No abstract

The mycotoxin ochratoxin A (OTA) is a potent nephrocarcinogen, mainly in male rats. The aim of this study was to determine the time course of gene expression (GeneChip® Rat Gene 2.0 ST Array, Affymetrix) in kidney samples from male and female F344 rats, treated daily (p.o) with 0.50 mg/kg b.w. (body weight) of OTA for 7 or 21 days, and evaluate if there were differences between both sexes. After OTA treatment, there was an evolution of gene expression in the kidney over time, with more differentially expressed genes (DEG) at 21 days. The gene expression time course was different between sexes with respect to the number of DEG and the direction of expression (up or down): the female response was progressive and consistent over time, whereas males had a different early response with more DEG, most of them up-regulated. The statistically most significant DEG corresponded to metabolism enzymes (Akr1b7, Akr1c2, Adh6 down-regulated in females; Cyp2c11, Dhrs7, Cyp2d1, Cyp2d5 down-regulated in males) or transporters (Slc17a9 down-regulated in females; Slco1a1 (OATP-1) and Slc51b and Slc22a22 (OAT) down-regulated in males). Some of these genes had also a basal sex difference and were over-expressed in males or females with respect to the other sex.

Some quinoxaline 1,4-di-N-oxides derivatives with very different substituents in 2, 3, 6 and 7 positions have been synthesized in order to obtain new hypoxia selective agents. Some of these products have been tested as antituberculosis agents and very interesting results have been obtained from the first screening.

The use of bioadhesive polymers as nanodevices has emerged as a promising strategy for oral delivery of therapeutics. In this regard, poly(anhydride) nanoparticles have shown great potential for oral drug delivery and vaccine purposes. However, despite extensive research into the biomedical and pharmaceutical applications of poly(anhydride) nanoparticles, there are no studies to evaluate the interaction of these nanoparticles at a cellular level. Therefore, the main objectives of this study were to evaluate the cytotoxicity as well as the cell interaction of different poly(anhydride) nanoparticles: conventional (NP), nanoparticles containing 2-hydroxypropyl-beta-cyclodextrin (NP-HPCD) and nanoparticles coated with poly(ethylene glycol) 6000 (PEG-NP). For this purpose, nanoparticles were prepared by solvent displacement method and labelled with BSA-FITC. Nanoparticles displayed a size about 175 nm with negative surface charge. Cytotoxicity studies were developed by MTS and LDH assays in HepG2 and Caco-2 cells. Results showed that only in HepG2 cells, NP and NP-HPCD induced significant cytotoxicity at the highest concentrations (1 and 2 mg/mL) and incubation times (48 and 72 h) tested. Studies to discriminate between cytoadhesion and cytoinvasion were performed at 4 degrees C and 37 degrees C in Caco-2 cell line as intestinal cell model. Nanoparticles showed cytoadhesion to the cell surface but not internalization; PEG-NP was the most bioadhesive followed by NP-HPCD and NP as demonstrated by flow cytometry. Finally, cellular localization of particles by fluorescence confocal microscopy confirmed the association of these nanoparticles with cells. Thus, this study demonstrated the safety of NP, NP-HPCD and PEG-NP at cellular level and its bioadhesive properties within cells.