Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mucins and other highly O-linked glycoproteins have been found to exist in random-coil conformations with peptide chain dimensions about 3-fold more expanded than found for deglycosylated mucins or denaturated proteins. We have examined the origin of the peptide chain expansion in mucins by stochastic dynamics simulations which include a treatment of solvation energy effects based on solvent-accessible surface area and polarizability [GB/SA; Still, C. W., et al. (1990) J. Am. Chem. Soc. 112, 6127]. The glycopeptides studied contained pairs of threonine residues (flanked by alanine residues) which were O-glycosylated by the di- and monooligosaccharide side chains alpha-NeuNAc(2-6)alpha-GalNAc and alpha-GalNAc. These glycopeptides serve as simple models for native and asialo ovine submaxillary mucin. Computer stochastic dynamic simulations show a significant decrease in end-to-end distance and radius of gyration (32% and 33%, respectively) upon complete removal of carbohydrate from the glycopeptide AAA(NeuNAc-(2-6)GalNAc)-T(NeuNAc(2-6)GalNAc)-TAAA. These changes are consistent with the extrapolations of the mucin chain dimension data to glycopeptides of this size. The simulations have identified two potentially strong peptide-carbohydrate hydrogen bonds that can influence the orientation of O-linked GalNAc. With two contiguous glycosylated sites, the lowest energy conformation obtained is characterized by a GalNAc amide proton hydrogen bond to the carbonyl of the peptide residue C-terminal to the site of glycosylation. This conformation differs from the glycopeptide conformations predicted for glycopeptides with single or widely spaced glycosylation sites. The results suggest that the experimentally determined mucin peptide chain dimensions can be fully accounted for by short-range (+/- 3 residue) intramolecular steric and hydrogen bond interactions resulting from the clustering of glycosylated residues.
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PMID:Structure and dynamics of mucin-like glycopeptides. Examination of peptide chain expansion and peptide-carbohydrate interactions by stochastic dynamics simulations. 844 22

With the ten WHO criteria for a screening program to be started, screening for abdominal aortic aneurysm is analyzed. Most of the criteria are fulfilled concerning the 65-year old male population, whereas concerning females we need more knowledge. Still the aneurysmal diameter is the most important factor to select patients for treatment meaning that many aneurysms are treated where rupture should never have occurred. Research projects giving more information on pathophysiological processes behind expansion and rupture should have priority.
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PMID:Abdominal aortic aneurysm--to screen or not to screen. 1790 5

Abdominal aortic aneurysms (AAAs), a prototypic proteolytic cardiovascular disorder, are localized expansions of the aortal wall. Chronically upregulated and overexpressed proteases irreversibly degrade and disrupt the elastic matrix, which provides stretch and recoil properties to the aortal wall. Adult vascular smooth muscle cells are inherently unable to produce sufficient elastin to form new elastic fibers to naturally repair the aortal wall and the AAA continues to grow until fatal rupture. Surgical intervention is reserved for AAAs with a high risk of rupture, but there is currently no treatment for small, still growing AAAs. We have previously developed matrix regenerative PEG-PLGA nanoparticles (NPs) with pro-elastogenic and anti-proteolytic properties that act synergistically with a released therapeutic. However, strategies are required to effectively deliver these NPs to the disease site to avail of these benefits. We have identified cathepsin K, a protease overexpressed in AAA tissue, as a potential substrate for antibody based active targeting. We sought to assess the safety and biocompatibility of NPs with anti-cathepsin K antibodies conjugated to the NP surface (cat K Ab-NPs) and then assess their biodistribution and retention in both the targeted aorta and non-target organs in a rat AAA model. In this work, we show that cat K Ab-NPs can selectively target the aneurysmal aorta in a rat AAA model. However, there is unwanted NP uptake and retention in non-target organs that can be addressed in future work. Still, cathepsin K is a viable target for active delivery of NPs in an AAA model. STATEMENT OF SIGNIFICANCE: We have previously developed elastic matrix regenerative polymer nanoparticles (NPs), but require strategies to efficiently target the disease site. Antibodies against cathepsin K, an overexpressed protease in abdominal aortic aneurysms, have been conjugated to the NP surface to act as a targeting moiety. In this work, we assessed NP safety and in vivo biodistribution in an aneurysmal rat model and demonstrated positive targeting and retention for up to 2 weeks within the aortal wall.
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PMID:Assessing the targeting and fate of cathepsin k antibody-modified nanoparticles in a rat abdominal aortic aneurysm model. 3250 90