Daniel Enriquez-Mendiola

The aim of this study was to assess the effect of sertraline on the gene expression of placental transporters for hormones, folates, nutrients and drugs over the course of pregnancy in rats. The studies were conducted on gestational days (GDs) 16 and 20 following oral treatment with 10 mg/kg/day sertraline or the vehicle, administered from weaning onward. The weight and area of the fetuses and placentas were analyzed, and maternal plasma sertraline concentrations were measured. Gene expression of ATP-binding cassette transporter b1a and b1b (Abcb1a and Abcb1b), organic anion-transporting polypeptide 4a1(Slco4A1/Oatp4a1), folate receptor-α (Folr1), reduced folate carrier (Slc19A1/Rfc), and L-type amino acid transporter (Slc7A5/Lat1) was evaluated in the placenta. Sertraline reduced fetal weight (p < 0.001) and fetal area (p < 0.01) at GD 16, while no significant differences were observed in placental weight or area between exposed and unexposed groups. Sertraline concentration was significantly lower at GD20 than at GD16 (p < 0.001). At GD 16, sertraline reduced the expression of Abcb1a (p = 0.027), Abcb1b (p < 0.01), and Oatp4a1 (p = 0.037) compared with controls. Conversely, sertraline induced Folr1 expression in both GDs and increased Rfc expression at GD 20, while Lat1 was not affected. These findings indicate that sertraline alters placental drug transporter gene expression and may impair nutrient transfer to the fetus.

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 K_i 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.

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.