A small-molecule inhibitor of HIV-1 Rev function detected by a diversity screen based on RRE-Rev interference.

The Rev protein of HIV-1 binds to the Rev Recognition Element (RRE) in the virus RNA to promote nuclear export of unspliced and partially spliced transcripts, an essential step in the virus transmission cycle. Here, we describe the screening of a library of chemically diverse compounds with an assay based on monitoring the interaction between the RNA-binding α-helix of Rev and its high-affinity binding site in the RRE. This screen allowed the identification of a benzofluorenone compound that inhibited the formation of the full-length RRE-Rev ribonucleoprotein by associating to the RRE, and blocked HIV-1 transcription and Rev action in cells. This molecule, previously studied as a cytostatic agent, had substantial antiretroviral activity. Together with other screening hits, it provides a new chemical scaffold for the development of antiretroviral agents based on blockage of HIV-1 RNA biogenesis.

Bioavailable inhibitors of HIV-1 RNA biogenesis identified through a Rev-based screen.

New antiretroviral agents with alternative mechanisms are needed to complement the combination therapies used to treat HIV-1 infections. Here we report the identification of bioavailable molecules that interfere with the gene expression processes of HIV-1. The compounds were detected by screening a small library of FDA-approved drugs with an assay based on measuring the displacement of Rev, and essential virus-encoded protein, from its high-affinity RNA binding site. The antiretroviral activity of two hits was based on interference with post-integration steps of the HIV-1 cycle. Both hits inhibited RRE-Rev complex formation in vitro, and blocked LTR-dependent gene expression and viral transcription in cellular assays. The best compound altered the splicing pattern of HIV-1 transcripts in a manner consistent with Rev inhibition. This mechanism of action is different from those used by current antiretroviral agents. The screening hits recognized the Rev binding site in the viral RNA, and the best compound did so with substantial selectivity, allowing the identification of a new RNA-binding scaffold. These results may be used for developing novel antiretroviral drugs.

Fast standardized therapeutic-efficacy assay for drug discovery against tuberculosis.

Murine models of Mycobacterium tuberculosis infection are essential tools in drug discovery. Here we describe a fast standardized 9-day acute assay intended to measure the efficacy of drugs against M. tuberculosis growing in the lungs of immunocompetent mice. This assay is highly reproducible, allows good throughput, and was validated for drug lead optimization using isoniazid, rifampin, ethambutol, pyrazinamide, linezolid, and moxifloxacin.

Guatemalan plants extracts as virucides against HIV-1 infection.

Prevention methods to avoid transmission of pathogens, including HIV, are crucial in the control of infectious diseases, not only to block epidemic spread but to avoid long-term treatments leading to emergence of resistances and drug associated side effects. Together with vaccine development, the discovery of new virucidal agents represents a research priority in this setting. In the screening of new compounds with antiviral activity, three Guatemalan plant extracts from Justicia reptans, Neurolaena lobata and Pouteria viridis were evaluated with a classic antiviral assay and were found to inhibit HIV replication. This activity was corroborated by an original recombinant virus assay, leading us to perform a deeper study of the virucidal activity. Active fractions were non-toxic in vitro and also inhibited other enveloped viruses. Moreover, these fractions were able to inhibit the transfer of HIV from dendritic cells (DCs) to lymphocytes, that represents the main way of HIV spread in vivo.

Hypertension is related to the degradation of dietary frying oils.

BACKGROUND: The family kitchen resembles an uncontrolled laboratory experiment, and some discrepancies in the relation between the risk of hypertension and dietary fat may be partly due to the manipulation to which the fats were subjected. OBJECTIVE: We investigated whether deterioration in the quality of the cooking oils in the family household contributes to the risk of high blood pressure. DESIGN: The study was cross-sectional. Anthropometric measurements were obtained for 1226 persons aged 18-65 y who were selected randomly from the municipal census of Pizarra, Spain. An oral-glucose-tolerance test was given to 1020 of these persons. Samples of the cooking oil being used were taken from the kitchens of a random subset of 538 persons. The concentrations of polar compounds and polymers were used as markers of the deterioration of the oils. The strength of association between variables was measured by calculating the odds ratio from logistic models. RESULTS: Hypertension was strongly associated with obesity and was influenced by sex, diabetes, and age. The presence of excess polar compounds in the cooking oil and the use of sunflower oil were related to the risk of hypertension, whereas the concentration of monounsaturated fatty acids in the serum phospholipids was negatively related to this risk. These associations remained after inclusion in the models of age, sex, obesity, and the presence of carbohydrate metabolism disorder. CONCLUSIONS: The risk of hypertension is positively and independently associated with the intake of cooking oil polar compounds and inversely related to blood concentrations of monounsaturated fatty acids.

Actividad física y factores de riesgo cardiovascular y metabólico en la población general / Physical activity and cardiovascular and metabolic risk factors in general population

FUNDAMENTO Y OBJETIVO: Evaluar en un estudio poblacional la asociación entre la actividad física diaria y diferentes factores de riesgo metabólico y cardiovascular. PACIENTES Y MÉTODO: En 1.226 personas (edad: 18-65 años) aleatoriamente seleccionadas en una población del sudeste español se ha evaluado la asociación entre el nivel de actividad física diaria laboral y extralaboral con las siguientes variables: índice de masa corporal, lípidos plasmáticos, presencia de hipertensión arterial, obesidad, glucemia basal alterada y tolerancia anormal de la glucosa. RESULTADOS: La intensidad de la actividad física en el trabajo se correlacionó de manera negativa con las concentraciones de colesterol ligado a lipoproteínas de baja densidad y positivamente con las de colesterol ligado a lipoproteínas de alta densidad. La probabilidad de presentar hipertensión arterial, glucemia basal alterada o tolerancia anormal de la glucosa fue mayor en aquellos que tuvieron una menor actividad física diaria. CONCLUSIONES: La actividad física diaria, considerada como uno de los componentes del estilo de vida, se asocia con la presencia de los componentes del síndrome metabólico. Un aumento de la actividad física diaria debe contribuir a mejorar los patrones favorables a la prevención de los factores de riesgo cardiovascular (AU)