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991.
Mattocks M Bagovich M De Rosa M Bond S Binnington B Rasaiah VI Medin J Lingwood C 《The FEBS journal》2006,273(9):2064-2075
We have shown that the ABC transporter, multiple drug resistance protein 1 (MDR1, P-glycoprotein) translocates glucosyl ceramide from the cytosolic to the luminal Golgi surface for neutral, but not acidic, glycosphingolipid (GSL) synthesis. Here we show that the MDR1 inhibitor, cyclosporin A (CsA) can deplete Gaucher lymphoid cell lines of accumulated glucosyl ceramide and Fabry cell lines of globotriaosyl ceramide (Gb3), by preventing de novo synthesis. In the Fabry mouse model, Gb3 is increased in the heart, liver, spleen, brain and kidney. The lack of renal glomerular Gb3 is retained, but the number of verotoxin 1 (VT1)-staining renal tubules, and VT1 tubular targeting in vivo, is markedly increased in Fabry mice. Adult Fabry mice were treated with alpha-galactosidase (enzyme-replacement therapy, ERT) to eliminate serum Gb3 and lower Gb3 levels in some tissues. Serum Gb3 was monitored using a VT1 ELISA during a post-ERT recovery phase +/- biweekly intra peritoneal CsA. After 9 weeks, tissue Gb3 content and localization were determined using VT1/TLC overlay and histochemistry. Serum Gb3 recovered to lower levels after CsA treatment. Gb3 was undetected in wild-type liver, and the levels of Gb3 (but not gangliosides) in Fabry mouse liver were significantly depleted by CsA treatment. VT1 liver histochemistry showed Gb3 accumulated in Kupffer cells, endothelial cell subsets within the central and portal vein and within the portal triad. Hepatic venule endothelial and Kupffer cell VT1 staining was considerably reduced by in vivo CsA treatment. We conclude that MDR1 inhibition warrants consideration as a novel adjunct treatment for neutral GSL storage diseases. 相似文献
992.
We present a method to produce vascular disruptions within rat brain parenchyma that targets single microvessels. We used two-photon microscopy to image vascular architecture, to select a vessel for injury and to measure blood-flow dynamics. We irradiated the vessel with high-fluence, ultrashort laser pulses and achieved three forms of vascular insult. (i) Vessel rupture was induced at the highest optical energies; this provides a model for hemorrhage. (ii) Extravasation of blood components was induced near the lowest energies and was accompanied by maintained flow in the target vessel. (iii) An intravascular clot evolved when an extravasated vessel was further irradiated. Such clots dramatically impaired blood flow in downstream vessels, in which speeds dropped to as low as approximately 10% of baseline values. This demonstrates that a single blockage to a microvessel can lead to local cortical ischemia. Lastly, we show that hemodilution leads to a restoration of flow in secondary downstream vessels. 相似文献
993.
994.
Nicolas Blouin Beth L. Calder Brian Perkins Susan H. Brawley 《Journal of applied phycology》2006,18(1):79-85
Sensory analyses were conducted to determine levels of consumer acceptability of Porphyra yezoensis, P. umbilicalis, and P. amplissima to select appropriate species for aquaculture development in Maine (USA). The subjects included children (n = 67) and adults (n = 84); the children participated in study design by helping to select the 9 point hedonic scale used in the affective sensory tests. Two substrates were used; Porphyra was baked in crackers and also used as a coating for popcorn. No significant differences (p > 0.5) in acceptability of one species over another were observed in either trial, which suggests that native Atlantic species of Porphyra such as P. amplissima and P. umbilicalis have developmental potential in foods for North American consumers. Fatty acids were analyzed in the taste test material and in freshly collected P. umbilicalis; eicosapentaenoic acid [EPA; 20:5 (n-3)] and palmitic acid were the most common fatty acids. Quantitative analysis of EPA determined that freshly collected (January 2005) P. umbilicalis contained 3.2 mg EPA g dry wt−1 (74 mg EPA 100 g fresh wt−1). This concentration is not high enough to make P. umbilicalis a primary source of daily omega-3 fatty acids, but the favorable n-3/n-6 ratio (2-3:1) in these species contributes to their nutritional value. 相似文献
995.
996.
Src tyrosine kinases are essential in numerous cell signaling pathways, and improper functioning of these enzymes has been implicated in many diseases. The activity of Src kinases is regulated by conformational activation, which involves several structural changes within the catalytic domain (CD): the orientation of two lobes of CD; rearrangement of the activation loop (A-loop); and movement of an alpha-helix (alphaC), which is located at the interface between the two lobes, into or away from the catalytic cleft. Conformational activation was investigated using biased molecular dynamics to explore the transition pathway between the active and the down-regulated conformation of CD for the Src-kinase family member Lyn kinase, and to gain insight into the interdependence of these changes. Lobe opening is observed to be a facile motion, whereas movement of the A-loop motion is more complex requiring secondary structure changes as well as communication with alphaC. A key result is that the conformational transition involves a switch in an electrostatic network of six polar residues between the active and the down-regulated conformations. The exchange between interactions links the three main motions of the CD. Kinetic experiments that would demonstrate the contribution of the switched electrostatic network to the enzyme mechanism are proposed. Possible implications for regulation conferred by interdomain interactions are also discussed. 相似文献
997.
Chen CW Tran JA Jiang W Tucci FC Arellano M Wen J Fleck BA Marinkovic D White NS Pontillo J Saunders J Madan A Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2006,16(18):4800-4803
A series of alpha-benzylpropionylpiperazines were synthesized and tested as antagonists of the melanocortin-4 receptor. In addition to its high potency and selectivity, R-11a had desirable pharmacokinetic properties including high brain penetration in mice. 相似文献
998.
Burgey CS Stump CA Nguyen DN Deng JZ Quigley AG Norton BR Bell IM Mosser SD Salvatore CA Rutledge RZ Kane SA Koblan KS Vacca JP Graham SL Williams TM 《Bioorganic & medicinal chemistry letters》2006,16(19):5052-5056
In our continuing effort to identify CGRP receptor antagonists for the acute treatment of migraine, we have undertaken a study to evaluate alternative 4-substituted piperidines to the lead dihydroquinazolinone 1. In this regard, we have identified the piperidinyl-azabenzimidazolone and phenylimidazolinone structures which, when incorporated into the benzodiazepine core, afford potent CGRP receptor antagonists (e.g., 18 and 29). These studies produced a potent analog (18) which overcomes the instability issues associated with the lead structure 1. A general pharmacophore for the 4-substituted piperidine component of these CGRP receptor antagonists is also presented. 相似文献
999.
Jiang W Tucci FC Chen CW Arellano M Tran JA White NS Marinkovic D Pontillo J Fleck BA Wen J Saunders J Madan A Foster AC Chen C 《Bioorganic & medicinal chemistry letters》2006,16(17):4674-4678
A series of 3-arylpropionylpiperazines were synthesized as antagonists of the melanocortin-4 receptor. Their potency was found to be increased by replacing the alpha-methyl substituent of the initial lead 11 with a larger s-Bu or i-Bu group. Further potency enhancement was observed when a glycine or beta-alanine was incorporated onto the benzylamine. Some compounds demonstrated good potency, moderate selectivity, and oral bioavailability. 相似文献
1000.
Kim N Meyers KM Mendez-Andino JL Warshakoon NC Ji W Wos JA Colson A Mitchell MC Davis JR Pinney BB Reizes O Hu XE 《Bioorganic & medicinal chemistry letters》2006,16(20):5445-5450
A substituted 4-aminopiperidine was identified as showing activity in an MCH assay from an HTS effort. Subsequent structural modification of the scaffold led to the identification of a number of active MCH antagonists. 3,5-Dimethoxy-N-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)benzamide (5c) was among those with the highest binding affinity to the MCH receptor (K(i)=27nM), when variations were made at benzoyl and naphthylmethyl substitution sites from the initial HTS hit. Further optimization via piperidine ring contraction resulted in enhanced MCH activity in a 3-aminopyrrolidine series, where (R)-3,5-dimethoxy-N-(1-(naphthalen-2-ylmethyl)-pyrrolidin-3-yl)benzamide (10i) was found to be an excellent MCH antagonist (K(i)=7nM). 相似文献