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排序方式: 共有452条查询结果,搜索用时 750 毫秒
61.
Ivano Amelio Vivien Landré Richard A. Knight Andrey Lisitsa Gerry Melino Alexey V. Antonov 《Oncotarget》2015,6(12):9646-9656
Targeting the ubiquitin–proteasome system (UPS) and ubiquitin-like signalling systems (UBL) has been considered a promising therapeutic strategy to treat cancer, neurodegenerative and immunological disorders. There have been multiple efforts recently to identify novel compounds that efficiently modulate the activities of different disease-specific components of the UPS-UBL. However, it is evident that polypharmacology (the ability to affect multiple independent protein targets) is a basic property of small molecules and even highly potent molecules would have a number of “off target” effects. Here we have explored publicly available high-throughput screening data covering a wide spectrum of currently accepted drug targets in order to understand polypharmacology of small molecules targeting different components of the UPS-UBL. We have demonstrated that molecules targeting a given UPS-UBL protein also have high odds to target a given off target spectrum. Moreover, the off target spectrum differs significantly between different components of UPS-UBL. This information can be utilized further in drug discovery efforts, to improve drug efficiency and to reduce the risk of potential side effects of the prospective drugs designed to target specific UPS-UBL components. 相似文献
62.
Phosphoinositide 3-kinase gamma-deficient hearts are protected from the PAF-dependent depression of cardiac contractility 总被引:3,自引:0,他引:3
Alloatti G Levi R Malan D Del Sorbo L Bosco O Barberis L Marcantoni A Bedendi I Penna C Azzolino O Altruda F Wymann M Hirsch E Montrucchio G 《Cardiovascular research》2003,60(2):242-249
OBJECTIVES: Following an ischemic insult, cardiac contractile recovery might be perturbed by the release of autacoids, like platelet-activating factor (PAF), that depress heart function by acting through G protein-coupled receptors (GPCRs). The signaling events downstream the PAF receptor that lead to the negative inotropic effect are still obscure. We thus investigated whether the GPCR-activated phosphoisositide 3-kinase gamma (PI3Kgamma) could play a role in the cardiac response to PAF. METHODS: The negative inotropic effect of PAF was studied ex vivo, in isolated electrically driven atria and in Langendorff-perfused whole hearts derived from wild-type and PI3Kgamma-null mice. Postischemic recovery of contractility was analyzed in normal and mutant whole hearts subjected to 30 min of ischemia and 40 min of reperfusion in the presence or absence of a PAF receptor antagonist. RESULTS: While wild-type hearts stimulated with PAF showed increased nitric oxide (NO) production and a consequent decreased cardiac contractility, PI3Kgamma-null hearts displayed reduced phosphorylation of nitric oxide synthase 3 (NOS3), blunted nitric oxide production and a complete protection from the PAF-induced negative inotropism. In addition, Langendorff-perfused PI3Kgamma-null hearts showed a better contractile recovery after ischemia/reperfusion, a condition where PAF is known to be an important player in depressing contractility. In agreement with a role of PI3Kgamma in this PAF-mediated signaling, postischemic contractile recovery in PI3Kgamma-null mice appeared overlapping with that of normal hearts treated with the PAF receptor antagonist WEB 2170. CONCLUSION: These data indicate a novel PAF-dependent signaling pathway that, involving PI3Kgamma and NOS3, contributes to postischemic contractile depression. 相似文献
63.
The molecular and crystal structure of 1,4-bis(chloroacetyl)-trans-2,5-dimethylpiperazine synthesized by us, was determined from X-ray diffractometer data. The structure was solved by Patterson and Fourier methods and refined by least-squares techniques to R 0,065 for 1081 independent reflections. The crystals are monoclinic, space group P21/n, with Z = 2 in a unit cell of dimensions: a = 9,486 (6), b = 9,139 (6), c = 7,036 (5) Å, β = 95,73 (10)°, the numbers in parentheses being the estimated standard deviations refering to the last significant digit. The trans-2,5-dimethylpiperazine ring is in a flattened-chair conformation with the side methyl groups in axial position. The atoms of the amide are nearly coplanar. It seems to be proved that the structure of the trans-2,5-dimethylpiperazine ring in poly(trans-2,5-dimethyl-1,4-piperazinediylfumaroyl) is similar to that found for 1,4-bis(chloroacetyl)-trans-2,5-dimethylpiperazine. 相似文献
64.
65.
Porpiglia F Renard J Billia M Cossu M Morra I Terrone C Scarpa RM 《Journal of endourology / Endourological Society》2006,20(9):651-653
PURPOSE: To present a simple alternative technique to close the membranous urethra during laparoscopic radical cystectomy. PATIENTS AND METHODS: A series of 18 laparoscopy-assisted cystectomies were performed in our institute from November 2002 to May 2005. In order to prevent neoplastic-cell spillage, in 14 of these patients, the membranous urethra was closed with Hem-o-lok clips after careful dissection of the urethra and withdrawal of the bladder catheter. RESULTS: In all cases, one or two Hem-o-lok clips were easily, safely, and quickly positioned. The remaining length of the membranous urethra was sufficient for anastomosis with the neobladder if appropriate. In follow-up (mean 14 months), no local recurrence has been recorded. CONCLUSION: The closing of the membranous urethra with Hem-o-lok clips during laparoscopy-assisted cystectomy is in our experience a simple, fast, safe, and effective alternative that should be considered when laparoscopic radical cystectomy is performed. 相似文献
66.
Glucose uptake in the developing chick embryo heart 总被引:3,自引:0,他引:3
67.
Genetic instability in Drosophila melanogaster: putative multiple insertion mutants at the singed bristle locus. 总被引:5,自引:0,他引:5 下载免费PDF全文
M D Golubovsky Y N Ivano M M Green 《Proceedings of the National Academy of Sciences of the United States of America》1977,74(7):2973-2975
A series of eleven independent mutants at the X chromosome singed bristle (sn) locus of Drosophila melanogaster is described. All mutants descend from flies caught in the wild and bred in the laboratory. On the basis of their inordinately high spontaneous mutation frequency, ten of the mutants are classified as putative insertion mutants. Reversions to wild type occur at frequencies of 10(-4)-10(-3). Some reversions appear to be losses of the inserted element, others appear (by analogy with prokaryotes) to be changes in the orientation of the inserted elements. Consistent with the insertion hypothesis, some sn mutants generate what are interpreted to be deletions at the sn locus. In their mutational properties, the sn mutants are analogous to insertion sequence (IS) elements and bacteriophage Mu of Escherichia coli, but the precise nature of the insertion remains unknown. 相似文献
68.
Pistelli L Bertoli A Morelli I Menichini F Musmanno RA Di Maggio T Coratza G 《Phytotherapy research : PTR》2005,19(9):787-791
Five extracts and pure compounds from the aerial parts of Hypericum triquetrifolium were tested for their antibacterial activity against 31 gram-positive and gram-negative strains using the agar dilution method (Lorian). The ethyl acetate extract exhibited a weak antibacterial activity against Staphylococcus strains, and pure constituents such as quercetin and I3,II8-biapigenin were the active components of this extract. 相似文献
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