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501.
Tumour growth is dependent on multiple factors, including the physiological process of angiogenesis. Several opportunities for inhibiting angiogenesis with targeted therapies have been identified and are currently being evaluated for clinical efficacy. Some of the most promising approaches include small-molecule inhibitors for the tyrosine receptor kinase VEGFR2. Other signal-transduction pathways have also been shown to regulate angiogenesis, including FGFR, PDGFR, Tie and EphB. 相似文献
502.
Loh XJ del Barrio J Toh PP Lee TC Jiao D Rauwald U Appel EA Scherman OA 《Biomacromolecules》2012,13(1):84-91
The synthesis of a supramolecular double hydrophilic block copolymer (DHBC) held together by cucurbit[8]uril (CB[8]) ternary complexation and its subsequent self-assembly into micelles is described. This system is responsive to multiple external triggers including temperature, pH and the addition of a competitive guest. The supramolecular block copolymer assembly consists of poly(N-isopropylacrylamide) (PNIPAAm) as a thermoresponsive block and poly(dimethylaminoethylmethacrylate) (PDMAEMA) as a pH-responsive block. Moreover, encapsulation and controlled drug release was demonstrated with this system using the chemotherapeutic drug doxorubicin (DOX). This triple stimuli-responsive DHBC micelle system represents an evolution over conventional double stimuli-responsive covalent diblock copolymer systems and displayed a significant reduction in the viability of HeLa cells upon triggered release of DOX from the supramolecular micellar nanocontainers. 相似文献
503.
George S Behl P DeGuzman R Lee M Rusyniak S Hotta Y Hiratsuka K Takase H Hasenkampf C 《Chromosoma》2002,111(2):96-105
We examined the distribution of meiotic epitopes for the Dmc1 protein of lilies in a normal diploid, a triploid, and in a diploid species-hybrid. The triploid has an extra chromosome set; all three sets align, but only two of the three axes intimately pair at a given location. Our findings with the triploid support the idea that retention of the foci until the pachytene stage requires a successful homology check and synaptonemal complex (SC) initiation; the number of foci in the triploid diminishes by approximately 30% from early zygotene to pachytene, and the triploid pachytene values are similar to the pachytene values of the diploid. The species-hybrid lacks chromosome homology, has reduced SC formation and few reciprocal genetic exchanges. In this species-hybrid the number of foci at early zygotene is similar to that in the normal diploid but is dramatically reduced by mid-zygotene. The extent to which the number of Dmc1 foci is reduced is similar to the extent that SC formation is reduced. In contrast the extent of the reduction in reciprocal genetic exchange in the species-hybrid is much greater than the reduction in the number of foci. We conclude that Dmc1 protein is involved in homology checking, but the impact of failure to find homology affects SC formation and reciprocal genetic exchange differentially. 相似文献
504.
Structure and specificity of the vertebrate anti-mutator uracil-DNA glycosylase SMUG1 总被引:1,自引:0,他引:1
Cytosine deamination is a major promutagenic process, generating G:U mismatches that can cause transition mutations if not repaired. Uracil is also introduced into DNA via nonmutagenic incorporation of dUTP during replication. In bacteria, uracil is excised by uracil-DNA glycosylases (UDG) related to E. coli UNG, and UNG homologs are found in mammals and viruses. Ung knockout mice display no increase in mutation frequency due to a second UDG activity, SMUG1, which is specialized for antimutational uracil excision in mammalian cells. Remarkably, SMUG1 also excises the oxidation-damage product 5-hydroxymethyluracil (HmU), but like UNG is inactive against thymine (5-methyluracil), a chemical substructure of HmU. We have solved the crystal structure of SMUG1 complexed with DNA and base-excision products. This structure indicates a more invasive interaction with dsDNA than observed with other UDGs and reveals an elegant water displacement/replacement mechanism that allows SMUG1 to exclude thymine from its active site while accepting HmU. 相似文献
505.
There is now considerable knowledge concerning neuron death following necrotic insults, and it is believed that the generation of reactive oxygen species (ROS) and oxidative damage play a pivotal role in the neuron death. Prompted by this, we have generated herpes simplex virus-1 amplicon vectors over-expressing the genes for the antioxidant enzymes catalase (CAT) or glutathione peroxidase (GPX), both of which catalyze the degradation of hydrogen peroxide. Over-expression of each of these genes in primary hippocampal or cortical cultures resulted in increased enzymatic activity of the cognate protein. Moreover, each enzyme potently decreased the neurotoxicity induced by kainic acid, glutamate, sodium cyanide and oxygen/glucose deprivation. Finally, these protective effects were accompanied by parallel decreases in hydrogen peroxide accumulation and the extent of lipid peroxidation. These studies not only underline the key role played by ROS in the neurotoxicity of necrotic insults, but also suggest potential gene therapy approaches. 相似文献
506.
W Jonathan Ryves Rana Dajani Laurence Pearl Adrian J Harwood 《Biochemical and biophysical research communications》2002,290(3):967-972
Lithium inhibits (Li(+)) glycogen synthase kinase-3 (GSK-3) by competition for magnesium (Mg(2+)), but not ATP or substrate. Here, we show that the group II metal ion beryllium (Be(2+)) is a potent inhibitor of GSK-3 and competes for both Mg(2+) and ATP. Be(2+) also inhibits the related protein kinase cdc2 at similar potency, but not MAP kinase 2. To compare the actions of Li(+) and Be(2+) on GSK-3, we have devised a novel dual inhibition analysis. When Be(2+) and ADP are present together each interferes with the action of the other, indicating that both agents inhibit GSK-3 at the ATP binding site. In contrast, Li(+) exerts no interference with ADP inhibition or vice versa. We find, however, that Li(+) and Be(2+) do interfere with each other. These results suggest that Be(2+) competes for two distinct Mg(2+) binding sites: one is Li(+)-sensitive and the other, which is Li(+)-insensitive, binds the Mg:ATP complex. 相似文献
507.
508.
Panaretou B Siligardi G Meyer P Maloney A Sullivan JK Singh S Millson SH Clarke PA Naaby-Hansen S Stein R Cramer R Mollapour M Workman P Piper PW Pearl LH Prodromou C 《Molecular cell》2002,10(6):1307-1318
Client protein activation by Hsp90 involves a plethora of cochaperones whose roles are poorly defined. A ubiquitous family of stress-regulated proteins have been identified (Aha1, activator of Hsp90 ATPase) that bind directly to Hsp90 and are required for the in vivo Hsp90-dependent activation of clients such as v-Src, implicating them as cochaperones of the Hsp90 system. In vitro, Aha1 and its shorter homolog, Hch1, stimulate the inherent ATPase activity of yeast and human Hsp90. The identification of these Hsp90 cochaperone activators adds to the complex roles of cochaperones in regulating the ATPase-coupled conformational changes of the Hsp90 chaperone cycle. 相似文献
509.
Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2 总被引:3,自引:1,他引:2 下载免费PDF全文
Poly(ADP-ribose) polymerase-1 (PARP-1) has become an important pharmacological target in the treatment of cancer due to its cellular role as a ‘DNA-strand break sensor’, which leads in part to resistance to some existing chemo- and radiological treatments. Inhibitors have now been developed which prevent PARP-1 from synthesizing poly(ADP-ribose) in response to DNA-breaks and potentiate the cytotoxicity of DNA damaging agents. However, with the recent discoveries of PARP-2, which has a similar DNA-damage dependent catalytic activity, and additional members containing the ‘PARP catalytic’ signature, the isoform selectivity and resultant pharmacological effects of existing inhibitors are brought into question. We present here the crystal structure of the catalytic fragment of murine PARP-2, at 2.8 Å resolution, and compare this to the catalytic fragment of PARP-1, with an emphasis on providing a possible framework for rational drug design in order to develop future isoform-specific inhibitors. 相似文献