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201.
IRAG is essential for relaxation of receptor-triggered smooth muscle contraction by cGMP kinase 下载免费PDF全文
Geiselhöringer A Werner M Sigl K Smital P Wörner R Acheo L Stieber J Weinmeister P Feil R Feil S Wegener J Hofmann F Schlossmann J 《The EMBO journal》2004,23(21):4222-4231
Signalling by cGMP-dependent protein kinase type I (cGKI) relaxes various smooth muscles modulating thereby vascular tone and gastrointestinal motility. cGKI-dependent relaxation is possibly mediated by phosphorylation of the inositol 1,4,5-trisphosphate receptor I (IP(3)RI)-associated protein (IRAG), which decreases hormone-induced IP(3)-dependent Ca(2+) release. We show now that the targeted deletion of exon 12 of IRAG coding for the N-terminus of the coiled-coil domain disrupted in vivo the IRAG-IP(3)RI interaction and resulted in hypomorphic IRAG(Delta12/Delta12) mice. These mice had a dilated gastrointestinal tract and a disturbed gastrointestinal motility. Carbachol- and phenylephrine-contracted smooth muscle strips from colon and aorta, respectively, of IRAG(Delta12/Delta12) mice were not relaxed by cGMP, while cAMP-mediated relaxation was unperturbed. Norepinephrine-induced increases in [Ca(2+)](i) were not decreased by cGMP in aortic smooth muscle cells from IRAG(Delta12/Delta12) mice. In contrast, cGMP-induced relaxation of potassium-induced smooth muscle contraction was not abolished in IRAG(Delta12/Delta12) mice. We conclude that cGMP-dependent relaxation of hormone receptor-triggered smooth muscle contraction essentially depends on the interaction of cGKI-IRAG with IP(3)RI. 相似文献
202.
Jablonowski JA Chai W Li X Rudolph DA Murray WV Youngman MA Dax SL Nepomuceno D Bonaventure P Lovenberg TW Carruthers NI 《Bioorganic & medicinal chemistry letters》2004,14(5):1239-1242
Through SAR studies of a piperidinylindoline cinnamide HTS lead, the first potent, non-peptide, low molecular weight selective Neuropeptide Y Y2 (NPY Y2) antagonists have been synthesized. The SAR studies around the piperidinyl, the indolinyl, and the cinnamyl moieties are discussed. 相似文献
203.
Aszodi J Rowlands DA Mauvais P Collette P Bonnefoy A Lampilas M 《Bioorganic & medicinal chemistry letters》2004,14(10):2489-2492
Anti-Bredt bridged bicyclo[3.2.1] gamma-lactams were designed as inhibitors of penicillin binding proteins (PBPs). The compounds were prepared by a carbenoid insertion into a lactam N-H bond. Their weak antibacterial activity could either be explained by a poor chemical stability or by unfavorable steric interactions of the methylene bridge of the gamma-lactam with the targeted enzymes. 相似文献
204.
Manley PW Breitenstein W Brüggen J Cowan-Jacob SW Furet P Mestan J Meyer T 《Bioorganic & medicinal chemistry letters》2004,14(23):5793-5797
The constitutively active Abl kinase activity of the Bcr-Abl oncoprotein is causative for chronic myelogenous leukemia. Urea derivatives, structurally related to the therapeutic agent STI571, have been identified, which potently inhibit the tyrosine kinase activity of recombinant Abl. In particular a dimethylamino-aniline derivative (18) inhibited c-Abl transphosphorylation with an IC(50) value of 56 nM. Although this activity was not translated into cellular activity against the constitutively activated oncogenic Bcr-Abl, a number of compounds from this series potently inhibited cellular PDGFR autophosphorylation. It was also possible to differentiate between c-Abl and PDGFR kinase inhibition, with compound 22 being selective towards Abl and 23 selective for PDGFR. 相似文献
205.
206.
Glomulin is predominantly expressed in vascular smooth muscle cells in the embryonic and adult mouse
McIntyre BA Brouillard P Aerts V Gutierrez-Roelens I Vikkula M 《Gene expression patterns : GEP》2004,4(3):351-358
Mutations in the glomulin gene result in dominantly inherited vascular lesions of the skin known as glomuvenous malformations (GVMs). These lesions are histologically distinguished by their distended vein-like channels containing characteristic 'glomus cells', which appear to be incompletely or improperly differentiated vascular smooth muscle cells (VSMCs). The function of glomulin is currently unknown. We studied glomulin expression during murine development (E9.5 days post-coitum until adulthood) by non-radioactive in situ hybridization. Glomulin was first detected at E10.5 dpc in cardiac outflow tracts. Later, it showed strong expression in VSMCs as well as a limited expression in the perichondrium. At E11.5-14.5 dpc glomulin RNA was most abundant in the walls of the large vessels. At E16.5 dpc expression was also detectable in smaller arteries and veins. The high expression of glomulin in murine vasculature suggests an important role for glomulin in blood vessel development and/or maintenance, which is supported by the vascular phenotype seen in GVM patients with mutations in this gene. 相似文献
207.
Complementary expression patterns of retinoid acid-synthesizing and -metabolizing enzymes in pre-natal mouse inner ear structures 总被引:1,自引:0,他引:1
Romand R Niederreither K Abu-Abed S Petkovich M Fraulob V Hashino E Dollé P 《Gene expression patterns : GEP》2004,4(2):123-133
Retinoic acid (RA) plays a pivotal role in patterning and differentiation of the embryonic inner ear. Despite its documented effects during embryonic development, the cellular sites that synthesize or metabolize RA in the inner ear have yet to be determined. Here we describe the distribution of three synthesizing enzymes, retinaldehyde dehydrogenases 1, 2 and 3 (RALDH1, RALDH2 and RALDH3) and two catabolizing enzymes (CYP26A1 and CYP26B1) in the mouse inner ear at embryonic day 18.5 when active cell differentiation is underway. Two detection methods, radioactive and non-radioactive in situ hybridization, were employed to elucidate the tissue distribution and cellular localization of these enzymes, respectively. All of the five enzymes examined, with the exception of CYP26A1, were expressed in both vestibular and cochlear end organs. While expression of the three RALDHs was observed in various cell types, CYP26B1 expression was found only in supporting cells of the vestibular and cochlear end organs. In the cochlea, expression domains of RALDH1-3 and CYP26B1 were complementary to one another. These results reveal specific tissue- and cellular expression patterns of RA synthesizing and catabolizing enzymes in the pre-natal inner ear, and suggest that a precise control of RA concentrations in various cell types of the inner ear is achieved by the balance between RALDHs and CYP26B1 activities. 相似文献
208.
Pascal?PernetEmail author Bénédicte?Bénéteau-Burnat Michel?Vaubourdolle 《Bio Tribune Magazine》2004,10(1):54-56
La biologie délocalisée prend une importance croissante dans le fonctionnement des services traitant les urgences à l’h?pital.
Elle devrait représenter une réele évolution pour la prise en charge du patient tout en améliorant l’organisation interne
des unités de soins. Le biologiste occupe un r?le clé pour mener un tel projet et la mise en place d’un système d’assurance
qualité adapté à cette pratique est indispensable. 相似文献
209.
Farce A Loge C Gallet S Lebegue N Carato P Chavatte P Berthelot P Lesieur D 《Journal of enzyme inhibition and medicinal chemistry》2004,19(6):541-547
Cancer is a major cause of mortality in developed countries, following only cardiovascular diseases. Death of cancerous cells can be achieved by stopping mitosis and the antimitotic class of drugs formed by the spindle poisons can be used for this purpose. Their role is to disorganize the mitotic spindle by targeting its main constituent, the microtubules, themselves made of heterodimers of alpha and beta-tubulin. They disrupt the dynamics of the microtubules either by stabilizing them, as do paclitaxel or epothilones, or destabilizing them, as do colchicine. The binding site of colchicine seems to lie between the two units of the tubulin dimer. Here, we report on the characterization of this site by the docking of a series of reference compounds, and the subsequent docking of ligands prepared in our laboratory. 相似文献
210.
Sanna V Kirschvink N Gustin P Gavini E Roland I Delattre L Evrard B 《AAPS PharmSciTech》2004,5(2):17-23
The purpose of this research was to investigate the effects of processing conditions on the characteristics of solid lipid
microparticles (SLM) with a potential application as carriers for pulmonary administration. Compritol (5.0% wt/wt) SLM dispersions
were prepared by rotor-stator homogenization, at different surfactant concentrations and emulsification times. The SLM were
characterized, in terms of morphology and size, after lyophilization and sterilization by autoclaving process. In vivo assessment
was carried out in rats by intratracheal instillation of either placebo or SLM dispersion, and by bronchoalveolar lavage for
cytological analysis. Mean particle size of 4 to 5 μm was achieved using 0.3% and 0.4% (wt/wt) of emulsifier (Poloxamer 188)
and emulsification times of 2 and 5 minutes. The particles showed spherical shape and smooth surface. The morphology of microparticles,
the size, and the size distribution were not substantially modified after lyophilization and sterilization. Total cell counts
showed no significant differences between placebo and SLM 0.5% or 2.5% groups. Regarding cytology, percentage of polymorphonuclear
neutrophils and macrophages did not significantly differ between groups. These results suggest that a single intratracheal
administration of the SLMs does not induce a significant inflammatory airway response in rats and that the SLMs might be a
potential carrier for encapsulated drug via the pulmonary route. 相似文献