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61.
Lounkine E Kutchukian P Petrone P Davies JW Glick M 《Bioorganic & medicinal chemistry》2012,20(18):5416-5427
The increasing amount of chemogenomics data, that is, activity measurements of many compounds across a variety of biological targets, allows for better understanding of pharmacology in a broad biological context. Rather than assessing activity at individual biological targets, today understanding of compound interaction with complex biological systems and molecular pathways is often sought in phenotypic screens. This perspective poses novel challenges to structure-activity relationship (SAR) assessment. Today, the bottleneck of drug discovery lies in the understanding of SAR of rich datasets that go beyond single targets in the context of biological pathways, potential off-targets, and complex selectivity profiles. To aid in the understanding and interpretation of such complex SAR, we introduce Chemotography (chemotype chromatography), which encodes chemical space using a color spectrum by combining clustering and multidimensional scaling. Rich biological data in our approach were visualized using spatial dimensions traditionally reserved for chemical space. This allowed us to analyze SAR in the context of target hierarchies and phylogenetic trees, two-target activity scatter plots, and biological pathways. Chemotography, in combination with the Kyoto Encyclopedia of Genes and Genomes (KEGG), also allowed us to extract pathway-relevant SAR from the ChEMBL database. We identified chemotypes showing polypharmacology and selectivity-conferring scaffolds, even in cases where individual compounds have not been tested against all relevant targets. In addition, we analyzed SAR in ChEMBL across the entire Kinome, going beyond individual compounds. Our method combines the strengths of chemical space visualization for SAR analysis and graphical representation of complex biological data. Chemotography is a new paradigm for chemogenomic data visualization and its versatile applications presented here may allow for improved assessment of SAR in biological context, such as phenotypic assay hit lists. 相似文献
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Allicin inhibits cell growth and induces apoptosis through the mitochondrial pathway in HL60 and U937 cells 总被引:2,自引:0,他引:2
Miron T Wilchek M Sharp A Nakagawa Y Naoi M Nozawa Y Akao Y 《The Journal of nutritional biochemistry》2008,19(8):524-535
In this article, the effects of allicin, a biological active compound of garlic, on HL60 and U937 cell lines were examined. Allicin induced growth inhibition and elicited apoptotic events such as blebbing, mitochondrial membrane depolarization, cytochrome c release into the cytosol, activation of caspase 9 and caspase 3 and DNA fragmentation. Pretreatment of HL60 cells with cyclosporine A, an inhibitor of the mitochondrial permeability transition pore (mPTP), inhibited allicin-treated cell death. HL60 cell survival after 1 h pretreatment with cyclosporine A, followed by 16 h in presence of allicin (5 microM) was approximately 80% compared to allicin treatment alone (approximately 50%). Also N-acetyl cysteine, a reduced glutathione (GSH) precursor, prevented cell death. The effects of cyclosporine A and N-acetyl cysteine suggest the involvement of mPTP and intracellular GSH level in the cytotoxicity. Indeed, allicin depleted GSH in the cytosol and mitochondria, and buthionine sulfoximine, a specific inhibitor of GSH synthesis, significantly augmented allicin-induced apoptosis. In HL60 cells treated with allicin (5 microM, 30 min) the redox state for 2GSH/oxidized glutathione shifted from EGSH -240 to -170 mV. The same shift was observed in U937 cells treated with allicin at a higher concentration for a longer period of incubation (20 microM, 2 h). The apoptotic events induced by various concentrations of allicin correlate to intracellular GSH levels in the two cell types tested (HL60: 3.7 nmol/10(6) cells; U937: 7.7 nmol/10(6) cells). The emerging mechanistic basis for the antiproliferative function of allicin, therefore, involves the activation of the mitochondrial apoptotic pathway by GSH depletion and by changes in the intracellular redox status. 相似文献
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65.
A laboratory culture of an Israeli benthic midge, Chironomus luridus, was exposed to two chemicals: copper and monochloramine. The objective of this study was to determine the protective nature of Chironomus' larval tube. Three experimental conditions were tested: larva with sand tubes, with silt tubes and without tubes. Larvae without tubes were significantly more sensitive to copper and chloramine than larvae that had sand or silt as tube building substrate. The tubes protected the insects against chemicals throughout 14 days of exposure time. Silt tubes had higher protective value than sand tubes, especially when exposed to copper for a short period of time (LC50/ 24 h, with silt, sand, or none: 80.0, 7.0 and 3.4 mg l–1 copper, respectively). C. luridus seemed to be better protected against copper than against chloramine (LC50/ 24 h, with silt, sand, or none: 12.2, 6.4 and 3.7 mg l–1 chloramine, respectively). The acute toxicity of copper to chironomid larvae was investigated using a cytochemical method. Larva in silt tubes had significantly higher non-specific esterase activity in midgut cells than larvae without tubes. We conclude that, in addition to its role in feeding, respiration and anti-predation shelter, the C. luridus tube protects its inhabitant from toxic substances. 相似文献
66.
The role of a spiny plant refuge in structuring grazed shortgrass steppe plant communities 总被引:5,自引:0,他引:5
This study evaluates the hypothesis that biological grazing refuges have an important role in plant-grazer interactions of grasslands with a long history of grazing. We assessed the hypothesis that clumps of the spiny cactus Opuntia polyacantha provide biological refuges from cattle grazing, affecting cover and seedhead production of associated vascular plants in the shortgrass steppe of the North America. The study was based on sampling inside and outside Opuntia clumps in eight long-term moderately grazed pastures established 60 yr ago and their respective ungrazed controls. Opuntia clumps provided a refuge for seedhead production of the dominant grass ( Bouteloua gracilis ) and for cover and seedhead production of many plant groups. Clumps were also a refuge for species sensitive to grazing (species that decrease with grazing) and barrel-cacti, but not for species preferred by cattle (species with greater proportion in the diet than in the field), exotics or weeds. Our results suggest that these effects were mainly through changes in the microenvironmental conditions resulting from protection effects, even though all potential microenvironmental effects could not be measured. Cacti promoted some negative effects on other plant groups, probably due to the space occupied by cladodes inside cactus clumps. The refuge effects observed at the group level did not translate into strong community level effects. Species diversity ( H' ) was greater in cactus clumps due to lower dominance rather than greater richness. The presence of Opuntia clumps increased landscape-scale diversity. This ecological role of Opuntia clumps as refuge from cattle grazing should be taken into consideration in management practices aimed at cactus eradication in order to increase forage availability for livestock. We discuss the potential role of plant community productivity and grazing history with regard to the importance of natural refuges in structuring grassland communities. 相似文献
67.
The mechanism of CNBr activation of polysaccharide resins like Sepharose and Sephadex has been elucidated using recently published analytical procedures for the determination of cyanate esters and imido carbonates. It was found that on agarose-based resins coupling of ligand occurs predominantly via cyanate esters, and not via imidocarbonates as in the case of Sephadex. This explains the different behaviours of Sepharose and Sephadex during CNBr activation. 相似文献
68.
The effect of implanted active corpora allata (CA) on the reproductive diapause in adult females of the grasshopper, Oedipoda miniata, was investigated. Implantation of two pairs of CA originating from sexually mature, adult male Locusta migratoria migratorioides donors effectively terminated reproductive diapause by inducing oöcyte development and intensive egg-laying in O. miniata recipients at any state of the reproductive diapause. The interval elapsing from implantation till oviposition was 15 days when recipients were at the beginning of the reproductive diapause. This interval shortened when recipients were in later stages of the reproductive diapause, thus, closer to its eventual termination. Reproductive diapause in female O. miniata, therefore, seems to be a slow process rather than a steady state. In all instances recipients laid eggs for quite short periods (up to 3 weeks). After cessation of egg-laying resorption of the proximal oöcytes occurred in the ovarioles. The implanted glands presumably became inactive.Implantation of two pairs of CA originating from sexually mature (already in post-diapause state) male O. miniata donors also induced oöcyte development and occasional egg-laying in female recipients which were still in reproductive diapause at the time of implantation. The effect, however, was markedly less intensive than that induced by heterospecific implantation. Practically no oöcyte development was obtained in sham-operated and unoperated controls.
Résumé L'implantation dans des femelles d'Oedipoda miniata en diapause génitale, de 2 paires de corpora allata (CA) prélevés sur des mâles adultes sexuellement mûrs de Locusta migratoria migratorioides, provoque la rupture de cette diapause, quel que soit son état d'évolution, en induisant le développement des ovocytes et une intense activité de ponte. La ponte est déclenchée dans un délai de 15 jours après l'implantation quand l'insecte receveur est en début de diapause génitale. Ce délai est plus court quand la diapause est déjà avancée, donc quand la greffe intervient à un moment plus proche de son achèvement normal. Par conséquent la diapause génitale chez la femelle d'Oedipoda miniata semble être un processus à évolution lente, plutôt qu'un état stable.Dans tous les cas les insectes ayant reçu un implant de CA pondent pendant une courte période (jusqu'à 3 semaines). Quand cesse la ponte la résorption des ovocytes proximaux survient dans les ovarioles; sans doute les glandes implantées sont devenues inactives.L'implantation de 2 paires de CA provenant de mâles d'Oedipoda miniata sexuellement mûrs (déjà dans un état de post-diapause) induit également le développement des ovocytes et occasionnellement la ponte chez des femelles en diapause génitale, mais l'effet est cependant nettement moins intense que celui induit par une greffe hétérospécifique. Pratiquement on n'observe aucun développement d'ovocytes chez les insectes témoins non-opérés ou ayant subi une pseudo-greffe.相似文献
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70.