ABSTRACT
Inhibitors of DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug discovery. They are also chemical tools to understand the biochemistry of epigenetic processes. Herein, we report five distinct inhibitors of DNMT1 characterized in enzymatic inhibition assays that did not show activity with DNMT3B. It was concluded that the dietary component theaflavin is an inhibitor of DNMT1. Two additional novel inhibitors of DNMT1 are the approved drugs glyburide and panobinostat. The DNMT1 enzymatic inhibitory activity of panobinostat, a known pan inhibitor of histone deacetylases, agrees with experimental reports of its ability to reduce DNMT1 activity in liver cancer cell lines. Molecular docking of the active compounds with DNMT1, and re-scoring with the recently developed extended connectivity interaction features approach, led to an excellent agreement between the experimental IC50 values and docking scores.
ABSTRACT
The aim was to evaluate the effect of perinatal BPA exposure of one or both parents on the implantation index and expression of talin, occludin and E-cadherin in the uterine epithelial cells (UEC) of the offspring. Pregnant Wistar dams (F0) received BPA or vehicle from gestational day (GD) 6 to lactation day 21. F1 animals were mated forming four groups: Control dam-Control sire (Câ-Câ), BPA dam -Control sire (Bâ-Câ), Control dam -BPA sire (Câ-Bâ), BPA dam -BPA sire (Bâ-Bâ). F1 dams were sacrificed at GD 6. Significantly decreased number of implantation sites was observed in the Bâ-Bâ group as compared to the Câ-Câ group, which correlated with decreased talin apical/basal expression ratio, occludin apical expression, and E-cadherin apical/lateral expression ratio in the UEC. Furthermore, decreased E-cadherin expression in the blastocyst was observed. Our data suggest that reduced protein expressions in F1 BPA offspring could result from decreased progesterone serum levels.
