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Dadun > Depósito Académico > CIMA (Centro de Investigación Médica Aplicada) > Área de Terapia génica y Hepatología > Genética molecular > DA - CIMA - Terapia génica y Hepatología - Genética molecular - Artículos de Revista >

Oral methylthioadenosine administration attenuates fibrosis and chronic liver disease progression in Mdr2-/- mice
Authors: Latasa, M.U. (María Ujué)
Gil-Puig, C. (Carmen)
Fernandez-Barrena, M.G. (Maite G.)
Rodriguez-Ortigosa, C.M. (Carlos M.)
Banales, J.M. (Jesús M.)
Urtasun, R. (Raquel)
Goñi, S. (Saioa)
Mendez, M. (Miriam)
Arcelus, S. (Sara)
Juanarena, N. (Nerea)
Recio, J.A. (Juan A.)
Lotersztajn, S. (Sophie)
Prieto, J. (Jesús)
Berasain, C. (Carmen)
Corrales, F.J. (Fernando José)
Lecanda, J. (Jon)
Avila, M.A. (Matías Antonio)
Keywords: Adenosine/analogs & derivatives
Fibrosis/drug therapy
Liver Diseases/genetics
Liver Diseases/pathology
P-Glycoproteins/genetics
Thionucleosides/administration & dosage
Issue Date: 2010
Publisher: Public Library of Science
Publisher version: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015690
ISSN: 1932-6203
Citation: Latasa MU, Gil-Puig C, Fernandez-Barrena MG, Rodriguez-Ortigosa CM, Banales JM, Urtasun R, et al. Oral methylthioadenosine administration attenuates fibrosis and chronic liver disease progression in Mdr2-/- mice. PLoS One 2010 Dec 29;5(12):e15690.
Abstract
BACKGROUND: Inflammation and fibrogenesis are directly related to chronic liver disease progression, including hepatocellular carcinoma (HCC) development. Currently there are few therapeutic options available to inhibit liver fibrosis. We have evaluated the hepatoprotective and anti-fibrotic potential of orally-administered 5'-methylthioadenosine (MTA) in Mdr2(-/-) mice, a clinically relevant model of sclerosing cholangitis and spontaneous biliary fibrosis, followed at later stages by HCC development. METHODOLOGY: MTA was administered daily by gavage to wild type and Mdr2(-/-) mice for three weeks. MTA anti-inflammatory and anti-fibrotic effects and potential mechanisms of action were examined in the liver of Mdr2(-/-) mice with ongoing fibrogenesis and in cultured liver fibrogenic cells (myofibroblasts). PRINCIPAL FINDINGS: MTA treatment reduced hepatomegaly and liver injury. α-Smooth muscle actin immunoreactivity and collagen deposition were also significantly decreased. Inflammatory infiltrate, the expression of the cytokines IL6 and Mcp-1, pro-fibrogenic factors like TGFβ2 and tenascin-C, as well as pro-fibrogenic intracellular signalling pathways were reduced by MTA in vivo. MTA inhibited the activation and proliferation of isolated myofibroblasts and down-regulated cyclin D1 gene expression at the transcriptional level. The expression of JunD, a key transcription factor in liver fibrogenesis, was also reduced by MTA in activated myofibroblasts. CONCLUSIONS/SIGNIFICANCE: Oral MTA administration was well tolerated and proved its efficacy in reducing liver inflammation and fibrosis. MTA may have multiple molecular and cellular targets. These include the inhibition of inflammatory and pro-fibrogenic cytokines, as well as the attenuation of myofibroblast activation and proliferation. Downregulation of JunD and cyclin D1 expression in myofibroblasts may be important regarding the mechanism of action of MTA. This compound could be a good candidate to be tested for the treatment of (biliary) liver fibrosis.
Permanent link: http://hdl.handle.net/10171/20237
Appears in Collections:DA - CIMA - Servicios de apoyo - Instalación radioactiva - Artículos
DA - CIMA - Terapia génica y Hepatología - Oncobiología - Artículos de revista
DA - CIMA - Terapia génica y Hepatología - Hepatología experimental - Artículos de revista
DA - CIMA - Unidad de Proteómica, Genómica y Bioinformática - Artículos de revista
DA - CIMA - Terapia génica y Hepatología - Hepatología bioquímica - Artículos de revista
DA - CIMA - Terapia génica y Hepatología - Genética molecular - Artículos de Revista

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