37 research outputs found

    Epigenetic Effects of Prenatal Stress on 11β-Hydroxysteroid Dehydrogenase-2 in the Placenta and Fetal Brain

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    Maternal exposure to stress during pregnancy is associated with significant alterations in offspring neurodevelopment and elevated maternal glucocorticoids likely play a central role in mediating these effects. Placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) buffers the impact of maternal glucocorticoid exposure by converting cortisol/corticosterone into inactive metabolites. However, previous studies indicate that maternal adversity during the prenatal period can lead to a down-regulation of this enzyme. In the current study, we examined the impact of prenatal stress (chronic restraint stress during gestational days 14–20) in Long Evans rats on HSD11B2 mRNA in the placenta and fetal brain (E20) and assessed the role of epigenetic mechanisms in these stress-induced effects. In the placenta, prenatal stress was associated with a significant decrease in HSD11B2 mRNA, increased mRNA levels of the DNA methyltransferase DNMT3a, and increased DNA methylation at specific CpG sites within the HSD11B2 gene promoter. Within the fetal hypothalamus, though we find no stress-induced effects on HSD11B2 mRNA levels, prenatal stress induced decreased CpG methylation within the HSD11B2 promoter and increased methylation at sites within exon 1. Within the fetal cortex, HSD11B2 mRNA and DNA methylation levels were not altered by prenatal stress, though we did find stress-induced elevations in DNMT1 mRNA in this brain region. Within individuals, we identified CpG sites within the HSD11B2 gene promoter and exon 1 at which DNA methylation levels were highly correlated between the placenta and fetal cortex. Overall, our findings implicate DNA methylation as a mechanism by which prenatal stress alters HSD11B2 gene expression. These findings highlight the tissue specificity of epigenetic effects, but also raise the intriguing possibility of using the epigenetic status of placenta to predict corresponding changes in the brain

    Cytotoxicity of advanced glycation endproducts in human micro- and astroglial cell lines depends on the degree of protein glycation

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    Advanced glycation endproducts (AGEs) arise from the reaction of sugars with side chains and the N-terminus of proteins and are thought to be involved in the pathogenesis of several diseases by inducing oxidative stress, inflammation and cell death presumably mediated through activation of the receptor of AGE (RAGE). To address the question whether the cell damaging effect of AGE depends on the degree of its protein glycation, differential modified AGEs derived from incubating human serum albumin with increasing concentrations of methyl glyoxal were tested on cell viability, reactive oxygen species (ROS) formation, intracellular ATP levels, and activation of caspases 3/7 in two human glial cell lines, which were used as a model for human glia cells. All AGEs tested, regardless of their degree of modification, were found to induce ROS formation in both microglial (CHME-5) and astroglial cells (U373 MG), while only highly modified AGEs were able to decrease the cell viability and to induce apoptosis. This indicates that apoptotic events may be involved in the change of physiological parameters

    Supramolecular macrocycles reversibly assembled by Te…O chalcogen bonding

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    Organic molecules with heavy main-group elements frequently form supramolecular links to electron-rich centres. One particular case of such interactions is halogen bonding. Most studies of this phenomenon have been concerned with either dimers or infinitely extended structures (polymers and lattices) but well-defined cyclic structures remain elusive. Here we present oligomeric aggregates of heterocycles that are linked by chalcogen-centered interactions and behave as genuine macrocyclic species. The molecules of 3-methyl-5-phenyl-1,2-tellurazole 2-oxide assemble a variety of supramolecular aggregates that includes cyclic tetramers and hexamers, as well as a helical polymer. In all these aggregates, the building blocks are connected by Te(…)O–N bridges. Nuclear magnetic resonance spectroscopic experiments demonstrate that the two types of annular aggregates are persistent in solution. These self-assembled structures form coordination complexes with transition-metal ions, act as fullerene receptors and host small molecules in a crystal
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