CYP1B1: A Promising Target in Cancer Drug Discovery.

CYP1B1 plays an essential role in cancer's pathogenesis since it activates procarcinogens. Significantly, this enzyme catalyzes the hydroxylation of 17ß-estradiol, leading to carcinogenic metabolites involved in carcinogenesis and cancer progression. Therefore, the inhibition of CYP1B1 activity is considered a therapeutic target for chemotherapy. In addition, CYP1B1 is overexpressed in hormone-dependent cancer cells and could be related to resistance to anticancer drugs. However, the activity of CYP1B1 in the tumor microenvironment can metabolize and activate prodrugs in cancer cells, providing more selectivity and being useful for chemoprevention or chemotherapy strategies. Furthermore, due to its importance in anticancer drug design, recent studies have reported using computational methods to understand the intermolecular interactions between possible ligands and CYP1B1. Therefore, in this perspective, we highlight recent findings in developing CYP1B1 inhibitors (flavonoids, trans-stilbenes, estradiol derivatives, and carbazoles) and CYP1B1-activated prodrugs (a chalcone DMU-135 and an oxime DMAKO-20). Finally, we have analyzed their possible molecular interactions with this enzymatic target by molecular docking, which can help to design new active substances.

Alternative nitrogenase of Paenibacillus sonchi genomovar Riograndensis: An insight in the origin of Fe-nitrogenase in the Paenibacillaceae family.

Paenibacillus sonchi genomovar Riograndensis is a nitrogen-fixing bacteria isolated from wheat that displays diverse plant growth-promoting abilities. Beyond conventional Mo-nitrogenase, this organism also harbors an alternative Fe-nitrogenase, whose many aspects related to regulation, physiology, and evolution remain to be elucidated. In this work, the origins of this alternative system were investigated, exploring the distribution and diversification of nitrogenases in the Panibacillaceae family. Our analysis showed that diazotrophs represent 17% of Paenibacillaceae genomes, of these, only 14.4% (2.5% of all Paenibacillaceae genomes) also contained Fe or V- nitrogenases. Diverse nif-like sequences were also described, occurring mainly in genomes that also harbor the alternative systems. The analysis of genomes containing Fe-nitrogenase showed a conserved cluster of nifEN anfHDGK across three genera: Gorillibacterium, Fontibacillus, and Paenibacillus. A phylogeny of anfHDGK separated the Fe-nitrogenases into three main groups. Our analysis suggested that Fe-nitrogenase was acquired by the ancestral lineage of Fontibacillus, Gorillibacterium, and Paenibacillus genera via horizontal gene transfer (HGT), and further events of transfer and gene loss marked the evolution of this alternative nitrogenase in these groups. The species phylogeny of N-fixing Paenibacillaceae separated the diazotrophs into five clades, one of these containing all occurrences of strains harboring alternative nitrogenases in the Paenibacillus genus. The pangenome of this clade is open and composed of more than 96% of accessory genes. Diverse functional categories were enriched in the flexible genome, including functions related to replication and repair. The latter involved diverse genes related to HGT, suggesting that such events may have an important role in the evolution of diazotrophic Paenibacillus. This study provided an insight into the organization, distribution, and evolution of alternative nitrogenase genes in Paenibacillaceae, considering different genomic aspects.

Evaluation of Cardiovascular Risk in Hypertensive Individuals Attending a Primary Health Care Center

Abstract Background: Cardiovascular risk (CVR) stratification has traditionally been used as a strategy for the prevention of cardiovascular diseases in asymptomatic people. Objective: To identify the CVR in hypertensive patients attending a primary health care center, using the Framingham risk score, and to evaluate possible associations and correlations with sociodemographic, clinical and laboratory variables not included in this score. This cross-sectional study was conducted with hypertensive patients treated in a primary health care center in Brazil (n = 166). Methods: Data collection, administration of questionnaires, anthropometric measurements and laboratory tests were performed from July to August 2013. Multiple linear regression was used in the analysis. A two-tailed p-value < 0.05 was considered significant. Results: High CVR was independently associated with male sex (B = 8.73; 95%CI: 6.27: 11.19), high serum levels of total cholesterol (B = 0.05; IC95%: 0.02: 0.08), number of drugs used (B = 0.55; 95%Ci: 0.12: 0.98) and a low glomerular filtration rate (GFR) (B = -0.11; 95%CI: -0.18 : -0.03). Conclusion: The results of this study reinforce the importance of continuous and longitudinal care practices directed to hypertensive patients aiming at early detection of risk factors and appropriate intervention to improve the prognosis of this population.

Glutamine synthetase stabilizes the binding of GlnR to nitrogen fixation gene operators.

Biological nitrogen fixation (BNF) is a high energy demanding process carried out by diazotrophic microorganisms that supply combined nitrogen to the biosphere. The genes related to BNF are strictly regulated, but these mechanisms are poorly understood in gram-positive bacteria. The transcription factor GlnR was proposed to regulate nitrogen fixation-related genes based on Paenibacillus comparative genomics. In order to validate this proposal, we investigated BNF regulatory sequences in Paenibacillus riograndensis SBR5T genome. We identified GlnR-binding sites flanking σA -binding sites upstream from BNF-related genes. GlnR binding to these sites was demonstrated by surface plasmon resonance spectroscopy. GlnR-DNA affinity is greatly enhanced when GlnR is in complex with feedback-inhibited (glutamine-occupied) glutamine synthetase (GS). GlnR-GS complex formation is also modulated by ATP and AMP. Thereby, gene repression exerted by the GlnR-GS complex is coupled with nitrogen (glutamine levels) and energetic status (ATP and AMP). Finally, we propose a DNA-looping model based on multiple operator sites that represents a strong and strict regulation for these genes.

INTERACTING DISCIPLINES: Cardiac natriuretic peptides and obesity: perspectives from an endocrinologist and a cardiologist.

Since their discovery in 1981, the cardiac natriuretic peptides (cNP) atrial natriuretic peptide (also referred to as atrial natriuretic factor) and brain natriuretic peptide have been well characterised in terms of their renal and cardiovascular actions. In addition, it has been shown that cNP plasma levels are strong predictors of cardiovascular events and mortality in populations with no apparent heart disease as well as in patients with established cardiac pathology. cNP secretion from the heart is increased by humoral and mechanical stimuli. The clinical significance of cNP plasma levels has been shown to differ in obese and non-obese subjects. Recent lines of evidence suggest important metabolic effects of the cNP system, which has been shown to activate lipolysis, enhance lipid oxidation and mitochondrial respiration. Clinically, these properties lead to browning of white adipose tissue and to increased muscular oxidative capacity. In human association studies in patients without heart disease higher cNP concentrations were observed in lean, insulin-sensitive subjects. Highly elevated cNP levels are generally observed in patients with systolic heart failure or high blood pressure, while obese and type-2 diabetics display reduced cNP levels. Together, these observations suggest that the cNP system plays a role in the pathophysiology of metabolic vascular disease. Understanding this role should help define novel principles in the treatment of cardiometabolic disease.

[The endocrine heart and inflammation]. / El corazón endocrino y el proceso inflamatorio.

The endocrine heart produces the polypeptide hormones Atrial Natriuretic Factor (ANF or ANP) and Brain Natriuretic Peptide (BNP). Through the peripheral actions of these hormones the heart contributes to the regulation of the cardiac preload and afterload. More recently, new functions for these hormones have been described including the modulation of the immune response. Plasma levels of BNP but not those of ANF, increase following an acute rejection episode of a cardiac allotransplant but return to levels pre-rejection with successful treatment. This observation constitutes the first observation leading to characterizing the interactions of BNP with the immune response. Several other pathologies with an inflammatory component are now known to be associated with an increase in the production of BNP. Such an increase is due to an increase in the transcriptional activity of the BNP gene induced by cytokines and related substances. In vitro investigations have shown that an increase in BNP directly modulates immunological activity. Inflammation and hemodynamic changes co-exist in several cardiovascular diseases and therefore it may be beneficial to measure circulating levels of both ANF and BNP as biomarkers of changes in intravascular volume and of changes in intravascular volume plus inflammation, respectively. Changes in plasma ANF, that are relatively larger than those of BNP, might be an indication of hemodynamic deterioration while important changes in circulating BNP could indicate a worsening of the inflammatory process.