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91.
92.
《Bioorganic & medicinal chemistry》2016,24(9):2097-2107
The drug resistance of CENUs induced by O6-alkylguanine-DNA alkyltransferase (AGT), which repairs the O6-alkylated guanine and subsequently inhibits the formation of dG–dC cross-links, hinders the application of CENU chemotherapies. Therefore, the discovery of CENU analogs with AGT inhibiting activity is a promising approach leading to novel CENU chemotherapies with high therapeutic index. In this study, a new combi-nitrosourea prodrug 3-(3-(((2-amino-9H-purin-6-yl)oxy)methyl)benzyl)-1-(2-chloroethyl)-1-nitrosourea (6), designed to release a DNA cross-linking agent and an inhibitor of AGT, was synthesized and evaluated for its antitumor activity and ability to induce DNA interstrand cross-links (ICLs). The results indicated that 6 exhibited higher cytotoxicity against mer+ glioma cells compared with ACNU, BCNU, and their respective combinations with O6-benzylguanine (O6-BG). Quantifications of dG–dC cross-links induced by 6 were performed using HPLC–ESI-MS/MS. Higher levels of dG–dC cross-link were observed in 6-treated human glioma SF763 cells (mer+), whereas lower levels of dG–dC cross-link were observed in 6-treated calf thymus DNA, when compared with the groups treated with BCNU and ACNU. The results suggested that the superiority of 6 might result from the AGT inhibitory moiety, which specifically functions in cells with AGT activity. Molecular docking studies indicated that five hydrogen bonds were formed between the O6-BG analogs released from 6 and the five residues in the active pocket of AGT, which provided a reasonable explanation for the higher AGT-inhibitory activity of 6 than O6-BG. 相似文献
93.
Salmonella enterica serovar Typhimurium is a Gram-negative bacterium that has a significant impact on both human and animal health. It is one of the most common food-borne pathogens responsible for a self-limiting gastroenteritis in humans and a similar disease in pigs, cattle and chickens. In contrast, intravenous challenge with S. Typhimurium provides a valuable model for systemic infection, often causing a typhoid-like infection, with bacterial replication resulting in the destruction of the spleen and liver of infected animals. Resistance to systemic salmonellosis in chickens is partly genetically determined, with bacterial numbers at systemic sites in resistant lines being up to 1000-fold fewer than in susceptible lines. Identification of genes contributing to disease resistance will enable genetic selection of resistant lines that will reduce Salmonella levels in poultry flocks. We previously identified a novel resistance locus on Chromosome 5, designated SAL1 . Through the availability of high-density SNP panels in the chicken, combined with advanced back-crossing of the resistant and susceptible lines, we sought to refine the SAL1 locus and identify potential positional candidate genes. Using a 6th generation backcross mapping population, we have confirmed and refined the SAL1 locus as lying between 54.0 and 54.8 Mb on the long arm of Chromosome 5 ( F = 8.72, P = 0.00475). This region spans 14 genes, including two very striking functional candidates; CD27-binding protein ( Siva ) and the RAC -alpha serine/threonine protein kinase homolog , AKT1 ( protein kinase B , PKB ). 相似文献
94.
Kirk A. Stowe 《Evolution; international journal of organic evolution》1998,52(3):703-712
The evolutionary response of plant populations to selection for increased defense may be constrained by costs of defense. The purpose of this study was to investigate such constraints on the evolution of defense due to a cost of defense manifested as a trade-off between defense and tolerance. Variation in the response to artificial damage (tolerance) among lines of Brassica rapa that had been artificially selected for foliar glucosinolate content (defense) was examined. Leaf area was removed from replicates of three selection lines (high glucosinolates, control, and low glucosinolates) at three damage levels (0%, 20%, and 60% damage). An external cost of defense would result in a statistically significant selection line by damage treatment interaction, with those selected for high defense expressing less tolerance than those selected for low defense. Damage treatment had a significant overall effect on estimated total fitness, with fitness declining with increasing damage level. Further, selection line also had a significant overall effect on estimated total fitness, with low-defense selection lines having higher fitness compared to both control and high-defense selection lines. More importantly, a cost of defense in terms of tolerance was demonstrated by a significant selection line-by-damage treatment interaction. This interaction was in the direction to demonstrate a genetic trade-off between defense and tolerance, with low-defense selection lines decreasing estimated total fitness in response to damage less than both control and high-defense selection lines. Variation in tolerance among selection lines was due to the greater ability of low-defense lines to maintain fruit and seed production despite the presence of damage. In terms of tolerance, this cost of glucosinolate production in B. rapa could constrain the evolution of increased defense and, in so doing, maintain individuals within the population that are poorly defended yet tolerant. 相似文献
95.
96.
97.
《Bioorganic & medicinal chemistry letters》2014,24(4):1031-1036
We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1–3, having the 3-arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure–activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner. 相似文献
98.
T. Miedaner F. J. Fromme H. H. Geiger 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》1995,91(6-7):862-868
The amount of genetic variation for resistance to foot rot caused by Pseudocercosporella herpotrichoides, Fusarium spp., and Microdochium nivale and for resistance to head blight caused by Fusarium culmorum are important parameters when estimating selection gain from recurrent selection in winter rye. One-hundred and eighty-six full-sib families of the selfincompatible population variety Halo, representing the Petkus gene pool, were tested for foot-rot resistance at five German location-year combinations (environments) and for head-blight resistance in three environments with artificial inoculation in all but one environment. Foot-rot rating was based on 25 stems per plot scored individually on a 1–9 scale. Head-blight resistance was plotwise scored on a 1–9 scale and, additionally, grain-weight per spike was measured relative to the non-inoculated control plots. Significant estimates of genotypic variance and medium-sized heritabilities (h
2=0.51–0.69) were observed in the combined analyses for all resistance traits. In four out of five environments, the amount of genetic variance was substantially smaller for foot-rot than for head-blight rating. Considerable environmental effects and significant genotype-environment interactions were found for both foot-rot and head-blight resistance. Coefficients of error-corrected correlation among environments were considerably closer than phenotypic correlations. No significant association was found between the resistances to both diseases (r=-0.20 to 0.17). In conclusion, intra-population improvement by recurrent selection should lead to substantial higher foot-rot and head-blight resistances due to significant quantitative genetic variation within Halo. Selection should be carried out in several environments. Lack of correlation between foot-rot and head-blight resistance requires separate infection tests for improving both resistances. 相似文献
99.
The early intracellular signaling pathway for the insulin/insulin-like growth factor receptor family in the mammalian central nervous system 总被引:8,自引:0,他引:8
Franco Folli Silvana Ghidella Luca Bonfanti C. Ronald Kahn Adalberto Merighi 《Molecular neurobiology》1996,13(2):155-183
Several studies support the idea that the polypeptides belonging to the family of insulin and insulin-like growth factors
(IGFs) play an important role in brain development and continue to be produced in discrete areas of the adult brain. In numerous
neuronal populations within the olfactory bulb, the cerebral and cerebellar cortex, the hippocampus, some diencephalic and
brainstem nuclei, the spinal cord and the retina, specific insulin and IGF receptors, as well as crucial components of the
intracellular receptor signaling pathway have been demonstrated. Thus, mature neurons are endowed with the cellular machinery
to respond to insulin and IGF stimulation. Studies in vitro and in vivo, using normal and transgenic animals, have led to
the hypothesis that, in the adult brain, IGF-I not only acts as a trophic factor, but also as a neuromodulator of some higher
brain functions, such as long-term potentiation and depression. Furthermore, a trophic effect on certain neuronal populations
becomes clearly evident in the ischemic brain or neurodegenerative disorders. Thus, the analysis of the early intracellular
signaling pathway for the insulin/IGF receptor family in the brain is providing us with new intriguing findings on the way
the mammalian brain is sculpted and operates. 相似文献
100.
Trichome-borne and artificially applied acylsugars of wild tomato deter feeding and oviposition of the leafminer Liriomyza trifolii 总被引:1,自引:0,他引:1
D. J. Hawthorne J. A. Shapiro W. M. Tingey M. A. Mutschler 《Entomologia Experimentalis et Applicata》1992,65(1):65-73
Oviposition and adult feeding of the leafminer Liriomyza trifollii (Burgess) (Diptera, Agromyzidae) on Lycopersicon pennellii (Corr.) D'Arcy and its F1 hybrid with Lycopersicon esculentum (Mill.) was significantly less than that on the cultivated tomato, L. esculentum. The resistance of L. pennellii and the F1 was reduced following rinsing of foliage with ethanol. Resistant attributes of L. pennellii were transferred to L. esculentum through appression of L. pennellii foliage to L. esculentum leaflets. Application of purified 2,3,4-tri-O-acylglucoses (the principal component of type IV glandular trichome exudate of L. pennellii) to L. esculentum significantly decreased feeding and oviposition on L. esculentum leaflets by 61–99%. Therefore the principal mechanism of resistance to this leafminer by L. pennellii is the secretion of these acylglucoses. Dose response analysis of acylglucoses applied to L. esculentum shows that dosages as low as 10% those found on L. pennellii provide large reductions (91%) in leaf punctures and mines. 相似文献