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191.
192.
Marie Bérubé 《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):832-843
Endocrine therapies are widely used for the treatment of estrogen-sensitive diseases. 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) is involved in the last step of the biosynthesis of potent estrogen estradiol (E2). This enzyme catalyzes the reduction of the C17-ketosteroid estrone (E1) into the C17β-hydroxy steroid E2 using the cofactor NAD(P)H. The X-ray analysis of E2/adenosine bisubstrate inhibitor EM-1745 proven that this compound interacts with both the substrate- and the cofactor-binding sites. However, E1 is a better substrate of 17β-HSD1 than E2. Thus, in order to improve the inhibitory potency of EM-1745, the C17-ketone analogue was prepared. During this work, a new and more efficient method for synthesizing EM-1745 was developed using an esterification and a cross-metathesis as key steps. Contrary to what was expected, the C17-ketone analogue of EM-1745 is a less potent inhibitor (IC50 = 12 nM) than the C17-alcohol (IC50 = 4 nM) in homogenated HEK-293 cells overexpressing 17β-HSD1. Our results contribute to the knowledge of an unexpected observation: the C17-ketone steroidal inhibitors of 17β-HSD1 are less potent than their corresponding C17-alcohol derivatives. 相似文献
193.
Raisa Turja Anna Soirinsuo Hélène Budzinski Marie Hélène Devier Kari K. Lehtonen 《Comparative biochemistry and physiology. Toxicology & pharmacology : CBP》2013,157(1):80-92
Baltic Sea blue mussels (Mytilus trossulus) were used as sentinel organisms to detect the biological effects of chemical contamination in the low salinity environment. Mussels naturally adapted to a salinity of ca. 6.0 PSU were caged for 30 days at four sites along an assumed pollution gradient (salinity ca. 4.5 PSU) in the vicinity of Finland's largest oil refinery and harbor Kilpilahti in the Gulf of Finland. Tissue concentrations and accumulation rates of especially organic contaminants (PAHs, PCBs and organotins) were clearly elevated at the innermost coastal stations near the harbor area. Biological effects of contaminant exposure on caged mussels were evaluated by measuring a suite of biomarkers including catalase, glutathione S-transferase, superoxide dismutase, glutathione reductase, lipid peroxidation, acetylcholinesterase activity and lysosomal membrane stability. Mussels transplanted near the harbor area were able to elevate their antioxidant defense in response to environmental contamination. Reduced morphometric condition index and soft tissue growth rate together with increased lipid peroxidation and low lysosomal membrane stability were also observed at the most contaminated site. The results suggest that caging of M. trossulus for four weeks at lower salinity is a feasible method for the detection of environmental pollution also in low salinity areas of the Baltic Sea. 相似文献
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195.
Prajakta Pradhan Marie L. Nguyen 《Apoptosis : an international journal on programmed cell death》2013,18(2):160-170
Herpes simplex virus 1 (HSV-1) is a enveloped, double stranded DNA virus that is the causative agent of various diseases including cold sores, encephalitis, and ocular keratitis. Previous research has determined that HSV-1 modulates cellular apoptotic pathways. Apoptosis is triggered in infected cells early in infection; however, later in the infection the apoptotic response is suppressed due to the expression of several viral apoptotic antagonists. This sets us a delicate balance between pro- and anti-apoptotic processes during the lytic phase of infection. Several studies have demonstrated that the apoptotic balance can be shifted during infection of certain cell types, leading to apoptosis of the infected cells (HSV-1-dependent apoptosis). For example, HEp-2 cells infected with an ICP27-null recombinant HSV-1 virus undergo HSV-1-dependent apoptosis. Differences in the sensitivity to HSV-1-dependent apoptosis have been revealed. Although many tumor cells have been found to be highly sensitive to this apoptotic response, with the exception hematological cells, all primary human cells tested prior to this study have been shown to be resistant to HSV-1-dependent apoptosis. Here, we demonstrate that early passage neonatal and adult human keratinocytes, which are usually the first cells to encounter HSV-1 in human infection and support the lytic stage of the life cycle, display membrane blebbing and ballooning, chromatin condensation, caspase activation, and cleavage of cellular caspase substrates when infected with an ICP27-null recombinant of HSV-1. Furthermore, caspase activation is needed for the efficient apoptotic response. These results suggest that apoptotic machinery may be a target for modulating HSV-disease in patients. 相似文献
196.
Ecosystems in the far north, including arctic and boreal biomes, are a globally significant pool of carbon (C). Global change is proposed to influence both C uptake and release in these ecosystems, thereby potentially affecting whether they act as C sources or sinks. Bryophytes (i.e., mosses) serve a variety of key functions in these systems, including their association with nitrogen (N2)‐fixing cyanobacteria, as thermal insulators of the soil, and producers of recalcitrant litter, which have implications for both net primary productivity (NPP) and heterotrophic respiration. While ground‐cover bryophytes typically make up a small proportion of the total biomass in northern systems, their combined physical structure and N2‐fixing capabilities facilitate a disproportionally large impact on key processes that control ecosystem C and N cycles. As such, the response of bryophyte‐cyanobacteria associations to global change may influence whether and how ecosystem C balances are influenced by global change. Here, we review what is known about their occurrence and N2‐fixing activity, and how bryophyte systems will respond to several key global change factors. We explore the implications these responses may have in determining how global change influences C balances in high northern latitudes. 相似文献
197.
Dispersal is a key process in population and evolutionary ecology. Individual decisions are affected by fitness consequences of dispersal, but these are difficult to measure in wild populations. A long‐term dataset on a geographically closed bird population, the Mauritius kestrel, offers a rare opportunity to explore fitness consequences. Females dispersed further when the availability of local breeding sites was limited, whereas male dispersal correlated with phenotypic traits. Female but not male fitness was lower when they dispersed longer distances compared to settling close to home. These results suggest a cost of dispersal in females. We found evidence of both short‐ and long‐term fitness consequences of natal dispersal in females, including reduced fecundity in early life and more rapid aging in later life. Taken together, our results indicate that dispersal in early life might shape life history strategies in wild populations. 相似文献
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199.
Jean-Luc Montillet Nathalie Leonhardt Samuel Mondy Sylvain Tranchimand Dominique Rumeau Marie Boudsocq Ana Victoria Garcia Thierry Douki Jean Bigeard Christiane Laurière Anne Chevalier Carmen Castresana Heribert Hirt 《PLoS biology》2013,11(3)
Plant stomata function in innate immunity against bacterial invasion and abscisic acid (ABA) has been suggested to regulate this process. Using genetic, biochemical, and pharmacological approaches, we demonstrate that (i) the Arabidopsis thaliana nine-specific-lipoxygenase encoding gene, LOX1, which is expressed in guard cells, is required to trigger stomatal closure in response to both bacteria and the pathogen-associated molecular pattern flagellin peptide flg22; (ii) LOX1 participates in stomatal defense; (iii) polyunsaturated fatty acids, the LOX substrates, trigger stomatal closure; (iv) the LOX products, fatty acid hydroperoxides, or reactive electrophile oxylipins induce stomatal closure; and (v) the flg22-mediated stomatal closure is conveyed by both LOX1 and the mitogen-activated protein kinases MPK3 and MPK6 and involves salicylic acid whereas the ABA-induced process depends on the protein kinases OST1, MPK9, or MPK12. Finally, we show that the oxylipin and the ABA pathways converge at the level of the anion channel SLAC1 to regulate stomatal closure. Collectively, our results demonstrate that early biotic signaling in guard cells is an ABA-independent process revealing a novel function of LOX1-dependent stomatal pathway in plant immunity. 相似文献
200.
Guillaume Nugue Marie Bidart Marie Arlotto Mireille Mousseau Fran?ois Berger Laurent Pelletier 《PloS one》2013,8(8)
Developing therapeutic monoclonal antibodies paves the way for new strategies in oncology using targeted therapy which should improve specificity. However, due to a lack of biomarkers, a personalized therapy scheme cannot always be applied with monoclonal antibodies. As a consequence, the efficacy or side effects associated with this type of treatment often appear to be sporadic. Bevacizumab is a therapeutic monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF). It is used to limit tumor vascularization. No prognosis or response biomarker is associated with this antibody, we therefore assessed whether the administration protocol could be a possible cause of heterogeneous responses (or variable efficacy). To do this, we developed a bevacizumab assay with a broad sensitivity range to measure blood bevacizumab concentrations. We then analyzed bevacizumab concentrations in 17 patients throughout the first quarter of treatment. In line with previously published data, average blood concentrations were 88+/−27 mg/L following the first dose administered, and 213+/−105 mg/L after the last (6th) dose administered. However, the individual values were scattered, with a mean 4-fold difference between the lowest and the highest concentration for each dose administered. We demonstrated that the bevacizumab administration schedule results in a high inter-individual variability in terms of blood concentrations. Comparison of assay data with clinical data indicates that blood concentrations above the median are associated with side effects, whereas values below the median favor inefficacy. In conclusion, bevacizumab-based therapy could benefit from a personalized administration schedule including follow-up and adjustment of circulating bevacizumab concentrations. 相似文献