Differences in Transcriptional Activation by the Two Allelic (L162V Polymorphic) Variants of PPARα after Omega-3 Fatty Acids Treatment

Omega-3 fatty acids (FAs) have the potential to regulate gene expression via the peroxisome proliferator-activated receptor α (PPARα); therefore, genetic variations in this gene may impact its transcriptional activity on target genes. It is hypothesized that the transcriptional activity by wild-type L162-PPARα is enhanced to a greater extent than the mutated variant (V162-PPARα) in the presence of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or a mixture of EPA:DHA. To examine the functional difference of the two allelic variants on receptor activity, transient co-transfections were performed in human hepatoma HepG2 cells activated with EPA, DHA and EPA:DHA mixtures. Results indicate that the addition of EPA or DHA demonstrate potential to increase the transcriptional activity by PPARα with respect to basal level in both variants. Yet, the EPA:DHA mixtures enhanced the transcriptional activity to a greater extent than individual FAs indicating possible additive effects of EPA and DHA. Additionally, the V162 allelic form of PPARα demonstrated consistently lower transcriptional activation when incubated with EPA, DHA or EPA:DHA mixtures than, the wild-type variant. In conclusion, both allelic variants of the PPARα L162V are activated by omega-3 FAs; however, the V162 allelic form displays a lower transcriptional activity than the wild-type variant

Alfred Golliard, préfet résistant (1881-1944): Matériaux pour une biographie

Éléments de biographie d'Alfred Émile Golliard, qui fut secrétaire général de la préfecture du Bas-Rhin (1925-1934) avant d'être nommé préfet du Jura en octobre 1934. Révoqué par le régime de Vichy en septembre 1940. Résistant dans le réseau 'Tiburce" (Ditcher) du Special Operation Executive britannique, à Cluny (Saône et Loire), il fut déporté et assassiné à Mauthausen en 1944

Pushing the limits of surface-enhanced raman spectroscopy (SERS) with deep learning : identification of multiple species with closely related molecular structures

Raman spectroscopy is a non-destructive and label-free molecular identification technique capable of producing highly specific spectra with various bands correlated to molecular structure. Moreover, the enhanced detection sensitivity offered by Surface-Enhanced Raman spectroscopy (SERS) allows analyzing mixtures of related chemical species in a relatively short measurement time. Combining SERS with deep learning algorithms allows in some cases to increase detection and classification capabilities even further. The present study evaluates the potential of applying deep learning algorithms to SERS spectroscopy to differentiate and classify different species of bile acids, a large family of molecules with low Raman cross sections and molecular structures that often differ by a single hydroxyl group. Moreover, the study of these molecules is of interest for the medical community since they have distinct pathological roles and are currently viewed as potential markers of gut microbiome imbalances. A Convolutional Neural Network (CNN) model was developed and used to classify SERS spectra from five bile acid species. The model succeeded in identifying the five analytes despite very similar molecular structures and was found to be reliable even at low analyte concentrations

Changes in pelvic orientation after total hip arthroplasty : a prospective study with EOS™

Changes in pelvic orientation after THA could alter the relationship between the femoral stem and the acetabular component and may be responsible of dislocation and implant degeneration. EOS™ technology allows three-dimensional analysis of the pelvis in functional position with low irradiation. The purpose of the study was to evaluate changes in pelvic orientation after THA in standing position with EOS™. In a prospective study, EOS™ was performed in standing position preoperatively and 3 months after computer assisted THA for primary hip osteoarthritis. Differences between pre- and postoperative pelvic parameters values were analyzed. 40 patients were included. Changes greater than 5° was noted in 12,5% of cases for pelvic incidence, 35% of cases for sacral slope and in 22,5% of cases for pelvic version. In conclusion, pelvic parameters could be modified after THA.No benefits or funds were received in support of this study

An early burst of IFN-γ induced by the pre-erythrocytic stage favours Plasmodium yoelii parasitaemia in B6 mice

<p>Abstract</p> <p>Background</p> <p>In murine models of malaria, an early proinflammatory response has been associated with the resolution of blood-stage infection. To dissect the protective immune mechanims that allow the control of parasitaemia, the early immune response of C57BL/6 mice induced during a non-lethal plasmodial infection was analysed.</p> <p>Methods</p> <p>Mice were infected with <it>Plasmodium yoelii </it>265BY sporozoites, the natural invasive form of the parasite, in order to complete its full life cycle. The concentrations of three proinflammatory cytokines in the sera of mice were determined by ELISA at different time points of infection. The contribution of the liver and the spleen to this cytokinic response was evaluated and the cytokine-producing lymphocytes were identified by flow cytometry. The physiological relevance of these results was tested by monitoring parasitaemia in genetically deficient C57BL/6 mice or wild-type mice treated with anti-cytokine neutralizing antibody. Finally, the cytokinic response in sera of mice infected with parasitized-RBCs was analysed.</p> <p>Results</p> <p>The early immune response of C57BL/6 mice to sporozoite-induced malaria is characterized by a peak of IFN-γ in the serum at day 5 of infection and splenic CD4 T lymphocytes are the major producer of this cytokine at this time point. Somewhat unexpected, the parasitaemia is significantly lower in <it>P. yoelii</it>-infected mice in the absence of IFN-γ. More precisely, at early time points of infection, IFN-γ favours parasitaemia, whereas helping to clear efficiently the blood-stage parasites at later time points. Interestingly, the early IFN-γ burst is induced by the pre-erythrocytic stage.</p> <p>Conclusion</p> <p>These results challenge the current view regarding the role of IFN-γ on the control of parasite growth since they show that IFN-γ is not an essential mediator of protection in <it>P. yoelii</it>-infected C57BL/6 mice. Moreover, the mice parasitaemia is more efficiently controlled in the absence of an early IFN-γ production, suggesting that this cytokine promotes parasite's growth. Finally, this early burst of IFN-γ is induced by the pre-erythrocytic stage, showing the impact of this stage on the immune response taking place during the subsequent erythrocytic stage.</p

Sciences et gouvernement des risques et des crises

La prégnance du risque dans les cadres d’action et d’organisation, comme dans l’énonciation de problèmes sociaux, constitue une caractéristique forte des sociétés industrielles. C’est là une évidence largement admise depuis la parution de l’ouvrage à succès d’Ulrich Beck en 1986. Des auteurs britanniques n’évoquent-ils pas une « colonisation des risques », voire « the risk management of everything » ? (...)

N-3 polyunsaturated fatty acids stimulate bile acid detoxification in human cell models

Cholestasis is characterized by the accumulation of toxic bile acids (BAs) in liver cells. The present study aimed to evaluate the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs), such as docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, on BA homeostasis and toxicity in human cell models. The effects of EPA and/or DHA on the expression of genes involved in the maintenance of BA homeostasis were analyzed in human hepatoma (HepG2) and colon carcinoma (Caco-2) cells, as well as in primary culture of human intestinal (InEpC) and renal (RPTEC) cells. Extracellular BA species were quantified in culture media using LC-MS/MS. BA-induced toxicity was evaluated using caspase-3 and flow cytometry assays. Gene expression analyses of HepG2 cells reveal that n-3 PUFAs reduce the expression of genes involved in BA synthesis (CYP7A1, CYP27A1) and uptake (NTCP), while activating genes encoding metabolic enzymes (SULT2A1) and excretion transporters (MRP2, MRP3). N-3 PUFAs also generate a less toxic BA pool and prevent the BA-dependent activation of apoptosis in HepG2 cells. Conclusion. The present study reveals that n-3 PUFAs stimulate BA detoxification

Role of glucuronidation for hepatic detoxification and urinary elimination of toxic bile acids during biliary obstruction

Biliary obstruction, a severe cholestatic condition, results in a huge accumulation of toxic bile acids (BA) in the liver. Glucuronidation, a conjugation reaction, is thought to protect the liver by both reducing hepatic BA toxicity and increasing their urinary elimination. The present study evaluates the contribution of each process in the overall BA detoxification by glucuronidation. Glucuronide (G), glycine, taurine conjugates, and unconjugated BAs were quantified in pre- and post-biliary stenting urine samples from 12 patients with biliary obstruction, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The same LC-MS/MS procedure was used to quantify intra- and extracellular BA-G in Hepatoma HepG2 cells. Bile acid-induced toxicity in HepG2 cells was evaluated using MTS reduction, caspase-3 and flow cytometry assays. When compared to post-treatment samples, pre-stenting urines were enriched in glucuronide-, taurine- and glycine-conjugated BAs. Biliary stenting increased the relative BA-G abundance in the urinary BA pool, and reduced the proportion of taurine- and glycine-conjugates. Lithocholic, deoxycholic and chenodeoxycholic acids were the most cytotoxic and pro-apoptotic/necrotic BAs for HepG2 cells. Other species, such as the cholic, hyocholic and hyodeoxycholic acids were nontoxic. All BA-G assayed were less toxic and displayed lower pro-apoptotic/necrotic effects than their unconjugated precursors, even if they were able to penetrate into HepG2 cells. Under severe cholestatic conditions, urinary excretion favors the elimination of amidated BAs, while glucuronidation allows the conversion of cytotoxic BAs into nontoxic derivatives

PPAR α

Hypolipidemic fibrates activate the peroxisome proliferator-activated receptor (PPAR) α to modulate lipid oxidation and metabolism. The present study aimed at evaluating how 3 PPARα agonists, namely, fenofibrate, gemfibrozil, and Wy14,643, affect bilirubin synthesis and metabolism. Human umbilical vein epithelial cells (HUVEC) and coronary artery smooth muscle cells (CASMC) were cultured in the absence or presence of the 3 activators, and mRNA, protein, and/or activity levels of the bilirubin synthesizing heme oxygenase- (HO-) 1 and biliverdin reductase (BVR) enzymes were determined. Human hepatocytes (HH) and HepG2 cells sustained similar treatments, except that the expression of the bilirubin conjugating UDP-glucuronosyltransferase (UGT) 1A1 enzyme and multidrug resistance-associated protein (MRP) 2 transporter was analyzed. In HUVECs, gemfibrozil, fenofibrate, and Wy14,643 upregulated HO-1 mRNA expression without affecting BVR. Wy14,643 and fenofibrate also caused HO-1 protein accumulation, while gemfibrozil and fenofibrate favored the secretion of bilirubin in cell media. Similar positive regulations were also observed with the 3 PPARα ligands in CASMCs where HO-1 mRNA and protein levels were increased. In HH and HepG2 cells, both UGT1A1 and MRP2 transcripts were also accumulating. These observations indicate that PPARα ligands activate bilirubin synthesis in vascular cells and metabolism in liver cells. The clinical implications of these regulatory events are discussed