The steroid compound cyproterone acetate was identified in a high-throughput screen for glucocorticoid receptor (GR) binding compounds. Cyproterone (Schering AG) is clinically used as an antiandrogen for inoperable prostate cancer, virilizing syndromes in women, and the inhibition of sex drive in men. Despite its progestin properties, cyproterone shares a similar pharmacological profile with the antiprogestin mifepristone (RU486; Roussel Uclaf SA). The binding affinities of cyproterone and RU486 for the GR and progesterone receptor were similar (K d , 15-70 nM). Both compounds were characterized as competitive antagonists of dexamethasone without intrinsic transactivating properties in rat hepatocytes (K i , 10 -30 nM). In osteosarcoma cells, RU486 revealed a higher potency than cyproterone acetate to prevent responses to dexamethasoneinduced GR transactivation and NFB transrepression. Upon administration to Sprague-Dawley rats, both compounds were found to be orally bioavailable and to inhibit transactivation of liver GR. Molecular docking of cyproterone acetate and RU486 into the homology model for the GR ligand binding domain illustrated overlapping steroid scaffolds in the binding pocket. However, in contrast to RU486, cyproterone lacks a bulky side chain at position C11 that has been proposed to trigger active antagonism of nuclear receptors by displacing the C-terminal helix of the ligand-binding domain, thereby affecting activation function 2. Cyproterone may therefore inhibit transactivation of the GR by a molecular mechanism recently described as passive antagonism. New therapeutic profiles may result from compounds designed to selectively stabilize the inactive and active conformations of certain nuclear receptors.Glucocorticoids are steroid hormones that are essential for normal growth and development, for liver and immune functions, and for mediating the stress response. Synthetic derivatives of glucocorticoids, such as dexamethasone, have immunosuppressive, anti-inflammatory, osteocatalytic, proteolytic, and hyperglycemic activities and are used to treat various pathological conditions (Sapolsky et al., 2000). The GR is a ligand-activated intracellular transcriptional regulator that is a member of the nuclear receptor superfamily. In the absence of a ligand, the GR is retained in the cytoplasm by association with chaperone proteins. Upon ligand binding, the GR dissociates from chaperones, dimerizes, and translocates into the nucleus. In the nucleus, the hormone-bound GR can modulate transcription of target genes by direct interaction with specific DNA sequences, called glucocorticoid response elements (GRE) in GR responsive promoters (Karin, 1998). Alternatively, activated GR can interact with nuclear factor B (NF-B) or with activator protein 1 (AP-1) to repress gene expression induced by these proinflammatory transcription factors. The anti-inflammatory and immunesuppressive properties of glucocorticoids have been largely attributed to the transrepression of NF-B and AP-1 function, whereas...
In this Perspective, we expand the notion of temporal regulation of RNA in the brain and propose that the qualitative nature of RNA and its metabolism, together with RNA abundance, are essential for the molecular mechanisms underlying experience-dependent plasticity. We discuss emerging concepts in the newly burgeoning field of epitranscriptomics, which are predicted to be heavily involved in cognitive function. These include activity-induced RNA modifications, RNA editing, dynamic changes in the secondary structure of RNA, and RNA localization. Each is described with an emphasis on its role in regulating the function of both protein-coding genes, as well as various noncoding regulatory RNAs, and how each might influence learning and memory.
DNA modification is known to regulate experience-dependent gene expression. However, beyond cytosine methylation and its oxidated derivatives, very little is known about the functional importance of chemical modifications on other nucleobases in the brain. Here we report that in adult mice trained in fear extinction the DNA modification N6-methyl-2’-deoxyadenosine (m6dA) accumulates along promoters and coding sequences in activated prefrontal cortical neurons. The deposition of m6dA is associated with increased genome-wide occupancy of the mammalian m6dA methyltransferase, N6amt1, and this correlates with extinction-induced gene expression. The accumulation of m6dA is associated with transcriptional activation at the brain-derived neurotrophic factor (Bdnf) P4 promoter, which is required for Bdnf exon IV mRNA expression and for the extinction of conditioned fear. These results expand the scope of DNA modifications in the adult brain and highlight changes in m6dA as an epigenetic mechanism associated with activity-induced gene expression and the formation of fear extinction memory.
Decision support models have been developed to assist management in dairy systems. This paper describes Farmax Dairy Pro (a pastoral grazing model of a dairy farm) and presents an evaluation of it using two independent farmlet studies carried out in Hamilton and Palmerston North, New Zealand with spring-calving dairy cows. Farmax Dairy Pro predicted, to a high degree of accuracy, mean annual yields (per cow and per hectare) for milk, fat, protein and milksolids (MS; fat'protein) and mean annual concentrations of MS. Monthly predictions were predicted with less accuracy than whole lactation values, but still with moderate degrees of accuracy compared with other comparable models. The general trajectory over time of yield and MS concentration was predicted well for all datasets, but in some instances the model over or under predicted the degree of variation between months. The trajectory of body condition score over time was reliably simulated in early lactation but with some discrepancies in late lactation. The model was then used to determine if it was possible to achieve 1750 kg MS/cow per ha using forages grown within the milking area for the Hamilton study. Managerial changes represented in the model, which included earlier calving dates, use of a chicory crop and additional intakes of pasture in summer, predicted increases in performance of 50Á190 kg MS/ha, still at least 81 kg MS/ha short of the target level of production. Farmax Dairy Pro can be used to predict animal, farm and financial performance for different management scenarios.
We have identified a member of the growth arrest and DNA damage (Gadd45) protein family, Gadd45␥, which is known to be critically involved in DNA repair, as a key player in the regulation of immediate early gene (IEG) expression underlying the consolidation of associative fear memory in adult male C57BL/6 mice. Gadd45␥ temporally influences learning-induced IEG expression in the prelimbic prefrontal cortex (PLPFC) through its interaction with DNA double-strand break (DSB)-mediated changes in DNA methylation. Our findings suggest a two-hit model of experience-dependent IEG activity and learning that comprises (1) a first wave of IEG expression governed by DSBs and followed by a rapid increase in DNA methylation, and (2) a second wave of IEG expression associated with the recruitment of Gadd45␥ and active DNA demethylation at the same site, which is necessary for memory consolidation.
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