Estrogen receptor beta selectively restricts proliferation and favors surveillance in mammary epithelial cells

Estrogen (17β-estradiol) has paradoxical effects in both promoting and preventing breast cancer as estrogen activates proliferation, but also promotes p53-mediated surveillance pathways. Estrogen mediates its effects in target tissues through the activation of estrogen receptor subtypes: ERα and ERβ. To examine the capability of these receptors in mediating surveillance as opposed to proliferation, selective estrogen receptor agonists were compared with 17β-estradiol for induction of proliferation and radiation induced apoptosis in vivo. Transcriptional regulation of estrogen-responsive genes was also compared in mouse mammary epithelium in vivo and in the human mammary MCF7 cell line transduced with a repressible ERβ. Selective activation of ERβ with the agonist diarylpropionitrile (DPN) in vivo enhances p53-mediated apoptosis in the mouse mammary epithelium without stimulating proliferation. In addition, radiation-induced apoptosis is significantly reduced in mice lacking ERβ (βERKO). As expected, 17β-estradiol or selective activation of ERα with pyrazole triol (PPT) induced the expression of estrogen-response genes including progesterone receptor, amphiregulin and trefoil factor 1. DPN and ERβ failed to induce the expression of these genes. Interestingly, the ERβ agonist DPN selectively induced the expression of genes that repress proliferation including TGFβ2 while inhibiting proliferative canonical wnt signaling via beta-catenin by inducing WNT5a and AXIN2. DPN was also more potent in stimulating the expression of EGR1, a modulator of p53 activity. These results suggest that ERα and ERβ have distinct roles in gene regulation. In addition, the ability of DPN and ERβ to potentiate surveillance pathways while limiting proliferation suggests that ERβ agonists may have therapeutic and chemopreventive value in breast cancer

RNase T1 mimicking artificial ribonuclease

Recently, artificial ribonucleases (aRNases)—conjugates of oligodeoxyribonucleotides and peptide (LR)4-G-amide—were designed and assessed in terms of the activity and specificity of RNA cleavage. The conjugates were shown to cleave RNA at Pyr-A and G–X sequences. Variations of oligonucleotide length and sequence, peptide and linker structure led to the development of conjugates exhibiting G–X cleavage specificity only. The most efficient catalyst is built of nonadeoxyribonucleotide of unique sequence and peptide (LR)4-G-NH2 connected by the linker of three abasic deoxyribonucleotides (conjugate pep-9). Investigation of the cleavage specificity of conjugate pep-9 showed that the compound is the first single-stranded guanine-specific aRNase, which mimics RNase T1. Rate enhancement of RNA cleavage at G–X linkages catalysed by pep-9 is 108 compared to non-catalysed reaction, pep-9 cleaves these linkages only 105-fold less efficiently than RNase T1 (kcat_RNase T1/kcat_pep-9 = 105)

The triple combination of tenofovir, emtricitabine and efavirenz shows synergistic anti-HIV-1 activity in vitro: a mechanism of action study

<p>Abstract</p> <p>Background</p> <p>Tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) are the three components of the once-daily, single tablet regimen (Atripla) for treatment of HIV-1 infection. Previous cell culture studies have demonstrated that the double combination of tenofovir (TFV), the parent drug of TDF, and FTC were additive to synergistic in their anti-HIV activity, which correlated with increased levels of intracellular phosphorylation of both compounds.</p> <p>Results</p> <p>In this study, we demonstrated the combinations of TFV+FTC, TFV+EFV, FTC+EFV, and TFV+FTC+EFV synergistically inhibit HIV replication in cell culture and synergistically inhibit HIV-1 reverse transcriptase (RT) catalyzed DNA synthesis in biochemical assays. Several different methods were applied to define synergy including median-effect analysis, MacSynergy^®II and quantitative isobologram analysis. We demonstrated that the enhanced formation of dead-end complexes (DEC) by HIV-1 RT and TFV-terminated DNA in the presence of FTC-triphosphate (TP) could contribute to the synergy observed for the combination of TFV+FTC, possibly through reduced terminal NRTI excision. Furthermore, we showed that EFV facilitated efficient formation of stable, DEC-like complexes by TFV- or FTC-monophosphate (MP)-terminated DNA and this can contribute to the synergistic inhibition of HIV-1 RT by TFV-diphosphate (DP)+EFV and FTC-TP+EFV combinations.</p> <p>Conclusion</p> <p>This study demonstrated a clear correlation between the synergistic antiviral activities of TFV+FTC, TFV+EFV, FTC+EFV, and TFV+FTC+EFV combinations and synergistic HIV-1 RT inhibition at the enzymatic level. We propose the molecular mechanisms for the TFV+FTC+EFV synergy to be a combination of increased levels of the active metabolites TFV-DP and FTC-TP and enhanced DEC formation by a chain-terminated DNA and HIV-1 RT in the presence of the second and the third drug in the combination. This study furthers the understanding of the longstanding observations of synergistic anti-HIV-1 effects of many NRTI+NNRTI and certain NRTI+NRTI combinations in cell culture, and provides biochemical evidence that combinations of anti-HIV agents can increase the intracellular drug efficacy, without increasing the extracellular drug concentrations.</p

A Flavonoid, Luteolin, Cripples HIV-1 by Abrogation of Tat Function

Despite the effectiveness of combination antiretroviral treatment (cART) against HIV-1, evidence indicates that residual infection persists in different cell types. Intensification of cART does not decrease the residual viral load or immune activation. cART restricts the synthesis of infectious virus but does not curtail HIV-1 transcription and translation from either the integrated or unintegrated viral genomes in infected cells. All treated patients with full viral suppression actually have low-level viremia. More than 60% of treated individuals also develop minor HIV-1 –associated neurocognitive deficits (HAND) due to residual virus and immune activation. Thus, new therapeutic agents are needed to curtail HIV-1 transcription and residual virus. In this study, luteolin, a dietary supplement, profoundly reduced HIV-1 infection in reporter cells and primary lymphocytes. HIV-1inhibition by luteolin was independent of viral entry, as shown by the fact that wild-type and VSV–pseudotyped HIV-1 infections were similarly inhibited. Luteolin was unable to inhibit viral reverse transcription. Luteolin had antiviral activity in a latent HIV-1 reactivation model and effectively ablated both clade-B- and -C -Tat-driven LTR transactivation in reporter assays but had no effect on Tat expression and its sub-cellular localization. We conclude that luteolin confers anti–HIV-1 activity at the Tat functional level. Given its biosafety profile and ability to cross the blood-brain barrier, luteolin may serve as a base flavonoid to develop potent anti–HIV-1 derivatives to complement cART

Representation and processing of French verb-noun compounds

International audienc

Autonomía y validismo en la tercera edad

Se realizó un estudio de intervención con el objetivo de conocer el grado de autonomía y validismo alcanzado por la tercera edad en 2 consultorios del Médico y la Enfermera de la Familia pertenecientes al Policlínico Comunitario "Tula Aguilera" del municipio Camagüey. El universo de trabajo correspondió a 215 pacientes entre los 60 y 89 años de edad a los que se les aplicó una encuesta antes y después de nuestra intervención. Los resultados muestran que antes del trabajo predominó una evaluación desfavorable en el comportamiento y conocimiento sobre autonomía y validismo que se incrementa con la edad y el sexo femenino. Después de la intervención se observó mejor comprensión de la autonomía y validismo por edad y sexoAn intervention study was carried out in order to know the degree of autonomy and soundness attained by the elderly from 2 family physician's offices of "Tula Aguilera" Community Polyclinic, in the municipality of Camagüey. 215 patients aged 60-89 were surveyed before and after our intervention. The results showed that before the intervention an unfavorable evaluation predominated in the behavior and knowledge about autonomy and soundness that increases with age in the females. After the intervention it was observed a better understanding of the autonomy and soundness by age and sex