38 results on '"Poitevin S"'
Search Results
2. Tissue factor up‐regulation in proinflammatory conditions confers thrombin generation capacity to endothelial colony‐forming cells without influencing non‐coagulant properties in vitro
- Author
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CUCCUINI, W., POITEVIN, S., POITEVIN, G., DIGNAT‐GEORGE, F., CORNILLET‐LEFEBVRE, P., SABATIER, F., and NGUYEN, P.
- Published
- 2010
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3. Type I collagen induces tissue factor expression and matrix metalloproteinase 9 production in human primary monocytes through a redox‐sensitive pathway
- Author
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POITEVIN, S., GARNOTEL, R., ANTONICELLI, F., GILLERY, P., and NGUYEN, P.
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- 2008
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4. IL-10 inhibits apoptosis and microvesiculation of human monocytes
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POITEVIN, S., BEN HADJ KALIFA KECHICHE, S., MACÉ, C., and NGUYEN, P.
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- 2009
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5. Comment aryl hydrocarbon receptor active-t-il l’expression du facteur tissulaire dans l’endothélium humain en réponse à l’indole-3 acétique acide ?
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Burtey, S., primary, Addi, T., additional, Mckay, N., additional, Poitevin, S., additional, and Dou, L., additional
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- 2018
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6. Type 1 collagen induces tissue factor expression and MMP-9 production in human primary monocytes through a redox-sensitive pathway
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Poitevin, S., Garnotel, R., Antonicelli, F., Gillery, P., Nguyen, P., Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2008
7. UVA-Mediated down-regulation of MMP-2 and MT1-MMP coincides with impaired angiogenic phenotype fo human dermal endothelial cells
- Author
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J.H., Cauchard, Robinet, A., Poitevin, S., Bobichon, H., J.C., Maziere, Bellon, G., Hornebeck, W., Matrice extracellulaire et régulations cellulaires (MERC), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), and Maquart, François-Xavier
- Published
- 2006
8. La toxine urémique, l’acide indole-3 acétique prédit la mortalité et la survenue d’un événement cardiovasculaire au cours de l’insuffisance rénale chronique
- Author
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Sallee, M., primary, Dou, L., additional, Cerini, C., additional, Poitevin, S., additional, Gondouin, B., additional, Jourde-Chiche, N., additional, Brunet, P., additional, and Burtey, S., additional
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- 2014
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9. Activation de p60-Src, de la PI-3 Kinase et de NF-kB induite par l'interaction entre les monocytes humains et le collagène de type I
- Author
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Poitevin, S., Garnotel, R., Gillery, P., Randoux, A., Matrice extracellulaire et régulations cellulaires (MERC), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), and Maquart, François-Xavier
- Abstract
Mai
- Published
- 2003
10. Comment une toxine urémique, l’acide indole-3 acétique, stresse-t-elle la cellule endothéliale ?
- Author
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Sallee, M., primary, Dou, L., additional, Gondouin, B., additional, Cerini, C., additional, Poitevin, S., additional, Brunet, P., additional, Dignat-George, F., additional, and Burtey, S., additional
- Published
- 2013
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11. Cell signalling / Pathophysiology
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Cerini, C., primary, Gondouin, B., additional, Dou, L., additional, Duval-Sabatier, A., additional, Brunet, P., additional, Dignat- George, F., additional, Burtey, S., additional, Okano, K., additional, Iwasaki, T., additional, Jinnai, H., additional, Hibi, A., additional, Miwa, N., additional, Kimata, N., additional, Nitta, K., additional, Akiba, T., additional, Dolley-Hitze, T., additional, Verhoest, G., additional, Jouan, F., additional, Arlot-Bonnemains, Y., additional, Lavenu, A., additional, Belaud-Rotureau, M.-A., additional, Rioux-Leclercq, N., additional, Vigneau, C., additional, Cox, S. N., additional, Sallustio, F., additional, Serino, G., additional, Loverre, A., additional, Pesce, F., additional, Gigante, M., additional, Zaza, G., additional, Stifanelli, P., additional, Ancona, N., additional, Schena, F. P., additional, Marc, P., additional, Jacques, T., additional, Green, J. M., additional, Mortensen, R. B., additional, Verma, R., additional, Leu, K., additional, Schatz, P. J., additional, Wojchowski, D. M., additional, Ihoriya, C., additional, Satoh, M., additional, Sasaki, T., additional, Kashihara, N., additional, Jung, Y. J., additional, Kang, K. P., additional, Lee, A. S., additional, Lee, J. E., additional, Lee, S., additional, Park, S. K., additional, Kim, W., additional, Florian, T., additional, Tepel, M., additional, Ying, L., additional, Katharina, K., additional, Nora, F., additional, Antje, W., additional, Alexandra, S., additional, Chiu, Y.-T., additional, Wu, M.-J., additional, Liu, Z.-H., additional, Liang, Y., additional, Zheng, C.-X., additional, Chen, Z.-H., additional, Zeng, C.-H., additional, Ranzinger, J., additional, Rustom, A., additional, Kihm, L., additional, Heide, D., additional, Scheurich, P., additional, Zeier, M., additional, Schwenger, V., additional, Liu, J., additional, Zhong, F., additional, Xu, L., additional, Zhou, Q., additional, Hao, X., additional, Wang, W., additional, Chen, N., additional, Liu, X., additional, Lu, Y., additional, Guo, S., additional, Lin, D., additional, Vilasi, A., additional, Deplano, S., additional, Cutillas, P., additional, Unwin, R., additional, Tam, F. W. K., additional, Medrano-Andres, D., additional, Lopez-Martinez, V., additional, Martinez-Miguel, P., additional, Cano, J. L., additional, Arribas, I., additional, Rodiguez-Puyol, M., additional, Lopez-Ongil, S., additional, Kadoya, H., additional, Nagasu, H., additional, Lindeberg, E., additional, Grundstrom, G., additional, Alexandra, M., additional, Ghosh, C. C., additional, David, S., additional, Mukherjee, A., additional, John, S. G., additional, Mcintyre, C. W., additional, Haller, H., additional, Parikh, S. M., additional, Troyano, N., additional, Del Nogal, M., additional, Olmos, G., additional, Mora, I., additional, DE Frutos, S., additional, Rodriguez-Puyol, M., additional, Ruiz, M. P., additional, Rothe, H., additional, Shapiro, W., additional, Ketteler, M., additional, Ramakrishnan, S. K., additional, Loupy, A., additional, Houillier, P., additional, Guilhermino Pereira, L., additional, Boim, M., additional, Aragao, D., additional, Casarini, D., additional, Jin, Y., additional, Moon, J.-Y., additional, Kim, Y.-G., additional, Lee, S.-H., additional, Lee, T.-W., additional, Ihm, C.-G., additional, Kim, E.-Y., additional, Lee, H.-J., additional, Wi, J.-G., additional, Jeong, K.-H., additional, Ruan, X. Z., additional, LI, L.-C., additional, Varghese, Z., additional, Chen, J.-B., additional, Lee, C.-T., additional, Moorhead, J., additional, Cerini, C., additional, Poitevin, S., additional, Dignat-George, F., additional, Stephane, B., additional, Bonanni, A., additional, Verzola, D., additional, Maggi, D., additional, Brunori, G., additional, Sofia, A., additional, Mannucci, I., additional, Maffioli, S., additional, Salani, B., additional, D'amato, E., additional, Saffioti, S., additional, Laudon, A., additional, Cordera, R., additional, Garibotto, G., additional, Maquigussa, E., additional, and Arnoni, C., additional
- Published
- 2012
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12. La toxine urémique acide indole-3-acétique induit un stress oxydant endothélial
- Author
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Dou, L., primary, Gondouin, B., additional, Cerini, C., additional, Duval-Sabatier, A., additional, Poitevin, S., additional, Brunet, P., additional, Dignat-George, F., additional, and Burtey, S., additional
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- 2011
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13. Malnutrition & inflammation in CKD 1-5
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Gursu, M., primary, Aydin, Z., additional, Karadag, S., additional, Uzun, S., additional, Ogul, S., additional, Kiris, A., additional, Doventas, Y., additional, Koldas, M., additional, Ozturk, S., additional, Kazancioglu, R., additional, Mandreoli, M., additional, Bellasi, A., additional, Baldrati, L., additional, Corradini, M., additional, Rigotti, A., additional, Russo, G., additional, David, S., additional, Malmusi, G., additional, DiNicolo', P., additional, Orsi, C., additional, Zambianchi, L., additional, Caruso, F., additional, Poisetti, P., additional, Fabbri, A., additional, Santoro, A., additional, Barton Pai, A., additional, Grabe, D., additional, Eisele, G., additional, Hutchison, C. A., additional, Bevins, A., additional, Lukacik, P., additional, Hughes, R. G., additional, Pratt, G., additional, Viana, J. L., additional, Bishop, N. C., additional, Kosmadakis, G., additional, Bevington, A., additional, Clapp, E. L., additional, Feehally, J., additional, Smith, A. C., additional, Joki, N., additional, Hase, H., additional, Tanaka, Y., additional, Iwasaki, M., additional, Yamaka, T., additional, Shigematsu, T., additional, Dou, L., additional, Gondouin, B., additional, Cerini, C., additional, Duval-Sabatier, A., additional, Poitevin, S., additional, Dignat-George, F., additional, Burtey, S., additional, Brunet, P., additional, Carrasco, F., additional, Salvador, F., additional, Origaca, C., additional, Nogueira, E., additional, Silva, N., additional, Silva, A., additional, Sikole, A., additional, Trajceska, L., additional, Selim, G., additional, Gelev, S., additional, Dzekova, P., additional, Amitov, V., additional, Arsov, S., additional, Dalboni, M., additional, Cruz, E., additional, Manfredi, S., additional, Mouro, M., additional, Quinto, M., additional, Grabulosa, C., additional, Batista, M., additional, Cendoroglo, M., additional, Hirayama, A., additional, Matsui, H., additional, Nagano, Y., additional, Ueda, A., additional, Aoyagi, K., additional, Owada, S., additional, Schepers, E., additional, Barreto, D., additional, Liabeuf, S., additional, Glorieux, G., additional, Eloot, S., additional, Barreto, F., additional, Massy, Z., additional, Vanholder, R., additional, Secara, I. F., additional, Oleniuc, M., additional, Nistor, I., additional, Onofriescu, M., additional, Covic, A., additional, Aguerrevere, S., additional, Granada, M., additional, Bayes, B., additional, Pastor, M., additional, Sancho, A., additional, Bonal, J., additional, Canas, L., additional, Lauzurica, R., additional, Teixido, J., additional, Troya, M., additional, Romero, R., additional, Capitanini, A., additional, D'Alessandro, C., additional, Ferretti, V., additional, Petrone, I., additional, Pasquariello, G., additional, Cupisti, A., additional, Parastayeva, M. M., additional, Berseneva, O. N., additional, Kucher, A. G., additional, Ivanova, G. T., additional, Smirnov, A. V., additional, Kayukov, I. G., additional, Kayabasi, H., additional, Esmer, S., additional, Yilmaz, Z., additional, Kadiroglu, A. K., additional, Yilmaz, M. E., additional, Radic, J., additional, Kovacic, V., additional, Radic, M., additional, Ljutic, D., additional, Sain, M., additional, Karakan, S., additional, Sezer, S., additional, Tutal, E., additional, Ozdemir Acar, F. N., additional, Bi, G., additional, Xing, C., additional, Chen, R., additional, Romero-Garcia, A., additional, Jacobo-Arias, F., additional, Martin del Campo, F., additional, Gonzalez-Espinoza, L., additional, Pazarin, L., additional, Cueto-Manzano, A. M., additional, Panagoutsos, S., additional, Kriki, P., additional, Mourvati, E., additional, Tziakas, D., additional, Chalikias, G., additional, Stakos, D., additional, Apostolakis, S., additional, Tsigalou, C., additional, Gioka, T., additional, Konstantinides, S., additional, Vargemezis, V., additional, Nascimento, M., additional, Hayashi, S., additional, Seeberger, A., additional, Yamamoto, T., additional, Qureshi, A. R., additional, Lind, B., additional, Riella, M., additional, Brodin, L.-A., additional, Lindholm, B., additional, Meier, P., additional, Menne, J., additional, Kruger, K., additional, Mooren, F. C., additional, Weissmann, N., additional, Seimetz, M., additional, Haller, H., additional, Gusev, E., additional, Solomatina, L., additional, Zhuravleva, J., additional, Striker, G., additional, Uribarri, J., additional, Cai, W., additional, Goodman, S., additional, Pyzik, R., additional, Grosjean, F., additional, Vlassara, H., additional, So, A., additional, Gimona, A., additional, Kiechle, T., additional, Shpilsky, A., additional, and Schlesinger, N., additional
- Published
- 2011
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14. P2-1 Prévalence des lésions vasculaires sous-corticales chez les patients MCI
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Bombois, S., primary, Debette, S., additional, Delbeuck, X., additional, Poitevin, S., additional, and Pasquier, F., additional
- Published
- 2005
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15. Assessment of the antiinvasive potential of the anthracycline aclacinomycin (Aclarubicin) in a human fibrosarcoma cell line
- Author
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Addadi-Rebbah, S., Poitevin, S., Fourre, N., Myriam POLETTE, Garnotel, R., Jeannesson, P., Birembaut, Philippe, Médicaments : Dynamique Intracellulaire et Architecture Nucléaire (MéDIAN), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Dynamique cellulaire et moléculaire de la muqueuse respiratoire, and Université de Reims Champagne-Ardenne (URCA)-IFR53-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Integrins ,Fibrosarcoma ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,MESH: Cell Adhesion ,CSK Tyrosine-Protein Kinase ,Cell Movement ,Cell Adhesion ,Tumor Cells, Cultured ,Humans ,Neoplasm Invasiveness ,MESH: Antibiotics, Antineoplastic ,Aclarubicin ,MESH: Cell Movement ,MESH: Focal Adhesion Protein-Tyrosine Kinases ,MESH: Humans ,Antibiotics, Antineoplastic ,MESH: Culture Media, Conditioned ,MESH: Fibrosarcoma ,MESH: Aclarubicin ,MESH: Matrix Metalloproteinase 9 ,MESH: Integrins ,Protein-Tyrosine Kinases ,MESH: Matrix Metalloproteinase 2 ,src-Family Kinases ,Matrix Metalloproteinase 9 ,Culture Media, Conditioned ,Focal Adhesion Kinase 1 ,Focal Adhesion Protein-Tyrosine Kinases ,Matrix Metalloproteinase 2 ,[SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,MESH: Focal Adhesion Kinase 1 - Abstract
Aclacinomycin (Aclarubicin) is a trisaccharide anthracycline anticancer drug active against a wide variety of solid tumors and haematological malignancies. We have evaluated its antimigrative and antiinvasive properties in a Boyden chamber with or without Matrigel and in wound repair assays. Aclacinomycin was demonstrated to inhibit HT-1080 cell migration and invasion while being more potent than the classical anthracycline doxorubicin. This decrease occurred in a dose-dependent manner and without affecting cell proliferation. Importantly, the antiinvasive effect was not associated to a modification in the production of the matrix-degrading enzymes MMP-2 and MMP-9 but rather to changes in cytoskeletal and focal contact formation. Indeed, the drug reduces cell polarity, impairs the actin-mediated membrane ruffling at the leading edge and decreases beta1 integrin expression and activation. Dramatic alterations in the distribution of vinculin and in the expression and phosphorylation state of both FAK and Src kinases were also detected. As a conclusion, these data suggest a novel application for this chemotherapeutic agent due to its ability to reduce tumor cell invasion. Combination of aclacinomycin with MMP inhibitors could have therapeutic potential in preventing tumor metastasis.
16. Mesenchymal stem cells potentiate angiogenic activity of endothelial progenitor cells through up-regulation of SPHK-1/S1P pathway
- Author
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Sabatier, F., Poitevin, S., Sarlon-Bartoli, G., Albinet, V., Andrieu-Abadie, N., Cussac, D., Parini, A., and Françoise DIGNAT-GEORGE
17. Indoxyl sulfate inhibits muscle cell differentiation via Myf6/MRF4 and MYH2 downregulation.
- Author
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Bataille S, McKay N, Koppe L, Beau A, Benoit B, Bartoli M, Da Silva N, Poitevin S, Aniort J, Chermiti R, Burtey S, and Dou L
- Subjects
- Animals, Mice, Down-Regulation, Cell Differentiation genetics, Muscle, Skeletal, RNA, Messenger, Indican pharmacology, Renal Insufficiency, Chronic
- Abstract
Background: Chronic kidney disease (CKD) is associated with a significant decrease in muscle strength and mass, possibly related to muscle cell damage by uremic toxins. Here, we studied in vitro and in vivo the effect of indoxyl sulfate (IS), an indolic uremic toxin, on myoblast proliferation, differentiation and expression of myogenic regulatory factors (MRF)-myoblast determination protein 1 (MyoD1), myogenin (Myog), Myogenic Factor 5 (Myf5) and myogenic regulatory factor 4 (Myf6/MRF4)-and expression of myosin heavy chain, Myh2., Methods: C2C12 myoblasts were cultured in vitro and differentiated in myotubes for 7 days in the presence of IS at a uremic concentration of 200 µM. Myocytes morphology and differentiation was analyzed after hematoxylin-eosin staining. MRF genes' expression was studied using reverse transcription polymerase chain reaction in myocytes and 5/6th nephrectomized mice muscle. Myf6/MRF4 protein expression was studied using enzyme-linked immunosorbent assay; MYH2 protein expression was studied using western blotting. The role of Aryl Hydrocarbon Receptor (AHR)-the cell receptor of IS-was studied by adding an AHR inhibitor into the cell culture milieu., Results: In the presence of IS, the myotubes obtained were narrower and had fewer nuclei than control myotubes. The presence of IS during differentiation did not modify the gene expression of the MRFs Myf5, MyoD1 and Myog, but induced a decrease in expression of Myf6/MRF4 and MYH2 at the mRNA and the protein level. AHR inhibition by CH223191 did not reverse the decrease in Myf6/MRF4 mRNA expression induced by IS, which rules out the implication of the ARH genomic pathway. In 5/6th nephrectomized mice, the Myf6/MRF4 gene was down-regulated in striated muscles., Conclusion: In conclusion, IS inhibits Myf6/MRF4 and MYH2 expression during differentiation of muscle cells, which could lead to a defect in myotube structure. Through these new mechanisms, IS could participate in muscle atrophy observed in CKD., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)
- Published
- 2023
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18. Mechanisms of myostatin and activin A accumulation in chronic kidney disease.
- Author
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Bataille S, Dou L, Bartoli M, Sallée M, Aniort J, Ferkak B, Chermiti R, McKay N, Da Silva N, Burtey S, and Poitevin S
- Subjects
- Activins metabolism, Animals, Humans, Indican, Mammals metabolism, Mice, Muscle, Skeletal metabolism, Myostatin genetics, Renal Insufficiency, Chronic pathology
- Abstract
Background: Myostatin and activin A induce muscle wasting by activating the ubiquitin proteasome system and inhibiting the Akt/mammalian target of rapamycin pathway. In chronic kidney disease (CKD), myostatin and activin A plasma concentrations are increased, but it is unclear if there is increased production or decreased renal clearance., Methods: We measured myostatin and activin A concentrations in 232 CKD patients and studied their correlation with estimated glomerular filtration rate (eGFR). We analyzed the myostatin gene (MSTN) expression in muscle biopsies of hemodialysis (HD) patients. We then measured circulating myostatin and activin A in plasma and the Mstn and Inhba expression in muscles, kidney, liver and heart of two CKD mice models (adenine and 5/6 nephrectomy models). Finally, we analyzed whether the uremic toxin indoxyl sulfate (IS) increased Mstn expression in mice and cultured muscle cells., Results: In patients, myostatin and activin A were inversely correlated with eGFR. MSTN expression was lower in HD patients' muscles (vastus lateralis) than in controls. In mice with CKD, myostatin and activin A blood concentrations were increased. Mstn was not upregulated in CKD mice tissues. Inha was upregulated in kidney and heart. Exposure to IS did not induce Mstn upregulation in mouse muscles and in cultured myoblasts and myocytes., Conclusion: During CKD, myostatin and activin A blood concentrations are increased. Myostatin is not overproduced, suggesting only an impaired renal clearance, but activin A is overproduced in the kidney and heart. We propose to add myostatin and activin A to the list of uremic toxins., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)
- Published
- 2022
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19. Tryptophan Metabolites Regulate Neuropentraxin 1 Expression in Endothelial Cells.
- Author
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Vial R, Poitevin S, McKay N, Burtey S, and Cerini C
- Subjects
- Animals, Carbazoles metabolism, Cells, Cultured, Disease Models, Animal, Humans, Indican metabolism, Indoleacetic Acids metabolism, Male, Mice, Mice, Inbred C57BL, Polychlorinated Dibenzodioxins metabolism, Receptors, Aryl Hydrocarbon metabolism, Renal Insufficiency, Chronic metabolism, Toxins, Biological metabolism, Uremia metabolism, C-Reactive Protein metabolism, Human Umbilical Vein Endothelial Cells metabolism, Nerve Tissue Proteins metabolism, Tryptophan metabolism
- Abstract
In patients with chronic kidney disease (CKD) and in animal models of CKD, the transcription factor Aryl Hydrocabon Receptor (AhR) is overactivated. In addition to the canonical AhR targets constituting the AhR signature, numerous other genes are regulated by this factor. We identified neuronal pentraxin 1 (NPTX1) as a new AhR target. Belonging to the inflammatory protein family, NPTX1 seems of prime interest regarding the inflammatory state observed in CKD. Endothelial cells were exposed to tryptophan-derived toxins, indoxyl sulfate (IS) and indole-3-acetic acid (IAA). The adenine mouse model of CKD was used to analyze NPTX1 expression in the burden of uremia. NPTX1 expression was quantified by RT-PCR and western blot. AhR involvement was analyzed using silencing RNA. We found that IS and IAA upregulated NPTX1 expression in an AhR-dependent way. Furthermore, this effect was not restricted to uremic indolic toxins since the dioxin 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) do the same. In CKD mice, NPTX1 expression was increased in the aorta. Therefore, NPTX1 is a new target of AhR and further work is necessary to elucidate its exact role during CKD.
- Published
- 2022
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20. Uremic Toxic Blood-Brain Barrier Disruption Mediated by AhR Activation Leads to Cognitive Impairment during Experimental Renal Dysfunction.
- Author
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Bobot M, Thomas L, Moyon A, Fernandez S, McKay N, Balasse L, Garrigue P, Brige P, Chopinet S, Poitevin S, Cérini C, Brunet P, Dignat-George F, Burtey S, Guillet B, and Hache G
- Subjects
- Adenine, Animals, Blood-Brain Barrier diagnostic imaging, Blood-Brain Barrier drug effects, Carbon pharmacology, Cognitive Dysfunction etiology, Disease Models, Animal, Indican blood, Indican cerebrospinal fluid, Male, Mice, Knockout, Nephrectomy, Neuropsychological Tests, Oxides pharmacology, Permeability, Radiopharmaceuticals metabolism, Rats, Rats, Sprague-Dawley, Receptors, Aryl Hydrocarbon genetics, Renal Insufficiency, Chronic complications, Single Photon Emission Computed Tomography Computed Tomography, Technetium Tc 99m Pentetate metabolism, Uremia complications, Blood-Brain Barrier metabolism, Cognitive Dysfunction metabolism, Indican pharmacology, Receptors, Aryl Hydrocarbon metabolism, Renal Insufficiency, Chronic physiopathology, Uremia blood
- Abstract
Background: Uremic toxicity may play a role in the elevated risk of developing cognitive impairment found among patients with CKD. Some uremic toxins, like indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AhR), which is widely expressed in the central nervous system and which we previously identified as the receptor of indoxyl sulfate in endothelial cells., Methods: To characterize involvement of uremic toxins in cerebral and neurobehavioral abnormalities in three rat models of CKD, we induced CKD in rats by an adenine-rich diet or by 5/6 nephrectomy; we also used AhR
-/- knockout mice overloaded with indoxyl sulfate in drinking water. We assessed neurologic deficits by neurobehavioral tests and blood-brain barrier disruption by SPECT/CT imaging after injection of99m Tc-DTPA, an imaging marker of blood-brain barrier permeability., Results: In CKD rats, we found cognitive impairment in the novel object recognition test, the object location task, and social memory tests and an increase of blood-brain barrier permeability associated with renal dysfunction. We found a significant correlation between99m Tc-DTPA content in brain and both the discrimination index in the novel object recognition test and indoxyl sulfate concentrations in serum. When we added indoxyl sulfate to the drinking water of rats fed an adenine-rich diet, we found an increase in indoxyl sulfate concentrations in serum associated with a stronger impairment in cognition and a higher permeability of the blood-brain barrier. In addition, non-CKD AhR-/- knockout mice were protected against indoxyl sulfate-induced blood-brain barrier disruption and cognitive impairment., Conclusions: AhR activation by indoxyl sulfate, a uremic toxin, leads to blood-brain barrier disruption associated with cognitive impairment in animal models of CKD., (Copyright © 2020 by the American Society of Nephrology.)- Published
- 2020
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21. Sera From Patients With Minimal Change Disease Increase Endothelial Permeability to Sodium.
- Author
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Daviet F, Blin MG, Fallague K, Bachelier R, Laforêt M, Carré M, Poitevin S, Dignat-George F, Blot-Chabaud M, Bardin N, Burtey S, Jourde-Chiche N, and Leroyer AS
- Published
- 2020
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22. Assessment of Thrombotic and Bleeding Tendency in Two Mouse Models of Chronic Kidney Disease: Adenine-Diet and 5/6th Nephrectomy.
- Author
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Makhloufi C, Crescence L, Darbousset R, McKay N, Massy ZA, Dubois C, Panicot-Dubois L, Burtey S, and Poitevin S
- Abstract
The coexistence of bleeding and thrombosis in patients with chronic kidney disease (CKD) is frequent and poorly understood. Mouse models are essential to understand complications of CKD and to develop new therapeutic approaches improving the health of patients. We evaluated the hemostasis in two models of renal insufficiency: adenine-diet and 5/6th nephrectomy (5/6Nx). Compared with 5/6Nx mice, mice fed with 0.25% adenine had more severe renal insufficiency and so higher levels of prothrombotic uremic toxins like indoxyl sulfate. More severe renal inflammation and fibrosis were observed in the adenine group, as demonstrated by histological and reverse transcription quantitative polymerase chain reaction experiments. Liver fibrinogen γ chain expression and level of plasma fibrinogen were increased only in adenine mice. In both CKD mouse models, tissue factor (TF) expression was increased in kidney and aorta extracts. Immunochemistry analysis of kidney sections showed that TF is localized in the vascular walls. Thrombin-antithrombin complexes were significantly increased in plasma from both adenine and 5/6Nx mice. Tail bleeding time increased significantly only in adenine mice, whereas platelet count was not significant altered. Finally, results obtained by intravital microscopy after laser-induced endothelial injury showed impaired platelet function in adenine mice and an increase in fibrin generation in 5/6Nx mice. To summarize, adenine diet causes a more severe renal insufficiency compared with 5/6Nx. The TF upregulation and the hypercoagulable state were observed in both CKD models. Bleeding tendency was observed only in the adenine model of CKD that recapitulates the whole spectrum of hemostasis abnormalities observed in advanced human CKD., Competing Interests: Conflict of Interest None declared.
- Published
- 2020
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23. Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease.
- Author
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Makhloufi C, Nicolas F, McKay N, Fernandez S, Hache G, Garrigue P, Brunet P, Guillet B, Burtey S, and Poitevin S
- Subjects
- Animals, Diet, Disease Models, Animal, Female, Male, Mice, Mice, Knockout, Mortality, Renal Insufficiency, Chronic chemically induced, Renal Insufficiency, Chronic mortality, Sex Characteristics, Xanthine Dehydrogenase metabolism, Adenine adverse effects, Basic Helix-Loop-Helix Transcription Factors genetics, Receptors, Aryl Hydrocarbon genetics, Renal Insufficiency, Chronic genetics
- Abstract
Cardiovascular complications observed in chronic kidney disease (CKD) are associated with aryl hydrocarbon receptor (AhR) activation by tryptophan-derived uremic toxins-mainly indoxyl sulfate (IS). AhR is a ligand-activated transcription factor originally characterized as a receptor of xenobiotics involved in detoxification. The aim of this study was to determine the role of AhR in a CKD mouse model based on an adenine diet. Wild-type (WT) and AhR
-/- mice were fed by alternating an adenine-enriched diet and a regular diet for 6 weeks. Our results showed an increased mortality rate of AhR-/- males. AhR-/- females survived and developed a less severe renal insufficiency that WT mice, reflected by urea, creatinine, and IS measurement in serum. The protective effect was related to a decrease of pro-inflammatory and pro-fibrotic gene expression, an attenuation of tubular injury, and a decrease of 2,8-dihydroxyadenine crystal deposition in the kidneys of AhR-/- mice. These mice expressed low levels of xanthine dehydrogenase, which oxidizes adenine into 2,8-dihydroxyadenine, and low levels of the IS metabolism enzymes. In conclusion, the CKD model of adenine diet is not suitable for AhR knockout mice when studying the role of this transcription factor in cardiovascular complications, as observed in human CKD.- Published
- 2020
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24. Aryl Hydrocarbon Receptor Activation and Tissue Factor Induction by Fluid Shear Stress and Indoxyl Sulfate in Endothelial Cells.
- Author
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Lano G, Laforêt M, Von Kotze C, Perrin J, Addi T, Brunet P, Poitevin S, Burtey S, and Dou L
- Subjects
- Basic Helix-Loop-Helix Transcription Factors, Cyclooxygenase 2 genetics, Cytochrome P-450 CYP1A1 genetics, Cytochrome P-450 CYP1B1 genetics, Gene Expression Regulation, Gene Knockdown Techniques, Humans, RNA, Messenger metabolism, Renal Insufficiency, Chronic metabolism, Stress, Mechanical, Human Umbilical Vein Endothelial Cells metabolism, Indican agonists, Indican toxicity, Receptors, Aryl Hydrocarbon drug effects, Receptors, Aryl Hydrocarbon metabolism, Thromboplastin drug effects, Thromboplastin metabolism
- Abstract
Endogenous agonists of the transcription factor aryl hydrocarbon receptor (AHR) such as the indolic uremic toxin, indoxyl sulfate (IS), accumulate in patients with chronic kidney disease. AHR activation by indolic toxins has prothrombotic effects on the endothelium, especially via tissue factor (TF) induction. In contrast, physiological AHR activation by laminar shear stress (SS) is atheroprotective. We studied the activation of AHR and the regulation of TF by IS in cultured human umbilical vein endothelial cells subjected to laminar fluid SS (5 dynes/cm2). SS and IS markedly increased the expression of AHR target genes PTGS2 (encoding for COX2), AHRR , CYP1A1 , and CYP1B1 , as well as F3 (encoding for TF), in an AHR-dependent way. IS amplified SS-induced TF mRNA and protein expression and upregulation of AHR target genes. Interestingly, tyrosine kinase inhibition by genistein decreased SS- but not IS-induced TF expression. Finally, the increase in TF expression induced by laminar SS was not associated with increased TF activity. In contrast, IS increased TF activity, even under antithrombotic SS conditions. In conclusion, IS and SS induce AHR activation and AHR-dependent TF upregulation by different mechanisms. Impairment of the antithrombotic properties of shear stressed endothelium by toxic AHR agonists could favor cardiovascular diseases in CKD.
- Published
- 2020
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25. Mechanisms of tissue factor induction by the uremic toxin indole-3 acetic acid through aryl hydrocarbon receptor/nuclear factor-kappa B signaling pathway in human endothelial cells.
- Author
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Addi T, Poitevin S, McKay N, El Mecherfi KE, Kheroua O, Jourde-Chiche N, de Macedo A, Gondouin B, Cerini C, Brunet P, Dignat-George F, Burtey S, and Dou L
- Subjects
- Adult, Aged, Aged, 80 and over, Basic Helix-Loop-Helix Transcription Factors genetics, Cells, Cultured, Female, Gene Knockdown Techniques, Humans, Male, Middle Aged, Promoter Regions, Genetic, Prospective Studies, RNA, Small Interfering, Receptors, Aryl Hydrocarbon genetics, Renal Insufficiency, Chronic, Young Adult, Basic Helix-Loop-Helix Transcription Factors metabolism, Human Umbilical Vein Endothelial Cells drug effects, Indoleacetic Acids toxicity, NF-kappa B metabolism, Receptors, Aryl Hydrocarbon metabolism, Signal Transduction, Thromboplastin metabolism
- Abstract
Chronic kidney disease (CKD) is associated with high risk of thrombosis. Indole-3 acetic acid (IAA), an indolic uremic toxin, induces the expression of tissue factor (TF) in human umbilical vein endothelial cells (HUVEC) via the transcription factor aryl hydrocarbon receptor (AhR). This study aimed to understand the signaling pathways involved in AhR-mediated TF induction by IAA. We incubated human endothelial cells with IAA at 50 µM, the maximal concentration found in patients with CKD. IAA induced TF expression in different types of human endothelial cells: umbilical vein (HUVEC), aortic (HAoEC), and cardiac-derived microvascular (HMVEC-C). Using AhR inhibition and chromatin immunoprecipitation experiments, we showed that TF induction by IAA in HUVEC was controlled by AhR and that AhR did not bind to the TF promoter. The analysis of TF promoter activity using luciferase reporter plasmids showed that the NF-κB site was essential in TF induction by IAA. In addition, TF induction by IAA was drastically decreased by an inhibitor of the NF-κB pathway. IAA induced the nuclear translocation of NF-κB p50 subunit, which was decreased by AhR and p38MAPK inhibition. Finally, in a cohort of 92 CKD patients on hemodialysis, circulating TF was independently related to serum IAA in multivariate analysis. In conclusion, TF up-regulation by IAA in human endothelial cells involves a non-genomic AhR/p38 MAPK/NF-κB pathway. The understanding of signal transduction pathways related to AhR thrombotic/inflammatory pathway is of interest to find therapeutic targets to reduce TF expression and thrombotic risk in patients with CKD.
- Published
- 2019
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26. Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease.
- Author
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Dou L, Poitevin S, Sallée M, Addi T, Gondouin B, McKay N, Denison MS, Jourde-Chiche N, Duval-Sabatier A, Cerini C, Brunet P, Dignat-George F, and Burtey S
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Basic Helix-Loop-Helix Transcription Factors agonists, Basic Helix-Loop-Helix Transcription Factors deficiency, Basic Helix-Loop-Helix Transcription Factors genetics, Basic Helix-Loop-Helix Transcription Factors metabolism, Cardiovascular Diseases blood, Cardiovascular Diseases mortality, Case-Control Studies, Cause of Death, Cell Line, Tumor, Cytochrome P-450 CYP1A1 genetics, Cytochrome P-450 CYP1A1 metabolism, Disease Models, Animal, Female, Humans, Indican administration & dosage, Indican blood, Male, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Prospective Studies, Receptors, Aryl Hydrocarbon agonists, Receptors, Aryl Hydrocarbon deficiency, Receptors, Aryl Hydrocarbon genetics, Renal Dialysis, Renal Insufficiency, Chronic diagnosis, Renal Insufficiency, Chronic mortality, Renal Insufficiency, Chronic therapy, Repressor Proteins genetics, Repressor Proteins metabolism, Risk Factors, Treatment Outcome, Basic Helix-Loop-Helix Transcription Factors blood, Receptors, Aryl Hydrocarbon blood, Renal Insufficiency, Chronic blood
- Abstract
Patients with chronic kidney disease (CKD) are exposed to uremic toxins and have an increased risk of cardiovascular disease. Some uremic toxins, like indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AHR). These toxins induce a vascular procoagulant phenotype. Here we investigated AHR activation in patients with CKD and in a murine model of CKD. We performed a prospective study in 116 patients with CKD stage 3 to 5D and measured the AHR-Activating Potential of serum by bioassay. Compared to sera from healthy controls, sera from CKD patients displayed a strong AHR-Activating Potential; strongly correlated with eGFR and with the indoxyl sulfate concentration. The expression of the AHR target genes Cyp1A1 and AHRR was up-regulated in whole blood from patients with CKD. Survival analyses revealed that cardiovascular events were more frequent in CKD patients with an AHR-Activating Potential above the median. In mice with 5/6 nephrectomy, there was an increased serum AHR-Activating Potential, and an induction of Cyp1a1 mRNA in the aorta and heart, absent in AhR
-/- CKD mice. After serial indoxyl sulfate injections, we observed an increase in serum AHR-AP and in expression of Cyp1a1 mRNA in aorta and heart in WT mice, but not in AhR-/- mice. Thus, the AHR pathway is activated both in patients and mice with CKD. Hence, AHR activation could be a key mechanism involved in the deleterious cardiovascular effects observed in CKD., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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27. Indoxyl Sulfate Upregulates Liver P-Glycoprotein Expression and Activity through Aryl Hydrocarbon Receptor Signaling.
- Author
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Santana Machado T, Poitevin S, Paul P, McKay N, Jourde-Chiche N, Legris T, Mouly-Bandini A, Dignat-George F, Brunet P, Masereeuw R, Burtey S, and Cerini C
- Subjects
- ATP Binding Cassette Transporter, Subfamily B genetics, Albumins pharmacology, Animals, Cyclosporine blood, Cyclosporine pharmacokinetics, Disease Models, Animal, Female, Gene Expression drug effects, Heart Transplantation, Hep G2 Cells, Humans, Immunosuppressive Agents blood, Immunosuppressive Agents pharmacokinetics, Indican pharmacology, Kidney Transplantation, Liver metabolism, Male, Mice, Middle Aged, Multidrug Resistance-Associated Protein 2, RNA, Messenger metabolism, Renal Insufficiency, Chronic physiopathology, Signal Transduction, Up-Regulation, ATP Binding Cassette Transporter, Subfamily B metabolism, Indican blood, Receptors, Aryl Hydrocarbon metabolism, Renal Insufficiency, Chronic blood
- Abstract
In patients with CKD, not only renal but also, nonrenal clearance of drugs is altered. Uremic toxins could modify the expression and/or activity of drug transporters in the liver. We tested whether the uremic toxin indoxyl sulfate (IS), an endogenous ligand of the transcription factor aryl hydrocarbon receptor, could change the expression of the following liver transporters involved in drug clearance: SLC10A1 , SLC22A1 , SLC22A7 , SLC47A1 , SLCO1B1 , SLCO1B3 , SLCO2B1 , ABCB1 , ABCB11 , ABCC2 , ABCC3 , ABCC4 , ABCC6 , and ABCG2 We showed that IS increases the expression and activity of the efflux transporter P-glycoprotein (P-gp) encoded by ABCB1 in human hepatoma cells (HepG2) without modifying the expression of the other transporters. This effect depended on the aryl hydrocarbon receptor pathway. Presence of human albumin at physiologic concentration in the culture medium did not abolish the effect of IS. In two mouse models of CKD, the decline in renal function associated with the accumulation of IS in serum and the specific upregulation of Abcb1a in the liver. Additionally, among 109 heart or kidney transplant recipients with CKD, those with higher serum levels of IS needed higher doses of cyclosporin, a P-gp substrate, to obtain the cyclosporin target blood concentration. This need associated with serum levels of IS independent of renal function. These findings suggest that increased activity of P-gp could be responsible for increased hepatic cyclosporin clearance. Altogether, these results suggest that uremic toxins, such as IS, through effects on drug transporters, may modify the nonrenal clearance of drugs in patients with CKD., (Copyright © 2018 by the American Society of Nephrology.)
- Published
- 2018
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28. CD146 mediates VEGF-induced melanoma cell extravasation through FAK activation.
- Author
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Jouve N, Bachelier R, Despoix N, Blin MG, Matinzadeh MK, Poitevin S, Aurrand-Lions M, Fallague K, Bardin N, Blot-Chabaud M, Vely F, Dignat-George F, and Leroyer AS
- Subjects
- Animals, Antigens, CD metabolism, CD146 Antigen genetics, CD146 Antigen metabolism, Cadherins metabolism, Endothelium, Vascular metabolism, Gene Expression Regulation, Neoplastic, Lung blood supply, Lung Neoplasms metabolism, Melanoma, Experimental genetics, Melanoma, Experimental metabolism, Mice, Mice, Knockout, Neoplasm Transplantation, Neovascularization, Pathologic metabolism, Tumor Cells, Cultured, Focal Adhesion Kinase 1 metabolism, Lung cytology, Lung Neoplasms secondary, Melanoma, Experimental pathology, Vascular Endothelial Growth Factor A metabolism
- Abstract
CD146 is an adhesion molecule expressed by both melanoma and endothelial cells and thus is well positioned to control melanoma extravasation. Nevertheless, during melanoma metastasis, the involvement of CD146 expressed within tumor microenvironment has never been analyzed. To investigate whether host CD146 mediates the extravasation of melanoma cells across the endothelium, we generated CD146 KO mice. We demonstrated that host CD146 did not affect melanoma growth or tumor angiogenesis but promoted hematogenous melanoma metastasis to the lung. Accordingly, the survival of CD146-deficient mice was markedly prolonged during melanoma metastasis. Interestingly, vascular endothelial growth factor-induced vascular permeability was significantly decreased in CD146 KO mice. We also provided evidence that VEGF-induced transendothelial migration of melanoma cells was significantly reduced across CD146 KO lung microvascular endothelial cells (LMEC). CD146 deficiency decreased the expression of VEGFR-2/Ve-cadherin and altered focal adhesion kinase (FAK) activation in response to VEGF. In addition, inhibition of FAK phosphorylation reduced transmigration of B16 melanoma cells across WT LMEC at the same level that across CD146 KO LMEC. Altogether, we propose a novel mechanism involving the VEGF/CD146/FAK/Ve-cadherin network in melanoma extravasation across the vessel barrier that identifies CD146-targeted therapy as a potential strategy for the treatment of melanoma metastasis., (© 2014 UICC.)
- Published
- 2015
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29. The cardiovascular effect of the uremic solute indole-3 acetic acid.
- Author
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Dou L, Sallée M, Cerini C, Poitevin S, Gondouin B, Jourde-Chiche N, Fallague K, Brunet P, Calaf R, Dussol B, Mallet B, Dignat-George F, and Burtey S
- Subjects
- Adult, Aged, Aged, 80 and over, Cardiovascular Diseases etiology, Cyclooxygenase 2 metabolism, Female, Human Umbilical Vein Endothelial Cells, Humans, Male, Middle Aged, Reactive Oxygen Species metabolism, Renal Insufficiency, Chronic complications, Renal Insufficiency, Chronic mortality, Signal Transduction, Uremia complications, Young Adult, Cardiovascular Diseases blood, Endothelium, Vascular metabolism, Indoleacetic Acids blood, Oxidative Stress, Renal Insufficiency, Chronic blood
- Abstract
In CKD, uremic solutes may induce endothelial dysfunction, inflammation, and oxidative stress, leading to increased cardiovascular risk. We investigated whether the uremic solute indole-3 acetic acid (IAA) predicts clinical outcomes in patients with CKD and has prooxidant and proinflammatory effects. We studied 120 patients with CKD. During the median study period of 966 days, 29 patients died and 35 experienced a major cardiovascular event. Kaplan-Meier analysis revealed that mortality and cardiovascular events were significantly higher in the higher IAA group (IAA>3.73 µM) than in the lower IAA group (IAA<3.73 µM). Multivariate Cox regression analysis demonstrated that serum IAA was a significant predictor of mortality and cardiovascular events after adjustments for age and sex; cholesterol, systolic BP, and smoking; C-reactive protein, phosphate, body mass index, and albumin; diastolic BP and history of cardiovascular disease; and uremic toxins p-cresyl sulfate and indoxyl sulfate. Notably, IAA level remained predictive of mortality when adjusted for CKD stage. IAA levels were positively correlated with markers of inflammation and oxidative stress: C-reactive protein and malondialdehyde, respectively. In cultured human endothelial cells, IAA activated an inflammatory nongenomic aryl hydrocarbon receptor (AhR)/p38MAPK/NF-κB pathway that induced the proinflammatory enzyme cyclooxygenase-2. Additionally, IAA increased production of endothelial reactive oxygen species. In conclusion, serum IAA may be an independent predictor of mortality and cardiovascular events in patients with CKD. In vitro, IAA induces endothelial inflammation and oxidative stress and activates an inflammatory AhR/p38MAPK/NF-κB pathway., (Copyright © 2015 by the American Society of Nephrology.)
- Published
- 2015
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30. Sphingosine kinase 1 expressed by endothelial colony-forming cells has a critical role in their revascularization activity.
- Author
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Poitevin S, Cussac D, Leroyer AS, Albinet V, Sarlon-Bartoli G, Guillet B, Hubert L, Andrieu-Abadie N, Couderc B, Parini A, Dignat-George F, and Sabatier F
- Subjects
- Animals, Cells, Cultured, Colony-Forming Units Assay, Culture Media, Conditioned, Gene Knockdown Techniques, Humans, Lysophospholipids metabolism, Mesenchymal Stem Cells metabolism, Mice, Mice, Nude, Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors, Phosphotransferases (Alcohol Group Acceptor) genetics, RNA, Small Interfering genetics, Receptors, Lysosphingolipid metabolism, Sphingosine analogs & derivatives, Sphingosine metabolism, Sphingosine-1-Phosphate Receptors, Endothelial Cells cytology, Endothelial Cells metabolism, Neovascularization, Physiologic, Phosphotransferases (Alcohol Group Acceptor) metabolism
- Abstract
Aims: Cell therapy based on endothelial colony-forming cells (ECFCs) is a promising option for ischaemic cardiovascular diseases. A better understanding of the mechanisms by which these cells promote revascularization remains a critical challenge to improving their therapeutic potential. We aimed to identify the critical mechanisms involved in the revascularization activity of ECFCs by using the paracrine properties of mesenchymal stem cells (MSC)., Methods and Results: Conditioned medium from human bone marrow-derived MSCs (MSC-CM) increased the angiogenic activity of cord blood ECFCs in vitro (proliferation, migration, and pseudo-tube formation), the survival of ECFCs in mice (Matrigel Plug assay), and the capacity of ECFCs to promote the recovery of blood perfusion in mice with hindlimb ischaemia. Furthermore, the capillary density in ischaemic gastrocnemius muscle was significantly increased in mice transplanted with the ECFCs pre-treated with the MSC-CM. The enhancement of ECFCs activity involved the up-regulation of sphingosine kinase 1 (SphK1) expression and activity. The inhibition of SphK1 in ECFCs by using an inhibitor or a siRNA knockdown of SphK1 prevented the stimulation of the ECFCs induced by the MSC-CM. The improvement of ECFC activity by MSC-CM also involved the up-regulation of sphingosine-1-phosphate receptor 1 (S1P1) and a S1P/S1P1/3-dependent mechanism. Finally, we showed that the stimulation of ECFCs with exogenous S1P increased angiogenesis and promoted blood perfusion in hindlimb ischaemia., Conclusion: The up-regulation of SphK1 and S1P-dependent pathways is critical for the angiogenic/vasculogenic activity of ECFCs. The identification of this pathway provides attractive targets to optimize cell-based therapy for revascularization in ischaemic diseases., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)
- Published
- 2014
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31. The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: a new concept to understand cardiovascular complications of chronic kidney disease.
- Author
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Sallée M, Dou L, Cerini C, Poitevin S, Brunet P, and Burtey S
- Subjects
- Animals, Cardiovascular Diseases etiology, Endothelium, Vascular physiopathology, Humans, Leukocytes immunology, Oxidative Stress, Renal Insufficiency, Chronic complications, Cardiovascular Diseases metabolism, Receptors, Aryl Hydrocarbon metabolism, Renal Insufficiency, Chronic metabolism, Toxins, Biological metabolism, Tryptophan metabolism, Uremia metabolism
- Abstract
Patients with chronic kidney disease (CKD) have a higher risk of cardiovascular diseases and suffer from accelerated atherosclerosis. CKD patients are permanently exposed to uremic toxins, making them good candidates as pathogenic agents. We focus here on uremic toxins from tryptophan metabolism because of their potential involvement in cardiovascular toxicity: indolic uremic toxins (indoxyl sulfate, indole-3 acetic acid, and indoxyl-β-d-glucuronide) and uremic toxins from the kynurenine pathway (kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid). Uremic toxins derived from tryptophan are endogenous ligands of the transcription factor aryl hydrocarbon receptor (AhR). AhR, also known as the dioxin receptor, interacts with various regulatory and signaling proteins, including protein kinases and phosphatases, and Nuclear Factor-Kappa-B. AhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and some polychlorinated biphenyls is associated with an increase in cardiovascular disease in humans and in mice. In addition, this AhR activation mediates cardiotoxicity, vascular inflammation, and a procoagulant and prooxidant phenotype of vascular cells. Uremic toxins derived from tryptophan have prooxidant, proinflammatory, procoagulant, and pro-apoptotic effects on cells involved in the cardiovascular system, and some of them are related with cardiovascular complications in CKD. We discuss here how the cardiovascular effects of these uremic toxins could be mediated by AhR activation, in a "dioxin-like" effect.
- Published
- 2014
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32. Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway.
- Author
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Gondouin B, Cerini C, Dou L, Sallée M, Duval-Sabatier A, Pletinck A, Calaf R, Lacroix R, Jourde-Chiche N, Poitevin S, Arnaud L, Vanholder R, Brunet P, Dignat-George F, and Burtey S
- Subjects
- Adult, Aged, Aged, 80 and over, Benzoquinones pharmacology, Case-Control Studies, Cells, Cultured, Dioxins pharmacology, Endothelium, Vascular cytology, Female, Humans, In Vitro Techniques, Indican metabolism, Indoleacetic Acids metabolism, Lactams, Macrocyclic pharmacology, Leukocytes, Mononuclear cytology, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear metabolism, Male, Middle Aged, Polymerase Chain Reaction, RNA, Small Interfering pharmacology, Receptors, Aryl Hydrocarbon antagonists & inhibitors, Receptors, Aryl Hydrocarbon drug effects, Renal Insufficiency, Chronic metabolism, Signal Transduction physiology, Tissue Array Analysis, Umbilical Veins cytology, Umbilical Veins drug effects, Umbilical Veins metabolism, Up-Regulation drug effects, Up-Regulation physiology, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, Indican pharmacology, Indoleacetic Acids pharmacology, Receptors, Aryl Hydrocarbon metabolism, Signal Transduction drug effects, Thromboplastin metabolism
- Abstract
In chronic kidney disease (CKD), uremic solutes accumulate in blood and tissues. These compounds probably contribute to the marked increase in cardiovascular risk during the progression of CKD. The uremic solutes indoxyl sulfate and indole-3-acetic acid (IAA) are particularly deleterious for endothelial cells. Here we performed microarray and comparative PCR analyses to identify genes in endothelial cells targeted by these two uremic solutes. We found an increase in endothelial expression of tissue factor in response to indoxyl sulfate and IAA and upregulation of eight genes regulated by the transcription factor aryl hydrocarbon receptor (AHR). The suggestion by microarray analysis of an involvement of AHR in tissue factor production was confirmed by siRNA inhibition and the indirect AHR inhibitor geldanamycin. These observations were extended to peripheral blood mononuclear cells. Tissue factor expression and activity were also increased by AHR agonist dioxin. Finally, we measured circulating tissue factor concentration and activity in healthy control subjects and in patients with CKD (stages 3-5d), and found that each was elevated in patients with CKD. Circulating tissue factor levels were positively correlated with plasma indoxyl sulfate and IAA. Thus, indolic uremic solutes increase tissue factor production in endothelial and peripheral blood mononuclear cells by AHR activation, evoking a 'dioxin-like' effect. This newly described mechanism of uremic solute toxicity may help understand the high cardiovascular risk of CKD patients.
- Published
- 2013
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33. Differential inhibitory effect of fondaparinux on the procoagulant potential of intact monocytes and monocyte-derived microparticles.
- Author
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Ben-Hadj-Khalifa-Kechiche S, Hezard N, Poitevin S, Remy MG, Florent B, Mahjoub T, and Nguyen P
- Subjects
- Adult, Blood Coagulation physiology, Cell-Derived Microparticles physiology, Dose-Response Relationship, Drug, Female, Fondaparinux, Humans, Male, Monocytes, Polysaccharides blood, Thrombin antagonists & inhibitors, Thrombin physiology, Young Adult, Anticoagulants pharmacology, Blood Coagulation drug effects, Cell-Derived Microparticles drug effects, Polysaccharides pharmacology
- Abstract
Monocytes and monocyte-derived microparticles (MMPs) play a major role in acute coronary syndrome (ASC). Activated monocytes (ac-M) and MMPs support thrombin generation via tissue factor (TF). The aim of this study was to evaluate the inhibitory effect of fondaparinux, a selective Xa inhibitor, on thrombin generation supported by activated monocytes and MMPs. Monocytes were purified by elutriation. They were activated by LPS, allowing to obtain both ac-M and MMPs. Thrombin generation was performed using Fluoroscan(®) in these two cell models, in comparison with a cell-free model (TF 5 pM final). Two concentrations of ac-M (0.2 × 10⁶ and 1 × 10⁶/well) and four concentrations of MMPs (40,000; 80,000; 120,000 and 160,000/well) were tested. TGT was evaluated for increasing fondaparinux concentrations (0, 0.1, 0.4, 0.7 and 1.2 μg/ml). Without fondaparinux, 0.2 × 10⁶ ac-M and 160,000 MMPs induced comparable results. Fondaparinux inhibited thrombin generation in the three models. Inhibition was fondaparinux concentration dependent. Rate index was the most sensitive parameter, compared to lag-time, peak and endogenous thrombin potential. The rate index IC(50) were 0.69 ± 0.03 μg/ml for ac-M, 0.20 ± 0.03 μg/ml for MMPs, and 0.22 ± 0.02 μg/ml for cell-free model. Fondaparinux exerted an inhibitory effect at all concentrations, including the lowest (0.1 μg/ml). The extend of inhibition was similar between MMPs and cell-free models, and stronger than ac-M model. We assume that the efficacy of fondaparinux 2.5 mg once daily in ACS patients may be in part attributed to its inhibitory effect on MMPs.
- Published
- 2010
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34. Elastin peptides antagonize ceramide-induced apoptosis.
- Author
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Cantarelli B, Duca L, Blanchevoye C, Poitevin S, Martiny L, and Debelle L
- Subjects
- Animals, Caspase 9 metabolism, Cells, Cultured, Enzyme Activation, Fibroblasts cytology, Fibroblasts drug effects, Fibroblasts physiology, Humans, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction drug effects, Skin cytology, Apoptosis drug effects, Ceramides pharmacology, Elastin pharmacology, Peptides pharmacology
- Abstract
Elastin peptides regulate proliferation, chemotaxis and protease expression. The aim of this work was to assess their influence on apoptosis. Human skin fibroblast cell death was induced using C(2)-ceramide in the presence or absence of elastin peptides. We show that ceramide-induced apoptosis could be blocked by elastin peptides. Using pharmacological inhibitors, we show that elastin peptide treatment leads to activation of the anti-apoptotic protein Akt that phosphorylates the pro-apoptotic protein Bad, the Foxo3a transcription factor and caspase-9. Importantly, the anti-apoptotic effects of elastin peptides were persistent in time. Our results suggest that elastin peptides could be potent cell survival factors.
- Published
- 2009
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35. Monocyte IL-10 produced in response to lipopolysaccharide modulates thrombin generation by inhibiting tissue factor expression and release of active tissue factor-bound microparticles.
- Author
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Poitevin S, Cochery-Nouvellon E, Dupont A, and Nguyen P
- Subjects
- Antibodies, Monoclonal, Blood Coagulation Factors antagonists & inhibitors, Cell Separation methods, Cells, Cultured, Cytoplasmic Vesicles metabolism, Dose-Response Relationship, Drug, Feedback, Physiological, Fluorometry methods, Humans, Interleukin-10 genetics, Interleukin-10 pharmacology, Interleukin-10 Receptor alpha Subunit immunology, Interleukin-10 Receptor alpha Subunit metabolism, Kinetics, Monocytes metabolism, RNA, Messenger metabolism, Recombinant Proteins pharmacology, Thromboplastin genetics, Thromboplastin immunology, Time Factors, Blood Coagulation Factors metabolism, Cytoplasmic Vesicles drug effects, Gene Expression drug effects, Interleukin-10 metabolism, Lipopolysaccharides pharmacology, Monocytes drug effects, Thrombin metabolism, Thromboplastin metabolism
- Abstract
Lipopolysaccharide (LPS)-stimulated monocytes are known to have a procoagulant effect. This property is currently explained by the fact that monocytes, in response to LPS, can express tissue factor (TF) and undergo a process of membrane microvesiculation. Interleukin-10 (IL-10) has been shown to downregulate TF expression and inhibit procoagulant activity (PCA). In order to further characterize the inhibitory effect of IL-10 on LPS-induced PCA, we used the integrated system of analysis of kinetics of thrombin generation in normal plasma (thrombinography). For this, we developed an original method of elutriation allowing to obtain a highly purified monocyte preparation, under endotoxin-free conditions. Thrombin generation was measured using a highly sensitive and specific fluorogenic method which we adapted to inhibit the contact factor pathway. Results show that recombinant human IL-10 decreased the kinetics of thrombin generation in a dose-dependent manner. Furthermore, the inhibition of endogenous IL-10 released by monocytes in response to LPS is associated with an increase in the kinetics of thrombin generation. We demonstrated that this effect was a consequence of the up-regulation of TF expression and TF-bound microparticle release. In conclusion, we report that IL-10 can regulate thrombin generation in conditions close to physiology as allowed by thrombinography, and that endogenous IL-10 regulates TF expression and release of active TF-bound microparticles by a negative feed back loop through IL-10 receptor alpha.
- Published
- 2007
36. UVA-mediated down-regulation of MMP-2 and MT1-MMP coincides with impaired angiogenic phenotype of human dermal endothelial cells.
- Author
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Cauchard JH, Robinet A, Poitevin S, Bobichon H, Maziere JC, Bellon G, and Hornebeck W
- Subjects
- Angiogenic Proteins genetics, Dose-Response Relationship, Radiation, Down-Regulation radiation effects, Elastin pharmacology, Endothelial Cells metabolism, Endothelium, Vascular cytology, Endothelium, Vascular physiology, Humans, Matrix Metalloproteinases, Membrane-Associated, Phenotype, Singlet Oxygen pharmacology, Tissue Inhibitor of Metalloproteinase-1 pharmacology, Angiogenic Proteins metabolism, Endothelial Cells radiation effects, Endothelium, Vascular radiation effects, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinases metabolism, Skin cytology, Ultraviolet Rays
- Abstract
UVA irradiation, dose-dependently (5-20 J/cm2), was shown to impair the morphogenic differentiation of human microvascular endothelial cells (HMECs) on Matrigel. Parallely, UVA down-regulated the expression of MMP-2 and MT1-MMP, both at the protein and the mRNA levels. On the contrary, the production of MMP-1 and TIMP-1 by HMECs increased following UVA treatment. The inhibitory effect of UVA on MMP expression and pseudotubes formation was mediated by UVA-generated singlet oxygen (1O2). The contribution of MT1-MMP, but not TIMP-1, to the regulation of HMECs' angiogenic phenotype following UVA irradiation was suggested using elastin-derived peptides and TIMP-1 blocking antibody, respectively.
- Published
- 2006
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37. Assessment of the antiinvasive potential of the anthracycline aclacinomycin (Aclarubicin) in a human fibrosarcoma cell line.
- Author
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Addadi-Rebbah S, Poitevin S, Fourre N, Polette M, Garnotel R, and Jeannesson P
- Subjects
- CSK Tyrosine-Protein Kinase, Cell Adhesion drug effects, Culture Media, Conditioned, Fibrosarcoma enzymology, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Humans, Integrins metabolism, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 metabolism, Protein-Tyrosine Kinases metabolism, Tumor Cells, Cultured, src-Family Kinases, Aclarubicin pharmacology, Antibiotics, Antineoplastic pharmacology, Cell Movement drug effects, Fibrosarcoma pathology, Neoplasm Invasiveness pathology
- Abstract
Aclacinomycin (Aclarubicin) is a trisaccharide anthracycline anticancer drug active against a wide variety of solid tumors and haematological malignancies. We have evaluated its antimigrative and antiinvasive properties in a Boyden chamber with or without Matrigel and in wound repair assays. Aclacinomycin was demonstrated to inhibit HT-1080 cell migration and invasion while being more potent than the classical anthracycline doxorubicin. This decrease occurred in a dose-dependent manner and without affecting cell proliferation. Importantly, the antiinvasive effect was not associated to a modification in the production of the matrix-degrading enzymes MMP-2 and MMP-9 but rather to changes in cytoskeletal and focal contact formation. Indeed, the drug reduces cell polarity, impairs the actin-mediated membrane ruffling at the leading edge and decreases beta1 integrin expression and activation. Dramatic alterations in the distribution of vinculin and in the expression and phosphorylation state of both FAK and Src kinases were also detected. As a conclusion, these data suggest a novel application for this chemotherapeutic agent due to its ability to reduce tumor cell invasion. Combination of aclacinomycin with MMP inhibitors could have therapeutic potential in preventing tumor metastasis.
- Published
- 2004
38. Human blood monocytes interact with type I collagen through alpha x beta 2 integrin (CD11c-CD18, gp150-95).
- Author
-
Garnotel R, Rittié L, Poitevin S, Monboisse JC, Nguyen P, Potron G, Maquart FX, Randoux A, and Gillery P
- Subjects
- Acids, Animals, Antibodies, Monoclonal pharmacology, Cations, Divalent pharmacology, Cell Adhesion drug effects, Cell Adhesion immunology, Collagen metabolism, Edetic Acid pharmacology, Humans, Hydrogen-Ion Concentration, Integrin alphaXbeta2, Kinetics, Monocytes metabolism, Protein Denaturation, Rats, Rats, Sprague-Dawley, Solubility, Superoxides antagonists & inhibitors, Superoxides blood, CD11 Antigens physiology, CD18 Antigens physiology, Collagen physiology, Membrane Glycoproteins physiology, Monocytes physiology
- Abstract
Human blood monocytes are attracted into connective tissues during early steps of inflammation and wound healing, and locally interact with resident cells and extracellular matrix proteins. We studied the effects of type I collagen on monocyte adhesion and superoxide anion production, using human monocytes elutriated from peripheral blood and type I collagen obtained from rat tail tendon. Both acid-soluble and pepsin-digested type I collagens promoted the adhesion of monocytes, whereas only acid-soluble collagen with intact telopeptides induced the production of superoxide. Adhesion and activation of monocytes on acid-soluble type I collagen depended on the presence of divalent cations. mAbs directed against integrin subunits CD11c and CD18 specifically inhibited adhesion and activation of monocytes on type I collagen. Protein membrane extracts obtained from monocytes were submitted to affinity chromatography on collagen I-Sepharose 4B, and analyzed by Western blotting using specific anti-integrin subunit Abs. In the case of both acid-soluble and pepsin-digested collagens, two bands were revealed with mAbs against CD11c and CD18 integrin subunits. Our results demonstrate that monocytes interact with type I collagen through CD11c-CD18 (alpha x beta 2) integrins, which promote their adhesion and activation. For monocyte activation, specific domains of the type I collagen telopeptides are necessary. Interactions between monocytes and collagen are most likely involved in the cascade of events that characterize the initial phases of inflammation.
- Published
- 2000
- Full Text
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