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151.
Myriaporones are naturally occurring compounds which structurally resemble the southern hemisphere of the tedanolide family of macrolide antitumor agents. Despite the fact that myriaporone 3/4 represents only a portion of tedanolide, it nonetheless retains much of its biological activity. We show here that like tedanolide, myriaporone 3/4 inhibits protein synthesis and proliferation of mammalian cells with low nanomolar potencies but displays no prokaryotic growth inhibitory effect. Moreover, myriaporone 3/4 displays a very rapid, reversible and p21-independent activity to block S phase progression in mammalian cells. Structure-activity relationship studies revealed that the C18-C19 epoxide and the C14 hydroxymethyl group (tedanolide numbering) of myriaporone 3/4 are required for cell cycle inhibition. These constitute previously unidentified and/or novel pharmacophores for myriaporone 3/4. Our results show that the important biological activities associated with the structurally complex tedanolides are present and can be harnessed in the chemically much simpler myriaporones. This greatly increases the value of the latter as investigative tools for biochemical research as well as for development of potential therapeutics. 相似文献
152.
Korolyov A Dorbes S Azéma J Guidetti B Danel M Lamoral-Theys D Gras T Dubois J Kiss R Martino R Malet-Martino M 《Bioorganic & medicinal chemistry》2010,18(24):8537-8548
A convenient route for the synthesis of some acyloxymethyl esters and carboxamides of levofloxacin (LV) with modulated lipophilicity is described. The synthesized compounds were evaluated in vitro for their growth inhibitory effect in five human cancer cell lines. The most efficient LV derivatives (ester 2e and amide 4d) displayed IC(50) values in the 0.2-2.2 μM range, while IC(50) values for parent LV ranged between 70 and 622 μM depending on the cell line. The esters displayed no in vivo toxicity up to 80 mg/kg when administered intraperitoneally. This study thus shows that LV analogs displayed antitumor efficacy, at least in vitro, a feature that appeared to be independent from the lipophilicity of the grafted substituent. 相似文献
153.
Molecular markers belonging to the three different genomes, mitochondrial (cox2‐cox3 spacer), plastid (rbcL), and nuclear (internal transcribed spacer [ITS] 2 region), were used to compare samples of the two morphologically related species Gracilaria gracilis (Stackh.) Steentoft, L. M. Irvine et Farnham and G. dura (C. Agardh) J. Agardh collected along Atlantic coasts. In northern Europe, the distinction between these two species is ambiguous, and they are currently recognized under the single name of G. gracilis. The low but congruent patterns of genetic divergence observed for markers of the three genomic compartments highly suggest that these two taxa correspond effectively to two different genetic entities as previously described 200 years ago, based on morphological traits. However, thanks to the combination of different DNA markers, occurrence of “incongruent” cytotypes (i.e., mitotypes of G. dura associated with chlorotypes of G. gracilis) in individuals collected from Brittany, suggests interspecific hybridization between the two sibling species studied. 相似文献
154.
Myriam Lazard Sylvain Blanquet Paola Fisicaro Guillaume Labarraque Pierre Plateau 《The Journal of biological chemistry》2010,285(42):32029-32037
Although the general cytotoxicity of selenite is well established, the mechanism by which this compound crosses cellular membranes is still unknown. Here, we show that in Saccharomyces cerevisiae, the transport system used opportunistically by selenite depends on the phosphate concentration in the growth medium. Both the high and low affinity phosphate transporters are involved in selenite uptake. When cells are grown at low Pi concentrations, the high affinity phosphate transporter Pho84p is the major contributor to selenite uptake. When phosphate is abundant, selenite is internalized through the low affinity Pi transporters (Pho87p, Pho90p, and Pho91p). Accordingly, inactivation of the high affinity phosphate transporter Pho84p results in increased resistance to selenite and reduced uptake in low Pi medium, whereas deletion of SPL2, a negative regulator of low affinity phosphate uptake, results in exacerbated sensitivity to selenite. Measurements of the kinetic parameters for selenite and phosphate uptake demonstrate that there is a competition between phosphate and selenite ions for both Pi transport systems. In addition, our results indicate that Pho84p is very selective for phosphate as compared with selenite, whereas the low affinity transporters discriminate less efficiently between the two ions. The properties of phosphate and selenite transport enable us to propose an explanation to the paradoxical increase of selenite toxicity when phosphate concentration in the growth medium is raised above 1 mm. 相似文献
155.
Prunetti L Infossi P Brugna M Ebel C Giudici-Orticoni MT Guiral M 《The Journal of biological chemistry》2010,285(53):41815-41826
Aquifex aeolicus, a hyperthermophilic and microaerophilic bacterium, obtains energy for growth from inorganic compounds alone. It was previously proposed that one of the respiratory pathways in this organism consists of the electron transfer from hydrogen sulfide (H(2)S) to molecular oxygen. H(2)S is oxidized by the sulfide quinone reductase, a membrane-bound flavoenzyme, which reduces the quinone pool. We have purified and characterized a novel membrane-bound multienzyme supercomplex that brings together all the molecular components involved in this bioenergetic chain. Our results indicate that this purified structure consists of one dimeric bc(1) complex (complex III), one cytochrome c oxidase (complex IV), and one or two sulfide quinone reductases as well as traces of the monoheme cytochrome c(555) and quinone molecules. In addition, this work strongly suggests that the cytochrome c oxidase in the supercomplex is a ba(3)-type enzyme. The supercomplex has a molecular mass of about 350 kDa and is enzymatically functional, reducing O(2) in the presence of the electron donor, H(2)S. This is the first demonstration of the existence of such a respirasome carrying a sulfide oxidase-oxygen reductase activity. Moreover, the kinetic properties of the sulfide quinone reductase change slightly when integrated in the supercomplex, compared with the free enzyme. We previously purified a complete respirasome involved in hydrogen oxidation and sulfur reduction from Aquifex aeolicus. Thus, two different bioenergetic pathways (sulfur reduction and sulfur oxidation) are organized in this bacterium as supramolecular structures in the membrane. A model for the energetic sulfur metabolism of Aquifex aeolicus is proposed. 相似文献
156.
Microarray technology provides a powerful tool for the expression profile of thousands of genes simultaneously, which makes it possible to explore the molecular and metabolic etiology of the development of a complex disease under study. However, classical statistical methods and technologies fail to be applicable to microarray data. Therefore, it is necessary and motivating to develop powerful methods for large-scale statistical analyses. In this paper, we described a novel method, called Ranking Analysis of Microarray Data (RAM). RAM, which is a large-scale two-sample t-test method, is based on comparisons between a set of ranked T statistics and a set of ranked Z values (a set of ranked estimated null scores) yielded by a "randomly splitting" approach instead of a "permutation" approach and a two-simulation strategy for estimating the proportion of genes identified by chance, i.e., the false discovery rate (FDR). The results obtained from the simulated and observed microarray data show that RAM is more efficient in identification of genes differentially expressed and estimation of FDR under undesirable conditions such as a large fudge factor, small sample size, or mixture distribution of noises than Significance Analysis of Microarrays. 相似文献
157.
Manesh R Hoffmann ML Stricker EM 《American journal of physiology. Regulatory, integrative and comparative physiology》2006,290(6):R1742-R1749
After surgical removal of all salivary secretions ("desalivation"), rats increase their consumption of water while eating dry laboratory chow. In the present experiments, desalivated rats drank even more water while they ate "powdered" high-salt food (i.e., <15-mg food particles). The Na+ concentration of systemic plasma in these animals was not elevated during or immediately after the meal, which suggests that cerebral osmoreceptors were not involved in mediating the increased water intake. A presystemic osmoregulatory signal likely stimulated thirst because the Na+ and water contents of the gastric chyme computed to a solution approximately 150 mM NaCl. In contrast, desalivated rats drank much smaller volumes of water while eating "pulverized" high-salt food (i.e., 60-140-mg food particles), and the fluid mixture in the gastric chyme computed to approximately 280 mM NaCl solution. These and other findings suggest that the NaCl ingested in the powdered high-salt diet was dissolved in the gastric fluid and that duodenal osmoreceptors (or Na+-receptors) detected when the concentration of fluid leaving the stomach was elevated after each feeding bout, and promptly stimulated thirst, whereupon rats drank water until the gastric fluid was diluted back to isotonicity. However, when rats ate the pulverized high-salt diet, much of the NaCl ingested may have been embedded in the gastric chyme and therefore was not accessible to visceral osmoreceptors once it emptied from the stomach. Consistent with that hypothesis, fluid intakes were increased considerably when desalivated rats drank 0.10 M NaCl instead of water while eating either powdered or pulverized high-salt food. 相似文献
158.
Granier C Aguirrezabal L Chenu K Cookson SJ Dauzat M Hamard P Thioux JJ Rolland G Bouchier-Combaud S Lebaudy A Muller B Simonneau T Tardieu F 《The New phytologist》2006,169(3):623-635
The high-throughput phenotypic analysis of Arabidopsis thaliana collections requires methodological progress and automation. Methods to impose stable and reproducible soil water deficits are presented and were used to analyse plant responses to water stress. Several potential complications and methodological difficulties were identified, including the spatial and temporal variability of micrometeorological conditions within a growth chamber, the difference in soil water depletion rates between accessions and the differences in developmental stage of accessions the same time after sowing. Solutions were found. Nine accessions were grown in four experiments in a rigorously controlled growth-chamber equipped with an automated system to control soil water content and take pictures of individual plants. One accession, An1, was unaffected by water deficit in terms of leaf number, leaf area, root growth and transpiration rate per unit leaf area. Methods developed here will help identify quantitative trait loci and genes involved in plant tolerance to water deficit. 相似文献
159.
Oocytes were recovered by ovum pick up (OPU) from nine pairs of monozygotic twin German Simmental cows. The hypothesis was that there is less variability between identical twins versus among non-related individuals in the variation in the recovery of oocytes by OPU and in the efficiency of in vitro embryo production. Estrous cycles were synchronized with two doses of cloprostenol, 11 days apart. Beginning 3-4 days after synchronized estrus, OPU was done twice weekly (every 3 or 4 days; total of 11 sessions). The influence of repeated OPU on estrous cyclicity was established by estrus detection, plasma progesterone concentrations, and ovarian ultrasonography. There were no differences among days of collection for the number and quality of cumulus oocyte-complexes (COCs), and rates of cleavage and blastocyst formation. A total of 1,661 COCs, including 657 (39.6%) good-quality COCs, were recovered. From 1,457 (87.7%) cultured COCs, 827 zygotes cleaved and 314 blastocysts were produced on Day 7. The total number of COCs and the blastocyst rates varied among pairs of monozygotic twins; within pairs, only slight differences were observed. In conclusion, recovery of COCs and production of embryos had substantially less variation within pairs of monozygotic twins than among non-related cattle. 相似文献
160.
Aguirrezabal L Bouchier-Combaud S Radziejwoski A Dauzat M Cookson SJ Granier C 《Plant, cell & environment》2006,29(12):2216-2227
Genetic variability in the plasticity of leaf area expansion in response to water deficit has been reported in Arabidopsis thaliana. Here, the objective was to identify the underlying dynamic and cellular processes involved in this variability. Twenty-five accessions were subjected to identical soil water deficit treatments. In all accessions, the plasticity of leaf production was low compared with that of individual leaf expansion. A subset of accessions was selected for further dissection of individual leaf expansion into its underlying variables: the rate and duration of leaf expansion and epidermal cell number and area. In all accessions, water deficit had opposite effects on the rate and duration of leaf expansion. The accumulation of these effects was reflected in changes in final leaf area. At the cellular level, moderate water deficits had opposite effects on cell number and cell size, but more severe ones reduced both variables. The importance of these opposing effects is highlighted by the behaviour of the accession An-1, for which the compensation between the decrease in leaf expansion rate and the increase in the duration of expansion is total. This dynamic plasticity in response to water deficit is not detectable when only final measurements are done. 相似文献