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201.
Braud E Duflos M Nourrisson MR Tonnerre A Picot C Le Baut G Renard P Pfeiffer B Tucker G 《Journal of enzyme inhibition and medicinal chemistry》2003,18(3):243-252
The synthesis and pharmacological evaluation of new 3-(imidazol-4(5)-ylmethylene)indolin-2-ones, analogues of SU-5416, are reported. The final compounds 20-51 were obtained by Knoevenagel coupling between the substituted indolin-2-ones 1-15 and either the formylimidazole derivatives 16-18 or 2-formyl-3,5-dimethylpyrrole 19. Methylation at the nitrogen atom of the indolin-2-one and/or imidazole moities was carried out in the presence of the couple NaH/DMF. A Mannich reaction afforded the 1-dimethylaminomethyl derivatives 43 and 48. The antiangiogenic activity of these compounds was evaluated in a three dimensional in vitro rat aortic ring assay. In this test, compound 20 induced a decrease of angiogenesis comparable to that observed with SU-5416; the vascular density indexes at 1 microM were 30 +/- 18 and 22 +/- 4% of control, respectively. The compounds were also evaluated, in an independent manner, as inhibitors of the human EGF-receptor tyrosine kinase activity. As expected, only minor activities were observed with four compounds, out of thirty-one, exerting inhibitory effects in the range of 40-55% at 10 microM concentration. 相似文献
202.
Savoye-Collet C Savoye G Smout A 《American journal of physiology. Gastrointestinal and liver physiology》2003,285(6):G1147-G1152
Intraluminal impedance recording has made it possible to record fluid transport across the pylorus during the interdigestive state without filling the stomach. During antral phase II, fluid transport occurs with and without manometrically detectable antral contraction. Our aim was to investigate the relationships between ultrasonographic patterns of antral contraction, manometric pressure waves, and transpyloric fluid transport during antral phase II. Antral wall movements were recorded by real-time ultrasound (US) in eight healthy volunteers (mean age 24 +/- 7 yr) during 17 +/- 5 min of antral phase II. Concomitantly, a catheter positioned across the pylorus, monitored by transmucosal potential difference measurement, recorded five impedance signals (1 antral, 1 pyloric, and 3 duodenal) and six manometric signals (2 antral, 1 pyloric, and 3 duodenal). Antral contractions detected by US at the level of the two antral impedance electrodes were classified according to their association with a pyloric opening or a duodenal contraction. Transpyloric liquid transport events (impedance drop of >40% of the baseline with an antegrade or retrograde propagation) and manometric pressure waves (amplitude and duration) were identified during the whole study and especially during each period of US antral contraction. A total of 110 antral contractions was detected by US. Of these, 79 were also recorded by manometry. Fluid transport across the pylorus was observed in 70.9% of the US-detected antral contractions. Pyloric opening was observed in 98.6% of the contractions associated with fluid transport compared with 50% in the absence of fluid transport (P < 0.05). Antral contractions associated with fluid transport were significantly (P < 0.05) more often propagated to the duodenum (92%) than those without fluid transport (53%). Pressure waves associated with fluid transport were of higher amplitude (208 mmHg, range 22-493) and longer duration (7 s, range 2.5-13.5 s) than those not associated with fluid transport (102 mmHg, range 18-329 mmHg, and 4.1 s, range 2-8.5 s; P < 0.05). The propagation of the antral contractions in the duodenum in US was always associated with a pyloric opening, whereas only 8 of the 25 contractions without duodenal propagation were associated with a pyloric opening (P < 0.05). The presence of duodenal contractile activity before the onset of an antral contraction in US was always accompanied by pyloric opening and with fluid transport in 93.3%, compared with 56.8% in its absence (P < 0.05). In antral phase II, US is the most sensitive technique to detect antral contractions. Transpyloric fluid transport observed in relation to antral contractions occurs mainly in association with contractions of high amplitude and long duration and is associated with pyloric opening and/or duodenal propagation. 相似文献
203.
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205.
Patient studies suggest that speech and environmental sounds are differentially processed by the left and right hemispheres. Here, using functional imaging in normal subjects, we compared semantic processing of spoken words to equivalent processing of environmental sounds, after controlling for low-level perceptual differences. Words enhanced activation in left anterior and posterior superior temporal regions, while environmental sounds enhanced activation in a right posterior superior temporal region. This left/right dissociation was unchanged by different attentional/working memory contexts, but it was specific to tasks requiring semantic analysis. While semantic processing involves widely distributed networks in both hemispheres, our results support the hypothesis of a dual access route specific for verbal and nonverbal material, respectively. 相似文献
206.
Marchand P Le Borgne M Palzer M Le Baut G Hartmann RW 《Bioorganic & medicinal chemistry letters》2003,13(9):1553-1555
Aromatase (P450 arom) is a target of pharmacological interest for the treatment of breast cancer. New series of 7-(alpha-azolylbenzyl)-1H-indoles and indolines were synthesized as non-steroidal inhibitors of P450 arom. Selectivity was studied towards P450 17alpha enzyme. The most active compound, 1-ethyl-7-[(imidazol-1-yl)(4-chlorophenyl)methyl]-1H-indole 12c exhibited promising relative potency (rp) of 336 (rp of aminoglutethimide=1) and most of the described azoles were active and selective towards P450 arom. 相似文献
207.
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most commonly inherited renal diseases. At least two genes, PKD2 and PKD1 are implicated in the development of this disease. Our pathogenetic studies showed that the human and murine polycystic kidney disease (PKD) involves failure to switch out of a renal developmental program. We have thus undertaken a detailed comparative expression analysis of Pkd2 and Pkd1 from the morula stage to adulthood. Pkd2 expression was detected as early as the morula and blastocyst stages as observed for Pkd1. Strong Pkd2 expression, similar to Pkd1, was displayed in all mesenchymal and cartilaginous tissues during mouse development. However major differences in Pkd2 expression in comparison to Pkd1 were identified. First, in contrast to Pkd1, the neural crest cell-derived tissues displayed a low to undetectable Pkd2 expression at all ages. Second, no increase in Pkd2 expression was detected during mesenchymal condensation. Third, high Pkd2 expression in the kidneys was localized mainly to the tubular epithelium of the cortical region from murine development to adulthood. 相似文献
208.
Lata JC Guillaume K Degrange V Abbadie L Lensi R 《Proceedings. Biological sciences / The Royal Society》2000,267(1443):595-600
Previous studies have shown that Lamto savannah exhibits two different types of nitrogen cycle with high and low nitrification sites and suggested that the perennial grass Hyparrhenia diplandra is responsible for this duality at a subpopulation level, with one ecotype being thought to be able to inhibit nitrification. The present work aimed to investigate the relationships between nitrification and the roots of H. diplandra at two scales. (i) Site-scale experiments gave new insight into the hypothesized control of nitrification by H. diplandra tussocks: the two ecotypes exhibited opposite influences, inhibition in a low nitrification site (A) and stimulation in a high nitrification site (B). (ii) Decimetric-scale experiments demonstrated close negative or positive relationships (in sites A or B, respectively) between the roots and nitrification (in the 0-10 cm soil layer), showing an unexpectedly high sensitivity of the nitrification process to root density. In both soils, the correlation between the roots and nitrification decreased with depth and practically disappeared in the 20-30 cm soil layer (where the nitrification potential was found to be very low). Therefore, the impact of H. diplandra on nitrification may be viewed as an inhibition-stimulation balance. 相似文献
209.
Floch V Delépine P Guillaume C Loisel S Chassé S Le Bolc'h G Gobin E Leroy JP Férec C 《Biochimica et biophysica acta》2000,1464(1):95-103
Performances of cationic lipid formulations for intravenous gene delivery to mouse lungs have been previously reported. We report in this study that cationic phosphonolipids, when appropriately formulated, can be good synthetic vectors for gene delivery to lung after intravenous administration. One of our reagents, GLB43, was capable of mediating a 500-fold higher expression in the lungs of mice than could be obtained with free pDNA alone (P=0.018). We demonstrate that the most important parameters for cationic phosphonolipid transfection activity after systemic administration are the chemical structure of the cationic phosphonolipid, the lipid to DNA charge ratio and the inclusion of co-lipid in the formulation. We report using a luciferase reporter gene that transfection activity in vivo 24 h after cationic phosphonolipid systemic administration could not be predicted from in vitro analysis. In contrast to in vitro studies, cationic phosphonolipids including the oleyl acyl chains (GLB43) were more effective than its analogue with the myristyl acyl chains (GLB73). Using pathological analysis of animal livers, we demonstrate that the toxicity level was correlated with the lipoplex formulation and the lipid to DNA ratio. 相似文献
210.
Odile Minella Odile Mulner-Lorillon Guillaume Bec Patrick Cormier Robert Bellé 《Bioscience reports》1998,18(3):119-127
The eukaryotic guanine-nucleotide exchange factor commonly called elongation factor-1 (EF-1), comprises four different subunits including valyl-tRNA synthetase (EF-1/ValRS). The factor is multiply-phosphorylated by three different protein kinases, protein kinase C, casein kinase II and cyclin dependent kinase 1 (CDK1). EF-1/ValRS is organized as a macromolecular complex for which we propose a new structural model. Evidence that EF-1/ValRS is a sophisticated supramolecular complex containing many phosphorylation sites, makes it a potential regulator of any of the functions of its partner EF-1, not only involved in protein synthesis elongation, but also in many other cellular functions. 相似文献