knockdown. In addition, specific migratory signatures detected in tumors under single IL6 or VEGF knockdown were partially erased in combined IL6/VEGF knockdown tumors. Our results show that treatment with a combination of IL6 and VEGF inhibitors brings synergistic antitumoral benefit and reduces global activity of major pathways of cell survival, proliferation and invasiveness in remaining tumor cells that may be induced by using VEGF or IL6 inhibitors alone
Proteomic analysis of gliomas during Pf4 – dlr antiangiogenesis treatment
No full textAngiogenesis, tumor cell proliferation, and migration are the hallmarks of solid tumors, such as gliomas. Recent study has shown that modified COOH-terminal PF4 peptide containing the sequence DLR (PF4-DLR) inhibits endothelial cell proliferation, migration, and microvessel assembly. Systemic administration of PF4-DLR to human glioma models in nude mice resulted in a significant inhibition of tumor growth. No data are available on the molecular determinants associated with the therapeutic response. Proteomics is a powerful technique which allows to identified group of pro- teins which expression change or is associated to treatment. In this study, we have used two-dimensional electrophoresis and mass spectrometry to directly analyze protein profile changes in gliomas during PF4-DLR treat- ment. Nude mice were intracranially inoculated with 50,000 U87 cells and implanted two weeks later with an osmotic minipump filled with PBS or 0.5 mg of PF4-DLR. Mice were sacrificed 10 and 20 days later, and protein analysis was performed by comparing at least seven 2-D SDS gels from each treatment group. Thirty-seven significant spots have been analyzed by mass spectrometry, resulting in the identification of 28 proteins significantly upregulated and 9 proteins significantly downregulated after PF4-DLR treatment. Only three identified proteins originated from the mouse hosttissue. Among all the tumor-derived proteins, 12 proteins seemed corre- lated to the tumor growth-inhibitory effect of PF4-DLR treatment, at both 10 and 20 days of treatment. At 20 days of treatment, 13 proteins seemed correlated to the presence of a subset of tumor cells undergoing to therapy escape growth. We have also found 4 proteins expressed only in the PF4- DLR–treated tumors. Interestingly, one of these proteins, the procollagen C-endopeptidase enhancer 1 precursor (PCPE) has a metalloproteinase- inhibitory activity. In conclusion, the proteins identified by 2-DGE analysis may aid comprehension of PF4-DLR molecular target
Elongation factor-2 phosphorylation in dendrites and the regulation of dendritic mRNA translation in neurons
Full text linkNeuronal activity results in long lasting changes in synaptic structure and function by regulating mRNA translation in dendrites. These activity dependent events yield the synthesis of proteins known to be important for synaptic modifications and diverse forms of synaptic plasticity. Worthy of note, there is accumulating evidence that the eukaryotic Elongation Factor 2 Kinase (eEF2K)/eukaryotic Elongation Factor 2 (eEF2) pathway may be strongly involved in this process. Upon activation, eEF2K phosphorylates and thereby inhibits eEF2, resulting in a dramatic reduction of mRNA translation. eEF2K is activated by elevated levels of calcium and binding of Calmodulin (CaM), hence its alternative name calcium/CaM-dependent protein kinase III (CaMKIII). In dendrites, this process depends on glutamate signaling and N-methyl-D-aspartate receptor (NMDAR) activation. Interestingly, it has been shown that eEF2K can be activated in dendrites by metabotropic glutamate receptor (mGluR) 1/5 signaling, as well. Therefore, neuronal activity can induce local proteomic changes at the postsynapse by altering eEF2K activity. Well-established targets of eEF2K in dendrites include brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal-associated protein (Arc), the alpha subunit of calcium/CaM-dependent protein kinase II (αCaMKII), and microtubule-associated protein 1B (MAP1B), all of which have well-known functions in different forms of synaptic plasticity. In this review we will give an overview of the involvement of the eEF2K/eEF2 pathway at dendrites in regulating the translation of dendritic mRNA in the context of altered NMDAR- and neuronal activity, and diverse forms of synaptic plasticity, such as metabotropic glutamate receptor-dependent-long-term depression (mGluR-LTD). For this, we draw on studies carried out both in vitro and in vivo
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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