Éditeur(s) : HAL CCSD Karger
Résumé : International audience
Cell Physiol Biochem
Tübingen, Germany

hal-01122597
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01122597
DOI : 10.1159/000335868

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
The early apoptotic events induced by environmental pollutants with carcinogenic properties are poorly understood. Here, we focus on the early cytotoxic effects of benzo[a]pyrene (B[a]P). In F258 rat hepatic epithelial cells, B[a]P induces intrinsic apoptosis via a mitochondrial dysfunction characterized by the release of hexokinase II (HKII) from the mitochondria. Cancer cells often have an anomalous cell energy metabolism; since HKII dysfunction regulates B[a]P-induced apoptosis in F258 cells, but may also alter cell energy metabolism, HKII release from the mitochondria may represent an important B[a]P-related carcinogenic issue. Thus in the present study, we aimed at deciphering the mechanisms underlying HKII dysfunction upon B[a]P exposure. We show that while glycogen synthase kinase 3 beta (GSK3β) regulated the expression of HKII at the transcriptional level, glycogen synthase kinase 3 alpha (GSK3α) was involved in B[a]P-induced apoptosis via a decrease in c-Myc expression. The reduced level of c-Myc caused the relocation of HKII from the mitochondria to the cytosol, thereby being involved in the formation of reactive oxygen species and apoptosis. In conclusion, we show that the couple GSK3α/c-Myc plays a key role in B[a]P-induced early apoptotic cell signaling via HKII dysfunction.
ISSN: 0887-2333

hal-00682104
https://hal.archives-ouvertes.fr/hal-00682104
https://hal.archives-ouvertes.fr/hal-00682104/document
https://hal.archives-ouvertes.fr/hal-00682104/file/1-s2.0-S0887233311003018-main%20Dendel%C3%A9_%7B75929874-2DF9-47C3-92F6-92AF398668E5%7D.pdf
DOI : 10.1016/j.tiv.2011.11.001

Éditeur(s) : HAL CCSD EDP Sciences
Résumé : Cette communication présente les principaux résultats du projet ExtraFlo sur l'estimation des pluies et crues extrêmes. A partir d'un jeu de données conséquent de plusieurs milliers de stations, une procédure d'inter-comparaison a permis d'évaluer les performances d'une trentaine d'implémentations différentes issues de différentes combinaisons (modèle probabiliste, méthode d'estimation, cadre local / régional / mixte local et régional). Le projet ExtraFlo a permis de mettre en évidence le manque de robustesse des approches basées sur le traitement statistique d'une série de quelques dizaines d'années d'observation. Des alternatives intéressantes existent, basées sur l'exploitation des records de pluie et de débit à l'échelle d'une région, de la collecte de données historiques quand cela est possible, de méthodes de simulation basées sur le couplage d'un générateur d'averses avec un modèle hydrologique pour la transformation des pluies en débit, ou des traces morphologiques laissées par les crues anciennes.
ISSN: 0018-6368

hal-01054313
https://hal.archives-ouvertes.fr/hal-01054313
DOI : 10.1051/1hb/2014010

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Plasma membrane is an early target of polycyclic aromatic hydrocarbons (PAH). We previously showed that the PAH prototype, benzo[a]pyrene (B[a]P), triggers apoptosis via DNA damage-induced p53 activation (genotoxic pathway) and via remodeling of the membrane cholesterol-rich microdomains called lipid rafts, leading to changes in pH homeostasis (non-genotoxic pathway). As omega-3 (n-3) fatty acids can affect membrane composition and function or hamper in vivo PAH genotoxicity, we hypothesized that addition of physiologically relevant levels of polyunsaturated n-3 fatty acids (PUFAs) might interfere with B[a]P-induced toxicity. The effects of two major PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), were tested on B[a]P cytotoxicity in the liver epithelial cell line F258. Both PUFAs reduced B[a]P-induced apoptosis. Surprisingly, pre-treatment with DHA increased the formation of reactive B[a]P metabolites, resulting in higher levels of B[a]P-DNA adducts. EPA had no apparent effect on B[a]P metabolism or related DNA damage. EPA and DHA prevented B[a]P-induced apoptotic alkalinization by affecting Na(+)/H(+) exchanger 1 activity. Thus, the inhibitory effects of omega-3 fatty acids on B[a]P-induced apoptosis involve a non-genotoxic pathway associated with plasma membrane remodeling. Our results suggest that dietary omega-3 fatty acids may have marked effects on the biological consequences of PAH exposure.
ISSN: 0009-2797

hal-00950341
https://hal.archives-ouvertes.fr/hal-00950341
https://hal.archives-ouvertes.fr/hal-00950341/document
https://hal.archives-ouvertes.fr/hal-00950341/file/DENDELE_et_al_2013-unmarked.pdf
PUBMED : 24246761

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na+/H+ exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration).
ISSN: 2045-2322

Droits : http://creativecommons.org/licenses/by/
hal-01359569
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569/file/The%20environmental%20carcinogen-CCBY%20%281%29.pdf
DOI : 10.1038/srep30776

Éditeur(s) : HAL CCSD IOS Press
Résumé : International audience
The hematocrit-to-viscosity ratio (HVR) has been widely used has an estimate of red blood cell (RBC) oxygen transport effectiveness into the microvasculature or as an oxygen delivery index. However, no study investigated the possibility of HVR to truly reflect RBC oxygen transport effectiveness or to be an oxygen delivery index. We measured blood viscosity at high shear rate (225 s −1), hematocrit, HVR, as well as the microvascular oxyhemoglobin saturation (TOI; tissue oxygen index) by spatial resolved near-infrared spectroscopy (NIRS) at cerebral and muscle levels in three population known to have various degrees of hemorheological abnormalities: healthy subjects (AA), patients with sickle cell SC disease (SC) characterized by moderate anemia and patients with sickle cell anemia (SS) marked by severe anemia. At both the cerebral and muscle level, HVR was positively correlated with TOI (r = 0.28; p = 0.03 and r = 0.38; p = 0.003, at the cerebral and muscle level, respectively). These findings suggest that HVR probably play a key role in blood flow and hemodynamic regulation in the microvasculature, hence modulating the amount of oxygen available for tissues. Nevertheless, the strengths of the associations are weak (R 2 < 0.50), suggesting that other determinants modulate microvascular blood flow and oxygenation, such as vascular geometry and vasomotor reserve.
ISSN: 1386-0291

hal-01163460
https://hal.univ-antilles.fr/hal-01163460
DOI : 10.3233/CH-131742

Éditeur(s) : HAL CCSD IOS Press
Résumé : International audience
Vascular function has been found to be impaired in patients with sickle cell disease (SCD). The present study investigated the determinants of systemic vascular resistance in two main SCD syndromes in children: sickle cell anemia (SCA) and sickle cell-hemoglobin C disease (SCC). Nitric oxide metabolites (NOx), hematological, hemorheological, and hemodynamical parameters were investigated in 61 children with SCA and 49 children with SCC. While mean arterial pressure was not different between SCA and SCC children, systemic vascular resistance (SVR) was greater in SCC children. Although SVR and blood viscosity (ηb) were not correlated in SCC children, the increase of ηb (+18%) in SCC children compared to SCA children results in a greater mean SVR in this former group. SVR was positively correlated with ηb, hemoglobin (Hb) level and RBC deformability, and negatively with NOx level in SCA children. Multivariate linear regression model showed that both NOx and Hb levels were independently associated with SVR in SCA children. In SCC children, only NOx level was associated with SVR. In conclusion, vascular function of SCC children seems to better cope with higher ηb compared to SCA children. Since the occurrence of vaso-occlusive like complications are less frequent in SCC than in SCA children, this finding suggests a pathophysiological link between the vascular function alteration and these clinical manifestations. In addition, our results suggested that nitric oxide metabolism plays a key role in the regulation of SVR, both in SCA and SCC.
ISSN: 1386-0291

inserm-00849031
http://www.hal.inserm.fr/inserm-00849031
http://www.hal.inserm.fr/inserm-00849031/document
http://www.hal.inserm.fr/inserm-00849031/file/2013_Lamarre_-_Relationships_between_SVR_BR_and_NO_in_children_with_sickle_cell_anemia_or_sickle_cell-hemoglobin_C_disease.pdf
DOI : 10.3233/CH-121661

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Metalloproteases involved in extracellular matrix remodeling play a pivotal role in cell response by regulating the bioavailability of cytokines and growth factors. Recently, the disintegrin and metalloprotease, ADAMTS1 has been demonstrated to be able to activate the transforming growth factor TGF-β, a major factor in fibrosis and cancer. The KTFR sequence from ADAMTS1 is responsible for the interaction with the LSKL peptide from the latent form of TGF-β, leading to its activation. While the atomic details of the interaction site can be the basis of the rational design of efficient inhibitory molecules, the binding mode of interaction is totally unknown. In this study, we show that recombinant fragments of human ADAMTS1 containing KTFR sequence keep the ability to bind the latent form of TGF-β. The recombinant fragment with the best affinity is modeled to investigate the binding mode of LSKL peptide with ADAMTS1 at the atomic level. Using a combined approach with molecular docking and multiple independent molecular dynamics (MD) simulations, we provide the binding mode of LSKL peptide with ADAMTS1. The MD simulations starting with the two lowest energy model predicted by molecular docking shows stable interactions characterized by 3 salt bridges (K3-NH3+ with E626-COO−; L4-COO− with K619-NH3+; L1-NH3+ with E624-COO−) and 2 hydrogen bonds (S2-OH with E623-COO−; L4-NH with E623-COO−). The knowledge of this interaction mechanism paves the way to the design of more potent and more specific inhibitors against the inappropriate activation of TGF-β by ADAMTS1 in liver diseases
ISSN: 1476-9271

hal-01269916
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01269916
DOI : 10.1016/j.compbiolchem.2016.01.012
PUBMED : 26878129

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
BACKGROUND: Surveillance of HIV-1 drug resistance in treated patients with plasma viral load (VL) >50 copies/mL. METHODS: The protease and reverse transcriptase (RT) genes were systematically sequenced in samples from 756 patients with VL >50 copies/mL in 2009. The genotyping results were interpreted for each antiretroviral drug (ARV) by using the ANRS algorithm v21. Weighted analyses were used to derive representative estimates of percentages of patients. Prevalence rates were compared with those obtained in 2004 among patients with VL >1000 copies/mL. RESULTS: Sequences were obtained for 506 patients. Sequencing was successful in 45%, 80% and 96% of samples with VL of 51-500, 501-1000 and >1000 copies/mL, respectively. Resistance or possible resistance to at least one ARV was observed in 59% of samples. Overall, 0.9% of samples contained viruses resistant to all drugs belonging to at least three drug classes. All resistance prevalence rates were significantly lower in 2009 than in 2004. CONCLUSION: In France, where 86% of patients were receiving combination antiretroviral therapy in 2009, only 15.0% of patients had a VL >50 copies/mL, suggesting that only 8.9% of treated patients could potentially transmit resistant viruses. Only 0.08% of patients harboured viruses fully resistant to at least three antiretroviral drug classes. Further studies are needed to determine whether resistance continues to decline over time.
ISSN: 0305-7453

hal-00875092
https://hal.archives-ouvertes.fr/hal-00875092
DOI : 10.1093/jac/dkt033
PUBMED : 23404192

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
BACKGROUND AND AIMS: Infection by hepatitis C virus is a worldwide health problem. An inadequate Th2 cytokine response promotes the fibrosis-cirrhosis fate. Immune-modulating molecules favoring a Th2 profile, such as HLA-G molecules of the HLA class Ib family, may play a role in chronic hepatitis. HLA-G contributes to the escape of tumors, and their involvement in viral infections has been increasingly described. The aim of this work was to study the expression of HLA-G in the liver, its cellular source and its regulation in cases of chronic C hepatitis. METHODS: HLA-G cells in blocks of liver derived from patients infected with HCV were labeled by immunohistochemistry and enumerated. Double immunofluorescence allowed the identification of the cellular source. HLA-G secretion by a human mast cell line was quantified by ELISA after various stimulations. After treatment with IFN-α real-time PCR was performed to determine the kinetics of cytokine expression profiles, followed by heat map clustering analysis. RESULTS: The number of HLA-G + cells was significantly associated with the area of fibrosis. For the first time, we identify the HLA-G+ cells as being mast cells. HLA-G secretion was significantly induced in human mast cells stimulated by IL-10 or interferons of class I. The transcriptome of the secretome of this cell line stimulated by IFN-α revealed that i) the HLA-G gene is upregulated late, ii) T lymphocytes and NK cells are recruited. CONCLUSIONS: These findings suggest an autocrine loop in the genesis of HCV liver fibrosis, based on mast cells expressing HLA-G.
ISSN: 0168-8278

hal-00874106
https://hal.archives-ouvertes.fr/hal-00874106
https://hal.archives-ouvertes.fr/hal-00874106/document
https://hal.archives-ouvertes.fr/hal-00874106/file/Amiot-Expression-HLA-G-revised.pdf
DOI : 10.1016/j.jhep.2013.09.006

Éditeur(s) : HAL CCSD European Centre for Disease Prevention and Control
Résumé : International audience
Following of the emergence of Zika virus in Brazil in 2015, an epidemiological surveillance system was quickly implemented in the French overseas Territories of America (FTA) according to previous experience with dengue and chikungunya and has detected first cases of Zika. General practitioners and medical microbiologists were invited to report all clinically suspectedcases of Zika, laboratory investigations were systematically conducted (RT-PCR). On 18 December, the first autochthonous case of Zika virus infection was confirmed by RT-PCR on French Guiana and Martinique, indicating introduction of Zika virus inFTA. The viral circulation of Zika virus was then also confirmed on Guadeloupe and Saint-Martin. We report here early findings on 203 confirmed cases of Zika virus infection identified by RT-PCR or seroneutralisation on Martinique Island between 24 November 2015 and 20 January 2016. All cases were investigated. Common clinical signs were observed (maculopapularrash, arthralgia, fever, myalgia and conjunctival hyperaemia) among these patients, but the rash, the foundation of our case definition, may be absent in a significant proportion of patients (16%). These results are important for the implementation of a suspected case definition, the main tool for epidemiological surveillance, in territories that may be affected by ZIKV emergence, including Europe.
ISSN: 1025-496X

Droits : info:eu-repo/semantics/OpenAccess
inserm-01415215
http://www.hal.inserm.fr/inserm-01415215
http://www.hal.inserm.fr/inserm-01415215/document
http://www.hal.inserm.fr/inserm-01415215/file/2016%2C%20Daudens-Vaysse%20-%20Zika%20emergence%20in%20the%20French%20Territories%20of%20America%20and%20description%20of%20first%20confirmed%20cases%20of%20Zika%20virus%20infection%20on%20Martinique%20.pdf
DOI : 10.2807/1560-7917.ES.2016.21.28.30285

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
ISSN: 1742-4690

inserm-00868818
http://www.hal.inserm.fr/inserm-00868818
http://www.hal.inserm.fr/inserm-00868818/document
http://www.hal.inserm.fr/inserm-00868818/file/1742-4690-10-S1-P26.pdf
DOI : 10.1186/1742-4690-10-S1-P26