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51.
Dumasia MC Houghton E Hyde W Greulich D Nelson T Peterson J 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2002,767(1):131-144
Studies related to the in vivo biotransforrmation and urinary excretion of fenspiride hydrochloride in the horse are described. After oral administration, the drug is metabolised by both phase I functionalisation and phase II conjugation pathways. Following enzymatic deconjugation, fenspiride and its phase I metabolites were isolated from post-administration biofluids using bonded co-polymeric mixed mode solid-phase extraction cartridges to isolate the basic compounds. Following trimethylsilylation (TMS), the parent drug and metabolites were identified by capillary gas chromatography-mass spectrometry (GC-MS). Fenspiride (A) and seven metabolites (B-->G) arising from oxidation on both the aromatic and heterocyclic substructures were detected in urine. The positive ion electron ionisation mass spectra of the TMS derivatives of fenspiride and its metabolites provided useful information on its metabolism. Positive ion methane chemical ionisation-GC-MS of the derivatives provided both derivatised molecular mass and structural information. Unchanged fenspiride can be detected in post-administration plasma and urine samples for up to 24 h. Maximum urinary levels of 100-200 ng ml(-1) were observed between 3 and 5 h after administration. After enzymatic deconjugation, the major phenolic metabolite (G) can be detected in urine for up to 72 h. This metabolite is the analyte of choice in the GC-MS screening of post-race equine urine samples for detection of fenspiride use. However, a distinct difference was observed in the urinary excretion of this metabolite between the thoroughbred horses used in UK study and the quarterbred and standardbred horses used for the USA administrations. 相似文献
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53.
Regulation of light-dependent Gqalpha translocation and morphological changes in fly photoreceptors 总被引:5,自引:0,他引:5
Kosloff M Elia N Joel-Almagor T Timberg R Zars TD Hyde DR Minke B Selinger Z 《The EMBO journal》2003,22(3):459-468
Heterotrimeric G-proteins relay signals between membrane-bound receptors and downstream effectors. Little is known, however, about the regulation of Galpha subunit localization within the natural endogenous environment of a specialized signaling cell. Here we show, using live Drosophila flies, that light causes massive and reversible translocation of the visual Gqalpha to the cytosol, associated with marked architectural changes in the signaling compartment. Molecular genetic dissection together with detailed kinetic analysis enabled us to characterize the translocation cycle and to unravel how signaling molecules that interact with Gqalpha affect these processes. Epistatic analysis showed that Gqalpha is necessary but not sufficient to bring about the morphological changes in the signaling organelle. Furthermore, mutant analysis indicated that Gqbeta is essential for targeting of Gqalpha to the membrane and suggested that Gqbeta is also needed for efficient activation of Gqalpha by rhodopsin. Our results support the 'two-signal model' hypothesis for membrane targeting in a living organism and characterize the regulation of both the activity-dependent Gq localization and the cellular architectural changes in Drosophila photoreceptors. 相似文献
54.
Ryan KA Moran AP Hynes SO Smith T Hyde D O'Morain CA Maher M 《FEMS immunology and medical microbiology》2000,28(2):113-120
Much work has focused on trying to identify markers in Helicobacter pylori that might allow the eventual disease outcome of an infection to be predicted. In this study we examined the cagA and vacA genotype, and Lewis status in a panel of 43 Irish H. pylori clinical isolates, and investigated a possible correlation with disease pathology. In addition, differences in the poly-(C) tract of the alpha(1,3)-fucosyltransferase gene were examined to identify a possible correlation with gene expression. Only three of 43 isolates were cagA-negative, whereas the remaining 40 isolates, independent of pathology, were cagA-positive. In all the strains we examined, the vacA signal-sequence was type s1a. For the vacA mid-region 12/43 isolates were type m1 and 31/43 isolates were type m2. These data, and examination of isolates from different pathology groups, suggests that there is no correlation between virulence and vacA genotype in the Irish population of H. pylori isolates. Western blotting of whole cell lysates from 32 H. pylori isolates showed 3/32 displayed only the Le(x) epitope, 12/32 only the Le(y), 13/32 both epitopes and 4/32 neither epitope. No apparent association between Lewis phenotype and disease pathology was evident. A range of lengths of poly-(C) tract were observed in the alpha(1, 3)-fucosyltransferase gene, however the length of the tract in an isolate did not correlate with the Lewis structures present. We conclude that future studies on H. pylori pathogenesis should not alone focus on the importance of molecular markers, but also on the host response, including genetic background and immune responsiveness. 相似文献
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56.
The membrane-bound form of mammalian aminopeptidase P (AP-P; EC 3.4. 11.9) is a mono-zinc-containing enzyme that lacks any of the typical metal binding motifs found in other zinc metalloproteases. To identify residues involved in metal binding and catalysis, sequence and structural information was used to align the sequence of porcine membrane-bound AP-P with other members of the peptidase clan MG, including Escherichia coli AP-P and methionyl aminopeptidases. Residues predicted to be critical for activity were mutated and the resultant proteins were expressed in COS-1 cells. Immunoelectrophoretic blot analysis was used to compare the levels of expression of the mutant proteins, and their ability to hydrolyze bradykinin and Gly-Pro-hydroxyPro was assessed. Asp449, Asp460, His523, Glu554, and Glu568 are predicted to serve as metal ion ligands in the active site, and mutagenesis of these residues resulted in fully glycosylated proteins that were catalytically inactive. Mutation of His429 and His532 also resulted in catalytically inactive proteins, and these residues, by analogy with E. coli AP-P, are likely to play a role in shuttling protons during catalysis. These studies indicate that mammalian membrane-bound AP-P has an active-site configuration similar to that of other members of the peptidase clan MG, which is compatible with either a dual metal ion model or a single metal ion in the active site. The latter model is consistent, however, with the known metal stoichiometry of both the membrane-bound and cytosolic forms of AP-P and with a recently proposed model for methionyl aminopeptidase. 相似文献
57.
T.K. Sasikumar Duane A. Burnett Theodros Asberom Wen-Lian Wu Chad Bennett David Cole Ruo Xu William J. Greenlee John Clader Lili Zhang Lynn Hyde 《Bioorganic & medicinal chemistry letters》2010,20(12):3645-3648
Complex tetracyclic sulfones were designed as γ-secretase inhibitors and a stereoselective synthesis was achieved. γ-Secretase activity was seen predominately in the (?) enantiomeric series. Compounds such as 2a and 2b showed remarkable in vitro and in vivo potency. 相似文献
58.
Timothy D. Rohrbach Nishi Shah William P. Jackson Erin V. Feeney Samantha Scanlon Robert Gish Ryan Khodadadi Stephen O. Hyde Patricia H. Hicks Joshua C. Anderson John S. Jarboe Christopher D. Willey 《PloS one》2015,10(10)
Translocation to the nucleus of diacylglycerol kinase (DGK)– ζ is dependent on a sequence homologous to the effector domain of Myristoylated Alanine Rich C-Kinase Substrate (MARCKS). These data would suggest that MARCKS could also localize to the nucleus. A single report demonstrated immunofluorescence staining of MARCKS in the nucleus; however, further experimental evidence confirming the specific domain responsible for this localization has not been reported. Here, we report that MARCKS is present in the nucleus in GBM cell lines. We then over-expressed wild-type MARCKS (WT) and MARCKS with the effector domain deleted (ΔED), both tagged with V5-epitope in a GBM cell line with low endogenous MARCKS expression (U87). We found that MARCKS-WT localized to the nucleus, while the MARCKS construct without the effector domain remained in the cytoplasm. We also found that over-expression of MARCKS-WT resulted in a significant increase in total cellular phosphatidyl-inositol (4,5) bisphosphate (PIP2) levels, consistent with prior evidence that MARCKS can regulate PIP2 levels. We also found increased staining for PIP2 in the nucleus with MARCKS-WT over-expression compared to MARCKS ΔED by immunofluorescence. Interestingly, we observed MARCKS and PIP2 co-localization in the nucleus. Lastly, we found changes in gene expression when MARCKS was not present in the nucleus (MARCKS ΔED). These data indicate that the MARCKS effector domain can function as a nuclear localization signal and that this sequence is critical for the ability of MARCKS to regulate PIP2 levels, nuclear localization, and gene expression. These data suggests a novel role for MARCKS in regulating nuclear functions such as gene expression. 相似文献
59.
Emma Holder Barbara Stevenson Raymond Farley Tom Hilliard Theresa Wodehouse Lucinda Somerton Mia Larsen Jean O'Donoghue Rebecca L. Coles Ronald K. Scheule Seng H. Cheng Deborah R. Gill Stephen C. Hyde Uta Griesenbach Eric W. F. W. Alton David J. Porteous A. Christopher Boyd 《The journal of gene medicine》2010,12(1):55-63
60.
Min Zhong Wang Shen Kenneth J. Barr Jennifer P. Arbitrario Michelle R. Arkin Minna Bui Teresa Chen Brian C. Cunningham Marc J. Evanchik Emily J. Hanan Ute Hoch Karen Huen Jennifer Hyde Jeffery L. Kumer Teresa Lac Chris E. Lawrence Jose R. Martell Johan D. Oslob Kumar Paulvannan Saileta Prabhu W. Mike Flanagan 《Bioorganic & medicinal chemistry letters》2010,20(17):5269-5273
This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model. 相似文献