Synthèse de composés nitrocyclopropanes et nitroarylcyclopropanes & étude électrochimique du radical anion correspondant

Ce mémoire présente l'ensemble des travaux accomplis sur la synthèse et l'analyse électrochimique en réduction des nitroarylcyclopropanes et des nitrocyclopropanes. Les analyses électrochimiques en réduction des composés nitro ont été réalisées en milieu aprotique sur platine au moyen d'un dispositif voltampérométrique cyclique spécifique et par électrolyse préparative à potentiel contrôlé. Les études furent réalisées dans l'acétonitrile sous atmosphère inerte en présence de hexafluorophosphate de tétrabutylammonium (c = 0,1M) comme électrolyte support et une électrode de référence Ag/AgNO[indice inférieur 3]0,1M. Dans la première partie de ce mémoire, la réduction électrochimique des p-nitroarylcyclopropanes a été réalisée. Cette étude consiste à mesurer l'effet qu'ont les substituants du cyclopropane (électroattracteurs ou donneurs) sur le potentiel de réduction du nitroaryle. Il a même été observé que les substituants qui influencent le potentiel de réduction du nitroaryle, influencent aussi l'allure de la vague de réduction en voltampérométrie cyclique. Par exemple, nos résultats ont montré que les groupements attracteurs donnent des pics de réduction irréversibles correspondant au transfert de deux électrons. Lorsque ces mêmes para-nitroarylcyclopropanes sont placés dans les conditions d'électrolyse, les produits d'ouverture du cycle cyclopropanique sont obtenus. D'autre part, lorsque le cyclopropane porte des groupements aryles donneurs, on note par voltampérométrie cyclique un comportement électrochimique similaire à celui du nitrobenzène, soit un système rédox nitro/radical anion nitro réversible ainsi que des potentiels de réduction semblables à celui du nitrobenzène. Lorsque ces mêmes composés sont soumis aux conditions d'électrolyse, ils ont des comportements non reproductibles et difficiles à analyser. L'autre partie de ce mémoire porte sur l'étude électrochimique des nitrocyclopropanes. Ils sont eux aussi substitués par des groupements attracteurs ou donneurs. Pour cette famille de composés, les résultats électrochimiques se ressemblent et ils sont reproductibles. La totalité des voltampérogrammes présente une vague de réduction irréversible à basse vitesse de balayage. Le potentiel de réduction et le nombre d'électrons transférés varient en fonction des substituants présents sur le cyclopropane. Lorsque ces composés sont soumis aux conditions d'électrolyse, les nitrocyclopropanes subissent une réduction menant à l'ouverture du cycle et dans quelques rares cas, des produits issus d'une dismutation peuvent être récupérés

In vitro assessment of skin sensitization, irritability and toxicity of bacteriocins and reuterin for possible topical applications

Bacteriocins and reuterin are promising antimicrobials for application in food, veterinary, and medical sectors. In the light of their high potential for application in hand sanitizer, we investigated the skin toxicity of reuterin, microcin J25, pediocin PA-1, bactofencin A, and nisin Z in vitro using neutral red and LDH release assays on NHEK cells. We determined their skin sensitization potential using the human cell line activation test (h-CLAT). Their skin irritation potential was measured on human epidermal model EpiDerm™. We showed that the viability and membrane integrity of NHEK cells remained unaltered after exposure to bacteriocins and reuterin at concentrations up to 400 µg/mL and 80 mg/mL, respectively. Furthermore, microcin J25 and reuterin showed no skin sensitization at concentrations up to 100 µg/mL and 40 mg/mL, respectively, while pediocin PA-1, bactofencin A, and nisin Z caused sensitization at concentrations higher than 100 µg/mL. Tissue viability was unafected in presence of bacteriocins and reuterin at concentrations up to 200 µg/mL and 40 mg/ mL, respectively, which was confrmed by measuring cytokine IL-1α and IL-8 levels and by histological analysis. In conclusion, the current study provides scientifc evidence that some bacteriocins and reuterin, could be safely applied topically as sanitizers at recommended concentration

Genome-wide association study of dietary pattern scores

Dietary patterns, representing global food supplies rather than specific nutrients or food intakes, have been associated with cardiovascular disease (CVD) incidence and mortality. The contribution of genetic factors in the determination of food intakes, preferences and dietary patterns has been previously established. The current study aimed to identify novel genetic factors associated with reported dietary pattern scores. Reported dietary patterns scores were derived from reported dietary intakes for the preceding month and were obtained through a food frequency questionnaire and genome-wide association study (GWAS) conducted in a study sample of 141 individuals. Reported Prudent and Western dietary patterns demonstrated nominal associations (p < 1 × 10−5) with 78 and 27 single nucleotide polymorphisms (SNPs), respectively. Among these, SNPs annotated to genes previously associated with neurological disorders, CVD risk factors and obesity were identified. Further assessment of SNPs demonstrated an impact on gene expression levels in blood for SNPs located within/near BCKDHB (p = 0.02) and the hypothalamic glucosensor PFKFB3 (p = 0.0004) genes, potentially mediated through an impact on the binding of transcription factors (TFs). Overrepresentations of glucose/energy homeostasis and hormone response TFs were also observed from SNP-surrounding sequences. Results from the current GWAS study suggest an interplay of genes involved in the metabolic response to dietary patterns on obesity, glucose metabolism and food-induced response in the brain in the adoption of dietary patterns

A common variant in ARHGEF10 alters delta-6 desaturase activity and influence susceptibility to hypertriglyceridemia

Background. Numbers of single nucleotide polymorphisms (SNPs) associated with fatty acid desaturase activities have been previously identified within the FADS1-FADS2 gene cluster, which encodes delta-5 (D5D) and delta-6 (D6D) desaturases, respectively. Objective. We aimed at further characterizing the genetic variability associated with D5D and D6D activities on a genome-wide scale. Methods. We conducted a genome-wide association study of D5D and D6D activities in a cohort of 141 individuals from the greater Quebec City metropolitan area using the Illumina HumanOmni5-Quad BeadChip. Estimates of D5D and D6D activities were computed using product-to-precursor fatty acid ratios, arachidonic acid (AA)/dihomogamma-linolenic acid (DGLA) for D5D, and DGLA/linoleic acid (LA) for D6D. Levels of fatty acids were measured by gas chromatography in plasma phospholipids. Results. We identified 24 previously reported SNPs associated with fatty acid levels and desaturase activities as significantly associated with D5D activity within the FADS1- FADS2 gene cluster (lead SNP rs174566/A>G). Furthermore, we identified 5 novel loci potentially associated with D5D activity at chromosomes 1, 6, 4, 8 and 19. A novel SNP associated with D6D activity and mapped to the ARHGEF10 locus (rs2280885/A>G) was identified, with carriers of the rare allele showing a significant increase in D6D activity and plasma triglyceride levels. After multiple testing correction by permutation, only rs174566 and rs2280885 remained significantly associated to D5D and D6D activity estimates, respectively. Conclusions. These results confirm previous genetic associations within the FADS1- FADS2 gene cluster with D5D activity. A novel genetic variation associated with higher D6D activity within the ARHGEF10 gene is potentially altering plasma triglyceride levels

Gastrointestinal stability and cytotoxicity of bacteriocins from gram-positive and gram-negative bacteria : a comparative in vitro study

Bacteriocins are receiving increased attention as potent candidates in food preservation and medicine. Although the inhibitory activity of bacteriocins has been studied widely, little is known about their gastrointestinal stability and toxicity toward normal human cell lines. The aim of this study was to evaluate the gastrointestinal stability and activity of microcin J25, pediocin PA-1, bactofencin A and nisin using in vitro models. In addition cytotoxicity and hemolytic activity of these bacteriocins were investigated on human epithelial colorectal adenocarcinoma cells (Caco-2) and rat erythrocytes, respectively. Pediocin PA-1, bactofencin A, and nisin were observed to lose their stability while passing through the gastrointestinal tract, while microcin J25 is only partially degraded. Besides, selected bacteriocins were not toxic to Caco-2 cells, and integrity of cell membrane was observed to remain unaffected in presence of these bacteriocins at concentrations up to 400 µg/mL. In hemolysis study, pediocin PA-1, bactofencin A, and nisin were observed to lyse rat erythrocytes at concentrations higher than 50 µg/mL, while microcin J25 showed no effect on these cells. According to data indicating gastrointestinal degradation and the absence of toxicity of pediocin PA-1, bactofencin A, and microcin J25 they could potentially be used in food or clinical applications

Novel genetic loci associated with the plasma triglyceride response to an omega-3 fatty acid supplementation

A recent genome-wide association study (GWAS) by our group identified 13 loci associated with the plasma triglyceride (TG) response to omega-3 (n-3) fatty acid (FA) supplementation. This study aimed to test whether single-nucleotide polymorphisms (SNPs) within the IQCJ, NXPH1, PHF17 and MYB genes are associated with the plasma TG response to an n-3 FA supplementation. Methods: A total of 208 subjects followed a 6-week n-3 FA supplementation of 5 g/day of fish oil (1.9-2.2 g of eicosapentaenoic acid and 1.1 g of docosahexaenoic acid). Measurements of plasma lipids were made before and after the supplementation. Sixty-seven tagged SNPs were selected to increase the density of markers near GWAS hits. Results: In a repeated model, independent effects of the genotype and the gene-supplementation interaction were associated with plasma TG. Genotype effects were observed with two SNPs of NXPH1, and gene-diet interactions were observed with ten SNPs of IQCJ, four SNPs of NXPH1 and three SNPs of MYB. Positive and negative responders showed different genotype frequencies with nine SNPs of IQCJ, two SNPs of NXPH1 and two SNPs of MYB. Conclusion: Fine mapping in GWAS-associated loci allowed the identification of SNPs partly explaining the large interindividual variability observed in plasma TG levels in response to an n-3 FA supplementation

Le calcanéus « Regourdou 2 » : étude morphométrique comparative et discussion autour de sa place dans la variabilité des Néandertaliens

1 - Introduction En 2008, lors du récolement des collections au Musée National de Préhistoire aux Eyzies-de-Tayac, des restes humains sont retrouvés dans les caisses de faune du site de Regourdou parmi lesquels des fragments de la ceinture pelvienne, un important fragment de fémur, une patella, des fragments du tibia et de la fibula gauche. Ces restes appartiennent au squelette Regourdou 1 (Madelaine et al. 2008) et ils complètent parfaitement l’inventaire des pièces découvertes en septembre ..

Fine mapping of GWAS signals to identify genetic markers of the plasma triglyceride response to an omega-3 fatty acid supplementation

Background: Using a genome-wide association study (GWAS) approach, our group previously computed a genetic risk score (GRS) from single nucleotide polymorphisms (SNPs) of ten loci which affect the plasma triglyceride (TG) response to an omega-3 (n-3) fatty acid (FA) supplementation. Objective: The objective was to compute a novel and more refined GRS using fine mapping to include a large number of genetic variants. Design: A total of 208 participants of the Fatty Acid Sensor (FAS) study received 5g of fish oil per day, containing 1.9–2.2g of eicosapentanoic acid and 1.1g of docosahexanoic acid, for six weeks. Plasma TG levels were measured before and after supplementation. Dense genotyping and genotype imputation were employed to refine mapping around GWAS hits. A GRS was computed by summing the number of at-risk alleles of tagging SNPs. Analyses were replicated in samples of the FINGEN study. Results: A total of 31 tagging SNPs associated with the TG response were used for GRS calculation in the FAS study. In a general linear model adjusted for age, sex and body mass index, the GRS explained 49.73% of TG response variance (p < 0.0001). Non-responders to the n-3 FA supplementation had a higher GRS than responders. In the FINGEN replication study, the GRS explained 3.67% of TG response variance (p = 0.0006). Conclusion: Fine mapping proved to be effective to refine the previous GRS. Carrying increasing numbers of at-risk alleles of 31 SNPs confers a higher risk of being non-responsive to n-3 FA. The genetic profile therefore appears to be an important determinant of the plasma TG response to an n-3 FA supplementation and could be used to target those most likely to gain clinical benefit

Implications of Proprotein Convertases in Ovarian Cancer Cell Proliferation and Tumor Progression: Insights for PACE4 as a Therapeutic Target

AbstractProprotein convertases are a family of kexin-like serine proteases that process proteins at single and multiple basic residues. Among the predicted and identified PC substrates, an increasing number of proteins having functions in cancer progression indicate that PCs may be potential targets for antineoplastic drugs. In support of this notion, we identified PACE4 as a vital PC involved in prostate cancer proliferation and progression, contrasting with the other co-expressed PCs. The aim of the present study was to test the importance of PCs in ovarian cancer cell proliferation and tumor progression. Based on tissue-expression profiles, furin, PACE4, PC5/6 and PC7 all displayed increased expression in primary tumor, ascites cells and metastases. These PCs were also expressed in variable levels in three model ovarian cell lines tested, namely SKOV3, CAOV3 and OVCAR3 cells. Since SKOV3 cells closely represented the PC expression profile of ovarian cancer cells, we chose them to test the effects of PC silencing using stable gene-silencing shRNA strategy to generate knockdown SKOV3 cells for each expressed PC. In vitro and in vivo assays confirmed the role of PACE4 in the sustainment of SKOV3 cell proliferation, which was not observed with the other three PCs. We also tested PACE4 peptide inhibitors on all three cell lines and observed consequent reduced cell proliferation which was correlated with PACE4 expression. Overall, these data support a role of PACE4 in promoting cell proliferation in ovarian cancer and provides further evidence for PACE4 as a potential therapeutic target