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1. Hepatocellular carcinoma hosts cholinergic neural cells and tumoral hepatocytes harboring targetable muscarinic receptors

Author

Charlotte A. Hernandez, Claire Verzeroli, Armando Andres Roca Suarez, Abud-José Farca-Luna, Laurie Tonon, Roger Esteban-Fabró, Roser Pinyol, Marie-Laure Plissonnier, Ievgeniia Chicherova, Anaëlle Dubois, Pascale Bellaud, Marine Seffals, Bruno Turlin, Alain Fautrel, Gabriel Ichim, Michel Rivoire, Guillaume Passot, Zuzana Macek-Jilkova, Thomas Decaens, Alain Viari, Barbara Testoni, Sandra Rebouissou, Josep M. Llovet, Fabien Zoulim, and Romain Parent

Subjects
HCC, autonomic nervous system, neuronal score, transcriptomics, scRNA-seq, cholinergic, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Owing to unexplained interpatient variation and treatment failure in hepatocellular carcinoma (HCC), novel therapeutic approaches remain an urgent clinical need. Hepatic neurons, belonging to the autonomic nervous system (ANS), mediate liver/whole body crosstalk. Pathological innervation of the ANS has been identified in cancer, nurturing tumor stroma and conferring stronger carcinogenic properties. Methods: We characterized the innervation of liver tumors from the French Liver Biobank, then applied bioinformatics to TCGA (The Cancer Genome Atlas), several other datasets and a European validation cohort, to re-evaluate patient stratification. Cell biology and pharmacology studies were also performed. Results: Densely packed nucleated DCX+, synaptophysin+, NeuN+, VAChT+, TH-, CD31-, CD45- clusters, to date undetected, were identified in human HCCs, and independently confirmed by single-cell RNA sequencing data. Using the new concept of a neuronal score, human and rat HCCs displayed tightly netrin-1-associated neural reconfiguration towards cholinergic polarity, which was associated with chronic liver disease progression, cancer onset and many features of aggressive (proliferative class) HCC, including shortened survival. This score was conditioned by tumoral hepatocytes, and predicted sorafenib efficacy in the STORM HCC phase III trial. Conversely, intratumoral adrenergic lymphocytes were enriched in TEMRA and cytotoxic phenotypes. Amongst all cholinergic transcripts, the medically targeted CHRM3 receptor was enriched and associated with pathogenic traits in HCC, as well as poor prognosis in HCC stages 1-2, while its level dropped upon experimental re-differentiation. Its pharmacological inhibition with low concentrations of anticholinergic drugs, but not cholinomimetics, decreased anchorage-independent growth and anoikis, synergized with sorafenib and lenvatinib in HCC class 1 to 3 lines, yet not in primary human hepatocytes, and preserved mature hepatocyte functions. Conclusion: These data identify cholinergic processes as instrumental in liver carcinogenesis and support the use of EMA/FDA-approved cholinergic drugs in HCC research. Impact and implications:: Hepatocellular carcinoma (HCC) care has long been hampered by the enigmatic nature of disease evolution, as well as of response or resistance to treatment. Hepatic neurons are likely the least studied liver cell type and mediate patients singularities from the ANS to the organ in real-time. Cholinergic inputs identified in this study as pathogenic may be targeted with the well charted pharmacopoeia of neurotropic drugs already available, for basic or clinical research purposes, with an expected high level of safety.

Published
2025
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2. Altered epithelial barrier functions in the colon of patients with spina bifida

Author

Charlène Brochard, Guillaume Bouguen, Raphael Olivier, Tony Durand, Sébastien Henno, Benoît Peyronnet, Mael Pagenault, Chloé Lefèvre, Gaëlle Boudry, Mikael Croyal, Alain Fautrel, Maxime Esvan, Alain Ropert, Anne Dariel, Laurent Siproudhis, and Michel Neunlist

Subjects
Medicine, Science
Abstract

Abstract Our objectives were to better characterize the colorectal function of patients with Spina Bifida (SB). Patients with SB and healthy volunteers (HVs) completed prospectively a standardized questionnaire, clinical evaluation, rectal barostat, colonoscopy with biopsies and faecal collection. The data from 36 adults with SB (age: 38.8 [34.1–47.2]) were compared with those of 16 HVs (age: 39.0 [31.0–46.5]). Compared to HVs, rectal compliance was lower in patients with SB (p = 0.01), whereas rectal tone was higher (p = 0.0015). Ex vivo paracellular permeability was increased in patients with SB (p = 0.0008) and inversely correlated with rectal compliance (r = − 0.563, p = 0.002). The expression of key tight junction proteins and inflammatory markers was comparable between SB and HVs, except for an increase in Claudin-1 immunoreactivity (p = 0.04) in SB compared to HVs. TGFβ1 and GDNF mRNAs were expressed at higher levels in patients with SB (p = 0.02 and p = 0.008). The levels of acetate, propionate and butyrate in faecal samples were reduced (p = 0.04, p = 0.01, and p = 0.02, respectively). Our findings provide evidence that anorectal and epithelial functions are altered in patients with SB. The alterations in these key functions might represent new therapeutic targets, in particular using microbiota-derived approaches. Clinical Trials: NCT02440984 and NCT03054415.

Published
2022
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3. Aerosol-Mediated Non-Viral Lung Gene Therapy: The Potential of Aminoglycoside-Based Cationic Liposomes

Author

Tony Le Gall, Mathieu Berchel, Lee Davies, Angélique Mottais, Rosy Ghanem, Alain Fautrel, Deborah Gill, Steve Hyde, Pierre Lehn, Jean-Marie Lehn, Loïc Lemiègre, Thierry Benvegnu, Paul-Alain Jaffrès, Bruno Pitard, and Tristan Montier

Subjects
aminoglycoside-based cationic lipids, cystic fibrosis, lipidic formulations, lung gene therapy, nebulization, structure-activity, Pharmacy and materia medica, RS1-441
Abstract

Aerosol lung gene therapy using non-viral delivery systems represents a credible therapeutic strategy for chronic respiratory diseases, such as cystic fibrosis (CF). Progress in CF clinical setting using the lipidic formulation GL67A has demonstrated the relevance of such a strategy while emphasizing the need for more potent gene transfer agents. In recent years, many novel non-viral gene delivery vehicles were proposed as potential alternatives to GL67 cationic lipid. However, they were usually evaluated using procedures difficult or even impossible to implement in clinical practice. In this study, a clinically-relevant administration protocol via aerosol in murine lungs was used to conduct a comparative study with GL67A. Diverse lipidic compounds were used to prepare a series of formulations inspired by the composition of GL67A. While some of these formulations were ineffective at transfecting murine lungs, others demonstrated modest-to-very-efficient activities and a series of structure-activity relationships were unveiled. Lipidic aminoglycoside derivative-based formulations were found to be at least as efficient as GL67A following aerosol delivery of a luciferase-encoding plasmid DNA. A single aerosol treatment with one such formulation was found to mediate long-term lung transgene expression, exceeding half the animal’s lifetime. This study clearly supports the potential of aminoglycoside-based cationic lipids as potent GL67-alternative scaffolds for further enhanced aerosol non-viral lung gene therapy for diseases such as CF.

Published
2021
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4. Gene expression profiling of the tumor microenvironment in human intrahepatic cholangiocarcinoma

Author

Laurent Sulpice, Mireille Desille, Bruno Turlin, Alain Fautrel, Karim Boudjema, Bruno Clément, and Cédric Coulouarn

Subjects
Genetics, QH426-470
Abstract

Intrahepatic cholangiocarcinoma (ICC) is the second most common type of malignant primary tumors in the liver. ICC is an aggressive cancer with a poor survival and limited therapeutic options. At the histological level, ICC is characterized by an abundant stroma (i.e. the tumor microenvironment that notably includes components of the extracellular matrix, stromal cells and soluble factors). Tumor microenvironment is known to play a key role in tumor onset and progression but it is poorly characterized at the molecular level. Thus, this study was specifically designed to identify genes that are significantly deregulated in the tumor microenvironment of human ICC. Here we provide a detailed description of the experimental design and methods used to acquire the genomic data deposited into Gene Expression Omnibus (GEO) under the accession number GSE45001. Our genomic dataset provides insights on the molecular pathways altered in the microenvironment of ICC and allows the identification of novel ICC biomarkers, as exemplified previously in Hepatology (PMID: 23775819). Keywords: Liver, Cancer, Cholangiocarcinoma, Microenvironment, Profiling

Published
2016
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5. Transcriptomic Analysis of Trout Gill Ionocytes in Fresh Water and Sea Water Using Laser Capture Microdissection Combined with Microarray Analysis.

Author

Isabelle Leguen, Aurélie Le Cam, Jérôme Montfort, Sandrine Peron, and Alain Fautrel

Subjects
Medicine, Science
Abstract

Fish gills represent a complex organ composed of several cell types that perform multiple physiological functions. Among these cells, ionocytes are implicated in the maintenance of ion homeostasis. However, because the ionocyte represents only a small percent of whole gill tissue, its specific transcriptome can be overlooked among the numerous cell types included in the gill. The objective of this study is to better understand ionocyte functions by comparing the RNA expression of this cell type in freshwater and seawater acclimated rainbow trout. To realize this objective, ionocytes were captured from gill cryosections using laser capture microdissection after immunohistochemistry. Then, transcriptome analyses were performed on an Agilent trout oligonucleotide microarray. Gene expression analysis identified 108 unique annotated genes differentially expressed between freshwater and seawater ionocytes, with a fold change higher than 3. Most of these genes were up-regulated in freshwater cells. Interestingly, several genes implicated in ion transport, extracellular matrix and structural cellular proteins appeared up-regulated in freshwater ionocytes. Among them, several ion transporters, such as CIC2, SLC26A6, and NBC, were validated by qPCR and/or in situ hybridization. The latter technique allowed us to localize the transcripts of these ion transporters in only ionocytes and more particularly in the freshwater cells. Genes involved in metabolism and also several genes implicated in transcriptional regulation, cell signaling and the cell cycle were also enhanced in freshwater ionocytes. In conclusion, laser capture microdissection combined with microarray analysis allowed for the determination of the transcriptional signature of scarce cells in fish gills, such as ionocytes, and aided characterization of the transcriptome of these cells in freshwater and seawater acclimated trout.

Published
2015
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6. Overexpression of active Aurora-C kinase results in cell transformation and tumour formation.

Author

Jabbar Khan, Frédéric Ezan, Jean-Yves Crémet, Alain Fautrel, David Gilot, Marine Lambert, Christelle Benaud, Marie-Bérengère Troadec, and Claude Prigent

Subjects
Medicine, Science
Abstract

Aurora kinases belong to a conserved family of serine/threonine kinases key regulators of cell cycle progression. Aurora-A and Aurora-B are expressed in somatic cells and involved mainly in mitosis while Aurora-C is expressed during spermatogenesis and oogenesis and is involved in meiosis. Aurora-C is hardly detectable in normal somatic cells. However all three kinases are overexpressed in many cancer lines. Aurora-A possesses an oncogenic activity while Aurora-B does not. Here we investigated whether Aurora-C possesses such an oncogenic activity. We report that overexpression of Aurora-C induces abnormal cell division resulting in centrosome amplification and multinucleation in both transiently transfected cells and in stable cell lines. Only stable NIH3T3 cell clones overexpressing active Aurora-C formed foci of colonies when grown on soft agar, indicating that a gain of Aurora-C activity is sufficient to transform cells. Furthermore, we reported that NIH-3T3 stable cell lines overexpressing Aurora-C induced tumour formation when injected into nude mice, demonstrating the oncogenic activity of enzymatically active Aurora kinase C. Interestingly enough tumor aggressiveness was positively correlated with the quantity of active kinase, making Aurora-C a potential anti-cancer therapeutic target.

Published
2011
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7. IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis.

Author

Paméla Gasse, Nicolas Riteau, Rachel Vacher, Marie-Laure Michel, Alain Fautrel, Franco di Padova, Lizette Fick, Sabine Charron, Vincent Lagente, Gérard Eberl, Marc Le Bert, Valérie F J Quesniaux, François Huaux, Maria Leite-de-Moraes, Bernhard Ryffel, and Isabelle Couillin

Subjects
Medicine, Science
Abstract

BackgroundIdiopathic pulmonary fibrosis is a devastating as yet untreatable disease. We demonstrated recently the predominant role of the NLRP3 inflammasome activation and IL-1β expression in the establishment of pulmonary inflammation and fibrosis in mice.MethodsThe contribution of IL-23 or IL-17 in pulmonary inflammation and fibrosis was assessed using the bleomycin model in deficient mice.ResultsWe show that bleomycin or IL-1β-induced lung injury leads to increased expression of early IL-23p19, and IL-17A or IL-17F expression. Early IL-23p19 and IL-17A, but not IL-17F, and IL-17RA signaling are required for inflammatory response to BLM as shown with gene deficient mice or mice treated with neutralizing antibodies. Using FACS analysis, we show a very early IL-17A and IL-17F expression by RORγt(+) γδ T cells and to a lesser extent by CD4αβ(+) T cells, but not by iNKT cells, 24 hrs after BLM administration. Moreover, IL-23p19 and IL-17A expressions or IL-17RA signaling are necessary to pulmonary TGF-β1 production, collagen deposition and evolution to fibrosis.ConclusionsOur findings demonstrate the existence of an early IL-1β-IL-23-IL-17A axis leading to pulmonary inflammation and fibrosis and identify innate IL-23 and IL-17A as interesting drug targets for IL-1β driven lung pathology.

Published
2011
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8. Merkel cell polyomavirus small T antigen mRNA level is increased following in vivo UV-radiation.

Author

Ariane Mogha, Alain Fautrel, Nicolas Mouchet, Na Guo, Sébastien Corre, Henri Adamski, Eric Watier, Laurent Misery, and Marie-Dominique Galibert

Subjects
Medicine, Science
Abstract

Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer involving Merkel cells. Recently, a new human polyomavirus was implicated in MCC, being present in 80% of the samples analyzed. In virus-positive MCC, the Merkel cell polyomavirus (MCPyV) is clonally integrated into the patients DNA, and carries mutations in its large T antigen, leading to a truncated protein. In non-symptomatic tissue MCPyV can reside at very low levels. MCC is also associated with older age, immunosuppression and sun exposure. However, the link with solar exposure remains unknown, as the precise mechanism and steps involved between time of infection by MCPyV and the development of MCC. We thus investigated the potential impact of solar simulated radiation (SSR) on MCPyV transcriptional activity. We screened skin samples of 20 healthy patients enrolled in a photodermatological protocol based on in vivo-administered 2 and 4 J/cm(2) SSR. Two patients were infected with two new variants of MCPyV, present in their episomal form and RT-QPCR analyses on SSR-irradiated skin samples showed a specific and unique dose-dependent increase of MCPyV small t antigen transcript. A luciferase based in vitro assay confirmed that small t promoter is indeed UV-inducible. These findings demonstrate that solar radiation has an impact on MCPyV mRNA levels that may explain the association between MCC and solar exposure.

Published
2010
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12. Data from Serum CD95L Level Correlates with Tumor Immune Infiltration and Is a Positive Prognostic Marker for Advanced High-Grade Serous Ovarian Cancer

Author

Vincent Lavoué, Patrick Legembre, Matthieu Le Gallo, Alain Fautrel, Jean Levêque, Véronique Catros, Bruno Laviolle, Estelle Le Pabic, Nathalie Rioux-Leclercq, Sébastien Henno, Clotilde Poupon, Marie Le Boulch, Aurélie Cauchois, Julien Corné, and Thibault De La Motte Rouge

Abstract

Soluble CD95L (s-CD95L) is a chemoattractant for certain lymphocyte subpopulations. We examined whether this ligand is a prognostic marker for high-grade serous ovarian cancer (HGSOC) and whether it is associated with accumulation of immune cells in the tumor. Serum s-CD95L levels in 51 patients with advanced ovarian cancer were tested by ELISA. IHC staining of CD3, CD4, CD8, CD20, CD163, CD31, FoxP3, CCR6, IL-17, Granzyme B, PD-L1, and membrane CD95L was used to assess tumor-infiltrating immune cells. Although the intensity of CD3, CD8, CD4, CD20, and CD163 in tumor tissues remained constant regardless of membrane CD95L expression, tumors in patients with HGSOC with s-CD95L levels ≥516 pg/mL showed increased infiltration by CD3+ T cells (P = 0.001), comprising both cytotoxic CD8+ (P = 0.01) and CD4+ (P = 0.0062) cells including FoxP3+ regulatory T cells (P = 0.0044). Also, the number of tumor-infiltrating CD20+ B cells (P = 0.0094) increased in these patients. Multivariate analyses revealed that low s-CD95L concentrations [+ (Granzyme B+) cells (HR, 2.63; 95% CI, 1.16–5.95) were independent poor prognostic factors for recurrence, whereas >6,000 CD3+ cells (HR, 0.34; 95% CI, 0.15–0.79) was a good prognostic factor. Thus, low levels of s-CD95L (+ and CD8+, and also CD4 and FoxP3 T cells) in advanced HGSOC and are a poor prognostic marker.Implications:Serum s-CD95L is correlated with a number of tumor-infiltrating immune cells in HGSOC and could be used as a noninvasive marker of tumor immune infiltration to select patients referred for immunotherapy trials that evaluate checkpoint inhibitor treatment.

Published
2023
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13. Supplementary Table 1 from Serum CD95L Level Correlates with Tumor Immune Infiltration and Is a Positive Prognostic Marker for Advanced High-Grade Serous Ovarian Cancer

Author

Vincent Lavoué, Patrick Legembre, Matthieu Le Gallo, Alain Fautrel, Jean Levêque, Véronique Catros, Bruno Laviolle, Estelle Le Pabic, Nathalie Rioux-Leclercq, Sébastien Henno, Clotilde Poupon, Marie Le Boulch, Aurélie Cauchois, Julien Corné, and Thibault De La Motte Rouge

Abstract

Table S1. Clinical characteristics of the patients

Published
2023
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14. Supplementary Data, Figure 1 from Serum CD95L Level Correlates with Tumor Immune Infiltration and Is a Positive Prognostic Marker for Advanced High-Grade Serous Ovarian Cancer

Author

Vincent Lavoué, Patrick Legembre, Matthieu Le Gallo, Alain Fautrel, Jean Levêque, Véronique Catros, Bruno Laviolle, Estelle Le Pabic, Nathalie Rioux-Leclercq, Sébastien Henno, Clotilde Poupon, Marie Le Boulch, Aurélie Cauchois, Julien Corné, and Thibault De La Motte Rouge

Abstract

Figure 1A: Membranous CD95 expression on ovarian cancer cell lines and primary cancer cells by cytometry Figure 1B: Evaluation of epithelial mesenchymal transition expression (EMT) profile using vimentin and E-cadherin expression on ovarian cancer cell line and primary cancer cells by Western Blot (A). Vimentin and E-cadherin expression ratio mean on ovarian cancer cells based on 3 experiments (B). Figure 1C: ALDH1 activity with or without s-CD95L (100 ng/mL) evaluated by cytometry. Figure 1D: Proliferation of OVCAR3 cell lines using cytometry and G1, G2 and S phase markers E: Proliferation of O170 primary cell lines using cytometry and G1, G2 and S phase markers F: Proliferation of various ovarian cancer cell lines or primary cell lines with or without s-CD95L (100 ng/mL) in medium using cytometry and G1, G2 and S phase markers

Published
2023
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15. The mechanosensitive <scp>TRPV2</scp> calcium channel promotes human melanoma invasiveness and metastatic potential

Author

Kenji F Shoji, Elsa Bayet, Sabrina Leverrier‐Penna, Dahiana Le Devedec, Aude Mallavialle, Séverine Marionneau‐Lambot, Florian Rambow, Raul Perret, Aurélie Joussaume, Roselyne Viel, Alain Fautrel, Amir Khammari, Bruno Constantin, Sophie Tartare‐Deckert, Aubin Penna, Pecqueret, Valérie, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Canaux et Connexines dans les Cancers et Cellules Souches (4CS), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire], Universität Duisburg-Essen [Essen], West German Cancer Center [Essen, Germany], Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Immunology and New Concepts in ImmunoTherapy (INCIT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), ANR‐12‐JSV2‐0004‐001, Agence Nationale de la Recherche, PJA20151203419, Fondation ARC pour la Recherche sur le Cancer, Ligue Contre le Cancer, Université de Rennes 1, and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]

Subjects
[SDV] Life Sciences [q-bio], migration, [SDV]Life Sciences [q-bio], Medizin, melanoma, Genetics, metastasis, calpain, Molecular Biology, Biochemistry, TRPV2 channel
Abstract

Melanoma is a highly aggressive cancer endowed with a unique capacity of rapidly metastasizing, which is fundamentally driven by aberrant cell motility behaviors. Discovering "migrastatics" targets, specifically controlling invasion and dissemination of melanoma cells during metastasis, is therefore of primary importance. Here, we uncover the prominent expression of the plasma membrane TRPV2 calcium channel as a distinctive feature of melanoma tumors, directly related to melanoma metastatic dissemination. In vitro as well as in vivo, TRPV2 activity is sufficient to confer both migratory and invasive potentials, while conversely TRPV2 silencing in highly metastatic melanoma cells prevents aggressive behavior. In invasive melanoma cells, TRPV2 channel localizes at the leading edge, in dynamic nascent adhesions, and regulates calcium-mediated activation of calpain and the ensuing cleavage of the adhesive protein talin, along with F-actin organization. In human melanoma tissues, TRPV2 overexpression correlates with advanced malignancy and poor prognosis, evoking a biomarker potential. Hence, by regulating adhesion and motility, the mechanosensitive TRPV2 channel controls melanoma cell invasiveness, highlighting a new therapeutic option for migrastatics in the treatment of metastatic melanoma. ispartof: EMBO REPORTS vol:24 issue:4 ispartof: location:England status: published

Published
2023
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16. Hepatocellular carcinoma hosts immature neurons and cholinergic tumors that correlate with adverse molecular features and outcomes

Author

Charlotte A. Hernandez, Claire Verzeroli, Ievgeniia Chicherova, Abud-José Farca-Luna, Laurie Tonon, Pascale Bellaud, Bruno Turlin, Alain Fautrel, Zuzana Macek-Jilkova, Thomas Decaens, Sandra Rebouissou, Alain Viari, Fabien Zoulim, and Romain Parent

Abstract

Background & aimsThe unexplained interpatient variation in hepatocellular carcinoma (HCC) remains a major challenge. We aimed at addressing the under-explored association between the disease and the hepatic autonomic nervous system (ANS).Methods & ResultsWe in-depth characterized the innervation of French biobanks HCC samples by conventional biochemistry methods. We also applied bioinformatics approaches to the TCGA dataset in order to stratify samples according to neural features and molecular correlates. We highlighted the predominant parasympathetic polarity of HCC nerves, and demonstrated that a cirrhotic rat model of aggressive HCC hosts liver neurogenesis with cholinergic features. Using the TCGA dataset, we then defined an HCC neural signature, derived from adrenergic and cholinergic receptor levels, that allowed patient stratification into two classes. Cholinergic tumors correlated with TP53 mutations (p ≤ 0.05), shorter progression-free interval (PFI) and overall survival (OS), displayed more pathogenic molecular traits (e.g., AFP-rich, proliferative tumors, mitotic functions including DNA repair, EMT, Ras, and Akt/mTOR pathways), aggressive HCC signatures and B cell accumulation. Instead, adrenergic tumors, predominant in patients aged >60 and with mutated CTNNB1, were correlated with better OS and PFI (p < 0.05), and numerous immune pathways.ConclusionsOur results depict neural features of HCC and how the existing tumor classification may also be shaped by neural inputs. Altogether, we show that the parasympathetic branch of the ANS is implicated in the pathobiology of HCC, and advocate for the use of ANS-targeting drugs in HCC research, many of which are clinically safe and well characterized.

Published
2022
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17. The mechanosensitive TRPV2 calcium channel controls human melanoma invasiveness and metastatic potential

Author

Elsa Bayet, Aurélie Joussaume, Amir Khammari, Raul Perret, Aude Mallavialle, Bruno Constantin, Florian Rambow, Alain Fautrel, Roselyne Viel, Sophie Tartare-Deckert, Sabrina Leverrier-Penna, Séverine Marionneau-Lambot, Dahiana Le Devedec, Aubin Penna, Kenji F. Shoji, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire], Leuven Center for Cancer Biology (VIB-KU-CCB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), and PENNA, Aubin

Subjects
Calcium channel, Melanoma, TRPV2, Regulator, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease, Metastasis, Focal adhesion, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Cancer research, Gene silencing, Mechanosensitive channels
Abstract

Discovery of therapeutic targets against metastasis is of primary importance since being the main cause of cancer-related death. Melanoma is a highly aggressive cancer endowed with a unique capacity of rapidly metastasizing. Deregulation of calcium homeostasis has been involved in numerous cellular metastatic behaviors, although the molecular determinants supporting these processes often remain unclear. Here, we evidenced a prominent expression of the plasma membrane TRPV2 calcium channel as a distinctive feature of melanoma tumors, directly related to melanoma metastatic progression and dissemination. In vitro as well as in vivo, TRPV2 activity was sufficient to confer both migratory and invasive phenotypes to non-invasive melanoma cells, while conversely upon TRPV2 silencing, highly metastatic melanoma cells failed to retain their malignant behaviors. We established a model whereupon activation of the mechanosensitive TRPV2 channel, localized in highly dynamic nascent adhesion clusters, directly regulates calpain-dependent cleavage of the adhesive protein talin together with F-actin network. By operating at the crossroad of the tumor microenvironment and the intracellular machinery, mechanosensitive TRPV2 channel controls melanoma cells aggressiveness. Finally in human melanoma tumor samples, TRPV2 overexpression represents a molecular marker of advanced malignancy and bad prognosis, highlighting a new therapeutic option for migrastatics in the treatment of metastatic melanoma.SignificanceOne essential feature of metastatic cells is enhanced motility and invasiveness. This study evidences TRPV2 channel control over metastatic melanoma invasiveness, highlights new migration regulatory mechanisms, and reveals this channel as a biomarker and migrastatic target for the treatment of advanced melanoma.

Published
2021
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18. Characterization of human airway epithelial cell lines as in vitro models of chronic obstructive pulmonary disease

Author

Vincent Lagente, Yann Verres, Pascale Bellaud, Tatiana Victoni, Thomas Gicquel, Alain Fautrel, Aude Bodin, Françoise Pons, Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Conception et application de molécules bioactives (CAMB), Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and ANR-17-CE18-0034,LuTher,Vecteurs pour la thérapie génique par voie pulmonaire : vaincre la barrière du mucus dans les maladies du poumon(2017)

Subjects
Inflammation, Pathology, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], Pulmonary disease, Human airway, Epithelium, In vitro, Epithelial cell, medicine.anatomical_structure, medicine, business, ComputingMilieux_MISCELLANEOUS, COPD - mechanism
Abstract

International audience

Published
2021
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19. Influence of inflammasome pathway activation in macrophages on the matrix metalloproteinase expression of human hepatic stellate cells

Author

Emiliano Barreto, Aude Bodin, Sacha Robert, Elisabeth Boichot, Alain Fautrel, Tatiana Victoni, Thomas Gicquel, Vincent Lagente, Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CNPqNational Council for Scientific and Technological Development (CNPq) [303452/2014-5, 203537/2014-9], Centre de Ressources Biologiques Sante (Rennes, France) [BB-0033-00056], Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, Lipopolysaccharide, Macrophage, Inflammasomes, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Interleukin-1beta, Immunology, Inflammasome, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Downregulation and upregulation, Hepatic Stellate Cells, medicine, Humans, Immunology and Allergy, Cytokine, Hepatic stellate cell, Metalloproteinase, Cells, Cultured, Pharmacology, Tissue Inhibitor of Metalloproteinase-1, Tumor Necrosis Factor-alpha, Macrophages, Actins, Matrix Metalloproteinases, Cell biology, 030104 developmental biology, chemistry, Cell culture, 030220 oncology & carcinogenesis, Tumor necrosis factor alpha, medicine.drug
Abstract

International audience; Inflammasomes are protein complexes that produce IL-1β in response to damage or pathogens. As such, inflammasomes are involved in several types of hepatic fibrosis. However, the mechanisms by which these complexes drive the liver's fibrogenic status remain unclear. We co-cultured differentiated macrophages (the THP-1 cell line or human monocyte-derived macrophages (MDMs)) with human hepatic fibroblasts (either the LX-2 cell line or primary human hepatic stellate cells (HSCs)). The inflammasome pathway was activated with lipopolysaccharide (LPS) and monosodium urate (MSU) crystals, and the HSCs' responses were analyzed. Our results show that co-culture of HSCs with THP-1 cells upregulated transcription of the genes coding for metalloproteinase (MMP)-3 and MMP-9. After inflammasome pathway activation, the HSCs' phenotype was the same in the presence of THP-1 cells or MDMs (i.e. upregulation of MMP-3, MMP-9, and the pro-inflammatory cytokine IL-1β). We found that two cytokines were involved in these changes IL-1β regulated MMP-3 and IL-1β mRNA expression, whereas TNF-α regulated MMP-9 mRNA expression. Experiments with primary cells revealed that a general inflammatory environment is responsible for the downregulation of pro-fibrotic markers. Our present results suggest that inflammasome pathway activation in macrophages leads to a pro-inflammatory environment for HSCs leading to MMP/TIMP imbalance and enhanced fibrolytic properties.

Published
2019
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20. Étude anatomique et immunohistochimique de l’innervation utérine

Author

Marion Pinsard, Vincent Lavoué, P. Bellaud, Jean Levêque, Alain Fautrel, K. Nyangoh Timoh, Xavier Morandi, and N. Mouchet

Subjects
Anatomy
Abstract

Introduction/Objectif L’adenomyose et l’endometriose sont des pathologies pelviennes benignes tres frequentes, responsables de symptomes douloureux secondaires a des anomalies de l’innervation uterine [1] , [2] , [3] , [4] , [5] . Cependant, les donnees disponibles concernant l’innervation precise de l’uterus sont tres pauvres. L’objectif etait de realiser une cartographie anatomique et fonctionnelle de l’innervation uterine, et d’elaborer le premier modele de reconstruction tridimensionnelle de l’innervation uterine. Materiels et methodes Des coupes seriees ont ete effectuees sur le bassin de 3 fœtus feminins humains. Les coupes etaient traitees par l’HES, puis immunomarquees pour detecter l’ensemble des nerfs (anticorps anti-proteine S100), puis caracteriser les differents types de fibres nerveuses (PMP 22+, TH+, VAChT+, CGRP1+, VIP+, NPY+, nNOS+, ocytocine+ et relaxine+). Une quantification automatisee de chaque type nerfs a ete realisee dans les differentes portions et couches de l’uterus. Une reconstruction tridimensionnelle a ete realisee grâce a la technique de dissection anatomique assistee par ordinateur (DAAO). Resultats Nous avons realise le premier modele de reconstruction tridimensionnelle de l’innervation uterine. Elle provenait du plexus hypogastrique inferieur, lui-meme alimente par les nerfs hypogastriques et splanchniques pelviens. Il existait un faisceau de fibres nerveuses accessoire emanant du plexus hypogastrique inferieur, qui contournait l’uretere pour venir aborder le bord lateral du col uterin au niveau de la zone d’insertion du vagin. La portion supra-vaginale du col etait la plus innervee. Il existait une innervation endometriale qui atteignait la couche fonctionnelle de l’endometre. Les nerfs intra-uterins etaient composes de fibres autonomes TH+ et VIP+, et de fibres sensitives NPY+ et CGRP1+. Enfin, l’artere uterine avait une innervation autonome mais aussi sensitive. Conclusion Nous avons effectue une etude complete de l’innervation uterine en situation physiologique, et realise le premier modele de reconstruction tridimensionnelle de l’innervation uterine. Cette base solide permettra l’etude de l’innervation uterine en situation pathologique, pour esperer trouver de nouvelles pistes therapeutiques.

Published
2021
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21. Towards a Reduced In Silico Model Predicting Biochemical Recurrence After Radiotherapy in Prostate Cancer

Author

Romain Mathieu, Nathalie Rioux-Leclercq, Alain Fautrel, Pierre Fontaine, François Paris, Carlos Sosa-Marrero, Renaud de Crevoisier, Oscar Acosta, Alfredo Hernandez, Bernardo, Elizabeth, Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Eugène Marquis (CRLCC), CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Endothelium Radiobiology and Targeting (CRCINA-ÉQUIPE 14), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Brittany Region, and FHU TECH-SAN, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
Oncology, Biochemical recurrence, Male, medicine.medical_specialty, Angiogenesis, medicine.medical_treatment, In silico, 0206 medical engineering, Biomedical Engineering, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, Logistic regression, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Prostate cancer, sensitivity analysis, [SDV.CAN] Life Sciences [q-bio]/Cancer, Prostate, Internal medicine, medicine, Humans, Computer Simulation, Mitotic catastrophe, radiotherapy, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, [SDV.IB] Life Sciences [q-bio]/Bioengineering, business.industry, Prostatic Neoplasms, prostate cancer, medicine.disease, multiscale modeling, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 020601 biomedical engineering, tumor control probability, Radiation therapy, medicine.anatomical_structure, [SDV.IB]Life Sciences [q-bio]/Bioengineering, business, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing
Abstract

Objective: Purposes of this work were i) to develop an in silico model of tumor response to radiotherapy, ii) to perform an exhaustive sensitivity analysis in order to iii) propose a simplified version and iv) to predict biochemical recurrence with both the comprehensive and the reduced model. Methods: A multiscale computational model of tumor response to radiotherapy was developed. It integrated the following radiobiological mechanisms: oxygenation, including hypoxic death; division of tumor cells; VEGF diffusion driving angiogenesis; division of healthy cells and oxygen-dependent response to irradiation, considering, cycle arrest and mitotic catastrophe. A thorough sensitivity analysis using the Morris screening method was performed on 21 prostate computational tissues. Tumor control probability (TCP) curves of the comprehensive model and 15 reduced versions were compared. Logistic regression was performed to predict biochemical recurrence after radiotherapy on 76 localized prostate cancer patients using an output of the comprehensive and the reduced models. Results: No significant difference was found between the TCP curves of the comprehensive and a simplified version which only considered oxygenation, division of tumor cells and their response to irradiation. Biochemical recurrence predictions using the comprehensive and the reduced models improved those made from pre-treatment imaging parameters (AUC = 0.81 $\pm$ 0.02 and 0.82 $\pm$ 0.02 vs. 0.75 $\pm$ 0.03, respectively). Conclusion: A reduced model of tumor response to radiotherapy able to predict biochemical recurrence in prostate cancer was obtained. Significance: This reduced model may be used in the future to optimize personalized fractionation schedules.

Published
2021
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22. Integration of Raman spectra with transcriptome data in glioblastoma multiforme defines tumour subtypes and predicts patient outcome

Author

Mari McMahon, Luis Cano, Aristotelis Chatziioannou, Marc Aubry, Alain Fautrel, Amandine Etcheverry, Eleftherios Pilalis, Eric Chevet, Pierre-Jean Le Reste, CHU Pontchaillou [Rennes], Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Rennes Brain Cancer Team (REACT), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), CRLCC Eugène Marquis (CRLCC), Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National du Cancer (INCa PLBIO) Institut National du Cancer (INCA) France, Fondation pour la Recherche Medicale (FRM) Fondation pour la Recherche Medicale [DEQ20180339169], EU H2020 MSCA [ITN-675448], MSCA [RISE-734749], Irish Research Council Irish Research Council for Science, Engineering and Technology, ARED International PhD fellowship from \'Region Bretagne\', INSERM International Research Project (TUPRIC), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Jonchère, Laurent

Subjects
Adult, Male, Cell type, Disease outcome, [SDV]Life Sciences [q-bio], Computational biology, Spectrum Analysis, Raman, Transcriptome, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, medicine, Humans, data integration, 030304 developmental biology, Aged, 0303 health sciences, Chemistry, Brain Neoplasms, glioblastoma, Cell Biology, Original Articles, Middle Aged, medicine.disease, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Raman spectroscopy, symbols, Molecular Medicine, Female, Original Article, Imaging technique, Glioblastoma
Abstract

International audience; Raman spectroscopy is an imaging technique that has been applied to assess molecular compositions of living cells to characterize cell types and states. However, owing to the diverse molecular species in cells and challenges of assigning peaks to specific molecules, it has not been clear how to interpret cellular Raman spectra. Here, we provide firm evidence that cellular Raman spectra (RS) and transcriptomic profiles of glioblastoma can be computationally connected and thus interpreted. We find that the dimensions of high-dimensional RS and transcriptomes can be reduced and connected linearly through a shared low-dimensional subspace. Accordingly, we were able to predict global gene expression profiles by applying the calculated transformation matrix to Raman spectra and vice versa. From these analyses, we extract a minimal gene expression signature associated with specific RS profiles and predictive of disease outcome.

Published
2021
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23. One-step nucleic acid amplification for detecting lymph node metastasis of head and neck squamous cell carcinoma

Author

Jeff Morcet, Alain Fautrel, Florence Godey, Mathieu Le Gallo, Lucie Peigné, Francois Le Gall, Franck Jegoux, CHU Pontchaillou [Rennes], CRLCC Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and CCSD, Accord Elsevier

Subjects
Oncology, Male, Cancer Research, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Metastasis, 0302 clinical medicine, Sentinel lymph node biopsy, OSNA, Prospective Studies, 10. No inequality, 030223 otorhinolaryngology, Lymph node, Aged, 80 and over, medicine.diagnostic_test, Middle Aged, Pathological analysis, Epithelial Cell Adhesion Molecule, Primary tumor, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Lymphatic Metastasis, Female, Oral Surgery, Sentinel Lymph Node, Nucleic Acid Amplification Techniques, Oligopeptides, Adult, medicine.medical_specialty, Micro metastasis, Sentinel lymph node, Sensitivity and Specificity, 03 medical and health sciences, Breast cancer, Internal medicine, Biopsy, medicine, Humans, RNA, Messenger, Aged, Keratin-19, business.industry, Squamous Cell Carcinoma of Head and Neck, CK19, Head and neck squamous cell carcinoma, medicine.disease, Head and neck squamous-cell carcinoma, Radiation therapy, Feasibility Studies, Lymph Node Excision, business
Abstract

International audience; Background - In head and neck squamous cell carcinoma (HNSCC) 30% of cN0 patients have occult metastasis. LN invasion is a major prognostic factor. Sentinel lymph node (SLN) is an option for cN0 neck management. One-step nucleic acid amplification (OSNA) used to analyze SLN in breast cancer is also a candidate to get more reliable intraoperative HNSCC lymph node (LN) staging. Objective - To compare OSNA analysis to pathological analysis in cN0 HNSCC. Materials and methods - 157 LN from 26 cN0 HNSCC patients were prospectively analyzed (6.3LN/patient). Exclusion criteria were previous surgery or radiotherapy. Each node was cut into 4 equal pieces alternatively sent to pathological analysis and OSNA technique. IHC CK19 was performed on the primary tumor biopsy and RT-qPCR of CK19, PVA and EPCAM on the LN lysate of discordant cases. Results - OSNA was able to provide intraoperative result in all patients. OSNA detected 21 metastases. There were 139 concordant LN (88.5%). There were 18 initial discordant LN (11.5%), 13 (8.3%) were OSNA positive/pathological analysis negative, 5 (3.2%) were OSNA negative/pathological analysis positive. After elimination of allocation bias, false negative rate was 1.3%, sensitivity and specificity were 90% and 95.6%, PPV and NPV were 75% and 98.5%. Conclusion - Our results suggest that OSNA should be considered to improve SNB analysis both for increasing micro metastasis diagnosis and offer extemporaneous results. Study registered under clinicaltrials.gov database number NCT02852343.

Published
2020
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24. Analysis of mucus secretion and inflammatory process in in vitro model of human airway epithelial cells able

Author

Aude Bodin, Tatiana Victoni, Pascale Bellaud, Françoise Pons, Thomas Gicquel, Yann Verres, Alain Fautrel, and Vincent Lagente

Subjects
Pulmonary and Respiratory Medicine, A549 cell, business.industry, medicine.medical_treatment, Mucin, Inflammation, respiratory system, Pharmacology, Mucus, CXCL1, Cytokine, parasitic diseases, medicine, Cytokine secretion, Interleukin 8, medicine.symptom, business
Abstract

Introduction Chronic Obstructive pulmonary disease (COPD) is a lung disease characterized by chronic inflammation, and mucus hypersecretion. Currently, curative treatment does not exist, and some patients develop resistance to corticosteroid drugs. Gene therapy could be a novel approach to treat the disease. However, the effectiveness of gene vectors in the airways is decreased by the presence of mucus that acts as a barrier. The aim of this study is to develop an in vitro model, able of cytokine production and mucus secretion; in the perspective of testing new drug including mucolytic gene therapy vectors. Methods We used three human airway epithelial lines (A549, Calu-3 and NCI-H292) stimulated with different concentrations of CSE (Cigarette Smoke Extract) alone or in association with LPS (lipopolysaccharides), for 24 or 48 hours. NCI-H292 and Calu-3 cells were also co-cultured in the same conditions. Then, we evaluated MUC5AC, IL8/CXCL8, GROα/CXCL1 and MCP1/CCL2 gene expression by RT-qPCR and their secretion by ELISA. Finally, we also observed MUC5AC production from NCI-H292 by immunohistochemistry. Results CSE alone or with LPS did not impact MUC5AC gene expression, in A549 cells. In contrast, LPS (0.1 μg/mL) increased IL8/CXCL8, GROα/CXCL1 and MCP1/CCL2 release. When CSE associated with LPS, there was an additive effect on cytokine release. Regarding Calu-3 cells, treatment with CSE, LPS, or both, did not affect MUC5AC gene expression, neither cytokine secretions. For NCI-H292 cells, CSE alone increased MUC5AC gene expression and an additive effect was observed when CSE was associated with LPS. LPS at low concentrations triggered some MUC5AC and IL8/CXCL8 release, which was more important when LPS was associated with CSE; but not for GROα/CXCL1. NCI-H292 cells did not release MCP1/CCL2. In the NCI-H292 and Calu-3 co-culture, CSE and LPS increased MUC5AC gene expression, but CSE did not affect cytokine secretion. LPS alone increased IL8/CXCL8 secretion, but not GROα/CXCL1 or MCP1/CCL2. Conclusion Our results show that NCI-H292 cells appear as the best model to evaluate the efficacy of gene vectors, as they are able to produce mucins and cytokines, after CSE and LPS exposure.

Published
2021
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25. Propolis reversed cigarette smoke-induced emphysema through macrophage alternative activation independent of Nrf2

Author

Marina Valente Barroso, Martina Schmidt, Vincent Lagente, Alain Fautrel, Lycia de Brito-Gitirana, Manuella Lanzetti, Bruna Romana-Souza, Luís Cristóvão Porto, Isabella Cattani-Cavalieri, Samuel Santos Valença, Universidade Federal do Rio de Janeiro (UFRJ), CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of Groningen [Groningen], Universidade do Estado do Rio de Janeiro [Rio de Janeiro] (UERJ), This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 400096/2014-5), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES 055-14) and Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ E-26/102.254/2013)., Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Jonchère, Laurent, Molecular Pharmacology, and Groningen Research Institute for Asthma and COPD (GRIAC)

Subjects
Male, 0301 basic medicine, Clinical Biochemistry, NF-KAPPA-B, Anti-Inflammatory Agents, Pharmaceutical Science, medicine.disease_cause, Biochemistry, Mice, Drug Discovery, Macrophage, OXIDATIVE STRESS, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, COPD, Lung repair, Chemistry, Smoking, respiratory system, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, M2 Macrophage, 3. Good health, INDUCED LUNG INJURY, medicine.anatomical_structure, Pulmonary Emphysema, Molecular Medicine, MOUSE LUNG, medicine.symptom, HEME OXYGENASE-1, NF-E2-Related Factor 2, Macrophage polarization, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, OBSTRUCTIVE PULMONARY-DISEASE, Propolis, M2 macrophage, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, LIVER-DISEASE, GROWTH-FACTOR-I, medicine, EXTRACELLULAR-MATRIX, Animals, Molecular Biology, Emphysema, Lung, Macrophages, Organic Chemistry, INFLAMMATORY RESPONSE, Nrf2 pathway, medicine.disease, respiratory tract diseases, Mice, Inbred C57BL, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, 030104 developmental biology, Immunology, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Oxidative stress
Abstract

Chronic obstructive pulmonary disease (COPD) is an incurable and progressive disease. Emphysema is the principal manifestation of COPD, and the main cause of this condition is cigarette smoke (CS). Natural products have shown antioxidant and anti-inflammatory properties that can prevent acute lung inflammation and emphysema, but there are few reports in the literature regarding therapeutic approaches to emphysema. We hypothesized that supplementation with natural extracts would repair lung damage in emphysema caused by CS exposure. Mice were exposed to 60 days of CS and then treated or not with three different natural extracts (mate tea, grape and propolis) orally for additional 60 days. Histological analysis revealed significant improvements in lung histoarchitecture, with recovery of alveolar spaces in all groups treated with natural extracts. Propolis was also able to recovery alveolar septa and elastic fibers. Propolis also increased MMP-2 and decreased MMP-12 expression, favoring the process of tissue repair. Additionally, propolis recruited leukocytes, including macrophages, without ROS release. These findings led us to investigate the profile of these macrophages, and we showed that propolis could promote macrophage alternative activation, thus increasing the number of arginase-positive cells and IL-10 levels and favoring an anti-inflammatory microenvironment. We further investigated the participation of Nrf2 in lung repair, but no Nrf2 translocation to the nucleus was observed in lung cells. Proteins and enzymes related to Nrf2 were not altered, other than NQO1, which seemed to be activated by propolis in a Nrf2-independent manner. Finally, propolis downregulated IGF1 expression. In conclusion, propolis promoted lung repair in a mouse emphysema model via macrophage polarization from M1 to M2 in parallel to the downregulation of IGF1 expression in a Nrf2-independent manner. (C) 2017 Elsevier Ltd. All rights reserved.

Published
2017
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26. [Autophagy and spermatozoa]

Author

Antoine, Buschiazzo, Marina, Yefimova, Nicolas, Bourmeyster, Alain, Fautrel, Agnès, Burel, Anne-Sophie, Neyroud, Céline, Pimentel, Sylvie, Jaillard, Bernard, Jégou, and Célia, Ravel

Subjects
Male, Autophagy, Humans, Spermatogenesis, Spermatozoa
Abstract

Spermiogenesis, the ultimate stage of spermatogenesis, is a process involving autophagy. At this stage, the acrosome is generated by vesicular fusion and most of the cytoplasm disappears. Autophagy, literally "eating oneself", allowing the elimination and replacement of proteins and nonfunctional organelles, ensures the recycling of cellular constituents and is a highly conserved cellular mechanism within eukaryotic cells. The machinery of autophagy is present in the spermatozoon, regulating the vitality and mobility of the cells. The environmental and behavioral impact on autophagy and the consequences on spermatogenesis are beginning to be studied. The purpose of this review is to synthesize current knowledge about autophagy in the mature male gamete.Autophagie et spermatozoïde.La spermiogenèse, étape ultime de la spermatogenèse, est un processus qui fait intervenir des acteurs qui participe à l’autophagie. C’est en effet lors de cette étape que se forme l’acrosome par fusion vésiculaire et que disparaît la majeure partie du cytoplasme du spermatozoïde. L’autophagie (littéralement « se manger soi-même »), en permettant l’élimination et le remplacement continuel des protéines et des organites non fonctionnels, assure le recyclage des constituants de la cellule. C’est un mécanisme cellulaire très conservé au sein des cellules eucaryotes. La machinerie de l’autophagie est également présente dans les spermatozoïdes. Elle régule la vitalité de ces cellules et leur mobilité. Les conséquences environnementales et comportementales sur l’autophagie et sur la spermatogenèse commencent à être étudiées. Le but de cette revue est de synthétiser les connaissances actuelles concernant les processus d’autophagie dans le gamète mâle mature.

Published
2019

27. Smooth muscle of the male pelvic floor: An anatomic study

Author

Gérard Benoit, Vincent Lavoué, Cedric Lebacle, Alain Fautrel, Jelena Martinovic, J Deffon, David Moszkowicz, Maud Creze, Djibril Diallo, Thomas Bessede, Krystel Nyangoh Timoh, Mazen Zaitouna, Petites Molécules de neuroprotection, neurorégénération et remyélinisation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Jonchère, Laurent

Subjects
Male, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Histology, [SDV]Life Sciences [q-bio], Rectum, smooth muscle, surgery, 03 medical and health sciences, 0302 clinical medicine, Fetus, Imaging, Three-Dimensional, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Cadaver, Medicine, rectum, Humans, anal canal, levator ani, 0303 health sciences, Core (anatomy), Pelvic floor, prostatectomy, business.industry, Abdominoperineal resection, Hypogastric Plexus, Muscle, Smooth, 030206 dentistry, General Medicine, Anatomy, Pelvic Floor, Anal canal, [SDV] Life Sciences [q-bio], body regions, medicine.anatomical_structure, Urethra, Levator ani, 030301 anatomy & morphology, proctectomy, neuro-anatomy, urethra, business
Abstract

Knowledge of the anatomy of the male pelvic floor is important to avoid damaging the pelvic floor muscles during surgery. We set out to explore the structure and innervation of the smooth muscle (SM) of the whole pelvic floor using male fetuses. We removed en-bloc the entire pelvis of three male fetuses. The specimens were serially sectioned before being stained with Masson's trichrome and hematoxylin and eosin, and immunostained for SMs, and somatic, adrenergic, sensory and nitrergic nerve fibers. Slides were digitized for three-dimensional reconstruction. We individualized a middle compartment that contains SM cells. This compartment is in close relation with the levator ani muscle (LAM), rectum, and urethra. We describe a posterior part of the middle compartment posterior to the rectal wall and an anterior part anterior to the rectal wall. The anterior part is split into (1) a centro-levator area of SM cells localized between the right and left LAM, (2) an endo-levator area that upholsters the internal aspect of the LAM, and (3) an infra-levator area below the LAM. All these areas are innervated by autonomic nerves coming from the inferior hypogastric plexus. The core and the infra-levator area receive the cavernous nerve and nerves supplying the urethra. We thus demonstrate that these muscular structures are smooth and under autonomic influence. These findings are relevant for the pelvic surgeon, and especially the urologist, during radical prostatectomy, abdominoperineal resection and intersphincteric resection. Clin. Anat., 2019. © 2019 Wiley Periodicals, Inc.

Published
2019
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28. Serum CD95L Level Correlates with Tumor Immune Infiltration and Is a Positive Prognostic Marker for Advanced High-Grade Serous Ovarian Cancer

Author

Jean Levêque, Julien Corné, Matthieu Le Gallo, Patrick Legembre, Alain Fautrel, Marie Le Boulch, Aurélie Cauchois, Sébastien Henno, Bruno Laviolle, Vincent Lavoué, Estelle Le Pabic, Clotilde Poupon, Thibault De La Motte Rouge, Nathalie Rioux-Leclercq, Véronique Catros, Centre Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CRLCC Eugène Marquis (CRLCC), 2017, Ligue Contre le Cancer, 2016, Fondation ARC pour la Recherche sur le Cancer, 2014, La Vannetaise, PLASTICO 2017, Canceropole Grand Ouest, 2017, INCa PLBIO, 2018, ANR PRCE, Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Cancer Research, Fas Ligand Protein, medicine.medical_treatment, CD3, [SDV]Life Sciences [q-bio], tumor immune infiltration, [SDV.CAN]Life Sciences [q-bio]/Cancer, Apoptosis, T-Lymphocytes, Regulatory, 03 medical and health sciences, 0302 clinical medicine, Immune system, Lymphocytes, Tumor-Infiltrating, Cell Movement, medicine, Biomarkers, Tumor, Cytotoxic T cell, Humans, Molecular Biology, Cell Proliferation, Neoplasm Staging, CD20, Ovarian Neoplasms, B-Lymphocytes, biology, business.industry, FOXP3, Forkhead Transcription Factors, Immunotherapy, soluble CD95 ligand, Middle Aged, Prognosis, High grade serous ovarian cancer, 3. Good health, Cystadenocarcinoma, Serous, Granzyme B, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, biology.protein, Female, business, CD8
Abstract

Soluble CD95L (s-CD95L) is a chemoattractant for certain lymphocyte subpopulations. We examined whether this ligand is a prognostic marker for high-grade serous ovarian cancer (HGSOC) and whether it is associated with accumulation of immune cells in the tumor. Serum s-CD95L levels in 51 patients with advanced ovarian cancer were tested by ELISA. IHC staining of CD3, CD4, CD8, CD20, CD163, CD31, FoxP3, CCR6, IL-17, Granzyme B, PD-L1, and membrane CD95L was used to assess tumor-infiltrating immune cells. Although the intensity of CD3, CD8, CD4, CD20, and CD163 in tumor tissues remained constant regardless of membrane CD95L expression, tumors in patients with HGSOC with s-CD95L levels ≥516 pg/mL showed increased infiltration by CD3+ T cells (P = 0.001), comprising both cytotoxic CD8+ (P = 0.01) and CD4+ (P = 0.0062) cells including FoxP3+ regulatory T cells (P = 0.0044). Also, the number of tumor-infiltrating CD20+ B cells (P = 0.0094) increased in these patients. Multivariate analyses revealed that low s-CD95L concentrations [6,000 CD3+ cells (HR, 0.34; 95% CI, 0.15–0.79) was a good prognostic factor. Thus, low levels of s-CD95L ( Implications: Serum s-CD95L is correlated with a number of tumor-infiltrating immune cells in HGSOC and could be used as a noninvasive marker of tumor immune infiltration to select patients referred for immunotherapy trials that evaluate checkpoint inhibitor treatment.

Published
2019
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29. Autophagie et spermatozoïde

Author

Alain Fautrel, Antoine Buschiazzo, Marina Yefimova, Sylvie Jaillard, Céline Pimentel, Nicolas Bourmeyster, Agnès Burel, Bernard Jégou, Célia Ravel, Anne-Sophie Neyroud, CHU Pontchaillou [Rennes], Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers-Université de Tours-Centre National de la Recherche Scientifique (CNRS), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Microscopie de Rennes (MRic), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), EHESP-Irset (EHESP-Irset), Université de Poitiers-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)

Subjects
0303 health sciences, Spermatozoon, Spermiogenesis, [SDV]Life Sciences [q-bio], Autophagy, General Medicine, Biology, General Biochemistry, Genetics and Molecular Biology, Cell biology, Gamète mâle, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Cytoplasm, 030220 oncology & carcinogenesis, Organelle, medicine, Gamete, Autophagie, Spermatozoïde, Acrosome, Spermatogenesis, Spermatogenèse, 030304 developmental biology
Abstract

La spermiogenèse, étape ultime de la spermatogenèse, est un processus qui fait intervenir des acteurs qui participe à l’autophagie. C’est en effet lors de cette étape que se forme l’acrosome par fusion vésiculaire et que disparaît la majeure partie du cytoplasme du spermatozoïde. L’autophagie (littéralement « se manger soi-même »), en permettant l’élimination et le remplacement continuel des protéines et des organites non fonctionnels, assure le recyclage des constituants de la cellule. C’est un mécanisme cellulaire très conservé au sein des cellules eucaryotes. La machinerie de l’autophagie est également présente dans les spermatozoïdes. Elle régule la vitalité de ces cellules et leur mobilité. Les conséquences environnementales et comportementales sur l’autophagie et sur la spermatogenèse commencent à être étudiées. Le but de cette revue est de synthétiser les connaissances actuelles concernant les processus d’autophagie dans le gamète mâle mature.

Published
2019
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30. Casein kinase 1ε and 1α as novel players in polycystic kidney disease and mechanistic targets for (R)-roscovitine and (S)-CR8

Author

Béatrice Josselin-Foll, Laurent Meijer, Katy Billot, Yannick Le Meur, Benoit Villiers, Alain Fautrel, Oxana Ibraghimov-Beskrovnaya, Darren P. Wallace, Pamela V. Tran, Alessandra Boletta, Nikolay O. Bukanov, Charlène Coquil, Nassima Oumata, Claire Delehouzé, Ralph Witzgall, Sophie Saunier, Thomas Weimbs, Melanie Grosch, Evelyne Fischer, Marie Trudel, Marco Pontoglio, Michal Mrug, Nathalie Desban, ManRos Therapeutics, Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Nephrologie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Division of Genetics and Cell Biology Dibit San Raffaele Scientific Institute, University of California [Santa Barbara] (UCSB), University of California, University of Regensburg - Institute for Molecular and Cellular Anatomy, Institute for Molecular and Cellular Anatomy, Universität Regensburg (UR), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Détoxication et réparation tissulaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of Alabama at Birmingham [ Birmingham] (UAB), University of Kansas [Kansas City], Institut De Recherches Cliniques De Montreal - IRCM [Canada], Sanofi Genzyme, University of California [Santa Barbara] (UC Santa Barbara), University of California (UC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Physiology, Casein Kinase 1 epsilon, Pyridines, [SDV]Life Sciences [q-bio], Mice, Transgenic, Kidney, Catalysis, Chromatography, Affinity, 03 medical and health sciences, 0302 clinical medicine, Cyclin-dependent kinase, Polycystic kidney disease, medicine, Roscovitine, Animals, Humans, Beneficial effects, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, Polycystic Kidney Diseases, biology, Kinase, Chemistry, Casein Kinase Ialpha, R-roscovitine, medicine.disease, 3. Good health, Disease Models, Animal, 030104 developmental biology, Purines, 030220 oncology & carcinogenesis, biology.protein, Cancer research, [SDV.IMM]Life Sciences [q-bio]/Immunology, Casein kinase 1, Research Article, Protein Binding, Signal Transduction
Abstract

Following the discovery of (R)-roscovitine’s beneficial effects in three polycystic kidney disease (PKD) mouse models, cyclin-dependent kinases (CDKs) inhibitors have been investigated as potential treatments. We have used various affinity chromatography approaches to identify the molecular targets of roscovitine and its more potent analog (S)-CR8 in human and murine polycystic kidneys. These methods revealed casein kinases 1 (CK1) as additional targets of the two drugs. CK1ε expression at the mRNA and protein levels is enhanced in polycystic kidneys of 11 different PKD mouse models as well as in human polycystic kidneys. A shift in the pattern of CK1α isoforms is observed in all PKD mouse models. Furthermore, the catalytic activities of both CK1ε and CK1α are increased in mouse polycystic kidneys. Inhibition of CK1ε and CK1α may thus contribute to the long-lasting attenuating effects of roscovitine and (S)-CR8 on cyst development. CDKs and CK1s may constitute a dual therapeutic target to develop kinase inhibitory PKD drug candidates.

Published
2018
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31. Propolis reverts cigarette smoke-induced emphysema through macrophage alternative activation

Author

Bruna R. Souza, Lycia de Brito Gitirana, Alain Fautrel, Isabella Cavalieri, Marina Valente Barroso, Martina Schmidt, Samuel Santos Valença, Manuella Lanzetti Daher de Deus, Luís Cristóvão Porto, and Vincent Lagente

Subjects
chemistry.chemical_classification, Lung, Antioxidant, business.industry, medicine.medical_treatment, Inflammation, respiratory system, Matrix metalloproteinase, Propolis, Pharmacology, Enzyme, medicine.anatomical_structure, chemistry, Downregulation and upregulation, medicine, Macrophage, medicine.symptom, business
Abstract

Emphysema is an incurable and progressive disease, and cigarette smoke (CS) is the main risk factor. Natural extracts have shown antioxidant and anti-inflammatory properties that can prevent acute lung inflammation and emphysema, but there are almost no reports in literature about therapeutics approaches to emphysema. We hypothesized if supplementation with propolis would repair lung damage in emphysema caused by CS exposure. C57BL/6 mice were exposed to 60 days of CS and then treated or not with propolis extract orally for more 60 days. Histological analysis revealed significant improvement in lung histoarchiteture, with recover of alveolar spaces, septa and elastic fibers in CS+propolis group. This natural extract also was able to increase MMP-2 and decrease MMP-12 expression, favoring the process of tissue repair. Propolis was also capable of recruiting leukocytes, among them macrophages, without ROS release. It leads us to investigate the profile of these macrophages and we showed that propolis could promote macrophage alternative activation and increase IL-10 levels, developing an anti-inflammatory microenvironment. We further investigated Nrf2 participation in lung repair promoted by propolis, but we showed that propolis did not stimulated Nrf2 translocation to nucleus. Proteins and enzymes related to Nrf2 was not altered, other than NQO1, that can be activate by propolis in a Nrf2-indepent manner. Propolis also acts downregulating IGF1. Beneficial effects of propolis supplementation in emphysema treatment likely result from it capacity of act in IGF1 downregulation and MMPs and change macrophage profile, in a Nrf2-independent manner.

Published
2017
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32. Molecular profiling of stroma identifies osteopontin as an independent predictor of poor prognosis in intrahepatic cholangiocarcinoma

Author

Laurent Sulpice, Michel Rayar, Mireille Desille, Cédric Coulouarn, Francisco Llamas-Gutierrez, Alain Fautrel, Karim Boudjema, Bruno Turlin, Bernard Meunier, Bruno Clément, Eveline Boucher, Service de Chirurgie Hépatobiliaire et Digestive [Rennes] = Hepatobiliary and Digestive Surgery [Rennes], CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Biologie, CRLCC Eugène Marquis (CRLCC), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Hépatotoxicité et xénobiotiques, Détoxication et réparation Tissulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Male, Pathology, medicine.medical_specialty, Stromal cell, [SDV]Life Sciences [q-bio], Laser Capture Microdissection, Cholangiocarcinoma, 03 medical and health sciences, 0302 clinical medicine, Stroma, Transforming Growth Factor beta, Laminin, medicine, Humans, Osteopontin, Aged, Laser capture microdissection, Hepatology, biology, Gene Expression Profiling, Liver Neoplasms, Transforming growth factor beta, Middle Aged, Cell cycle, Prognosis, Up-Regulation, 3. Good health, Gene expression profiling, Bile Ducts, Intrahepatic, Bile Duct Neoplasms, Liver, 030220 oncology & carcinogenesis, biology.protein, Female, 030211 gastroenterology & hepatology, Stromal Cells
Abstract

International audience; Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well-established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling, we demonstrate that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 nonredundant genes that significantly discriminate the tumor stroma from nontumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up-regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix, and transforming growth factor beta (TGFβ) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increased expression of collagen 4A1/COL4A1, laminin gamma 2/LAMC2, osteopontin/SPP1, KIAA0101, and TGFβ2 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of osteopontin, TGFβ2, and laminin in the stroma of ICC was significantly correlated with overall patient survival. More important, multivariate analysis demonstrated that the stromal expression of osteopontin was an independent prognostic marker for overall and disease-free survival. CONCLUSION: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidate biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression.

Published
2013
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33. Slice correspondence estimation using SURF descriptors and context-based search for prostate whole-mount histology MRI registration

Author

Oscar Acosta, Frederic Commandeur, Renaud de Crevoisier, Antoine Simon, Alain Fautrel, Lina Guzman, Eduardo Romero, Nathalie Rioux-Leclercq, Romain Mathieu, Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Service d'urologie [Rennes] = Urology [Rennes], Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service de radiothérapie, CRLCC Eugène Marquis (CRLCC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Male, medicine.medical_specialty, Computer science, Context (language use), 01 natural sciences, 030218 nuclear medicine & medical imaging, 010309 optics, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Prostate, 0103 physical sciences, medicine, Humans, Computer vision, Prospective Studies, Image resolution, Ground truth, medicine.diagnostic_test, business.industry, Histological Techniques, Prostatic Neoplasms, Magnetic resonance imaging, Histology, Pattern recognition, medicine.disease, Magnetic Resonance Imaging, medicine.anatomical_structure, Principal component analysis, Histopathology, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Artificial intelligence, business, Algorithms
Abstract

International audience; Registration of histopathology volumes to Magnetic Resonance Images(MRI) is a crucial step for finding correlations in Prostate Cancer (PCa) and assessing tumor agressivity. This paper proposes a two-stage framework aimed at registering both modalities. Firstly, Speeded-Up Robust Features (SURF) algorithm and a context-based search is used to automatically determine slice correspondences between MRI and histology volumes. This step initializes a multimodal nonrigid registration strategy, which allows to propagate histology slices to MRI. Evaluation was performed on 5 prospective studies using a slice index score and landmark distances. With respect to a manual ground truth, the first stage of the framework exhibited an average error of 1,54 slice index and 3,51 mm in the prostate specimen. The reconstruction of a three-dimensional Whole-Mount Histology (WMH) shows promising results aimed to perform later PCa pattern detection and staging. © 2016 IEEE.

Published
2016
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34. CD95-Mediated Calcium Signaling Promotes T Helper 17 Trafficking to Inflamed Organs in Lupus-Prone Mice

Author

Patrick Blanco, Patrick Legembre, Paul A. Barrow, Aubin Penna, Cécile Contin-Bordes, Marine Malleter, Robin J. Flynn, Jerome Ritz, Thomas Ducret, Roselyne Viel, Florence Poizeau, Julien Seneschal, Alain Dupuy, Nathalie Rioux, Lucie Morere, Florence Jouan, Pierre Vacher, Matthieu Le Gallo, Alain Fautrel, Amanda Poissonnier, Edouard Forcade, Doriane Sanséau, Anne-Marie Vacher, Nicolas Levoin, Oncogenesis Stress Signaling (OSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), CRLCC Eugène Marquis (CRLCC), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire Bioprojet, H2P2 - Histo Pathologie Hight Precision (H2P2), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Service d'immunologie et d'immunogénétique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2, INCa PLBIO, Ligue Contre le Cancer, INSERM Transfert, Fondation ARC, Region Bretagne, Rennes Metropole, University of Nottingham Faculty of Medicine, Biotechnology and Biological Sciences Research Council [BB/M018369/1], ANR [ANR-12-JSV2-0004-001], ANR-12-JSV2-0004,Ca-DoS,Vivre ou Mourir : Le calcium comme point de contrôle déterminant le destin d'une cellule suite à la stimulation des récepteurs de mort.(2012), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
0301 basic medicine, Mice, Inbred MRL lpr, Lymphocyte, receptor, cd95, ligand, T-Lymphocytes, Regulatory, chemistry.chemical_compound, Mice, Sphingosine, Immunology and Allergy, Lupus Erythematosus, Systemic, Interferon gamma, Cells, Cultured, Th17 cell, Systemic lupus erythematosus, Interleukin-17, apoptosis, Fas receptor, autoimmune lymphoproliferative syndrome, 3. Good health, Cell biology, Infectious Diseases, medicine.anatomical_structure, sh3 domain, Female, Interleukin 17, Signal transduction, medicine.drug, Immunology, fas gene-mutations, Biology, 03 medical and health sciences, Interferon-gamma, Immune system, sphingosine-1 phosphate, death, medicine, Animals, Humans, Protein Interaction Domains and Motifs, Sphingosine-1-phosphate, Calcium Signaling, fas Receptor, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Phospholipase C gamma, pathway, Transendothelial and Transepithelial Migration, lupus, medicine.disease, Peptide Fragments, Disease Models, Animal, 030104 developmental biology, chemistry, inflammation, Th17 Cells, Calcium, Lysophospholipids, Transcriptome, protein
Abstract

International audience; CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase C gamma 1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment.

Published
2016
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35. LOXL2 is a prognosis biomarker and a potential therapeutic target in intrahepatic cholangiocarcinoma

Author

Damien Bergeat, Bruno Turlin, L Sulpice, Karim Boudjema, Bernard Meunier, Alain Fautrel, Cédric Coulouarn, Michel Rayar, Aude Merdrignac, Bruno Clément, CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Chirurgie Hépatobiliaire et Digestive [Rennes] = Hepatobiliary and Digestive Surgery [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, medicine.medical_specialty, LOXL2, Hepatology, business.industry, [SDV]Life Sciences [q-bio], Gastroenterology, 030230 surgery, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Prognosis biomarker, Internal medicine, medicine, 030211 gastroenterology & hepatology, business, ComputingMilieux_MISCELLANEOUS, Intrahepatic Cholangiocarcinoma
Abstract

International audience; no abstract

Published
2016
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36. Pentoxifylline aggravates fatty liver in obese and diabetic ob/ob mice by increasing intestinal glucose absorption and activating hepatic lipogenesis

Author

Marie-Anne Robin, Alain Fautrel, André Bado, Fanny Noury, Bernard Fromenty, Julie Massart, Philippe Lettéron, and Pierre-Antoine Eliat

Subjects
2. Zero hunger, Pharmacology, 0303 health sciences, medicine.medical_specialty, Glucose tolerance test, medicine.diagnostic_test, Fatty liver, Biology, medicine.disease, medicine.disease_cause, Intestinal absorption, 3. Good health, Pentoxifylline, Diabetic nephropathy, 03 medical and health sciences, 0302 clinical medicine, Postprandial, Endocrinology, Internal medicine, Lipogenesis, medicine, 030211 gastroenterology & hepatology, Oxidative stress, 030304 developmental biology, medicine.drug
Abstract

BACKGROUND AND PURPOSE Pentoxifylline is in clinical trials for non-alcoholic fatty liver disease and diabetic nephropathy. Metabolic and hepatic effects of pentoxifylline were assessed in a murine model of obesity and type 2 diabetes. EXPERIMENTAL APPROACH Pentoxifylline (100 mg·kg−1·day−1) was administered for 4 days or 3 weeks in lean and obese/diabetic ob/ob mice. Plasma lipids, glucose, other metabolites and relevant enzymes were measured by standard assays. Hepatic lipids in vivo were assessed with magnetic resonance spectroscopy and by histology. Hepatic extracts were also analysed with RT-PCR and Western blotting. KEY RESULTS Four days of pentoxifylline treatment slightly increased liver lipids in ob/ob mice. After 3 weeks, pentoxifylline exacerbated fatty liver and plasma transaminases in ob/ob mice but did not induce liver steatosis in lean mice. Plasma glucose was highest in fed, but not fasted, ob/ob mice treated with pentoxifylline. During the first 10 min of an oral glucose tolerance test, blood glucose increased more rapidly in pentoxifylline-treated mice. Jejunal expression of glucose transporter 2 isoform was increased in pentoxifylline-treated obese mice. Hepatic activity of carbohydrate response element binding protein (ChREBP) increased after pentoxifylline in ob/ob, but not lean, mice. Hepatic expression of lipogenic enzymes was highest in pentoxifylline-treated ob/ob mice. However, pentoxifylline reduced markers of oxidative stress and inflammation in ob/ob liver. CONCLUSION AND IMPLICATIONS Pentoxifylline exacerbated fatty liver in ob/ob mice through enhanced intestinal glucose absorption, increased postprandial glycaemia and activation of hepatic lipogenesis. Long-term treatment with pentoxifylline could worsen fatty liver in some patients with pre-existing hyperglycaemia.

Published
2012
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37. Identification of early target genes of aflatoxin B1 in human hepatocytes, inter-individual variability and comparison with other genotoxic compounds

Author

André Guillouzo, Julie Dumont, Alain Fautrel, Marie-Anne Robin, Rozenn Jossé, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, ANR (contracts 06-SEST-17 and 09-CESA-003-002), the Ligue 35 contre le Cancer, ANR-06-SEST-0017,HEPACELLTOX,Effets chroniques et mutagènes/cancérogenèses de contaminants de l'environnement évaluées à l'aide de cellule d'un hépatome humain (HepaRG) métaboliquement compétentes(2006), ANR-09-CESA-0003,NISTEC,Nouvelles stratégies in vitro pour l'évaluation de la cytotoxicite et la genotoxicite des contaminants de l'environnement(2009), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
MESH: Signal Transduction, Aflatoxin B1, DNA Repair, Human hepatocytes, MESH: Cell Cycle, Toxicology, MESH: Dose-Response Relationship, Drug, MESH: Hepatocytes, 0302 clinical medicine, FHIT, BCAS3, Gene expression, MESH: Tumor Suppressor Protein p53, Cells, Cultured, Oligonucleotide Array Sequence Analysis, MESH: DNA Repair, 0303 health sciences, Cell Cycle, MESH: Aflatoxin B1, MESH: Gene Expression Regulation, Cell biology, 030220 oncology & carcinogenesis, HepaRG cells, DNA microarray, Signal Transduction, MESH: Cells, Cultured, DNA repair, DNA damage, Biology, Genotoxic compounds, MESH: Gene Expression Profiling, 03 medical and health sciences, MESH: Mutagens, Humans, Transcriptomics, Gene, 030304 developmental biology, MESH: DNA Damage, Pharmacology, MESH: Humans, Dose-Response Relationship, Drug, Gene Expression Profiling, Non-genotoxic compounds, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Biomarker, AFB1, Molecular biology, Gene expression profiling, Gene Expression Regulation, MESH: Oligonucleotide Array Sequence Analysis, Hepatocytes, Tumor Suppressor Protein p53, DNA Damage, Mutagens
Abstract

International audience; Gene expression profiling has recently emerged as a promising approach to identify early target genes and discriminate genotoxic carcinogens from non-genotoxic carcinogens and non-carcinogens. However, early gene changes induced by genotoxic compounds in human liver remain largely unknown. Primary human hepatocytes and differentiated HepaRG cells were exposed to aflatoxin B1 (AFB1) that induces DNA damage following enzyme-mediated bioactivation. Gene expression profile changes induced by a 24h exposure of these hepatocyte models to 0.05 and 0.25μM AFB1 were analyzed by using oligonucleotide pangenomic microarrays. The main altered signaling pathway was the p53 pathway and related functions such as cell cycle, apoptosis and DNA repair. Direct involvement of the p53 protein in response to AFB1 was verified by using siRNA directed against p53. Among the 83 well-annotated genes commonly modulated in two pools of three human hepatocyte populations and HepaRG cells, several genes were identified as altered by AFB1 for the first time. In addition, a subset of 10 AFB1-altered genes, selected upon basis of their function or tumor suppressor role, was tested in four human hepatocyte populations and in response to other chemicals. Although they exhibited large variable inter-donor fold-changes, several of these genes, particularly FHIT, BCAS3 and SMYD3, were found to be altered by various direct and other indirect genotoxic compounds and unaffected by non-genotoxic compounds. Overall, this comprehensive analysis of early gene expression changes induced by AFB1 in human hepatocytes identified a gene subset that included several genes representing potential biomarkers of genotoxic compounds.

Published
2012
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38. Chronic Ethanol Consumption Lessens the Gain of Body Weight, Liver Triglycerides, and Diabetes in Obese ob/ob Mice

Author

Marie-Anne Robin, Bernard Fromenty, Philippe Lettéron, Nadège Barri-Ova, Julie Massart, Alain Fautrel, Nathalie Vadrot, and Bruno Turlin

Subjects
Male, medicine.medical_specialty, Alcohol Drinking, Mice, Obese, Blood sugar, Blood lipids, Type 2 diabetes, Carbohydrate metabolism, Weight Gain, Diabetes Mellitus, Experimental, Mice, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, Animals, Humans, Lipolysis, Triglycerides, Pharmacology, Ethanol, Chemistry, Body Weight, medicine.disease, Mice, Inbred C57BL, Endocrinology, Diabetes Mellitus, Type 2, Liver, Molecular Medicine, Liver function
Abstract

Clinical studies suggest that moderate alcohol consumption can have beneficial effects, in particular regarding cardiovascular events, insulin resistance, and type 2 diabetes. In this study, lean and obese diabetic ob/ob mice were submitted or not to chronic ethanol intake via the drinking water for 6 months, which was associated with moderate levels of plasma ethanol. Plasma levels of alanine aminotransferase and aspartate aminotransferase were not increased by alcohol intake. Ethanol consumption progressively reduced the gain of body weight in ob/ob mice, but not in lean mice, and this was observed despite higher calorie intake. Increased plasma free fatty acids and glycerol in ethanol-treated ob/ob mice suggested peripheral lipolysis. Glycemia and insulinemia were significantly reduced, whereas adiponectinemia was increased in ethanol-treated ob/ob mice. Liver weight and triglycerides were significantly decreased in ethanol-treated ob/ob mice, and this was associated with less microvesicular steatosis. Hepatic levels of AMP-activated protein kinase and the phosphorylated form of acetyl-CoA carboxylase were higher in ethanol-treated ob/ob mice, suggesting better fatty acid oxidation. However, hepatic mRNA expression of several lipogenic genes was not reduced by ethanol consumption. Finally, mild oxidative stress was noticed in the liver of ethanol-treated mice, regardless of their genotype. Hence, our data are in keeping with clinical studies suggesting that moderate ethanol intake can have beneficial effects on type 2 diabetes and insulin sensitivity, at least in part through increased levels of plasma adiponectin. However, further studies are needed to determine whether long-term drinking of light-to-moderate amounts of ethanol is safe for the liver.

Published
2009
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39. Prostate whole-mount histology reconstruction and registration to MRI for correlating in-vivo observations with biological findings

Author

Alain Fautrel, Romain Mathieu, Frederic Commandeur, Pascal Haigron, Renaud de Crevoisier, K. Gnep, Oscar Acosta, Antoine Simon, Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'urologie [Rennes] = Urology [Rennes], Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Hépatotoxicité et xénobiotiques, Détoxication et réparation Tissulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CRLCC Eugène Marquis (CRLCC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, Prostate cancer, In vivo, Prostate, Diagnosis, Image Processing, Computer-Assisted, Medicine, Humans, Prospective Studies, Cancer, Whole mount, Prostatectomy, medicine.diagnostic_test, business.industry, Histological Techniques, Prostatic Neoplasms, Magnetic resonance imaging, Histology, Clinical routine, medicine.disease, Magnetic Resonance Imaging, 3. Good health, images, medicine.anatomical_structure, specimens, histopathology, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Radiology, business, Algorithms
Abstract

International audience; Multi-parametric magnetic resonance imaging (mMRI) is the standard exam for prostate cancer diagnosis, staging and risk assessment in current clinical routine. Correlating mMRI in-vivo observations with biological findings from radical prostatectomy specimen would improve the optimal therapy selection. Thus, we proposed a method for reconstructing and registering the prostate whole-mount histology (WMH) to the MRI, considering a thin slicing of the prostatectomy specimen. The method was evaluated on 3 patients, included in a prospective study, for which hematein-eosin-safran and immunohistochemistry stainings were performed. The registration error was assessed by measuring the Euclidean distance between landmarks, previously identified by an expert on both mMRI and histological slices. The mean error was 4.90 +/- 1.34 mm. Our method demonstrated promising results for registering prostate WMH to in-vivo mMRI, thus allowing for spatial accurate correlation between radiologic observations and biological information

Published
2016
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40. L’analyse du sérum par spectroscopie moyen infrarouge permet d’obtenir une signature du statut métabolique du foie chez la souris

Author

Martine Ropert, M. Le Corvec, Alain Fautrel, Karima Begriche, Coralie Allain, Olivier Loréal, Patricia Leroyer, Bruno Turlin, Olivier Sire, Pascal Guggenbuhl, Salim Lardjane, Bernard Fromenty, Valérie Monbet, Thibault Cavey, Laboratoire dÍngénierie des Matériaux de Bretagne, Equipe E2PIC, Université de Bretagne Sud, France, Laboratoire d'Ingénierie des Matériaux de Bretagne (LIMATB), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de Mathématiques de Bretagne Atlantique (LMBA), Université de Brest (UBO)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Recherche Mathématique de Rennes (IRMAR), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Applications of interacting particle systems to statistics (ASPI), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-AGROCAMPUS OUEST, Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de rhumatologie [Rennes] = Rheumatology [Rennes], IRMAR-STAT, Laboratoire d'Ingénierie des Matériaux de Bretagne ( LIMATB ), Université de Bretagne Sud ( UBS ) -Université de Brest ( UBO ) -Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université de Brest ( UBO ) -Université de Bretagne Sud ( UBS ) -Université de Brest ( UBO ) -Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université de Brest ( UBO ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de Mathématiques de Bretagne Atlantique ( LMBA ), Université de Bretagne Sud ( UBS ) -Université de Brest ( UBO ) -Centre National de la Recherche Scientifique ( CNRS ), H2P2 - Histo Pathologie Hight Precision ( H2P2 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Recherche Mathématique de Rennes ( IRMAR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -AGROCAMPUS OUEST-École normale supérieure - Rennes ( ENS Rennes ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National des Sciences Appliquées ( INSA ) -Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Applications of interacting particle systems to statistics ( ASPI ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique ( Inria ), Nutrition, Métabolismes et Cancer ( NuMeCan ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de rhumatologie, Hôpital Sud, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École normale supérieure - Rennes (ENS Rennes)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-INSTITUT AGRO Agrocampus Ouest, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Inria Rennes – Bretagne Atlantique, Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-11-LABX-0020,LEBESGUE,Centre de Mathématiques Henri Lebesgue : fondements, interactions, applications et Formation(2011)

Subjects
0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Nutrition and Dietetics, 030309 nutrition & dietetics, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Endocrinology, Diabetes and Metabolism, Internal Medicine, 030209 endocrinology & metabolism, [ MATH.MATH-ST ] Mathematics [math]/Statistics [math.ST], ComputingMilieux_MISCELLANEOUS, 3. Good health
Abstract

Introduction et but de l’etude Les hepatopathies steatosiques non alcooliques (NAFLD) sont potentiellement observees lorsque existent une obesite, un syndrome metabolique et/ou un diabete. La NASH favorise la survenue de complications hepatiques, et est une etape majeure dans l’histoire naturelle de la maladie. La possibilite de detecter, de facon non invasive, une alteration de l’etat hepatique pourrait ameliorer le suivi des patients. Il est possible d’evaluer, chez la souris, par l’analyse du serum, le potentiel de la spectroscopie moyen infrarouge (MIR) pour preciser l’etat hepatique au cours des NAFLD. Materiel et methodes Des souris ont recu une alimentation controle ou riche en lipides (HF) ou riche en lipides et glucides (HFHC) (n = 25 par groupe). Nous avons analyse : (i) les parametres biochimiques seriques du metabolisme glucido-lipidiques, les transaminases, (ii) les niveaux d’ARNm de genes hepatiques impliques dans le controle de ces deux metabolismes et ceux de la C-reactive proteine, l’interleukine 6 et la chaine α1 du collagene 1 (Col1α1). Les steatoses hepatiques micro- et macrovesiculaires ont ete quantifiees (histologie et analyse d’image). Les spectres MIR ont ete analyses afin de mettre au point un modele predictif de la steatose hepatique. Resultats et analyse statistique Les animaux soumis aux regimes enrichis etaient obeses. Une steatose hepatique, sans lesions de NASH, etait retrouvee chez tous les animaux et etait plus severe dans les groupes HF et HFHC. La relation entre les niveaux de steatose predits (analyse spectroscopique) et ceux observes histologiquement faisait apparaitre une zone de transition a 10 % de steatose macrovesiculaire. De part et d’autre de cette zone, les variables spectrales contribuant aux modeles predictifs etaient differentes, suggerant l’existence de differences metaboliques. Chez les animaux ayant une steatose superieure a 10 % (HF : n = 3 ; HFHC : n = 7), il existait une augmentation statistiquement significative des ALAT et du niveau des ARNm du col1α1 hepatique. Conclusion Ces donnees indiquent que la spectroscopie MIR combinee a l’analyse statistique peut identifier, dans le serum, des signatures spectrales qui refletent l’etat hepatique au cours des NAFLD. Financements MLC a beneficie d’une bourse de these cofinancee par Diafir et l’ ANRT .

Published
2016
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41. Mid-infrared fibre evanescent wave spectroscopy of serum allows fingerprinting of the hepatic metabolic status in mice

Author

Bernard Fromenty, Maëna Le Corvec, Bruno Turlin, Martine Ropert, Olivier Loréal, Pascal Guggenbuhl, Alain Fautrel, Karima Begriche, Coralie Allain, Thibault Cavey, Salim Lardjane, Valérie Monbet, Olivier Sire, Patricia Leroyer, DIAFIR, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de Mathématiques de Bretagne Atlantique (LMBA), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], H2P2 - Histo Pathologie Hight Precision (H2P2), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Applications of interacting particle systems to statistics (ASPI), Institut de Recherche Mathématique de Rennes (IRMAR), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-AGROCAMPUS OUEST, Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Service de rhumatologie [Rennes] = Rheumatology [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'Ingénierie des Matériaux de Bretagne (LIMATB), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO), ANRT, Association Nationale de la Recherche et de la Technologie, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École normale supérieure - Rennes (ENS Rennes)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-INSTITUT AGRO Agrocampus Ouest, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Inria Rennes – Bretagne Atlantique, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de Mathématiques de Bretagne Atlantique ( LMBA ), Université de Bretagne Sud ( UBS ) -Université de Brest ( UBO ) -Centre National de la Recherche Scientifique ( CNRS ), H2P2 - Histo Pathologie Hight Precision ( H2P2 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Applications of interacting particle systems to statistics ( ASPI ), Institut de Recherche Mathématique de Rennes ( IRMAR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -AGROCAMPUS OUEST-École normale supérieure - Rennes ( ENS Rennes ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National des Sciences Appliquées ( INSA ) -Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique ( Inria ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Service de rhumatologie, Hôpital Sud, Nutrition, Métabolismes et Cancer ( NuMeCan ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire d'Ingénierie des Matériaux de Bretagne ( LIMATB ), Université de Bretagne Sud ( UBS ) -Université de Brest ( UBO ) -Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université de Brest ( UBO ), and ANR-11-LABX-0020,LEBESGUE,Centre de Mathématiques Henri Lebesgue : fondements, interactions, applications et Formation(2011)

Subjects
Male, medicine.medical_specialty, spectroscopy, Spectrophotometry, Infrared, [ STAT ] Statistics [stat], [SDV]Life Sciences [q-bio], Disease, Biology, Biochemistry, [ CHIM ] Chemical Sciences, Analytical Chemistry, Mice, 03 medical and health sciences, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Internal medicine, Diabetes mellitus, Electrochemistry, medicine, genetic algorithm, Animals, Environmental Chemistry, [CHIM]Chemical Sciences, Obesity, medicine.diagnostic_test, [ SDV ] Life Sciences [q-bio], Fatty liver, Cross-validation, Carbohydrate, medicine.disease, Mice, Inbred C57BL, [STAT]Statistics [stat], Endocrinology, Liver, 030220 oncology & carcinogenesis, Liver biopsy, 030211 gastroenterology & hepatology, Metabolic syndrome, Steatosis, variable selection
Abstract

International audience; Non-alcoholic fatty liver disease is associated with obesity, diabetes, and metabolic syndrome. The detection of systemic metabolic changes associated with alterations in the liver status during non-alcoholic fatty liver disease could improve patient follow-up. The aim of the present study was to evaluate the potential of mid-infrared fibre evanescent wave spectroscopy as a minimum-invasive method for evaluating the liver status during non-alcoholic fatty liver disease. Seventy-five mice were subjected to a control, high-fat or high-fat–high carbohydrate diets. We analysed the serum biochemical parameters and mRNA levels of hepatic genes by quantitative RT-PCR. Steatosis was quantified by image analysis. The mid-infrared spectra were acquired from serum, and then analysed to develop a predictive model of the steatosis level. Animals subjected to enriched diets were obese. Hepatic steatosis was found in all animals. The relationship between the spectroscopy-predicted and observed levels of steatosis, expressed as percentages of the liver biopsy area, was not linear. A transition around 10% steatosis was observed, leading us to consider two distinct predictive models (10%) based on two different sets of discriminative spectral variables. The model performance was evaluated using random cross-validation (10%). The hypothesis that additional metabolic changes occur beyond this transition was supported by the fact that it was associated with increased serum ALT levels, and Col1α1 chain mRNA levels. Our data suggest that mid-infrared spectroscopy combined with statistical analysis allows identifying serum mid-infrared signatures that reflect the liver status during non-alcoholic fatty liver disease.

Published
2016
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42. Gene expression profiling of the tumor microenvironment in human intrahepatic cholangiocarcinoma

Author

Karim Boudjema, Alain Fautrel, Cédric Coulouarn, Laurent Sulpice, Bruno Turlin, Mireille Desille, Bruno Clément, Service de Chirurgie Hépatobiliaire et Digestive [Rennes] = Hepatobiliary and Digestive Surgery [Rennes], CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], The authors thank Biosit and Biogenouest for access to Plateforme Génomique Santé, Centre de Ressources Biologiques Santé, and H2P2 histopathological platform. This work was supported by Grants from Inserm, Université de Rennes 1, Institut National du Cancer (Cancéropoles IDF & GO), Ligue contre le cancer and Novartis Oncology., Jonchère, Laurent, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, medicine.medical_specialty, Stromal cell, Microenvironment, lcsh:QH426-470, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Bioinformatics, Biochemistry, Extracellular matrix, Cholangiocarcinoma, 03 medical and health sciences, 0302 clinical medicine, Stroma, Internal medicine, Data in Brief, Genetics, medicine, Gene, Intrahepatic Cholangiocarcinoma, Cancer, Tumor microenvironment, [SDV.GEN]Life Sciences [q-bio]/Genetics, Profiling, Hepatology, 3. Good health, Gene expression profiling, lcsh:Genetics, 030104 developmental biology, Liver, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, Biotechnology
Abstract

Intrahepatic cholangiocarcinoma (ICC) is the second most common type of malignant primary tumors in the liver. ICC is an aggressive cancer with a poor survival and limited therapeutic options. At the histological level, ICC is characterized by an abundant stroma (i.e. the tumor microenvironment that notably includes components of the extracellular matrix, stromal cells and soluble factors). Tumor microenvironment is known to play a key role in tumor onset and progression but it is poorly characterized at the molecular level. Thus, this study was specifically designed to identify genes that are significantly deregulated in the tumor microenvironment of human ICC. Here we provide a detailed description of the experimental design and methods used to acquire the genomic data deposited into Gene Expression Omnibus (GEO) under the accession number GSE45001. Our genomic dataset provides insights on the molecular pathways altered in the microenvironment of ICC and allows the identification of novel ICC biomarkers, as exemplified previously in Hepatology (PMID: 23775819). Keywords: Liver, Cancer, Cholangiocarcinoma, Microenvironment, Profiling

Published
2016
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43. A Spontaneous KRT16 Mutation in a Dog Breed: A Model for Human Focal Non-Epidermolytic Palmoplantar Keratoderma (FNEPPK)

Author

Emmanuel Bensignor, Alain Fautrel, Pascale Bellaud, Frédérique Degorce-Rubiales, Catherine André, Caroline Dufaure de Citres, Éric Guaguère, Jocelyn Plassais, Amaury Vaysse, Guillaume Queney, Pascale Quignon, Christophe Hitte, Céline Bleuart, Anne-Sophie Guillory, Anne Thomas, Emmanuelle Bourrat, Maxence Delverdier, Laetitia Lagoutte, Cécile Kaerle, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Clinique Vétérinaire Saint Bernard, Laboratoire d'Anatomie Pathologique Vétérinaire du Sud-Ouest, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140-Centre National de la Recherche Scientifique (CNRS), Cancer Genetics Branch, National Institute of Health (NIH)-National Human Genome Research Institute (NHGRI), Animal Genetics Laboratory, Antagene, Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Plate-forme d'histopathologie, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-IFR140, Clinique Vétérinaire de la Boulais, Service de dermatologie [Paris], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Keratoderma, Palmoplantar, Diffuse, Male, 040301 veterinary sciences, [SDV]Life Sciences [q-bio], Dermatology, Biology, Keratin 16, Real-Time Polymerase Chain Reaction, Biochemistry, 0403 veterinary science, Immunoenzyme Techniques, 03 medical and health sciences, Exon, Focal Non-Epidermolytic Palmoplantar Keratoderma, Dogs, Species Specificity, medicine, Animals, Humans, RNA, Messenger, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Papilloma, Keratin-16, 04 agricultural and veterinary sciences, Exons, Cell Biology, medicine.disease, Molecular biology, Immunohistochemistry, Breed, Disease Models, Animal, Real-time polymerase chain reaction, Microscopy, Fluorescence, Mutation (genetic algorithm), Mutation, Female
Abstract

International audience

Published
2015
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44. Aryl Hydrocarbon Receptor Activation and Cytochrome P450 1A Induction by the Mitogen-Activated Protein Kinase Inhibitor U0126 in Hepatocytes

Author

Sophie Langouët, Frédéric Ezan, F. Peter Guengerich, Alain Fautrel, André Guillouzo, Lise Andrieux, Jean F. Savouret, Georges Baffet, and Joel A. Krauser

Subjects
Male, MAPK/ERK pathway, Time Factors, MAP Kinase Signaling System, Mitogen-activated protein kinase kinase, Rats, Sprague-Dawley, Nitriles, Butadienes, Cytochrome P-450 CYP1A1, Animals, Humans, Enzyme Inhibitors, Enzyme inducer, Protein kinase A, Cells, Cultured, Mitogen-Activated Protein Kinase Kinases, Pharmacology, Dose-Response Relationship, Drug, biology, Kinase, Mitogen-Activated Protein Kinase Inhibitor, Aryl hydrocarbon receptor, Molecular biology, Rats, Receptors, Aryl Hydrocarbon, Enzyme Induction, Hepatocytes, biology.protein, Molecular Medicine, Mitogen-Activated Protein Kinases, Signal transduction, Signal Transduction
Abstract

The aryl hydrocarbon receptor (AhR) is involved in various processes such as cytochrome P450 (P450) 1A induction after xenobiotic exposure. It is also considered to play a major role in cell proliferation and differentiation. Recent evidences have suggested a cross-talk between AhR functions and the mitogen-activated protein kinase (MAPK) cascade. We now report that 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126), a specific inhibitor of MAPK kinase (MEK) MEK1/2, elicits a marked increase in CYP1A1 expression at both mRNA and protein levels associated with a significant increase of enzyme activity in primary rat hepatocytes and a human hepatoma cell line. This induction occurred independently of MEK/extracellular signal-regulated kinase (ERK) activation and in the absence of ERK1 and ERK2 expression. The effect of U0126 was mediated by its ability to transactivate xenobiotic responsive element (XRE)-driven genes, as demonstrated by transfection assays with an XRE-driven luciferase construct in the human B16A2 hepatoma cell line. CYP1A1 modulation was abolished by a cotreatment with resveratrol, an established AhR antagonist, arguing for AhR activation by U0126. Such an effect was demonstrated by direct in vitro ligand binding competition assays using rabbit liver cytosol, showing that this compound binds AhR with an EC(50) = 25 x 10(-6) M. Moreover, we demonstrated that U0126 is a substrate for several P450s including human CYP1A2, -1A1, and -1B1. We conclude that the widely used specific inhibitor of MEK/ERK, U0126, also acts as a potent AhR activator and an inducer of related genes. Such effects on the AhR may have an impact on biological functions attributed previously to MAPK inhibition.

Published
2004
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45. Excessive dietary linoleic acid induces proinflammatory markers in rat

Author

Maryline Kouba, Philippe Legrand, Alain Fautrel, Daniel Catheline, Benjamin Choque, Justine Marchix, Systèmes d'élevage, nutrition animale et humaine (SENAH), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Hépatotoxicité et xénobiotiques, Détoxication et réparation Tissulaire, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de Biochimie et Nutrition Humaine, AGROCAMPUS OUEST, Sofiprotéol-PROLEA, Valorex, AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)

Subjects
Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Interleukin-1beta, endothelial activation, 030204 cardiovascular system & hematology, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, adhesion molecules, Aorta, chemistry.chemical_classification, 0303 health sciences, Nutrition and Dietetics, Cell adhesion molecule, Fatty Acids, NF-kappa B, Intercellular Adhesion Molecule-1, Immunohistochemistry, Lipids, Tumor necrosis factor alpha, Polyunsaturated fatty acid, linoleic acid, medicine.medical_specialty, Linoleic acid, Vascular Cell Adhesion Molecule-1, Biology, Proinflammatory cytokine, Endothelial activation, 03 medical and health sciences, Internal medicine, medicine, Animals, saturated fatty acids, Rats, Wistar, Cell adhesion, Molecular Biology, 030304 developmental biology, Inflammation, Triglyceride, Tumor Necrosis Factor-alpha, Body Weight, Endothelial Cells, Rats, Diet, Endocrinology, chemistry, Cyclooxygenase 2, tumor necrosis factor-α
Abstract

Fautrel U991; International audience; Following the historical dietary recommendations, the substitution of polyunsaturated fatty acids (PUFA) for saturated fatty acids (SFA) resulted in a dramatic increase of linoleic acid (LA) in the western diet. While pro-atherogenic properties of SFA have been described, the involvement of LA on the inflammatory process remains controversial. Herein, we evaluated the effects of an excessive LA intake on the cytokine-induced expression of endothelial adhesion molecules, vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1), through the nuclear factor (NF)-κB pathway, in comparison with a control diet and regarding a “positive” SFA-diet. Wistar rats were fed experimental diets: a control diet or diets enriched with LA or SFA for 11 weeks. Plasma lipid parameters and proinflammatory cytokine production such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α were analysed. Expression of endothelial adhesion molecules and NF-κB was determined by immunohistochemical analysis. No difference was observed in body weight. The enriched diets did not affect triglyceride and total cholesterol levels in plasma. Our results demonstrated that excessive dietary LA intake increased TNF-α levels (p

Published
2015
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46. Transcriptomic analysis of trout gill ionocytes in fresh water and sea water using laser capture microdissection combined with microarray analysis

Author

Jérôme Montfort, Isabelle Leguen, Aurélie Le Cam, Alain Fautrel, Sandrine Peron, Laboratoire de Physiologie et Génomique des Poissons (LPGP), Institut National de la Recherche Agronomique (INRA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Plateforme Génomique Santé Biogenouest®, Institut Fédératif de Recherche - Génétique Fonctionnelle Agronomie et Santé (IFR 140 GFAS), Hépatotoxicité et xénobiotiques, Détoxication et réparation Tissulaire, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Jonchère, Laurent

Subjects
Gill, [SDV]Life Sciences [q-bio], lcsh:Medicine, adaptation, Transcriptome, 0302 clinical medicine, poisson, immune system proteins, salmonids, lcsh:Science, Oligonucleotide Array Sequence Analysis, Laser capture microdissection, seawater, salmonidae, 0303 health sciences, trout, oncorhynchus mykiss, Multidisciplinary, gills, biology, homéostasie ionique, rainbow trout, 6. Clean water, Cell biology, [SDV] Life Sciences [q-bio], Trout, fresh water, protein metabolism, ionocyte, Research Article, expression des gènes, sea water, DNA-binding proteins, gene regulation, animal structures, Laser Capture Microdissection, 03 medical and health sciences, rainbow, Animals, 14. Life underwater, 030304 developmental biology, fish, Ion Transport, Microarray analysis techniques, Gene Expression Profiling, lcsh:R, gill, branchie, sweet water, biology.organism_classification, Molecular biology, Fold change, Gene expression profiling, Ion homeostasis, eau douce, eau de mer, Tissue Array Analysis, lcsh:Q, 030217 neurology & neurosurgery, truite arc en ciel
Abstract

International audience; Fish gills represent a complex organ composed of several cell types that perform multiple physiological functions. Among these cells, ionocytes are implicated in the maintenance of ion homeostasis. However, because the ionocyte represents only a small percent of whole gill tissue, its specific transcriptome can be overlooked among the numerous cell types included in the gill. The objective of this study is to better understand ionocyte functions by comparing the RNA expression of this cell type in freshwater and seawater acclimated rainbow trout. To realize this objective, ionocytes were captured from gill cryosections using laser capture microdissection after immunohistochemistry. Then, transcriptome analyses were performed on an Agilent trout oligonucleotide microarray. Gene expression analysis identified 108 unique annotated genes differentially expressed between freshwater and seawater ionocytes, with a fold change higher than 3. Most of these genes were up-regulated in freshwater cells. Interestingly, several genes implicated in ion transport, extracellular matrix and structural cellular proteins appeared up-regulated in freshwater ionocytes. Among them, several ion transporters, such as CIC2, SLC26A6, and NBC, were validated by qPCR and/or in situ hybridization. The latter technique allowed us to localize the transcripts of these ion transporters in only ionocytes and more particularly in the freshwater cells. Genes involved in metabolism and also several genes implicated in transcriptional regulation, cell signaling and the cell cycle were also enhanced in freshwater ionocytes. In conclusion, laser capture microdissection combined with microarray analysis allowed for the determination of the transcriptional signature of scarce cells in fish gills, such as ionocytes, and aided characterization of the transcriptome of these cells in freshwater and seawater acclimated trout

Published
2015
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47. Inhibition of cytochrome P450 2E1 by propofol in human and porcine liver microsomes

Author

Yannick Mallédant, André Guillouzo, Alain Fautrel, and Corinne Lejus

Subjects
Pharmacology, CYP3A4, Swine, Metabolite, CYP1A2, Biochemistry, Cytochrome P-450 CYP2E1 Inhibitors, Hydroxylation, chemistry.chemical_compound, Non-competitive inhibition, chemistry, Chlorzoxazone, Microsomes, Liver, Microsome, medicine, Animals, Humans, Halothane, Propofol, Anesthetics, Intravenous, medicine.drug
Abstract

While almost anesthetics are metabolized by the cytochrome P450 (CYP) 3A4, some major volatile ones such as halothane and sevoflurane are metabolized by CYP2E1 in humans. To determine whether 2,6-diisopropylphenol (propofol), a widely used intravenous anesthetic agent, known to inhibit CYP3A4 and CYP1A2, also inhibits CYP2E1, 6-OH hydroxylation of chlorzoxazone, a prototypical CYP2E1 substrate, was estimated using two pools of human microsomes and one pool of porcine microsomes from seven livers. Basal human enzyme activities were characterized by a V(max) of 1426+/-230 and 288+/-29 pmol min(-1)mg(-1) protein and a K(m) of 122+/-47 and 149+/-42 microM, while the corresponding porcine activities were associated with a V(max) of 352+/-42 pmol min(-1)mg(-1) protein and a K(m) of 167+/-38 microM. A competitive inhibition of CYP2E1 by propofol was observed with low inhibition constants in the therapeutic range in both porcine (19 microM) and human (48 microM) liver microsomes. These in vitro results suggest that propofol could have a protective effect on toxic metabolite activation of compounds catalyzed by CYP2E1.

Published
2002
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48. Investigations on the effects of oltipraz on the nucleotide excision repair in the liver

Author

Alain Fautrel, André Guillouzo, Sophie Langouët, Lydie Sparfel, and Bernard Salles

Subjects
Male, Aflatoxin B1, DNA Repair, DNA repair, Thiophenes, Biology, Biochemistry, DNA Adducts, chemistry.chemical_compound, In vivo, Oltipraz, medicine, Animals, Humans, Rats, Wistar, Carcinogen, Pharmacology, Cisplatin, Thiones, DNA, Rats, medicine.anatomical_structure, Liver, chemistry, Pyrazines, Hepatocyte, Hepatocytes, Reverse Transcriptase Inhibitors, Nucleotide excision repair, medicine.drug
Abstract

Recent studies support the view that in addition to its effect on both phase I and phase II xenobiotic metabolizing enzymes, the synthetic chemopreventive agent oltipraz also increases the nucleotide excision repair (NER) which represents the major pathway of elimination of chemical carcinogen DNA adducts. Since most carcinogens are activated in the liver, we investigated the influence of oltipraz on NER activity of this target tissue by using two different approaches. First, we employed an assay based on the measurement of DNA repair in cisplatin-damaged plasmid DNA incubated in the presence of cell-free extracts prepared from either rat liver or human hepatoma HepG2 cells treated by oltipraz. Secondly, we analyzed the removal of aflatoxin B 1 -derived DNA adducts formed in primary human hepatocytes exposed to oltipraz after treatment with this mycotoxin. Whatever the strategy used, NER activity was not altered in liver cells. These data demonstrated that liver cells actively repair bulky DNA adducts by NER and that oltipraz does not influence their NER activity neither in vivo nor in vitro , consequently strongly suggesting that the chemopreventive agent oltipraz is acting before the initiation step of cancer development.

Published
2002
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49. Comparative transcriptional profiling of human Merkel cells and Merkel cell carcinoma

Author

Marie-Dominique Galibert, N. Coquart, Laurent Misery, Brigitte Dréno, Nicolas Lebonvallet, Nicolas Mouchet, Weiguo Hu, Christelle Le Gall-Ianotto, Nicholas Boulais, Alain Fautrel, Ludovic Martin, Ariane Mogha, Laboratoire sur les interactions Epithéliums Neurones (LIEN), Université de Brest (UBO), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de dermatologie, Hôpital Augustin Morvan-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Facteurs nerveux et structuration tissulaire, Laboratoire de Neurosciences de Brest (LNB), Hépatotoxicité et xénobiotiques, Détoxication et réparation Tissulaire, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire d'Anatomie Pathologique, Hôpital Morvan Brest-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de dermatologie, CHU Angers, PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan Brest

Subjects
Pathology, medicine.medical_specialty, animal structures, Microarray, [SDV]Life Sciences [q-bio], Merkel cell polyomavirus, Dermatology, Biology, medicine.disease_cause, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Carcinoma, skin and connective tissue diseases, Molecular Biology, Gene, Microdissection, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, integumentary system, Merkel cell carcinoma, virus diseases, food and beverages, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, biology.organism_classification, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Merkel cell, Carcinogenesis, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

Merkel cell carcinoma is believed to be derived from Merkel cells after infection by Merkel cell polyomavirus (MCPyV) and other poorly understood events. Transcriptional profiling using cDNA microarrays was performed on cells from MCPy-negative and MCPy-positive Merkel cell carcinomas and isolated normal Merkel cells. This microarray revealed numerous significantly upregulated genes and some downregulated genes. The extensive list of genes that were identified in these experiments provides a large body of potentially valuable information of Merkel cell carcinoma carcinogenesis and could represent a source of potential targets for cancer therapy.

Published
2014
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50. Prognostic and predictive values of oncogenic BRAF, NRAS, c-KIT and MITF in cutaneous and mucous melanoma

Author

Marc Pracht, Ariane Mogha, Marie-Dominique Galibert, E. Oger, C. Lefeuvre-Plesse, A. Lespagnol, Thierry Lesimple, V Paumier, N. Rioux-Leclerc, Alain Fautrel, H. Adamski, F. Le Gall, Nicolas Mouchet, J. Mosser, CRLCC Eugène Marquis (CRLCC), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Hôpital Pontchaillou, Centre Hospitalier Universitaire [Rennes], Department of Medical Oncology, CIC-IT Rennes, Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pharmacologie [Rennes], CHU Pontchaillou [Rennes], Service de Dermatologie [Rennes] = Dermatology [Rennes], Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Neuroblastoma RAS viral oncogene homolog, Adult, Male, Proto-Oncogene Proteins B-raf, Pathology, medicine.medical_specialty, Skin Neoplasms, Adolescent, [SDV]Life Sciences [q-bio], Dermatology, Nodular melanoma, medicine.disease_cause, GTP Phosphohydrolases, Young Adult, medicine, Humans, Prospective Studies, Prospective cohort study, neoplasms, Melanoma, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Aged, 80 and over, Mutation, Microphthalmia-Associated Transcription Factor, Mucous Membrane, business.industry, Mucous membrane, Membrane Proteins, Middle Aged, Microphthalmia-associated transcription factor, medicine.disease, Prognosis, 3. Good health, Superficial spreading melanoma, Proto-Oncogene Proteins c-kit, Infectious Diseases, medicine.anatomical_structure, Cancer research, Female, business
Abstract

Background Mutations of BRAF, NRAS and c-KIT oncogenes are preferentially described in certain histological subtypes of melanoma and linked to specific histopathological features. BRAF-, MEK- and KIT-inhibitors led to improvement in overall survival of patients harbouring mutated metastatic melanoma. Objectives To assess the prevalence and types of BRAF, NRAS, c-KIT and MITF mutations in cutaneous and mucous melanoma and to correlate mutation status with clinicopathological features and outcome. Methods Clinicopathological features and mutation status of 108 samples and of 98 consecutive patients were, respectively, assessed in one retrospective and one prospective study. Clinicopathological features were correlated with mutation status and the predictive value of these mutations was studied. Results This work identified significant correlations between BRAF mutations and melanoma occurring on non-chronic sun-damaged skin and superficial spreading melanoma (P < 0.05) on one hand, and between NRAS mutations and nodular melanoma (P < 0.05) on the other hand. Younger age (P < 0.05), microscopic (P < 0.05) and macroscopic (P < 0.05) lymphatic involvement at diagnosis of primary melanoma were significantly linked to BRAF mutations. A mutated status was a positive predictive factor of a response to BRAF inhibitors (OR = 3.44). Mutated melanoma showed a significantly (P = 0.038) higher objective response rate to cytotoxic chemotherapy (26.3%) than wild-type tumours (6.7%). Conclusion Clinical and pathological characteristics of the primary melanoma differed between wild-type and BRAFor NRAS-mutated tumours. Patients with BRAF-mutated tumours were younger at diagnosis of primary melanoma. Patients carrying mutations showed better responses better to specific kinase inhibitors and interestingly also to systemic cytotoxic chemotherapy.

Published
2014
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