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“Interferons (IFNs) have proven antitumor activity against a variety of human malignancies, which may result, at least in part, from inhibition of angiogenesis. The objective of this study was to identify IFN-stimulated genes (ISGs) that played a role in mediation

of angiogenic inhibition. IFN-beta was a more potent antiangiogenic agent compared to IFN-alpha 2b (80% versus 20%, respectively) and suggests that IFNs inhibited angiogenesis by preventing endothelial cell differentiation, and not by direct antiproliferative effects. To identify ISGs that were key inhibitors of angiogenesis, we utilized an in vitro fibrin gel angiogenic assay which closely recapitulated the in vivo processes of angiogenesis. DNA microarray analysis selleck compound of IFN-beta-treated endothelial cells in the fibrin gel assay identified 11 ISGs that were induced > 10-fold during angiogenesis inhibition. Recombinant IP-10 inhibited angiogenesis in a dose-dependent fashion, but was a less effective inhibitor compared to IFN-beta, suggesting that additional ISGs are involved in inhibiting angiogenesis. ISG20 was upregulated by microarray analysis, but did not inhibit angiogenesis when overexpressed in human umbilical vein endothelial cells (HUVECs). However, a dominant negative mutant of ISG20

inhibited angiogenesis by 43%. Results suggest that IFN-induced angiogenic inhibition was likely mediated by multiple ISGs; our novel finding is that decreased exonuclease activity JNK-IN-8 in HUVECs associated with expression of the ISG20 ExoII mutant inhibited angiogenesis.”
“The flow of ions through cation-selective members of the pentameric ligand-gated ion channel family is inhibited by a structurally diverse class of molecules that bind to the transmembrane pore in the open state of the protein. To obtain insight into the mechanism find more of channel block, we have investigated the binding of positively charged inhibitors

to the open channel of the bacterial homolog GLIC by using X-ray crystallography and electrophysiology. Our studies reveal the location of two regions for interactions, with larger blockers binding in the center of the membrane and divalent transition metal ions binding to the narrow intracellular pore entry. The results provide a structural foundation for understanding the interactions of the channel with inhibitors that is relevant for the entire family.”
“The amyloid precursor protein (APP) is cleaved by beta- and gamma-secretases to generate the beta-amyloid (A beta) peptides, which are present in large amounts in the amyloid plaques of Alzheimer disease (AD) patient brains. Non-amyloidogenic processing of APP by alpha-secretases leads to proteolytic cleavage within the A beta peptide sequence and shedding of the soluble APP ectodomain (sAPP alpha), which has been reported to be endowed with neuroprotective properties.