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 Elsevier Masson
Résumé : International audience
Four lyophilizated liver flüke antigens and one of hydatid fluid were examined for the presence of blood group like antigens P1, A, B, M and N by an hemagglutination inhibition test with hyperimmune and natural hemagglutinating sera. P1 or P1-like substance was found in the extracts of "Fasciola hepatica" and "F. gigantica" in a lower concentration than in echinoccocal fluid. This presence may explain the occurrence of anti-P1 antibodies in patients infected with liver flüke and belonging to the P2 blood group. However biochemical studies will be necessary to determine if the P1 activity is due to the blood group P1 substance of the red cell itself or due to a P1 like substance.
ISSN: 0369-8114

hal-00715431
https://hal.univ-antilles.fr/hal-00715431
PUBMED : 392420

Éditeur(s) : HAL CCSD
Résumé : International audience
To assess prognostic factors for survival and describe Model for End-Stage liver disease (MELD) dynamics in human immunodeficiency virus+/hepatitis C virus+ (HIV+/HCV+) patients after an initial episode of hepatic decompensation.An HIV+/HCV+ cohort of patients experiencing an initial decompensation episode within the year preceding enrollment were followed prospectively. Clinical and biological data were collected every 3 months. Predictors for survival were identified using Kaplan-Meier curves and Cox models. A 2-slope-mixed linear model was used to estimate MELD score changes as a function of survival.Sixty seven patients were included in 32 centers between 2009 and 2012 (72% male; median age: 48 years [interquartile ratio (IQR):45-52], median follow-up: 22.4 months [range: 0.5-65.3]). Overall survival rates were 86%, 78%, and 59% at 6, 12, and 24 months, respectively. Under multivariate analysis, the MELD score at initial decompensation was predictive of survival, adjusted for age, type of decompensation, baseline CD4 counts, and further decompensation during follow-up as a time-dependent variable. The adjusted hazard ratio of death was 1.32 for a score 3 points higher (95% CI: [1.06-1.63], P = 0.012). MELD score kinetics within the 6 months after initial decompensation differed significantly between non-deceased and deceased patients, with a decreased (-0.49/month; P = 0.016), versus a flat (+0.06/month, P = 0.753) mean change in score.MELD is an effective tool to predict survival in HIV+/HCV+ patients with decompensated cirrhosis. A non-decreasing MELD score within 6 months following this initial decompensation episode may benefit from privileged access to liver transplantation in this poor prognosis population
Medicine

hal-01205351
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01205351
DOI : 10.1097/MD.0000000000001239
PUBMED : 26222860

Éditeur(s) : HAL CCSD MDPI
Résumé : International audience
Hand disinfection with alcohols-based hand rubs (ABHRs) are known to be the most effective measure to prevent nosocomial infections in healthcare. ABHRs contain on average 70% by weight of one or more alcohols. During the hand rubbing procedure, users are exposed to these alcohols not only through dermal contact, but also via inhalation, due to the physical and chemical properties of alcohols volatilizing from alcoholic solutions or gels into the air. Ethanol ingestion is well known to increase risks of several diseases (affecting the pancreas, liver, cardiovascular system…), but there is a lack of knowledge about the effects of exposure to other alcohols (including n- or isopropanol) via inhalation and dermal contact, despite the worldwide use of ABHRs. This work aims at discussing possible health effects related to unintentional alcoholization (via inhalation and dermal contact) from professional ABHR usage to suggest the need for more research in this area (but not to question the value of ABHRs). Based upon an average of 30 hand rubbings per healthcare professional per day, it can be assumed that a healthcare worker may be exposed to a maximum 5,500 mg/m(3) per work shift, five times above the recommended occupational time weighted average limit. Thus, in order to answer the question posed in the title, studies on spatial and temporal variability of alcohol emission from ABHRs in real world situations and studies on certain high risk individuals are needed.
ISSN: 1660-4601

hal-01122305
https://hal.archives-ouvertes.fr/hal-01122305
PUBMED : 20948945
DOI : 10.3390/ijerph7083038
PUBMEDCENTRAL : PMC2954566

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Hepatocyte death is a central event during liver disease progression, in which immune cells play key roles by activating members of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF), including TNFR1 (TNFRSF1A), Fas (TNFRSF6) and TRAIL-R2 (TNFRSF10B). Receptor Interacting Protein Kinase 1 (RIPK1) emerged as a signaling node downstream of these receptors. In the case of TNFR1, RIPK1 has been demonstrated to paradoxically serve as a scaffold to promote the survival of hepatocytes and as a kinase to kill them. To evaluate whether RIPK1 also protects hepatocytes from death in response to FasL or TRAIL, we took advantage of liver parenchymal cell-specific Ripk1 knockout mice (Ripk1 (LPC-KO)). We found that Ripk1 (LPC-KO) mice, as well as primary hepatocytes derived from them, were more susceptible to Fas-mediated apoptosis than their respective WT counterparts. Fas-induced hepatocyte death was independent of TNF-α signaling. Interestingly, while TRAIL administration did not induce hepatitis in Ripk1 (LPC-KO) mice or in their WT counterparts, its combination with IFN-γ only induced TNF-α dependent apoptosis in the Ripk1 (LPC-KO) mice. Together, our data demonstrate the protective role of RIPK1 downstream of Fas and highlight the general protective function of RIPK1 in hepatocytes exposed to inflammatory conditions, where TNF-α, FasL and/or TRAIL are present.
ISSN: 2045-2322

hal-01579612
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01579612
DOI : 10.1038/s41598-017-09789-8
PUBMED : 28835677

Éditeur(s) : HAL CCSD
Résumé : International audience
Necroptosis is a regulated form of cell death involved in several disease models including in particular liver diseases. Receptor-interacting protein kinases, RIPK1 and RIPK3, are the main serine/threonine kinases driving this cell death pathway. We screened a noncommercial, kinase-focused chemical library which allowed us to identify Sibiriline as a new inhibitor of necroptosis induced by tumor necrosis factor (TNF) in Fas-associated protein with death domain (FADD)-deficient Jurkat cells. Moreover, Sib inhibits necroptotic cell death induced by various death ligands in human or mouse cells while not protecting from caspase-dependent apoptosis. By using competition binding assay and recombinant kinase assays, we demonstrated that Sib is a rather specific competitive RIPK1 inhibitor. Molecular docking analysis shows that Sib is trapped closed to human RIPK1 adenosine triphosphate-binding site in a relatively hydrophobic pocket locking RIPK1 in an inactive conformation. In agreement with its RIPK1 inhibitory property, Sib inhibits both TNF-induced RIPK1-dependent necroptosis and RIPK1-dependent apoptosis. Finally, Sib protects mice from concanavalin A-induced hepatitis. These results reveal the small-molecule Sib as a new RIPK1 inhibitor potentially of interest for the treatment of immune-dependent hepatitis. © 2017 Federation of European Biochemical Societies
ISSN: 1742464X

hal-01616420
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616420
DOI : 10.1111/febs.14176
PUBMED : 28715128

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
: Previously, we demonstrated that eicosapentaenoic acid enhanced ethanol-induced oxidative stress and cell death in primary rat hepatocytes via an increase in membrane fluidity and lipid raft clustering. In this context, another n-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA), was tested with a special emphasis on physical and chemical alteration of lipid rafts. Pretreatment of hepatocytes with DHA reduced significantly ethanol-induced oxidative stress and cell death. DHA protection could be related to an alteration of lipid rafts. Indeed, rafts exhibited a marked increase in membrane fluidity and packing defects leading to the exclusion of a raft protein marker, flotillin. Furthermore, DHA strongly inhibited disulfide bridge formation, even in control cells, thus suggesting a disruption of protein-protein interactions inside lipid rafts. This particular spatial organization of lipid rafts due to DHA subsequently prevented the ethanol-induced lipid raft clustering. Such a prevention was then responsible for the inhibition of phospholipase C-γ translocation into rafts, and consequently of both lysosome accumulation and elevation in cellular low-molecular-weight iron content, a prooxidant factor. In total, the present study suggests that DHA supplementation could represent a new preventive approach for patients with alcoholic liver disease based upon modulation of the membrane structures.
ISSN: 0278-6915

hal-00860153
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00860153
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00860153/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-00860153/file/Sergent-et-al-incl-figures-accepted.pdf
DOI : 10.1016/j.fct.2013.07.061

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Introduction: The selection of patients with metastatic clear cell renal cell carcinoma (ccRCC) who may benefit from targeted tyrosine kinase inhibitors has been a challenge, even more so now with the advent of new therapies. Hilar fat infiltration (HFI) is a validated prognostic factor in nonmetastatic ccRCC (TNM 2009 staging system) but has never been studied in metastatic patients. We aimed to assess its phenotype and prognostic effect in patients with metastatic ccRCC treated with first-line sunitinib.Materials and methods: In a multicentric study, we retrospectively included 90 patients and studied the corresponding ccRCC at the pathological, immunohistochemical, and molecular levels. Patient and tumor characteristics were compared using univariate and multivariate analysis. All the features were then studied by Cox models for prognostic effect.Results: HFI was found in 42 patients (46.7%), who had worse prognosis (Heng criteria) (P = 0.003), liver metastases (P = 0.036), and progressive diseases at first radiological evaluation (P = 0.024). The corresponding ccRCC was associated with poor pathological prognostic factors that are well known in nonmetastatic ccRCC. For these patients, median progression-free survival was 4 months vs. 13 months (P = 0.02), and median overall survival was 14 months vs. 29 months (P = 0.006). In a multivariate Cox model integrating all the variables, only poor prognosis, according to the Heng criteria and HFI, remained independently associated with both progression-free survival and overall survival.Conclusion: HFI was demonstrated for the first time to be an independent poor prognostic factor. Its potential role in predicting resistance to antiangiogenic therapy warrants further investigation.
ISSN: 1078-1439

hal-01632553
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01632553
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01632553/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01632553/file/Hilar%20fat%20infiltration_accepted.pdf
DOI : 10.1016/j.urolonc.2017.05.015

Éditeur(s) : HAL CCSD
Résumé : International audience
Lewis blood group specificities are detected in the liver Fluke: Fasciola hepatica. Such specificities had never been reported in nature, other than in the human body. The investigation of this phenomenon might contribute to a better understanding of the mechanisms involved in parasite-host relationship.
C R Seances Acad Sci D

hal-00715437
https://hal.univ-antilles.fr/hal-00715437
PUBMED : 120793

Éditeur(s) : HAL CCSD
Résumé : Hepatitis C virus (HCV) is one of the leading causes of hepatocellular carcinoma. Therapeutic treatment against the virus has been recently improved by a tritherapy including pegylated interferon, ribavirin and antiviral protease. Nevertheless, the importance of side effects and the emergence of resistant mutants require the development of new antivirals. In this context, our team has recently discovered that Type III phosphatidylinositol 4-kinases (PI4KIIIα and PI4KIIIβ) are essential for the propagation of the virus in a human hepatic cell line at the entry and replication steps. To further characterize these potential therapeutic targets, we investigate the implication of these kinases during the HCV entry, using primary human hepatocytes, a model closer to the in vivo conditions. Two lines of research were developed: Verification of the importance of the kinase activity of PI4KIIIs during HCV entry in primary human hepatocytes, through a chemical approach; Validation of the involvement of these kinases and their enzymatic activity during viral entry through a genetic approach based on RNA interference and phenotype rescue. In parallel, we studied the expression of PI4KIIIα in liver diseases. Our results suggest the involvement of PI4KIIIα in HCV entry; the involvement of PI4KIIIIβ needs to be confirmed. The analysis of PI4KIIIα expression in hepatocellular carcinoma led us to propose this kinase as a new molecular marker, which could improve the already established prognosis models and could lead to the development of new therapeutic approaches.
Le virus de l’hépatite C (VHC) est l’un des principaux facteurs étiologiques du carcinome hépatocellulaire. Le traitement des hépatites virales C a été récemment amélioré grâce à une trithérapie (interféron, ribavirine et anti-protéase virale). Néanmoins l’importance des effets secondaires et l’émergence de mutants résistants nécessitent de découvrir de nouveaux antiviraux. Dans ce contexte, notre équipe a récemment découvert que les phosphatidylinositol 4-kinases de type III (PI4KIIIα et PI4KIIIβ) étaient indispensables à la propagation du virus dans une lignée hépatique humaine, et ce, à 2 étapes de son cycle biologique : l’entrée et la réplication. L’objectif du présent travail était de poursuivre la validation de ces nouvelles cibles thérapeutiques potentielles, en approfondissant nos connaissances sur la dépendance du virus à l’égard de ces kinases au cours de son entrée. Pour cela, nous avons utilisé le modèle des hépatocytes humains primaires, système in vitro plus proche du contexte physiologique que les modèles utilisés jusqu’à présent et qui étaient basés sur l’exploitation de lignées. Deux axes ont été développés : Vérification de l’importance de l’activité kinase des PI4KIIIs au cours de l’entrée du VHC dans les hépatocytes humains primaires, à travers une approche chimique ; Validation de l’implication de ces kinases et de leur activité enzymatique au cours de l’entrée virale grâce à une approche génétique basée sur l’ARN interférence et la restauration de phénotype. En parallèle, nous avons étudié l’expression de PI4KIIIα au cours de pathologies hépatiques. Nos résultats suggèrent une implication de PI4KIIIα au cours de l’entrée du VHC dans les hépatocytes humains primaires, mais restent à confirmer quant à l’implication de PI4KIIIβ. Par ailleurs, l’analyse de l’expression de PI4KIIIα dans le carcinome hépatocellulaire (CHC) conduit à proposer cette kinase comme un nouveau marqueur moléculaire, qui pourrait améliorer les modèles de pronostic déjà établis et pourrait conduire au développement de nouvelles approches thérapeutiques pour les patients atteints d’un CHC, quelque soit l’étiologie.
https://tel.archives-ouvertes.fr/tel-00950335

Droits : info:eu-repo/semantics/OpenAccess
NNT : 2013REN1B006
tel-00950335
https://tel.archives-ouvertes.fr/tel-00950335
https://tel.archives-ouvertes.fr/tel-00950335/document
https://tel.archives-ouvertes.fr/tel-00950335/file/ILBOUDOAdeodat.pdf

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 BioMed Central
Résumé : International audience
An important objective on diagnosis of patients with Langerhans cell histiocytosis (LCH) is to determine the extent of disease. However, whether systematic extrathoracic investigation is needed in adult patients with clinically isolated pulmonary LCH (PLCH) has not been evaluated
ISSN: 1750-1172

hal-01269910
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01269910
DOI : 10.1186/s13023-016-0387-1
PUBMED : 26833097

Éditeur(s) : HAL CCSD American Society for Microbiology
Résumé : International audience
Coronaviruses (CoVs) have shown neuroinvasive properties in human and animal secondary to replication in peripheral organ but the mechanism of neuroinvasion is unknown. The major aim of our work was to evaluate the ability of CoVs to enter the central nervous system (CNS) through the blood brain barrier (BBB). Using the high hepatotropic mouse hepatitis virus (MHV) type 3, its attenuated variant 51.6-MHV3, showing low tropism for endothelial cells, and the low hepatotropic MHV-A59 strains from murine coronavirus group, we investigated the viral-induced dysfunctions of BBB in vivo and in brain microvascular endothelial cells (BMECs) in vitro. We report here a MHV strain-specific ability to cross the BBB during acute infection according to their virulence for liver. Brain invasion was only observed in MHV3-infected mice and correlated with enhanced BBB permeability associated with decreased expression of ZO-1, VE-cadherin and occludin but not claudin-5 in the brain or in cultured BMECs. BBB breakdown in MHV3 infection was not related to production of barrier-dysregulating inflammatory cytokines or chemokines by infected BMECs but rather to a downregulation of barrier protective IFN-β production. Our findings highlight the importance of IFN-β production by infected BMECs in preserving BBB function and preventing access of blood-borne infectious viruses to the brain. IMPORTANCE: Coronaviruses (CoVs) infect several mammals including humans and are associated with respiratory, gastrointestinal and/or neurological diseases. Some evidences suggest that human respiratory CoVs may show neuroinvasive properties. Indeed, the SARS-CoV, causing severe acute respiratory syndrome, and the CoVs OC43 and 229E were found in the brains of SARS and multiple sclerosis patients respectively. These finding suggest that hematogenous spread CoVs may gain access to CNS at the BBB level. Herein we report for the first time that CoVs exhibit ability to cross the BBB according to strain virulence. BBB invasion by CoVs correlates with viral-induced disruption of tight junctions on BMECs, leading to BBB dysfunction and enhanced permeability. We provide evidence that production of IFN-β by BMECs during CoV infection may prevent BBB breakdown and brain viral invasion
ISSN: 0022-538X

hal-01187308
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01187308
DOI : 10.1128/JVI.01501-15
PUBMED : 26202229