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221.
Antonio Garrido Montalban Erik Boman Chau-Dung Chang Susana Conde Ceide Russell Dahl David Dalesandro Nancy G.J. Delaet Eric Erb Justin T. Ernst Andrew Gibbs Jeffrey Kahl Linda Kessler Jeff Kucharski Christopher Lum Jan Lundström Stephen Miller Hiroshi Nakanishi Edward Roberts Eddine Saiah Robert Sullivan Christopher J. Larson 《Bioorganic & medicinal chemistry letters》2010,20(16):4819-4824
We have optimized a novel series of potent p38 MAP kinase inhibitors based on an α-ketoamide scaffold through structure based design that due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME, in vivo PK and efficacy studies show these compounds to have drug-like characteristics and have resulted in the nomination of a development candidate which is currently in phase II clinical trials for the oral treatment of inflammatory conditions. 相似文献
222.
Carmen Alicia Peña 《Phytochemistry》1979,18(8):1419-1420
223.
Neuronal and Glial Expression of the Multidrug Resistance Gene Product in an Experimental Epilepsy Model 总被引:8,自引:0,他引:8
Lazarowski A Ramos AJ García-Rivello H Brusco A Girardi E 《Cellular and molecular neurobiology》2004,24(1):77-85
1. Failure of anticonvulsive drugs to prevent seizures is a common complication of epilepsy treatment known as drug-refractory epilepsy but their causes are not well understood. It is hypothesized that the multidrug resistance P-glycoprotein (Pgp-170), the product of the MDR-1 gene that is normally expressed in several excretory tissues including the blood brain barrier, may be participating in the refractory epilepsy. 2. Using two monoclonal antibodies against Pgp-170, we investigated the expression and cellular distribution of this protein in the rat brain during experimentally induced epilepsy. Repeated seizures were induced in male Wistar rats by daily administration of 3-mercaptopropionic acid (MP) 45 mg/kg i.p. for either 4 days (MP-4) or 7 days (MP-7). Control rats received an equivalent volume of vehicle. One day after the last injection, rats were sacrificed and brains were processed for immunohistochemistry for Pgp-170. As it was previously described, Pgp-170 immunostaining was observed in some brain capillary endothelial cells of animals from control group. 3. Increased Pgp-170 immunoreactivity was detected in MP-treated animals. Besides the Pgp-170 expressed in blood vessels, neuronal, and glial immunostaining was detected in hippocampus, striatum, and cerebral cortex of MP-treated rats. Pgp-170 immunolabeled neurons and glial cells were observed in a nonhomogeneous distribution. MP-4 animals presented a very prominent Pgp-170 immunostaining in the capillary endothelium, surrounding astrocytes and some neighboring neurons while MP-7 group showed increased neuronal labeling. 4. Our results demonstrate a selective increase in Pgp-170 immunoreactivity in the brain capillary endothelial cells, astrocytes, and neurons during repetitive MP-induced seizures. 5. The role for this Pgp-170 overexpression in endothelium and astrocytes as a clearance mechanism in the refractory epilepsy, and the consequences of neuronal Pgp-170 expression remain to be disclosed. 相似文献
224.
Gómez-Miranda B Prieto A Leal JA Ahrazem O Jiménez-Barbero J Bernabé M 《Glycoconjugate journal》2004,20(4):239-246
The alkali extractable and water-soluble cell wall polysaccharides F1SS from Aspergillus wentii and Chaetosartorya chrysella have been studied by methylation analysis, 1D- and 2D-NMR, and MALDI-TOF analysis. Their structures are almost identical, corresponding to the following repeating unit: [--> 3)-beta-D-Gal f -(1 --> 5)-beta-D-Gal f-(1 -->]n --> mannan core. The structure of this galactofuranose side chain differs from that found in the pathogenic fungus Aspergillus fumigatus, in other Aspergillii and members of Trichocomaceae: [--> 5)-beta-D-Gal f-(1 -->]n --> mannan core. The mannan cores have also been investigated, and are constituted by a (1 --> 6)-alpha-mannan backbone, substituted at positions 2 by chains from 1 to 7 residues of (1 --> 2) linked alpha-mannopyranoses. 相似文献
225.
226.
Phylogenetic relationships in Bupleurum (apiaceae) based on nuclear ribosomal DNA its sequence data 总被引:2,自引:0,他引:2
BACKGROUND AND AIMS: The genus Bupleurum has long been recognized as a natural group, but its infrageneric classification is controversial and has not yet been studied in the light of sequence data. METHODS: Phylogenetic relationships among 32 species (35 taxa) of the genus Bupleurum were investigated by comparative sequencing of the ITS region of the 18-26S nuclear ribosomal DNA repeat. Exemplar taxa from all currently accepted sections and subsections of the genus were included, along with outgroups from four other early branching Apioideae genera (Anginon, Heteromorpha, Physospermum and Pleurospermum). RESULTS: Phylogenies generated by maximum parsimony, maximum likelihood, and neighbour-joining methods show similar topologies, demonstrating monophyly of Bupleurum and the division of the genus into two major clades. This division is also supported by analysis of the 5.8S coding sequence alone. The first branching clade is formed by all the species of the genus with pinnate-reticulate veined leaves and B. rigidum with a unique type of leaf venation. The other major clade includes the remaining species studied, all of which have more or less parallel-veined leaves. CONCLUSIONS: These phylogenetic results do not agree with any previous classifications of the genus. Molecular data also suggest that the endemic Macaronesian species B. salicifolium is a neoendemic, as the sequence divergence between the populations in Madeira and Canary Islands, and closer mainland relatives in north-west Africa is small. All endemic north-west African taxa are included in a single unresolved but well-supported clade, and the low nucleotide variation of ITS suggests a recent radiation within this group. The only southern hemisphere species, B. mundii (southern Africa), is shown to be a neoendemic, apparently closely related to B. falcatum, a Eurasian species. 相似文献
227.
Boán F Blanco MG Quinteiro J Mouriño S Gómez-Márquez J 《Molecular biology and evolution》2004,21(2):228-235
One of the most exciting challenges in human biology is the understanding of how our genome was constructed during evolution. Here we explore the evolutionary history of the low polymorphic human minisatellite MsH42 and its flanking sequences. We show that the evolutionary birth of MsH42 took place within an intron, early in primate lineage evolution, more than 40 MYA. Then, single base-pair changes and duplications/deletions of repeat blocks by mispairing were probably the main forces governing the generation of this minisatellite and its polymorphism throughout primate evolution. Moreover, we detected several phylogenetic footprints at both sides of MsH42. We believe that our findings will contribute to the understanding of low-variability minisatellite evolution. 相似文献
228.
Bcl-2 family proteins regulate mitochondrial reactive oxygen production and protect against oxidative stress 总被引:6,自引:0,他引:6
Bcl-2 family proteins protect against a variety of forms of cell death, including acute oxidative stress. Previous studies have shown that overexpression of the antiapoptotic protein Bcl-2 increases cellular redox capacity. Here we report that cell lines transfected with Bcl-2 paradoxically exhibit increased rates of mitochondrial H(2)O(2) generation. Using isolated mitochondria, we determined that increased H(2)O(2) release results from the oxidation of reduced nicotinamide adenine dinucleotide-linked substrates. Antiapoptotic Bcl-2 family proteins Bcl-xL and Mcl-1 also increase mitochondrial H(2)O(2) release when overexpressed. Chronic exposure of cells to low levels of the mitochondrial uncoupler carbonyl cyanide 4-(triflouromethoxy)phenylhydrazone reduced the rate of H(2)O(2) production by Bcl-xL overexpressing cells, resulting in a decreased ability to remove exogenous H(2)O(2) and enhanced cell death under conditions of acute oxidative stress. Our results indicate that chronic and mild elevations in H(2)O(2) release from Bcl-2, Bcl-xL, and Mcl-1 overexpressing mitochondria lead to enhanced cellular antioxidant defense and protection against death caused by acute oxidative stress. 相似文献
229.
230.
Ferreira M Fiorito PA Oliveira ON Córdoba de Torresi SI 《Biosensors & bioelectronics》2004,19(12):1611-1615
Glucose oxidase (GOD) has been immobilized in Layer-by-Layer (LbL) films, adsorbed alternately with poly(allylamine) hydrochloride (PAH) layers, onto an ITO substrate modified with a Prussian Blue (PB) layer. The ITO/PB/GOD-PAH heterostructures were tested in amperometric glucose biosensors, with a high sensitivity of 16 μA mmol−1 l cm-2 and a limit of detection of 0.20 mmol l−1 being achieved. This high sensitivity is attributed to the ultrathin nature of the film in addition to the low operating potentials that could be used due to the efficient catalysis of H2O2 produced in the enzymatic reaction in the presence of Prussian Blue. The biosensors are highly selective to glucose, as demonstrated by the lack of interference from possible interferents such as ascorbic and uric acids and acetominophen. The stability of the biosensors was checked by observing an almost constant sensitivity for a period of approximately 20 days, thus indicating a stable adsorption of GOD. 相似文献