Red wine and components flavonoids inhibit UGT2B17 in vitro

Background The metabolism and excretion of the anabolic steroid testosterone occurs by glucuronidation to the conjugate testosterone glucuronide which is then excreted in urine. Alterations in UGT glucuronidation enzyme activity could alter the rate of testosterone excretion and thus its bioavailability. The aim of this study is to investigate if red wine, a common dietary substance, has an inhibitory effect on UGT2B17. Methods Testosterone glucuronidation was assayed using human UGT2B17 supersomes with quantification of unglucuronidated testosterone over time using HPLC with DAD detection. The selected red wine was analysed using HPLC and the inhibitory effects of the wine and phenolic components were tested independently in a screening assay. Further analyses were conducted for the strongest inhibitors at physiologically relevant concentrations. Control experiments were conducted to determine the effects of the ethanol on UGT2B17. Results Over the concentration range of 2 to 8% the red wine sample inhibited the glucuronidation of testosterone by up to 70% over 2 hours. The ethanol content had no significant effect. Three red wine phenolics, identified by HLPC analyses, also inhibited the enzyme by varying amounts in the order of quercetin (72%), caffeic acid (22%) and gallic acid (9%); using a ratio of phenolic:testosterone of 1:2.5. In contrast p-coumaric acid and chlorogenic acid had no effect on the UGT2B17. The most active phenolic was selected for a detailed study at physiologically relevant concentrations, and quercetin maintained inhibitory activity of 20% at 2 M despite a ten-fold excess of testosterone. Conclusion This study reports that in an in vitro supersome-based assay, the key steroid-metabolising enzyme UGT2B17 is inhibited by a number of phenolic dietary substances and therefore may reduce the rate of testosterone glucuronidation in vivo. These results highlight the potential interactions of a number of common dietary compounds on testosterone metabolism. Considering the variety of foodstuffs that contain flavonoids, it is feasible that diet can elevate levels of circulating testosterone through reduction in urinary excretion. These results warrant further investigation and extension to a human trial to delineate the healt

Aerosolized Delivery of Antifungal Agents

Pulmonary infections caused by Aspergillus species are associated with significant morbidity and mortality in immunocompromised patients. Although the treatment of pulmonary fungal infections requires the use of systemic agents, aerosolized delivery is an attractive option in prevention because the drug can concentrate locally at the site of infection with minimal systemic exposure. Current clinical evidence for the use of aerosolized delivery in preventing fungal infections is limited to amphotericin B products, although itraconazole, voriconazole, and caspofungin are under investigation. Based on conflicting results from clinical trials that evaluated various amphotericin B formulations, the routine use of aerosolized delivery cannot be recommended. Further research with well-designed clinical trials is necessary to elucidate the therapeutic role and risks associated with aerosolized delivery of antifungal agents. This article provides an overview of aerosolized delivery systems, the intrapulmonary pharmacokinetic properties of aerosolized antifungal agents, and key findings from clinical studies

The Changing Face of Neolithic and Bronze Age Ireland: A Big Data Approach to the Settlement and Burial Records

This paper synthesizes and analyses the spatial and temporal patterns of archaeological sites in Ireland spanning the Neolithic period and the Bronze Age transition (4300-1900 cal BC). Included are a large number of unpublished, newly discovered sites excavated through development-led projects. Data were also sourced from national archives, published excavation reports and on-line databases. Software tools were developed to deal with the varying nature and resolution of these datasets, allowing chronology to be considered in the analysis to a degree that is usually not possible in prehistoric studies. Summed radiocarbon probabilities are used to examine the dataset using context- and sample-sensitive approaches. Visualisations of spatial and chronological data illustrate the expansion of Early Neolithic settlement, followed by an apparent attenuation of all settlement activity. The Late Neolithic and Chalcolithic periods are characterised by a resurgence and diversification of activity. To assess the significance of these observations, Irish radiocarbon data are compared to an idealized model derived from North American data. Even after taking various considerations into account, human population increases can be suggested to have occurred during the Early and Late Neolithic periods. Gaps and biases in the data are discussed and priorities for future work are identified

From influence to impact: the multifunctional land-use in Mediterranean prehistory emerging from palynology of archaeological sites (8.0-2.8 ka BP)

Archaeobotany is used to discover details on local land uses in prehistoric settlements developed during the middle and beginning of late Holocene. Six archaeological sites from four countries (Spain, Italy, Greece, and Turkey) have pollen and charcoal records showing clear signs of the agrarian systems that had developed in the Mediterranean basin during different cultural phases, from pre-Neolithic to Recent Bronze Age. A selected list of pollen taxa and sums, including cultivated trees, other woody species, crops and annual or perennial synanthropic plants are analysed for land use reconstructions. In general, cultivation has a lower image in palynology than forestry, and past land uses became visible when oakwoods were affected by human activities. On-site palynology allows us to recognise the first influence of humans even before it can be recognised in off-site sequences, and off-site sequences can allow us to determine the area of influence of a site. Neolithic and Bronze Age archaeological sites show similar land use dynamics implying oak exploitation, causing local deforestation, and cultivation of cereal fields in the area or around the site. Although a substantial difference makes the Neolithic influence quite distant from the Bronze Age impact, mixed systems of land exploitation emerged everywhere. Multiple land use activities exist (multifunctional landscapes) at the same time within the area of influence of a site. Since the Neolithic, people have adopted a diffuse pattern of land use involving a combination of diverse activities, using trees\u2013crops\u2013domesticated animals. The most recurrent combination included wood exploitation, field cultivation and animal breeding. The lesson from the past is that the multifunctional land use, combining sylvo-pastoral and crop farming mixed systems, has been widely adopted for millennia, being more sustainable than the monoculture and a promising way to develop our economy

Decoupling Environment-Dependent and Independent Genetic Robustness across Bacterial Species

The evolutionary origins of genetic robustness are still under debate: it may arise as a consequence of requirements imposed by varying environmental conditions, due to intrinsic factors such as metabolic requirements, or directly due to an adaptive selection in favor of genes that allow a species to endure genetic perturbations. Stratifying the individual effects of each origin requires one to study the pertaining evolutionary forces across many species under diverse conditions. Here we conduct the first large-scale computational study charting the level of robustness of metabolic networks of hundreds of bacterial species across many simulated growth environments. We provide evidence that variations among species in their level of robustness reflect ecological adaptations. We decouple metabolic robustness into two components and quantify the extents of each: the first, environmental-dependent, is responsible for at least 20% of the non-essential reactions and its extent is associated with the species' lifestyle (specialized/generalist); the second, environmental-independent, is associated (correlation = ∼0.6) with the intrinsic metabolic capacities of a species—higher robustness is observed in fast growers or in organisms with an extensive production of secondary metabolites. Finally, we identify reactions that are uniquely susceptible to perturbations in human pathogens, potentially serving as novel drug-targets