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21.
Misagh Alipour Zacharias E. Suntres Majed Halwani Ali O. Azghani Abdelwahab Omri 《PloS one》2009,4(5)
Background
To compare the effectiveness of liposomal tobramycin or polymyxin B against Pseudomonas aeruginosa in the Cystic Fibrosis (CF) sputum and its inhibition by common polyanionic components such as DNA, F-actin, lipopolysaccharides (LPS), and lipoteichoic acid (LTA).Methodology
Liposomal formulations were prepared from a mixture of 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC) or 1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC) and Cholesterol (Chol), respectively. Stability of the formulations in different biological milieus and antibacterial activities compared to conventional forms in the presence of the aforementioned inhibitory factors or CF sputum were evaluated.Results
The formulations were stable in all conditions tested with no significant differences compared to the controls. Inhibition of antibiotic formulations by DNA/F-actin and LPS/LTA was concentration dependent. DNA/F-actin (125 to 1000 mg/L) and LPS/LTA (1 to 1000 mg/L) inhibited conventional tobramycin bioactivity, whereas, liposome-entrapped tobramycin was inhibited at higher concentrations - DNA/F-actin (500 to 1000 mg/L) and LPS/LTA (100 to 1000 mg/L). Neither polymyxin B formulation was inactivated by DNA/F-actin, but LPS/LTA (1 to 1000 mg/L) inhibited the drug in conventional form completely and higher concentrations of the inhibitors (100 to 1000 mg/L) was required to inhibit the liposome-entrapped polymyxin B. Co-incubation with inhibitory factors (1000 mg/L) increased conventional (16-fold) and liposomal (4-fold) tobramycin minimum bactericidal concentrations (MBCs), while both polymyxin B formulations were inhibited 64-fold.Conclusions
Liposome-entrapment reduced antibiotic inhibition up to 100-fold and the CFU of endogenous P. aeruginosa in sputum by 4-fold compared to the conventional antibiotic, suggesting their potential applications in CF lung infections. 相似文献22.
Iris Alchanati Carmit Teicher Galit Cohen Vivian Shemesh Haim M. Barr Philippe Nakache Danny Ben-Avraham Anna Idelevich Itzchak Angel Nurit Livnah Shmuel Tuvia Yuval Reiss Daniel Taglicht Omri Erez 《PloS one》2009,4(12)
Background
The topoisomerases Top1, Top2α and Top2β are important molecular targets for antitumor drugs, which specifically poison Top1 or Top2 isomers. While it was previously demonstrated that poisoned Top1 and Top2β are subject to proteasomal degradation, this phenomena was not demonstrated for Top2α.Methodology/Principal Findings
We show here that Top2α is subject to drug induced proteasomal degradation as well, although at a lower rate than Top2β. Using an siRNA screen we identified Bmi1 and Ring1A as subunits of an E3 ubiquitin ligase involved in this process. We show that silencing of Bmi1 inhibits drug-induced Top2α degradation, increases the persistence of Top2α-DNA cleavage complex, and increases Top2 drug efficacy. The Bmi1/Ring1A ligase ubiquitinates Top2α in-vitro and cellular overexpression of Bmi1 increases drug induced Top2α ubiquitination. A small-molecular weight compound, identified in a screen for inhibitors of Bmi1/Ring1A ubiquitination activity, also prevents Top2α ubiquitination and drug-induced Top2α degradation. This ubiquitination inhibitor increases the efficacy of topoisomerase 2 poisons in a synergistic manner.Conclusions/Significance
The discovery that poisoned Top2α is undergoing proteasomal degradation combined with the involvement of Bmi1/Ring1A, allowed us to identify a small molecule that inhibits the degradation process. The Bmi1/Ring1A inhibitor sensitizes cells to Top2 drugs, suggesting that this type of drug combination will have a beneficial therapeutic outcome. As Bmi1 is also a known oncogene, elevated in numerous types of cancer, the identified Bmi1/Ring1A ubiquitin ligase inhibitors can also be potentially used to directly target the oncogenic properties of Bmi1. 相似文献23.
Widiez T Hartman TG Dudai N Yan Q Lawton M Havkin-Frenkel D Belanger FC 《Plant molecular biology》2011,76(6):475-488
Caffeoyl CoA O-methyltransferases (OMTs) have been characterized from numerous plant species and have been demonstrated to be involved in
lignin biosynthesis. Higher plant species are known to have additional caffeoyl CoA OMT-like genes, which have not been well
characterized. Here, we identified two new caffeoyl CoA OMT-like genes by screening a cDNA library from specialized hair cells
of pods of the orchid Vanilla planifolia. Characterization of the corresponding two enzymes, designated Vp-OMT4 and Vp-OMT5, revealed that in vitro both enzymes preferred
as a substrate the flavone tricetin, yet their sequences and phylogenetic relationships to other enzymes are distinct from
each other. Quantitative analysis of gene expression indicated a dramatic tissue-specific expression pattern for Vp-OMT4, which was highly expressed in the hair cells of the developing pod, the likely location of vanillin biosynthesis. Although
Vp-OMT4 had a lower activity with the proposed vanillin precursor, 3,4-dihydroxybenzaldehyde, than with tricetin, the tissue
specificity of expression suggests it may be a candidate for an enzyme involved in vanillin biosynthesis. In contrast, the
Vp-OMT5 gene was mainly expressed in leaf tissue and only marginally expressed in pod hair cells. Phylogenetic analysis suggests
Vp-OMT5 evolved from a cyanobacterial enzyme and it clustered within a clade in which the sequences from eukaryotic species
had predicted chloroplast transit peptides. Transient expression of a GFP-fusion in tobacco demonstrated that Vp-OMT5 was
localized in the plastids. This is the first flavonoid OMT demonstrated to be targeted to the plastids. 相似文献
24.
Enantioselectivity of the Bioconversion of Chiral Citronellal during the Inhibition of Wheat Seeds Germination
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Citronellal is one of the most prominent monoterpenes present in many essential oils. Low persistence of essential oils as bioherbicides has often been addressed because of the high volatility of these compounds. Bioconversion of citronellal by wheat seeds releases less aggressive and injurious compounds as demonstrated by their diminished germination. We demonstrated that optically pure citronellal enantiomers were reduced to optically pure citronellol enantiomers with retention of the configuration both in isolated wheat embryos and endosperms. Our findings reveal the potential of essential oils as allelopathic agents providing an insight into their mechanism of action and persistence. 相似文献
25.
Summary The influence of nerve growth factor (NGF) on Na currents of rat dorsal root ganglia (DRG) was studied in neurons obtained from newborns and cultured for 2–30 hr inserum-free defined medium (SFM). Cell survival for the period studied was 78–87% both with and without NGF. Na currents were detected in all cells cultured for 6–9 hr. They were also detected after 2 hr in culture in 21.5% of the cells cultured without NGF (–NGF cells), and in 91.5% of the cells cultured with NGF (+NGF cells). Current density of the -NGF cells was 2.3 and 2 pA/m2 after growth for 2 and 6–9 hr, respectively, compared to 3.0 and 3.9 pA/m2 for the +NGF cells. The +NGF cells were separated into fast (F), Intermediate (I) and slow (S) cells, based on the Na current they expressed, while -NGF cells were all of theI type.F, I andS currents differed in their voltage-dependent inactivation (Vh
50=–79, –28 and –20 mV), kinetics of inactivation (tau
h
=0.55, 1.3 and 7.75 msec), and TTX sensitivity (K
i=60, 550 and 1100nm). All currents were depressed by [Ca]
o
with aKd
Ca of 22, 17 and 8mm forF, I andS currents, respectively. Current density ofF andS currents was 5.5 and 5 pA/m2 for theI current. The concentration-dependent curve ofI currentvs. TTX indicated thatI current has two sites: one withF-like and another withS-likeK
i for TTX. Hybridization ofF andS currents yieldI-like currents. Thus, the major effect of NGF on Na currents in SFM is the accleration of Na current acquisition and diversity, reflected in an increase of either theS orF type in a cell. 相似文献
26.
Peroxidase and catalase activity in leaves of Halimione portulacoides exposed to salinity 总被引:1,自引:0,他引:1
The effect of high NaCl concentrations on the activity of catalase (EC 1.11.1.6), peroxidase (EC 1.11.1.7) and malate dehydrogenase (NAD+ -linked; EC 1.1.1.37) from leaves of Halimione portulacoides (L.) Aellen was studied. The plants were exposed to high salinity during growth and enzyme activity was measured either in the absence or in the presence of various concentrations of NaCl. Increasing salinity in vitro induced three types of effects: (1) an increase in activity (peroxidase); (2) a decrease in activity (catalase); (3) stimulation by low salt concentration but inhibition by higher concentrations (malate dehydrogenase). Salinity in vivo induced a marked decrease in catalase and malate dehydrogenase activities. However, peroxidase in vivo showed an optimum curve of activity vs external NaCl concentration, with an optimum at ca 1 M NaCl. Exposure of plants to salinity induced changes in the properties of the enzyme proteins: they precipitated at a higher (NH4 )2 SO4 concentration, were eluted later during Sephadex G-200 filtration, and showed a shift in the maximal, minimal and optimal temperatures. These data are interpreted as evidence for conformational changes in the enzymes due to prolonged exposure to high salinity stress; such changes could be disruption into monomers (catalase and malate dehydrogenase), or changes in molecular shape (in the peroxidase). 相似文献
27.
B Omri M F Breton B Haye C Jacquemin M Pavlovic-Hournac 《European journal of biochemistry》1988,175(1):125-133
The potent tumor promoter 12-O-tetradecanoyl-phorbol 13-acetate (TPA) affects several thyroid cell functions and interacts with thyroid-stimulating hormone (TSH) either by inhibiting or potentiating its action on different cellular parameters. Since phorbol ester acts mainly through the activation of protein kinase C, which is its receptor, we studied this activation and its interaction with TSH and forskolin in suspension cultures of porcine thyroid cells. In thyroid cell cultures, TPA has a dual effect on protein kinase C activity: immediately (2-5 min) after exposure of cells to TPA, it began to be translocated from the cytosol to the particulate fraction. The transfer of the cytosolic enzyme was total and could occur with or without a loss of activity. The translocated enzyme still needed Ca2+ and phospholipids for its activation. The basal activity increased transiently (2-4 h) in both the cytosol and particulate fractions during translocation. The peak activity in the particulate fraction was reached 10-30 min after exposure of cells to TPA, and was followed by down-regulation of protein kinase C and almost complete disappearance of its activity. The residual activity was about 13% of control after a 2-day exposure to TPA. It was unequally distributed between cytosol (4%) and particulate fraction (9%). Prolonged exposure of cells to TPA did not affect either the activity or the subcellular distribution of the cAMP-dependent protein kinase activity. TPA interacted with TSH and prevented the decrease of this activity induced by prolonged exposure of cells to the hormone not only when it was introduced simultaneously with TSH, but also when it was added 24 h after TSH. However, the forskolin-induced decrease in cAMP-dependent protein kinase activity was not prevented by the presence of TPA. TPA also affected the increases in cAMP accumulation mediated by TSH and forskolin. The TSH-induced increase was significantly stimulated by TPA after short contacts (5-15 min), while longer preincubations of cells with TPA provoked a very strong inhibition of the TSH action. However, the forskolin-induced stimulation of the cAMP accumulation was maintained and even further increased in the presence of TPA. Consequently, the actions of TSH and TPA are apparently interdependent, while those of forskolin and TPA seem to be parallel and independent. Neither TSH nor forskolin prevented the TPA-induced down regulation of protein kinase C. The biologically inactive phorbol ester analogue 4 alpha-phorbol 12,13-didecanoate had no effect on protein kinase C activity, and did not interact with either TSH or forskolin.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
28.
Persistent activity states (attractors), observed in several neocortical areas after the removal of a sensory stimulus, are believed to be the neuronal basis of working memory. One of the possible mechanisms that can underlie persistent activity is recurrent excitation mediated by intracortical synaptic connections. A recent experimental study revealed that connections between pyramidal cells in prefrontal cortex exhibit various degrees of synaptic depression and facilitation. Here we analyze the effect of synaptic dynamics on the emergence and persistence of attractor states in interconnected neural networks. We show that different combinations of synaptic depression and facilitation result in qualitatively different network dynamics with respect to the emergence of the attractor states. This analysis raises the possibility that the framework of attractor neural networks can be extended to represent time-dependent stimuli. 相似文献
29.
A comparative evaluation of presence-only methods for modelling species distribution 总被引:2,自引:0,他引:2
Asaf Tsoar Omri Allouche Ofer Steinitz Dotan Rotem Ronen Kadmon 《Diversity & distributions》2007,13(4):397-405
In spite of increasing application of presence-only models in ecology and conservation and the growing number of such models, little is known about the relative performance of different modelling methods, and some of the leading models (e.g. GARP and ENFA) have never been compared with one another. Here we compare the performance of six presence-only models that have been selected to represent an increasing level of model complexity [BIOCLIM, HABITAT, Mahalanobis distance (MD), DOMAIN, ENFA, and GARP] using data on the distribution of 42 species of land snails, nesting birds, and insectivorous bats in Israel. The models were calibrated using data from museum collections and observation databases, and their predictions were evaluated using Cohen's Kappa based on field data collected in a standardized sampling design covering most parts of Israel. Predictive accuracy varied between modelling methods with GARP and MD showing the highest accuracy, BIOCLIM and ENFA showing the lowest accuracy, and HABITAT and DOMAIN showing intermediate accuracy levels. Yet, differences between the various models were relatively small except for GARP and MD that were significantly more accurate than BIOCLIM and ENFA. In spite of large differences among species in prevalence and niche width, neither prevalence nor niche width interacted with the modelling method in determining predictive accuracy. However, species with relatively narrow niches were modelled more accurately than species with wider niches. Differences among species in predictive accuracy were highly consistent over all modelling methods, indicating the need for a better understanding of the ecological and geographical factors that influence the performance of species distribution models. 相似文献
30.
Protein phosphorylation plays a major role in regulating cellular functions. We have previously demonstrated that Sky1p, the SR protein kinase of the budding yeast Saccharomyces cerevisiae, is a regulator of polyamine transport and ion homeostasis. Since its kinase activity was demonstrated essential for fulfilling these roles, we assumed that Sky1p function via substrates phosphorylation. Using an in vitro phosphorylation assay, we have identified Hrb1p as a putative Sky1p substrate. However, phosphorylation analysis in WT and sky1Delta cells and localization studies disproved Hrb1p as a true Sky1p substrate, although a segment of the RS domain is required for determining its subcellular localization. Furthermore, we demonstrate that Hrb1p and additional putative Sky1p substrates, identified by computational approach, are not involved in mediating the spermine tolerant phenotype of sky1Delta cells. 相似文献