Androgen receptor GGC polymorphism and testosterone levels associated with high risk of prostate cancer and benign prostatic hyperplasia

Polymorphic GGC repeats in the androgen receptor (AR) gene can alter transactivation of androgen-responsive genes and increase the risk of benign prostatic hyperplasia (BPH) and prostate cancer (PCa). We investigated the association between GGC repeat length, testosterone levels and the risk of developing PCa and BPH in a population from southern Brazil. A sample comprising 130 PCa, 126 BPH and 88 control patients was evaluated. DNA was extracted from leukocytes and the AR gene was analyzed by fragment analysis. The hazard ratio (HR) was estimated. GGC mean length was not different between the three study groups. The risk of developing PCa in individuals with GGC > 19 was 3.300 (95 %CI 1.385–7.874) higher when compared to the GGC ≤ 19 group (p = 0.007). The risk of developing PCa and BPH in individuals with total testosterone levels <4 ng/mL was 2.799 (95 % CI 1.362–5.754). (p = 0.005) and 2.786 (95 % CI 1.470–5.280) (p = 0.002), respectively. Total testosterone levels in patients with GGC > 19 were significantly lower when compared to patients in the GGC ≤ 19 group. Our data suggest that the presence of a high number of polymorphic GGC repeats in the AR gene is associated with an increased risk of developing PCa and BPH, and that lower testosterone levels also increase the risk of developing these diseases.     

Analysis of binding properties and specificity through identification of the interface forming residues (IFR) for serine proteases <Emphasis Type="Italic">in silico</Emphasis> docked to different inhibitors

Background  

Enzymes belonging to the same super family of proteins in general operate on variety of substrates and are inhibited by wide selection of inhibitors. In this work our main objective was to expand the scope of studies that consider only the catalytic and binding pocket amino acids while analyzing enzyme specificity and instead, include a wider category which we have named the Interface Forming Residues (IFR). We were motivated to identify those amino acids with decreased accessibility to solvent after docking of different types of inhibitors to sub classes of serine proteases and then create a table (matrix) of all amino acid positions at the interface as well as their respective occupancies. Our goal is to establish a platform for analysis of the relationship between IFR characteristics and binding properties/specificity for bi-molecular complexes.     

Acute administration of the organochalcogen 3‐methyl‐1‐phenyl‐2‐(phenylseleno)oct‐2‐en‐1‐one induces biochemical and hematological disorders in male rats

Organochalcogens are extensively produced and employed by industry and agriculture, and the risk of occupational and environmental toxicity to them has been poorly understood. Here, we investigated the acute effect of a new organochalcogen 3‐methyl‐1‐phenyl‐2‐(phenylseleno)oct‐2‐en‐1‐one on biochemical and hematological parameters in male Wistar rats. The animals were treated with a single intraperitoneal injection of the organochalcogen at doses of 125, 250 or 500 µg·kg^–1. After 60 min, the animals were sacrificed by decapitation, and the trunk blood was collected for determination of glucose, triglycerides, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase, lactate dehydrogenase, urea, creatinine, C‐reactive protein, red blood cells, hematocrit, hemoglobin and white blood cells (WBC). Our results showed a reduction in cholesterol levels in all treated groups, an increase in ALT activity at doses of 250 and 500 µg·kg^–1, a decrease of hemoglobin and an increase in WBC in animals that received 250 and 500 µg·kg^–1 of the organoselenium. In addition, we observed an increase in neutrophil counts at 125 µg·kg^–1 dose and a decrease at 500 µg·kg^–1 dose. We also verified an increase in lymphocyte counts at the dose of 500 µg·kg^–1. Thus, the present study shows that the acute treatment with this new organochalcogen causes biochemical changes and hematological disorders in male rats. Copyright © 2012 John Wiley & Sons, Ltd.     

Common repair pathways acting upon U.V.- and X-ray induced damage in diploid cells of Saccharomyces cerevisiae

Studies on X-ray sensitive mutants of Saccharomyces cerevisiae (Benathen 1973, Benathen and Beam 1977) show that the XS6, XS8 and XS9 genes are not only involved in the repair of X-ray-induced damage but also in the repair of U.V.-induced damage. Analysis of the U.V. sensitivity of multiple xs mutants indicates the participation of three repair pathways which differ from excision repair. Under conditions which can influence repair, such as plating of the U.V.-irradiated cells in the presence of caffeine, followed or not by hyperthermic incubation, the wild type strain shows a diphasic survival curve, consisting of an exponential component for low doses and a sigmoidal one for higher doses. Comparison with the survival curves obtained for the sensitive mutants suggests that the first component of the wild type survival curve corresponds to the inhibition of the XS6 and XS8 gene products while the appearance of a radio-resistant fraction in the population relies on the induction of another repair pathway. A sequential model of repair with two branching points is proposed to explain the results.     

Effect of progesterone on the expression of GABAA receptor subunits in the prefrontal cortex of rats: implications of sex differences and brain hemisphere

Progesterone is a neuroactive hormone with non‐genomic effects on GABA_A receptors (GABA_AR). Changes in the expression of GABA_AR subunits are related to depressive‐like behaviors in rats. Moreover, sex differences and depressive behaviors have been associated with prefrontal brain asymmetry in rodents and humans. Thus, our objective was to investigate the effect of progesterone on the GABA_AR α1 and γ2 subunits mRNA expression in the right and left prefrontal cortex of diestrus female and male rats exposed to the forced swimming test (FST). Male and female rats (n = 8/group) were randomly selected to receive a daily dose of progesterone (0·4 mg·kg^–1) or vehicle, during two complete female estrous cycles (8–10 days). On the experiment day, male rats or diestrus female rats were euthanized 30 min after the FST. Our results showed that progesterone significantly increased the α1 subunit mRNA in both hemispheres of male and female rats. Moreover, there was an inverse correlation between depressive‐like behaviors and GABA_AR α1 subunit mRNA expression in the right hemisphere in female rats. Progesterone decreased the GABA_AR γ2 mRNA expression only in the left hemisphere of male rats. Therefore, we conclude that the GABA_A system displays an asymmetric distribution according to sex and that progesterone, at lower doses, presents an antidepressant effect after increasing the GABA_AR α1 subunit expression in the right prefrontal cortex of female rats. Copyright © 2012 John Wiley & Sons, Ltd.