Éditeur(s) : HAL CCSD National Institute of Environmental Health Sciences (NIEHS) National Institute of Environmental Health Sciences
Résumé : International audience
Long-term exposure to persistent pollutants with hormonal properties (endocrine-disrupting chemicals, EDCs) may contribute to the risk of prostate cancer (PCa). However, epidemiological evidence remains limited. We investigated the relationship between PCa and plasma concentrations of universally widespread pollutants, in particular p,p'-dichlorodiphenyl dichloroethene (DDE) and the non-dioxin like polychlorinated biphenyl congener 153 (PCB153). We evaluated before treatment 576 men with newly diagnosed PCa and 655 controls in Guadeloupe (French West Indies). Exposure was analyzed according to case-control status. Associations were assessed by unconditional logistic regression analysis, controlling for confounding factors. Missing data were handled by multiple imputation. We estimated a significant positive association between DDE and PCa (adjusted odds ratio [OR] 1.53; 95% CI 1.02, 2.30 for the highest versus lowest quintile of exposure; PTrend = 0.01). PCB153 was inversely associated with PCa (OR 0.30; 95% CI 0.19, 0.47 for the highest versus lowest quintile of exposure values; PTrend < 0.001). Also, PCB153 was more strongly associated to low-grade than high grade PCa. Associations of PCa with DDE and PCB153 were in opposite directions. This may reflect differences in the mechanisms of action of these EDCs, and although our findings need to be replicated in other populations, they are consistent with complex effects of EDCs on human health.
ISSN: 0091-6765

hal-01118553
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118553
DOI : 10.1289/ehp.1408407
PUBMED : 25493337

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The hypothalamic-pituitary-adrenal (HPA) axis response to chronic stress is far from straight forward, particularly with regards to animal welfare. There are reports of no effect as well as both decreases and increases in cortisol after chronic stressors. Therefore, the first aim of the present study was to determine how measures of compromised welfare, such as chronic pain and haematological anomalies, related to cortisol levels in domestic horses (Equus caballus). Domestic horses are an informative model to investigate the impact of chronic stress (due to environment, pain, work, housing conditions…) on the HPA axis. The second aim was to determine whether levels of fecal cortisol metabolites (FCM) may be used as an indicator of welfare measures. The present study used fifty-nine horses (44 geldings and 15 mares), from three riding centres in Brittany, France. The primary findings show that horses whose welfare was clearly compromised (as indicated by an unusual ears backward position, presence of vertebral problems or haematological anomalies, e.g. anaemia) also had lower levels of both FCM and plasma cortisol. This work extends our previous findings showing that withdrawn postures, indicators of depressive-like behavior in horses, are associated with lower plasma cortisol levels. We also found that evening plasma cortisol levels positively correlated with FCM levels in horses. Future research aims to determine the extent to which factors of influence on welfare, such as living conditions (e.g. single stalls versus group housing in pasture or paddocks), early life factors, and human interaction, act as mediators of cortisol levels in horses.
ISSN: 1932-6203

hal-01588159
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01588159
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01588159/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01588159/file/Pawluski_et_al_-_PLOSONE-2017.pdf
DOI : 10.1371/journal.pone.0182257

Éditeur(s) : HAL CCSD
Résumé : International audience
In vitro evaluation of P-glycoprotein (P-gp) inhibitory potential is now a regulatory issue during drug development, in order to predict clinical inhibition of P-gp and subsequent drug-drug interactions. Assays for this purpose, commonly based on P-gp-expressing cell lines and digoxin as a reference P-gp substrate probe, unfortunately exhibit high variability, raising thus the question of developing alternative or complementary tests for measuring inhibition of P-gp activity. In this context, the present study was designed to investigate the use of the fluorescent dye rhodamine 123 as a reference P-gp substrate probe for characterizing P-gp inhibitory potential of 16 structurally-unrelated drugs known to interact with P-gp. 14/16 of these P-gp inhibitors were found to increase rhodamine 123 accumulation in P-gp-overexpressing MCF7R cells, thus allowing the determination of their P-gp inhibitory potential, i.e., their half maximal inhibitor concentration (IC50) value towards P-gp-mediated transport of the dye. These IC50 values were in the range of variability of previously reported IC50 for P-gp and can be used for the prediction of clinical P-gp inhibition according to Food and Drug Administration (FDA) criteria, with notable sensitivity (80%). Therefore, the data demonstrated the feasibility of the use of rhodamine 123 for evaluating the P-gp inhibitory potential of drugs
Pharmaceutics

hal-01305488
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01305488
DOI : 10.3390/pharmaceutics8020012
PUBMED : 27077878

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Evolution involves interplay between natural selection and developmental constraints(1-3). This is seen, for example, when digits are lost from the limbs during evolution(1,3,4). Extant archosaurs (crocodiles and birds) show several instances of digit loss(3,5,6) under different selective regimes, and show limbs with one, two, three, four or the ancestral number of five digits. The `lost' digits sometimes persist for millions of years as developmental vestiges(7-10). Here we examine digit loss in the Nile crocodile and five birds, using markers of three successive stages of digit development. In two independent lineages under different selection, wing digit I and all its markers disappear. In contrast, hindlimb digit V persists in all species sampled, both as cartilage, and as Sox9-expressing precartilage domains, 250 million years after the adult digit disappeared. There is therefore a mismatch between evolution of the embryonic and adult phenotypes. All limbs, regardless of digit number, showed similar expression of sonic hedgehog (Shh). Even in the one-fingered emu wing, expression of posterior genes Hoxd11 and Hoxd12 was conserved, whereas expression of anterior genes Gli3 and Alx4 was not. We suggest that the persistence of digit V in the embryo may reflect constraints, particularly the conserved posterior gene networks associated with the zone of polarizing activity (ZPA(11)). The more rapid and complete disappearance of digit I may reflect its ZPA-independent specification, and hence, weaker developmental constraints. Interacting with these constraints are selection pressures for limb functions such as flying and perching. This model may help to explain the diverse patterns of digit loss in tetrapods. Our study may also help to understand how selection on adults leads to changes in development.
ISSN: 0028-0836

hal-01545485
https://hal.archives-ouvertes.fr/hal-01545485
DOI : 10.1038/nature12336

Éditeur(s) : HAL CCSD American Chemical Society
Résumé : International audience
Constitutive activation of the PI3K/mTOR signaling pathway contributes to carcinogenesis and metastasis in most, if not all, breast cancers. From a chromene backbone reported to inhibit class I PI3K catalytic subunits, several rounds of chemical syntheses led to the generation of a new collection of chromologues that showed enhanced ability to kill PI3K-addicted cancer cells and to inhibit Akt phosphorylation at serine 473, a hallmark of PI3K/mTOR activation. This initial screen uncovered a chromene designated DHM25 that exerted potent antitumor activity against breast tumor cell lines. Strikingly, DHM25 was shown to be a selective and covalent inhibitor of mTOR using biochemical and cellular analyses, modeling, and a large panel of kinase activity assays spanning the human kinome (243 kinases). Finally, in vivo, this novel drug was an efficient inhibitor of growth and metastasis of triple-negative breast cancer cells, paving the way for its clinical application in oncology
ISSN: 0022-2623

hal-01187307
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187307
DOI : 10.1021/acs.jmedchem.5b00991
PUBMED : 26237138

Éditeur(s) : HAL CCSD
Résumé : International audience
Introduction: Diabetes mellitus results from the loss of tolerance to insulin and alters glycemia and the glycogen content. Oxidative stress and inflammation are linked to theses alterations, especially with insulin-resistance. The therapy management of diabetes includes nutritional recommendations. Several nutrients are developed to improve glycemia, oxidative stress, inflammation and glycogen content. More interestingly, ?-GOS exhibits anti-inflammatory and insulin-sensitive effects in vitro (Efstathiou and Fathi 2010) and in vivo (Boucher et al. 2003). Thus, ?-GOS is a potential functional food for the treatment of diabetes. But, less is known about the in vivo effect of ?-GOS on inflammatory, glycoxidation markers and glycogen content in diabetes. In this context, the aim of this work was to study the effect of ?-GOS developed by Sojasun technologies (from fermented soy product) compared to a synthetic ?-GOS produced by Sigma on inflammatory, glycoxidation markers and glycogen content in a streptozotocin-induced diabetic rat model. Methods: Twenty-four male Wistar streptozotocin-diabetic rat (STZ) were divided into three group: control group, supplemented with natural ?-GOS (20 mg/kg/day) group and supplemented with synthetic ?-GOS (20 mg/kg/day). The supplementation protocol duration was 8 weeks. At the end of the protocol, blood and skeletal muscle (gastrocnemius) were obtained to measure glucose , insulin, fructosamine in plasma and N-(carboxymethyl)lysine, glycogen synthase activity and glycogen content, in muscle. Results-Discussion: Diabetes was confirmed with the measure of insuline and glucose levels. All the diabetic groups had significantly higher glucose and insuline levels compared to control healthy group (data not shown). Insuline level in plasma and storage of glycogen in muscle were increased only in both ?-GOS groups. Fructosamine, TNF?and glycogen synthase activity was also decreased in the two supplemented groups (synthetic ?-GOS and natural ?-GOS). CML remained unchanged in all groups. Natural ?-OGT and synthetic ?-OGT only differed on muscular glucose level: only natural ?-OGT induced a significant decrease in muscular glucose. To conclude, our results suggest that ?-GOS alters positively glucose level, increases the glycogen content in diabetique population, improves glycemic control in the long term and decreases the inflammatory effects in streptozotocin-diabetic rat . Keywords: ?-GOS, inflammatory and glycoxidation markers, diabetes. Acknowledgment : Brittany region References Efstathiou, T. and D. Fathi. Sojasun Technologies. 2010 Boucher J et al. J Physiol Biochem. 59(3):169-73, 2003
5e congrès international de "Nutrition, Oxygen Biology and Medicine", Paris 5-7 juin 2013
Paris, France

hal-01159375
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01159375

Éditeur(s) : HAL CCSD Elsevier Masson
Résumé : International audience
The present study tested different sounds that could disturb eagle rays (Aetobatus ocellatus) during their foraging activities at Moorea, French Polynesia. Results showed that artificial white sound and single-frequency tones (40 Hz, 600 Hz or 1 kHz) did not have an effect on rays (at least 90% of rays continued to forage over sand), while playbacks of boat motor sound significantly disturbed rays during foraging activity (60% exhibited an escape behaviour). Overall, our study highlighted the negative effect of boat noises on the foraging activity of eagle rays. These noises produced by boat traffic could, however, have some positive effects for marine aquaculture if they could be used as a deterrent to repel the eagle rays, main predators of the pearl oysters.
Notre étude teste différents types de sons qui pourraient perturber les raies-aigles (Aetobatus ocellatus) pendant leur prise de nourriture dans le lagon de Moorea, en Polynésie française. Les résultats montrent que le bruit artificiel blanc ou des fréquences uniques (40 Hz, 600 Hz ou 1 kHz) n’ont aucun effet sur les raies (au moins 90 % des raies continuent de se nourrir dans le sable), tandis que l’enregistrement d’un moteur de bateau les perturbe significativement dans cette activité (60 % des individus ont un comportement de fuite). Notre étude met ainsi en évidence l’effet négatif des bruits anthropogéniques sur les activités de nourrissage des raies-aigles. Ces bruits produits par les bateaux pourraient néanmoins avoir un effet positif pour l’aquaculture marine s’ils pouvaient être utilisés comme répulsifs des raies, principaux prédateurs de l’huître perlière.
ISSN: 1631-0691

Droits : http://creativecommons.org/licenses/by-nc-nd/
hal-01297683
https://hal-univ-perp.archives-ouvertes.fr/hal-01297683
https://hal-univ-perp.archives-ouvertes.fr/hal-01297683/document
https://hal-univ-perp.archives-ouvertes.fr/hal-01297683/file/1-s2.0-S1631069116000020-main.pdf
DOI : 10.1016/j.crvi.2016.01.001

Éditeur(s) : HAL CCSD Impact journals
Résumé : International audience
TNF-Related Apoptosis-Inducing Ligand (TRAIL) is a well-known apoptosis inducer, which activates the extrinsic death pathway. TRAIL is pro-apoptotic on colon cancer cells, while not cytotoxic towards normal healthy cells. However, its clinical use is limited by cell resistance to cell death which occurs in approximately 50% of cancer cells. Short Chain Fatty Acids (SCFA) are also known to specifically induce apoptosis of cancer cells. In accordance, we have shown that food grade dairy propionibacteria induce intrinsic apoptosis of colon cancer cells, via the production and release of SCFA (propionate and acetate) acting on mitochondria. Here, we investigated possible synergistic effect between Propionibacterium freudenreichii and TRAIL. Indeed, we hypothesized that acting on both extrinsic and intrinsic death pathways may exert a synergistic pro-apoptotic effect. Whole transcriptomic analysis demonstrated that propionibacterial supernatant or propionibacterial metabolites (propionate and acetate), in combination with TRAIL, increased pro-apoptotic gene expression (TRAIL-R2/DR5) and decreased anti-apoptotic gene expression (FLIP, XIAP) in HT29 human colon cancer cells. The revealed synergistic pro-apoptotic effect, depending on both death receptors (TRAIL-R1/DR4, TRAIL-R2/DR5) and caspases (caspase-8, -9 and -3) activation, was lethal on cancer cells but not on normal human intestinal epithelial cells (HIEC), and was inhibited by Bcl-2 expression. Finally, milk fermented by P. freudenreichii induced HT29 cells apoptosis and enhanced TRAIL cytotoxic activity, as did P. freudenreichii DMEM culture supernatants or its SCFA metabolites. These results open new perspectives for food grade P. freudenreichii-containing products in order to potentiate TRAIL-based cancer therapy in colorectal cancer
ISSN: 1949-2553

hal-01259215
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01259215
DOI : 10.18632/oncotarget.6881
PUBMED : 26771233

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
The shallow water bivalve Codakia orbicularis lives in symbiotic association with a sulfur-oxidizing bacterium in its gills. The endosymbiont fixes CO2 and thus generates organic carbon compounds, which support the host's growth. To investigate the uncultured symbiont's metabolism and symbiont-host interactions in detail we conducted a proteogenomic analysis of purified bacteria. Unexpectedly, our results reveal a hitherto completely unrecognized feature of the C. orbicularis symbiont's physiology: the symbiont's genome encodes all proteins necessary for biological nitrogen fixation (diazotrophy). Expression of the respective genes under standard ambient conditions was confirmed by proteomics. Nitrogenase activity in the symbiont was also verified by enzyme activity assays. Phylogenetic analysis of the bacterial nitrogenase reductase NifH revealed the symbiont's close relationship to free-living nitrogen-fixing Proteobacteria from the seagrass sediment. The C. orbicularis symbiont, here tentatively named `Candidatus Thiodiazotropha endolucinida', may thus not only sustain the bivalve's carbon demands. C. orbicularis may also benefit from a steady supply of fixed nitrogen from its symbiont-a scenario that is unprecedented in comparable chemoautotrophic symbioses.
ISSN: 2058-5276

hal-01545904
https://hal.archives-ouvertes.fr/hal-01545904
DOI : 10.1038/nmicrobiol.2016.193

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Lung cancer is a serious public health problem. Although there has been significant progress in chemotherapy, non-small cell lung cancer is still resistant to current treatments, primarily because of the slow rate of cell development. It is thus important to find new molecules directed against targets other than proliferation agents. Considering the high proportion of mutant proteins in tumor cells, and the high rate of mutation of the TP53 gene in all cancers, and in NSCLC in particular, this gene is a perfect target. Certain new molecules have been shown to restore the activity of mutated p53 protein, for example PRIMA-1, which reactivates the His273 mutant p53. In a previous study, we presented triazine A190, a molecule with a cytostatic activity that blocks cells in the G1 phase and induces apoptosis. Here, we show that A190 not only restores mutant p53 activity, but also induces an overexpression of the NEDD9 gene, leading to apoptotic death. These findings might offer hope for the development of new targeted therapies, specific to tumor cells, which spare healthy cells
ISSN: 2045-2322

hal-01165439
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01165439
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01165439/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01165439/file/TP53%20transcription%20factor.pdf
DOI : 10.1038/srep10356

Éditeur(s) : HAL CCSD
Résumé : International audience
Previous studies have reported respiratory, cardiac and muscle changes at rest in triathletes 24 h after completion of the event. To examine the effects of these changes on metabolic and cardioventilatory variables during exercise, eight male triathletes of mean age 21.1 (SD 2.5) years (range 17-26 years) performed an incremental cycle exercise test (IET) before (pre) and the day after (post) an official classic triathlon (1.5-km swimming, 40-km cycling and 10-km running). The IET was performed using an electromagnetic cycle ergometer. Ventilatory data were collected every minute using a breath-by-breath automated system and included minute ventilation (V(E)), oxygen uptake (VO2), carbon dioxide production (VCO2), respiratory exchange ratio, ventilatory equivalent for oxygen (V(E)/VO2) and for carbon dioxide (V(E)/VCO2), breathing frequency and tidal volume. Heart rate (HR) was monitored using an electrocardiogram. The oxygen pulse was calculated as VO2/HR. Arterialized blood was collected every 2 min throughout IET and the recovery period, and lactate concentration was measured using an enzymatic method. Maximal oxygen uptake (VO2max) was determined using conventional criteria. Ventilatory threshold (VT) was determined using the V-slope method formulated earlier. Cardioventilatory variables were studied during the test, at the point when the subject felt exhausted and during recovery. Results indicated no significant differences (P > 0.05) in VO2max [62.6 (SD 5.9) vs 64.6 (SD 4.8) ml x kg(-1) x min(-1)], VT [2368 (SD 258) vs 2477 (SD 352) ml x min(-1)] and time courses of VO2 between the pre- versus post-triathlon sessions. In contrast, the time courses of HR and blood lactate concentration reached significantly higher values (P < 0.05) in the pre-triathlon session. We concluded that these triathletes when tested 24 h after a classic triathlon displayed their pre-event aerobic exercise capacity, bud did not recover pretriathlon time courses in HR or blood lactate concentration.
EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY

hal-00720432
https://hal.univ-antilles.fr/hal-00720432
https://hal.univ-antilles.fr/hal-00720432/document
https://hal.univ-antilles.fr/hal-00720432/file/Article_2.pdf

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
The activity of diethylcarbamazine (DEC) and suramin (S) on Litomosoides carinii filariasis was assessed by the study of microfilaraemia in 30 cotton-rats (Sigmodon hispidus). DEC (per os) and S (injected subcutaneously) were administered alone or in combination, at doses of 50 mg/kg/day for five consecutive days. 15 rats were treated at day 91 after infection and 15 others at day 184. The immediate but temporary efficacy observed with DEC was in contrast to the delayed and long-lasting effect of S. With combined therapy there was neither antagonism nor synergism. The demonstration of an apparently smaller reduction of parasitaemia in the rats treated with DEC before the plateau phase of the microfilaraemia was consistent with the lack of action of this drug on microfilariae outside the blood system.
ISSN: 0035-9203

hal-00717073
https://hal.univ-antilles.fr/hal-00717073
PUBMED : 7034313

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
BACKGROUND: A prospective study of infectious encephalitis was conducted in France in 2007. In total, 253 patients were enrolled with a proven etiological diagnosis for 52%. The cohort of surviving patients with encephalitis was assessed for sequelae and impairment 3 years after enrollment. METHODS: Patients, their family, and general practitioners (GPs) were interviewed by phone to document persisting symptoms, return to work, and past and current leisure activities, with standardized questionnaires. The IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly) was completed with relatives. The global outcome was determined in all patients with the Glasgow outcome scale. RESULTS: In 2010, 20 patients (10%) were unavailable for follow-up, 2 (1%) were excluded, and 18 (9%) had died since hospital discharge. Data were available for 167 survivors and 9 patients whose death was related to the encephalitis. The outcome was favorable in 108 of 176 patients (61%) (71 with complete resolution), 31 (18%) were mildly impaired, 25 (14%) were severely impaired, and 3 (1%) were in a vegetative state. The most frequent symptoms were difficulty concentrating (42%), behavioral disorders (27%), speech disorders (20%), and memory loss (19%). Fifteen of 63 patients (24%) previously employed were still unable to resume work. Long-term outcome was significantly associated with comorbid conditions, age, level of education, and the causative agent of encephalitis. CONCLUSIONS: Most patients with encephalitis experienced a favorable outcome 3 years after hospital discharge. However, minor to severe disability persists in a high number of cases with consequences for everyday life. Physical and mental impairment should be evaluated in all patients with encephalitis, and neuropsychological rehabilitation implemented whenever needed.
ISSN: 1058-4838

hal-00875190
https://hal.archives-ouvertes.fr/hal-00875190
DOI : 10.1093/cid/cis226
PUBMED : 22460967

Éditeur(s) : HAL CCSD Royal Society, The
Résumé : International audience
Bathymodiolin mussels occur at hydrothermal vents and cold seeps, where they thrive thanks to symbiotic associations with chemotrophic bacteria. Closely related genera Idas and Adipicola are associated with organic falls, ecosystems that have been suggested as potential evolutionary 'stepping stones' in the colonization of deeper and more sulphide-rich environments. Such a scenario should result from specializations to given environments from species with larger ecological niches. This study provides molecular-based evidence for the existence of two mussel species found both on sunken wood and bones. Each species specifically harbours one bacterial phylotype corresponding to thioautotrophic bacteria related to other bathymodiolin symbionts. Phylogenetic patterns between hosts and symbionts are partially congruent. However, active endocytosis and occurrences of minor symbiont lineages within species which are not their usual host suggest an environmental or horizontal rather than strictly vertical transmission of symbionts. Although the bacteria are close relatives, their localization is intracellular in one mussel species and extracellular in the other, suggesting that habitat choice is independent of the symbiont localization. The variation of bacterial densities in host tissues is related to the substrate on which specimens were sampled and could explain the abilities of host species to adapt to various substrates.
ISSN: 0950-1193

hal-00755293
https://hal.univ-antilles.fr/hal-00755293
DOI : 10.1098/rspb.2008.1101

Éditeur(s) : HAL CCSD Thieme Publishing
Résumé : International audience
To determine the effect of triathlete performance level on the cardiorespiratory responses elicited by the cycle-run succession, eight regionally and nationally-ranked (Competitive) and five internationally-ranked (Elite) male triathletes underwent four successive laboratory trials: 1) an incremental treadmill test, 2) an incremental cycle test, 3) 30 min of cycling followed by 20 min of running (C-R), and 4) a 20-min control run (R) at the same speed as the run in C-R. Before and 10 min after the third and fourth trials the triathletes underwent lung function testing: spirometry and diffusing capacity testing for carbon monoxide (DL(CO)). During the C-R trial blood samples were drawn to measure venous lactate concentration. During all trials ventilatory data were collected every minute using an automated breath-by-breath system. The results showed that 1) the oxygen uptake (VO2) of post-cycling running versus running alone was similar for both groups; 2) the ventilatory responses (VE, VE/VO2, VE/VC02 and f) of C-R running versus R were significantly higher (P < 0.005) for the Competitive group; and 3) a significant decrease (P< 0.05) in DL(CO) was also noted after the C-R trial in the Competitive group but not in the Elite group. We concluded that 1) the ventilatory responses during a run subsequent to cycling may be related to the triathlete performance level, and 2) the C-R trial induced specific alterations in pulmonary function that may be associated with respiratory muscle alteration and exercise-induced hypoxemia in the Competitive triathletes.
ISSN: 0172-4622

hal-00720719
https://hal.univ-antilles.fr/hal-00720719

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: Heat and air pollution are both associated with increases in mortality. However, the interactive effect of temperature and air pollution on mortality remains unsettled. Similarly, the relationship between air pollution, air temperature, and social deprivation has never been explored. METHODS: We used daily mortality data from 2004 to 2009, daily mean temperature variables and relative humidity, for Paris, France. Estimates of chronic exposure to air pollution and social deprivation at a small spatial scale were calculated and split into three strata. We developed a stratified Poisson regression models to assess daily temperature and mortality associations, and tested the heterogeneity of the regression coefficients of the different strata. Deaths due to ambient temperature were calculated from attributable fractions and mortality rates were estimated. RESULTS: We found that chronic air pollution exposure and social deprivation are effect modifiers of the association between daily temperature and mortality. We found a potential interactive effect between social deprivation and chronic exposure with regards to air pollution in the mortality-temperature relationship. CONCLUSION: Our results may have implications in considering chronically polluted areas as vulnerable in heat action plans and in the long-term measures to reduce the burden of heat stress especially in the context of climate change.
ISSN: 1476-069X

hal-01070538
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01070538
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01070538/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01070538/file/1476-069X-13-53.pdf
DOI : 10.1186/1476-069X-13-53

Éditeur(s) : HAL CCSD MDPI
Résumé : International audience
Drug transporters are now recognized as major actors in pharmacokinetics, involved notably in drug-drug interactions and drug adverse effects. Factors that govern their activity, localization and expression are therefore important to consider. In the present review, the implications of protein kinases C (PKCs) in transporter regulations are summarized and discussed. Both solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters can be regulated by PKCs-related signaling pathways. PKCs thus target activity, membrane localization and/or expression level of major influx and efflux drug transporters, in various normal and pathological types of cells and tissues, often in a PKC isoform-specific manner. PKCs are notably implicated in membrane insertion of bile acid transporters in liver and, in this way, are thought to contribute to cholestatic or choleretic effects of endogenous compounds or drugs. The exact clinical relevance of PKCs-related regulation of drug transporters in terms of drug resistance, pharmacokinetics, drug-drug interactions and drug toxicity remains however to be precisely determined. This issue is likely important to consider in the context of the development of new drugs targeting PKCs-mediated signaling pathways, for treating notably cancers, diabetes or psychiatric disorders.
ISSN: 1422-0067

hal-01516024
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01516024
DOI : 10.3390/ijms18040764
PUBMED : 28375174

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
The Hedgehog (Hh) family of secreted proteins act as morphogens to control embryonic patterning and development in a variety of organ systems. Post-translational covalent attachment of cholesterol and palmitate to Hh proteins are critical for multimerization and long range signaling potency. However, the biological impact of lipid modifications on Hh ligand distribution and signal reception in humans remains unclear. In the present study, we report a unique case of autosomal recessive syndromic 46,XY Disorder of Sex Development (DSD) with testicular dysgenesis and chondrodysplasia resulting from a homozygous G287V missense mutation in the hedgehog acyl-transferase (HHAT) gene. This mutation occurred in the conserved membrane bound O-acyltransferase (MBOAT) domain and experimentally disrupted the ability of HHAT to palmitoylate Hh proteins such as DHH and SHH. Consistent with the patient phenotype, HHAT was found to be expressed in the somatic cells of both XX and XY gonads at the time of sex determination, and Hhat loss of function in mice recapitulates most of the testicular, skeletal, neuronal and growth defects observed in humans. In the developing testis, HHAT is not required for Sertoli cell commitment but plays a role in proper testis cord formation and the differentiation of fetal Leydig cells. Altogether, these results shed new light on the mechanisms of action of Hh proteins. Furthermore, they provide the first clinical evidence of the essential role played by lipid modification of Hh proteins in human testicular organogenesis and embryonic development.
ISSN: 1553-7390

hal-01063929
https://hal.archives-ouvertes.fr/hal-01063929
DOI : 10.1371/journal.pgen.1004340
PUBMED : 24784881

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
BACKGROUND: Studies relating long-term exposure to persistent organochlorine pollutants (POPs) with endocrine activities (endocrine disrupting chemicals) on circulating levels of steroid hormones have been limited to a small number of hormones and reported conflicting results. OBJECTIVE: We examined the relationship between serum concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulphate, androstenedione, androstenediol, testosterone, free and bioavailable testosterone, dihydrotestosterone, estrone, estrone sulphate, estradiol, sex-hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone as a function of level of exposure to three POPs known to interfere with hormone-regulated processes in different way: dichlorodiphenyl dichloroethene (DDE), polychlorinated biphenyl (PCB) congener 153, and chlordecone. METHODS: We collected fasting, morning serum samples from 277 healthy, non obese, middle-aged men from the French West Indies. Steroid hormones were determined by gas chromatography-mass spectrometry, except for dehydroepiandrosterone sulphate, which was determined by immunological assay, as were the concentrations of sex-hormone binding globulin, follicle-stimulating hormone and luteinizing hormone. Associations were assessed by multiple linear regression analysis, controlling for confounding factors, in a backward elimination procedure, in multiple bootstrap samples. RESULTS: DDE exposure was negatively associated to dihydrotestosterone level and positively associated to luteinizing hormone level. PCB 153 was positively associated to androstenedione and estrone levels. No association was found for chlordecone. CONCLUSIONS: These results suggested that the endocrine response pattern, estimated by determining blood levels of steroid hormones, varies depending on the POPs studied, possibly reflecting differences in the modes of action generally attributed to these compounds. It remains to be investigated whether this response pattern is predictive of the subsequent occurrence of disease.
ISSN: 1932-6203

hal-00876025
https://hal.archives-ouvertes.fr/hal-00876025
https://hal.archives-ouvertes.fr/hal-00876025/document
https://hal.archives-ouvertes.fr/hal-00876025/file/Persistent_Organochlorine-accepted.pdf
DOI : 10.1371/journal.pone.0066460

Éditeur(s) : HAL CCSD Public Library of Science
Résumé : International audience
Chaperone synthesis in response to proteotoxic stress is dependent on a family of transcription factors named heat shock factors (HSFs). The two main factors in this family, HSF1 and HSF2, are co-expressed in numerous tissues where they can interact and form heterotrimers in response to proteasome inhibition. HSF1 and HSF2 exhibit two alternative splicing isoforms, called α and β, which contribute to additional complexity in HSF transcriptional regulation, but remain poorly examined in the literature. In this work, we studied the transcriptional activity of HSF1 and HSF2 splicing isoforms transfected into immortalized Mouse Embryonic Fibroblasts (iMEFs) deleted for both Hsf1 and Hsf2, under normal conditions and after proteasome inhibition. We found that HSF1α is significantly more active than the β isoform after exposure to the proteasome inhibitor MG132. Furthermore, we clearly established that, while HSF2 had no transcriptional activity by itself, short β isoform of HSF2 exerts a negative role on HSF1β-dependent transactivation. To further assess the impact of HSF2β inhibition on HSF1 activity, we developed a mathematical modelling approach which revealed that the balance between each HSF isoform in the cell regulated the strength of the transcriptional response. Moreover, we found that cellular stress such as proteasome inhibition could regulate the splicing of Hsf2 mRNA. All together, our results suggest that relative amounts of each HSF1 and HSF2 isoforms quantitatively determine the cellular level of the proteotoxic stress response.
ISSN: 1932-6203

inserm-00814784
http://www.hal.inserm.fr/inserm-00814784
http://www.hal.inserm.fr/inserm-00814784/document
http://www.hal.inserm.fr/inserm-00814784/file/journal.pone.0056085.pdf
DOI : 10.1371/journal.pone.0056085