Effect of levetiracetam on the gene expression of placental transporters in a murine model.

OBJECTIVE: Levetiracetam (LEV) is an antiseizure medication prescribed to women during childbearing age. The impact of LEV on placental transporters is poorly understood. This study aimed to assess the effect of LEV exposure on the messenger RNA (mRNA) expression of placental transporters for hormones and nutrients and to correlate their expression with the drug's serum concentration in pregnant mice. METHODS: Studies were conducted on gestational days (GD) 13 and 18, following oral treatment with 100 mg/kg LEV or the vehicle every 24 h after weaning. Serum LEV measurements were performed by High-performance liquid chromatography with a UV detector (HPLC-UV). The weight, height, and width of the fetuses were also analyzed. In addition, the placental expression of transporters xCt, Lat1, Oatp4a1, Fr-α, Rfc, and Snat4 was evaluated through semi-quantitative real-time polymerase chain reaction (qPCR). The Kruskal-Wallis and the Mann-Whitney U tests were used to determine the statistical significance (p < .05). The correlation between serum LEV concentration and placental gene expression was evaluated using the Spearman test. RESULTS: The weight, height, and width were lower in the fetuses exposed to LEV compared with the control group (p < .05). The number of fetuses was lower in the LEV-exposed group than in the control GD 13 group (p < .001). No significant differences were detected in the mRNA expression level at GD 13. At GD 18, the expression of Lat1, Oatp4a1, xCT, and Snat4 was higher in the group treated with LEV compared with the control group (p < .05), whereas the expression of Rfc was lower (p < .05). No correlation was identified between serum LEV concentrations and gene expression levels. SIGNIFICANCE: The repression of the Rfc transcript by LEV at GD 18 suggests that the protein expression would be abolished contributing to the observed intrauterine growth restriction (IUGR). Furthermore, the significant increase in mRNA of xCt, Snat4, Oatp4a1, and Lat1 might be a compensatory mechanism for fetal survival at GD 18.

Kinetic and molecular dynamic studies of inhibitors of shikimate dehydrogenase from methicillin-resistant Staphylococcus aureus.

Due to its resistance to many antibiotics, methicillin-resistant Staphylococcus aureus (MRSA) have become a worldwide health problem creating the urgent necessity of developing new drugs against this pathogen. In this sense, one approach is to search for inhibitors of important enzymes in its metabolism. According to this, the shikimate pathway is an important metabolic route in bacteria and its enzymes are considered as great targets for the development of new antibiotic drugs. One of these enzymes is the shikimate dehydrogenase that catalyzes the reversal reduction from 3-dehydroshikimate to shikimate using NADPH as cofactor. In this work, four new compounds were found capable of inhibiting the shikimate dehydrogenase (SDH) from S. aureus (SaSDH) activity. A detailed kinetic characterization showed that the most potent inhibitor presented a Ki of 8 and 10 µM with respect to shikimate and NADP+ , respectively, and a mixed partial inhibition mechanism for both substrates. Molecular dynamics studies revealed that the four inhibitors perturb the structure of SaSDH affecting important domains. Toxicological and physicochemical parameters indicated that these compounds can be considered as potential drugs. Therefore, these compounds are good hits that will help in the process to obtain a new drug against MRSA.

Novel Mixed-Type Inhibitors of Protein Tyrosine Phosphatase 1B. Kinetic and Computational Studies.

The Atlas of Diabetes reports 415 million diabetics in the world, a number that has surpassed in half the expected time the twenty year projection. Type 2 diabetes is the most frequent form of the disease; it is characterized by a defect in the secretion of insulin and a resistance in its target organs. In the search for new antidiabetic drugs, one of the principal strategies consists in promoting the action of insulin. In this sense, attention has been centered in the protein tyrosine phosphatase 1B (PTP1B), a protein whose overexpression or increase of its activity has been related in many studies with insulin resistance. In the present work, a chemical library of 250 compounds was evaluated to determine their inhibition capability on the protein PTP1B. Ten molecules inhibited over the 50% of the activity of the PTP1B, the three most potent molecules were selected for its characterization, reporting Ki values of 5.2, 4.2 and 41.3 µM, for compounds 1, 2, and 3, respectively. Docking and molecular dynamics studies revealed that the three inhibitors made interactions with residues at the secondary binding site to phosphate, exclusive for PTP1B. The data reported here support these compounds as hits for the design more potent and selective inhibitors against PTP1B in the search of new antidiabetic treatment.