Bulky DNA adducts, 4-aminobiphenyl-haemoglobin adducts and diet in the European Prospective Investigation into Cancer and Nutrition (EPIC) prospective study

In contrast to some extensively examined food mutagens, for example, aflatoxins, N-nitrosamines and heterocyclic amines, some other food contaminants, in particular polycyclic aromatic hydrocarbons (PAH) and other aromatic compounds, have received less attention. Therefore, exploring the relationships between dietary habits and the levels of biomarkers related to exposure to aromatic compounds is highly relevant. We have investigated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort the association between dietary items (food groups and nutrients) and aromatic DNA adducts and 4-aminobiphenyl-Hb adducts. Both types of adducts are biomarkers of carcinogen exposure and possibly of cancer risk, and were measured, respectively, in leucocytes and erythrocytes of 1086 (DNA adducts) and 190 (Hb adducts) non-smokers. An inverse, statistically significant, association has been found between DNA adduct levels and dietary fibre intake (P = 0·02), vitamin E (P = 0·04) and alcohol (P = 0·03) but not with other nutrients or food groups. Also, an inverse association between fibre and fruit intake, and BMI and 4-aminobiphenyl-Hb adducts (P = 0·03, 0·04, and 0·03 respectively) was observed. After multivariate regression analysis these inverse correlations remained statistically significant, except for the correlation adducts v. fruit intake. The present study suggests that fibre intake in the usual range can modify the level of DNA or Hb aromatic adducts, but such role seems to be quantitatively modest. Fibres could reduce the formation of DNA adducts in different manners, by diluting potential food mutagens and carcinogens in the gastrointestinal tract, by speeding their transit through the colon and by binding carcinogenic substances.

Sources of pre-analytical variations in yield of DNA extracted from blood samples: analysis of 50,000 DNA samples in EPIC.

The European Prospective Investigation into Cancer and nutrition (EPIC) is a long-term, multi-centric prospective study in Europe investigating the relationships between cancer and nutrition. This study has served as a basis for a number of Genome-Wide Association Studies (GWAS) and other types of genetic analyses. Over a period of 5 years, 52,256 EPIC DNA samples have been extracted using an automated DNA extraction platform. Here we have evaluated the pre-analytical factors affecting DNA yield, including anthropometric, epidemiological and technical factors such as center of subject recruitment, age, gender, body-mass index, disease case or control status, tobacco consumption, number of aliquots of buffy coat used for DNA extraction, extraction machine or procedure, DNA quantification method, degree of haemolysis and variations in the timing of sample processing. We show that the largest significant variations in DNA yield were observed with degree of haemolysis and with center of subject recruitment. Age, gender, body-mass index, cancer case or control status and tobacco consumption also significantly impacted DNA yield. Feedback from laboratories which have analyzed DNA with different SNP genotyping technologies demonstrate that the vast majority of samples (approximately 88%) performed adequately in different types of assays. To our knowledge this study is the largest to date to evaluate the sources of pre-analytical variations in DNA extracted from peripheral leucocytes. The results provide a strong evidence-based rationale for standardized recommendations on blood collection and processing protocols for large-scale genetic studies.

Targeting aquaporin function: potent inhibition of aquaglyceroporin-3 by a gold-based compound.

Aquaporins (AQPs) are membrane channels that conduct water and small solutes such as glycerol and are involved in many physiological functions. Aquaporin-based modulator drugs are predicted to be of broad potential utility in the treatment of several diseases. Until today few AQP inhibitors have been described as suitable candidates for clinical development. Here we report on the potent inhibition of AQP3 channels by gold(III) complexes screened on human red blood cells (hRBC) and AQP3-transfected PC12 cells by a stopped-flow method. Among the various metal compounds tested, Auphen is the most active on AQP3 (IC(50) = 0.8±0.08 µM in hRBC). Interestingly, the compound poorly affects the water permeability of AQP1. The mechanism of gold inhibition is related to the ability of Au(III) to interact with sulphydryls groups of proteins such as the thiolates of cysteine residues. Additional DFT and modeling studies on possible gold compound/AQP adducts provide a tentative description of the system at a molecular level. The mapping of the periplasmic surface of an homology model of human AQP3 evidenced the thiol group of Cys40 as a likely candidate for binding to gold(III) complexes. Moreover, the investigation of non-covalent binding of Au complexes by docking approaches revealed their preferential binding to AQP3 with respect to AQP1. The high selectivity and low concentration dependent inhibitory effect of Auphen (in the nanomolar range) together with its high water solubility makes the compound a suitable drug lead for future in vivo studies. These results may present novel metal-based scaffolds for AQP drug development.

Higher red blood cell distribution width is associated with a worse virologic and clinical situation in HIV-infected patients.

Background A high level of red blood cell distribution width (RDW) is a novel prognostic marker that may reflect an underlying inflammatory state. It has recently shown that when increased, it is related to cardiovascular disease, mortality, and metabolic syndrome (MetS) in the general population. Objectives To analyse the potential relation between high levels of RDW and cardiovascular risk (CVR) and MetS in HIVpatients. Patients and methods Observational, cross-sectional study of a series of HIVoutpatients attended in our Hospital. Demographic, anthropometric, clinical, and fasting lab data were recorded in all cases. CVR at 10 years was evaluated by Framingham equation, and MetS diagnosed according to the National Cholesterol Education Program criteria. Statistic program: SPSS 17.0. Results 666 patients were included, 79.3% were men, and mean age was 44.7 years. Mean CD4 count was 506 cells/ mm3 , 87.5% of the patients were on antiretroviral therapy, and 85.3% had undetectable HIV viral load. Mean RDW was 13.07% (range: 7.7-33.6%; 75th percentile 14,1%), with a prevalence of MetS of 15.7, 9.3, 18.8 and 16.6% first through fourth RDW quartile, and of patients with CVR >20% of 8.4, 4.0, 4.4 and 6.4%, respectively (p>0,05). The highest quartile of RDW (>14.1%) was associated with AIDS (OR 1.6, 95%CI 1.0-2.4; p 0.02), detectable HIV viral load (OR 1.5, 95%CI 1.01-2.4; p 0.04), and hypertension (OR 2.3, 95%CI 1.4-4.0; p 0.001). Conclusions In HIV-infected outpatients, higher RDW is related with detectable HIV viral load and with AIDS. Although it was associated with a traditional CVR factor as hypertension, we found no relation with MetS nor with higher CVR.

Deficient selenium status of a healthy adult Spanish population.

INTRODUCTION Selenium is an essential micronutrient for human health, being a cofactor for enzymes with antioxidant activity that protect the organism from oxidative damage. An inadequate intake of this mineral has been associated with the onset and progression of chronic diseases such as hypertension, diabetes, coronary diseases, asthma, and cancer. For this reason, knowledge of the plasma and erythrocyte selenium levels of a population makes a relevant contribution to assessment of its nutritional status. OBJECTIVE The objective of the present study was to determine the nutritional status of selenium and risk of selenium deficiency in a healthy adult population in Spain by examining food and nutrient intake and analyzing biochemical parameters related to selenium metabolism, including plasma and erythrocyte levels and selenium-dependent glutathione peroxidase (GPx) enzymatic activity. MATERIAL AND METHODS We studied 84 healthy adults (31 males and 53 females) from the province of Granada, determining their plasma and erythrocyte selenium concentrations and the association of these levels with the enzymatic activity of glutathione peroxidase (GPx) and with life style factors. We also gathered data on their food and nutrient intake and the results of biochemical analyses. Correlations were studied among all of these variables. RESULTS The mean plasma selenium concentration was 76.6 ± 17.3 μg/L (87.3 ± 17.4 μg/L in males, 67.3 ± 10.7 μg/L in females), whereas the mean erythrocyte selenium concentration was 104.6 μg/L (107.9 ± 26.1 μg/L in males and 101.7 ± 21.7 μg/L in females). The nutritional status of selenium was defined by the plasma concentration required to reach maximum GPx activity, establishing 90 μg/L as reference value. According to this criterion, 50% of the men and 53% of the women were selenium deficient. CONCLUSIONS Selenium is subjected to multiple regulation mechanisms. Erythrocyte selenium is a good marker of longer term selenium status, while plasma selenium appears to be a marker of short-term nutritional status. The present findings indicate a positive correlation between plasma selenium concentration and the practice of physical activity. Bioavailability studies are required to establish appropriate reference levels of this mineral for the Spanish population.

Accumulation of scandium in plasma in patients with chronic renal failure.

Scandium (Sc) is an element with many industrial applications, but relatively little is known about its physiological and/or toxicological effects, and very little data are available concerning the role of Sc in chronic renal failure (CRF). This paper examines the changes in plasma levels of Sc in predialysis patients with CRF and the relationship with blood parameters. The participants in this trial were 48 patients with CRF in predialysis and 53 healthy controls. Erythrocyte, haemoglobin, and haematocrit counts in blood were determined, and levels of creatinine, urea, uric acid, albumin, total protein and Sc were measured in plasma. The glomerular filtration rate (GFR) was calculated using the Cockcroft-Gault index. The CRF patients were found to have higher plasma levels of creatinine, urea, uric acid, albumin, total protein, and Sc and a lower GFR than that the controls. Scandium in plasma was positively correlated with creatinine and plasma urea and negatively correlated with GFR, haemoglobin, and haematocrit and was associated with the risk of lower levels of erythrocytes, haemoglobin, and haematocrit. CRF was associated with increases in the circulating levels of scandium.