1,232 research outputs found
Targeting tumor angiogenesis with TSP-1-based compounds: rational design of antiangiogenic mimetics of endogenous inhibitors
No full textInhibitors of angiogenesis are an important addition to conventional
chemotherapy. Among different ``druggable'' angiogenic factors,
fibroblast growth factor-2 (FGF-2) is an attractive target for novel
therapies because of its intricated involvement in tumor
neovascularization, tumor cell proliferation and migration, and the
acquisition of resistance to antiangiogenic therapies. FGF-2
bioavailability and activity is affected by several natural ligands,
including the endogenous inhibitor of angiogenesis thrombospondin-1
(TSP-1). We hypothesized that the FGF-2-binding sequence of TSP-1 might
serve as a template for the development of non-peptide inhibitors of
angiogenesis. Computational biology and nuclear magnetic resonance
spectroscopy approaches, major investigative tools in the
characterizations of protein-protein interaction (PPI), were used to map
the residues at the TSP1/FGF-2 interface. The translation of this
three-dimensional information into a pharmacophore model allowed
screening a small molecule databases, identifying three FGF-2-binding,
antiangiogenic small molecules, mimetic of TSP-1. Pharmacophore-based
approaches are thus feasible tools to exploit naturally occurring PPI,
by generating a set of lead compounds mimetic of endogenous proteins, as
a starting point for the development of novel therapeutic agents
ERK1-2 and p38 MAPK regulate MMP/TIMP balance and function in response to thrombospondin-1 fragments in the microvascular endothelium
No full textWe found that thrombospondin-1 (TSP-1) has opposite functions on angiogenesis depending on the nature of the proteolytic fragment released in vivo by the action of proteases. We studied the effect of the 25 and 140 kDa fragments of TSP-1 generated by its proteolytic cleavage on the cascade of mitogen activated protein kinase (MAPK) activation and matrix-metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) function and expression in microvascular endothelium. Post-capillary endothelial cells (CVEC) isolated from bovine heart were used. The 25 kDa fragment enhanced the upregulation of MMP-2 and -9 and reduced TIMP-2 expression leading to CVEC chemoinvasion. Conversely, the 140 kDa fragment blocked MMP-2 and -9 stimulation and doubled TIMP-2 expression, leading to inhibition of endothelial chemoinvasion induced by fibroblast growth factor-2 (FGF-2). MAPK activity (ERK1-2) was induced by TSP-1 and by the 25 kDa fragment, but not by the 140 kDa fragment which, however, promoted MAPK p38 activation. This evidence indicates that fragments originating from TSP-1 switch the pro- or anti-angiogenic phenotype in endothelium by targeting MAPK cascades with opposite functions on MMP/TIMP balance. © 2004 Elsevier Inc. All rights reserved
Giulia Veronica Varisco
No full textThe headword explains the biography and the contribution of the author Giulia Varisco to the children's literatur
Vascular-targeting activity of ZD6126, a novel tubulin-binding agent
No full textThe tubulin-binding agent ZD6126 is a novel vascular-targeting agent in clinical development for the treatment of solid tumors. In vivo, ZD6126 is rapidly converted into N-acetylcolchinol (ZD6126 phenol). In this study, we have explored the antivascular property of N-acetylcolchinol in vitro and ZD6126 in vivo. In cell culture, N-acetylcolchinol induced rapid changes in the morphology of human umbilical vein and lung microvessel endothelial cells. Within 40 min, the compound induced endothelial cell contraction, destabilization of the tubulin cytoskeleton, induction of actin stress fibers, and membrane blebbing. These effects occurred at noncytotoxic concentrations and were rapidly reversed on removal of the drug. Nonconfluent endothelial cells were more sensitive than confluent, quiescent cells. Among different cell types, endothelial cells were the most sensitive to the induction of morphological changes, whereas smooth muscle cells were not affected. In vitro, N-acetylcolchinol rapidly disrupted a network of newly formed cords. In vivo, ZD6126 caused shut down of newly formed vessels in the Matrigel plug assay, shortly after injection. This study indicates that rapid alteration of endothelial cell morphology may be responsible for the loss of tumor blood vessel integrity, vessel shut down, and extensive tumor necrosis induced by ZD6126 in experimental tumor models
Identification of a novel extracellular inhibitor of FGF2/FGFR signaling axis by combined virtual screening and NMR spectroscopy approach
No full textThe aberrant activation of the fibroblast growth factor 2 (FGF2)/fibroblast growth factor receptor (FGFR) signalling pathway drives severe pathologies, including cancer development and angiogenesis-driven pathologies. The perturbation of the FGF2/FGFR axis via extracellular allosteric small inhibitors is a promising strategy for developing FGFR inhibitors with improved safety and efficacy for cancer treatment. We have previously investigated the role of new extracellular inhibitors, such as rosmarinic acid (RA), which bind the FGFR-D2 domain and directly compete with FGF2 for the same binding site, enabling the disruption of the functional FGF2/FGFR interaction. To select ligands for the previously identified FGF2/FGFR RA binding site, NMR data-driven virtual screening has been performed on an in-house library of non-commercial small molecules and metabolites. A novel drug-like compound, a resorcinol derivative named RBA4 has been identified. NMR interaction studies demonstrate that RBA4 binds the FGF2/FGFR complex, in agreement with docking prediction. Residue-level NMR perturbations analysis highlights that the mode of action of RBA4 is similar to RA in terms of its ability to target the FGF2/FGFR-D2 complex, inducing perturbations on both proteins and triggering complex dissociation. Biological assays proved that RBA4 inhibited FGF2 proliferative activity at a level comparable to the previously reported natural product, RA. Identification of RBA4 chemical groups involved in direct interactions represents a starting point for further optimization of drug-like extracellular inhibitors with improved activity
Anti-angiogenic, vascular-disrupting and anti-metastatic activities of vinflunine, the latest vinca alkaloid in clinical development
No full textCharacterization of circulating and tumor infiltrating Natural Killer cells in patients with pancreatic ductal adenocarcinoma: polarization state and effects of TGFβRI blockade
No full textYtterbium Disilicate/Monosilicate Multilayer Environmental Barrier Coatings: Influence of Atmospheric Plasma Spray Parameters on Composition and Microstructure
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Open AccessArticle
Ytterbium Disilicate/Monosilicate Multilayer Environmental Barrier Coatings: Influence of Atmospheric Plasma Spray Parameters on Composition and Microstructure
by Giulia Di Iorio,Laura Paglia *ORCID,Giulia PedrizzettiORCID,Virgilio GenovaORCID,Francesco MarraORCID,Cecilia BartuliORCID andGiovanni PulciORCID
INSTM Reference Laboratory for Materials and Surface Engineering, Sapienza University of Rome, Eudossiana 18, 00184 Rome, Italy
*
Author to whom correspondence should be addressed.
Coatings 2023, 13(9), 1602; https://doi.org/10.3390/coatings13091602
Original submission received: 10 August 2023 / Revised: 31 August 2023 / Accepted: 11 September 2023 / Published: 13 September 2023
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Abstract
SiC/SiC ceramic matrix composites (SiCf/SiC CMCs) are regarded as the new materials for the hot-section components of aircraft gas turbine engines, since they have one-third of the density of metallic superalloys, a higher temperature capability, good mechanical strength, and excellent thermal shock resistance. However, high-temperature water-vapor-rich combustion gases can induce severe surface recession phenomena in SiC/SiC leading to component failure. For this reason, it is necessary to design protective coatings, i.e., environmental barrier coatings (EBCs), able to protect the SiC/SiC surface in combustion environments. In the present work, ytterbium monosilicate (Yb2SiO5), stable when exposed to water vapor at high temperatures, and ytterbium disilicate (Yb2Si2O7), characterized by a thermal expansion coefficient closer to that of the substrate, were selected for a multilayer EBC system. EBCs were processed using the atmospheric plasma spray (APS) technique. A set of deposition parameters were tested, varying the power of the torch, and the composition and microstructure of the deposited coatings were studied in terms of porosity, crack density, and post-deposition phase retention by performing SEM, EDS, and XRD analysis. The results allow for the definition of the influence of deposition parameters on the final properties of multilayer EBC coatings
Correction to: Safety and Psychological Outcomes of Tandem t:Slim X2 Insulin Pump with Control-IQ Technology in Children, Adolescents, and Young Adults with Type 1 Diabetes: A Systematic Review
No full textThe second author name was incorrectly published as Giula Maria Smylie. The correct name is Giulia Marie Smylie. The original article has been corrected
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