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51.
Kevin K.-C. Liu Peter Cornelius Terrell A. Patterson Yuan Zeng Stephanie Santucci Elizabeth Tomlinson Colleen Gibbons Tristan S. Maurer Ravi Marala Janice Brown Jimmy X. Kong Eunsun Lee Wendy Werner Zane Wenzel Chandra Vage 《Bioorganic & medicinal chemistry letters》2010,20(1):266-271
Based on our original pyrazine hit, CP-0809101, novel conformationally-restricted 5HT2c receptor agonists with 2-piperazin-azaindane scaffold were designed. Synthesis and structure–activity relationship (SAR) studies are described with emphasis on optimization of the selectivity against 5HT2a and 5HT2b receptors with excellent 2c potency. Orally-active and selective compounds were identified with dose–responsive in vivo efficacy in our pre-clinical food intake model. 相似文献
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Gastric juice is the most proximal fluid surrounding the stomach tissue. The analysis of gastric juice protein contents will thus be able to accurately reflect the pathophysiology of the stomach. This biological fluid is also a potential reservoir of secreted biomarkers in higher concentration as compared to the serum. Unlike the rest of the gastrointestinal fluids, there were very few studies reported on gastric juice proteome. To date, the proteins that routinely populate this biofluid are largely unknown. This is partly due to the technical difficulties in processing a sample that contains a collection of other gastrointestinal fluids, especially saliva. In this study, we attempt to profile the protein components of the gastric fluids from chronic gastritis patients using a direct shotgun proteomics approach. These data represent the first report of the proteome of human gastric juice with gastritis background. 相似文献
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Dikeakos JD Lacombe MJ Mercure C Mireuta M Reudelhuber TL 《The Journal of biological chemistry》2007,282(2):1136-1143
Many endocrine and neuroendocrine cells contain specialized secretory organelles called dense core secretory granules. These organelles are the repository of proteins and peptides that are secreted in a regulated manner when the cell receives a physiological stimulus. The targeting of proteins to these secretory granules is crucial for the generation of certain peptide hormones, including insulin and ACTH. Although previous work has demonstrated that proteins destined to a variety of cellular locations, including secretory granules, contain targeting sequences, no single consensus sequence for secretory granule-sorting signals has emerged. We have shown previously that alpha-helical domains in the C-terminal tail of the prohormone convertase PC1/3 play an important role in the ability of this region of the protein to direct secretory granule targeting (Jutras, I. Seidah, N. G., and Reudelhuber, T. L. (2000) J. Biol. Chem. 275, 40337-40343). In this study, we show that a variety of alpha-helical domains are capable of directing a heterologous secretory protein to granules. By testing a series of synthetic alpha-helices, we also demonstrate that the presence of charged (either positive or negative) amino acids spatially segregated from a hydrophobic patch in the alpha-helices of secretory proteins likely plays a critical role in the ability of these structures to direct secretory granule sorting. 相似文献
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Du L Chen J Qi Y Li D Yuan C Lin MC Yew DT Kung HF Yu JC Lai L 《International journal of nanomedicine》2007,2(4):805-812
We report the preparation of a non-polymer coated superparamagnetic nanoparticle that is stable and biocompatible both in vitro and in vivo. The non-polymer, betaine, is a natural methylating agent in mammalian liver with active surface property. Upon systemic administration, the nanoparticle has preferential biodistribution in mammalian liver and exhibits good reduction of relaxivity time and negative enhancement for the detection of hepatoma nodules in rats using MRI. Our data demonstrate that the non-polymer coated superparamagnetic nanoparticle should have potential applications in biomedicine. 相似文献
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Fibrin gel-immobilized VEGF and bFGF efficiently stimulate angiogenesis in the AV loop model 总被引:5,自引:0,他引:5
Arkudas A Tjiawi J Bleiziffer O Grabinger L Polykandriotis E Beier JP Stürzl M Horch RE Kneser U 《Molecular medicine (Cambridge, Mass.)》2007,13(9-10):480-487
The modulation of angiogenic processes in matrices is of great interest in tissue engineering. We assessed the angiogenic effects of fibrin-immobilized VEGF and bFGF in an arteriovenous loop (AVL) model in 22 AVLs created between the femoral artery and vein in rats. The loops were placed in isolation chambers and were embedded in 500 microL fibrin gel (FG) (group A) or in 500 microL FG loaded with 0.1 ng/microL VEGF and 0.1 ng/microL bFGF (group B). After two and four weeks specimens were explanted and investigated using histological, morphometrical, and ultramorphological [scanning electron microscope (SEM) of vascular corrosion replicas] techniques. In both groups, the AVL induced formation of densely vascularized connective tissue with differentiated and functional vessels inside the fibrin matrix. VEGF and bFGF induced significantly higher absolute and relative vascular density and a faster resorption of the fibrin matrix. SEM analysis in both groups revealed characteristics of an immature vascular bed, with a higher vascular density in group B. VEGF and bFGF efficiently stimulated sprouting of blood vessels in the AVL model. The implantation of vascular carriers into given growth factor-loaded matrix volumes may eventually allow efficient generation of axially vascularized, tissue-engineered composites. 相似文献
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Role of protein phosphatase 2A in calcium-dependent chloride secretion by human colonic epithelial cells 总被引:1,自引:0,他引:1
EGF inhibits carbachol-induced chloride secretion by regulating a basolateral potassium channel via phosphatidylinositol 3-kinase (PI 3-kinase) and PKC activation. Although both EGF and carbachol cause tyrosine phosphorylation of p85 of PI 3-kinase, only EGF activates the enzyme. Serine phosphorylation of p85 is thought to suppress the lipid kinase of PI 3-kinase. Our present study examined whether the differential effects of carbachol and EGF on PI 3-kinase activity correspond to varying phosphorylation of p85, and the mechanisms and consequences. T84 colonic epithelial cells were treated with either EGF or carbachol. Cell lysates were immunoprecipitated with p85 antibody and blotted with either phosphotyrosine or phosphoserine antibodies. Protein phosphatase (PP) 1 and 2A activities were also measured. Both tyrosine and serine residues of p85 were phosphorylated by carbachol, whereas EGF induced only tyrosine phosphorylation. Moreover, EGF abolished carbachol-induced serine phosphorylation of p85 and activated PP2A without affecting PP1. Carbachol did not affect either phosphatase. Calyculin A or okadaic acid pretreatment reversed the inhibitory action of EGF on carbachol-induced chloride secretion and restored serine phosphorylation of p85. Although carbachol recruits p85, it phosphorylates both serine and tyrosine residues so that the lipid kinase of PI 3-kinase is inhibited. EGF results in p85 tyrosine phosphorylation as well as dephosphorylation of serine residues via the activation of PP2A. This explains the differential induction of PI 3-kinase enzyme activity in response to EGF and/or carbachol and has functional implications. Our data provide further insights into negative signals that regulate chloride secretion and into the molecular basis of signaling diversification in the intestinal epithelium. epithelial secretion; PI 3-kinase; EGF 相似文献
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