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Hepatocarcinogenesis Prevention by Pirfenidone Is PPARγ Mediated and Involves Modification of Nuclear NF-kB p65/p50 Ratio

Targeted therapies for regulating processes such as inflammation, apoptosis, and fibrogenesis might modulate human HCC development. Pirfenidone (PFD) has shown anti-fibrotic and anti-inflammatory functions in both clinical and experimental studies. The aim of this study was to evaluate PPARγ express...

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Autores principales: Silva-Gomez, Jorge Antonio, Galicia-Moreno, Marina, Sandoval-Rodriguez, Ana, Miranda-Roblero, Hipolito Otoniel, Lucano-Landeros, Silvia, Santos, Arturo, Monroy-Ramirez, Hugo Christian, Armendariz-Borunda, Juan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583060/
https://www.ncbi.nlm.nih.gov/pubmed/34768791
http://dx.doi.org/10.3390/ijms222111360
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author Silva-Gomez, Jorge Antonio
Galicia-Moreno, Marina
Sandoval-Rodriguez, Ana
Miranda-Roblero, Hipolito Otoniel
Lucano-Landeros, Silvia
Santos, Arturo
Monroy-Ramirez, Hugo Christian
Armendariz-Borunda, Juan
author_facet Silva-Gomez, Jorge Antonio
Galicia-Moreno, Marina
Sandoval-Rodriguez, Ana
Miranda-Roblero, Hipolito Otoniel
Lucano-Landeros, Silvia
Santos, Arturo
Monroy-Ramirez, Hugo Christian
Armendariz-Borunda, Juan
author_sort Silva-Gomez, Jorge Antonio
collection PubMed
description Targeted therapies for regulating processes such as inflammation, apoptosis, and fibrogenesis might modulate human HCC development. Pirfenidone (PFD) has shown anti-fibrotic and anti-inflammatory functions in both clinical and experimental studies. The aim of this study was to evaluate PPARγ expression and localization in samples of primary human tumors and assess PFD-effect in early phases of hepatocarcinogenic process. Human HCC tissue samples were obtained by surgical resection. Experimental hepatocarcinogenesis was induced in male Fischer-344 rats. TGF-β1 and α-SMA expression was evaluated as fibrosis markers. NF-kB cascade, TNFα, IL-6, and COX-2 expression and localization were evaluated as inflammation indicators. Caspase-3, p53, and PARP-1 were used as apoptosis markers, PCNA for proliferation. Finally, PPARα and PPARγ expression were evaluated to understand the effect of PFD on the activation of such pathways. PPARγ expression was predominantly localized in cytoplasm in human HCC tissue. PFD was effective to prevent histopathological damage and TGF-β1 and α-SMA overexpression in the experimental model. Anti-inflammatory effects of PFD correlate with diminished IKK and decrease in both IkB-phosphorylation/NF-kB p65 expression and p65-translocation into the nucleus. Pro-apoptotic PFD-induced effects are related with p53 expression, Caspase-3 p17 activation, and PARP-1-cleavage. In conclusion, PFD acts as a tumor suppressor by preventing fibrosis, reducing inflammation, and promoting apoptosis in MRHM.
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spelling pubmed-85830602021-11-12 Hepatocarcinogenesis Prevention by Pirfenidone Is PPARγ Mediated and Involves Modification of Nuclear NF-kB p65/p50 Ratio Silva-Gomez, Jorge Antonio Galicia-Moreno, Marina Sandoval-Rodriguez, Ana Miranda-Roblero, Hipolito Otoniel Lucano-Landeros, Silvia Santos, Arturo Monroy-Ramirez, Hugo Christian Armendariz-Borunda, Juan Int J Mol Sci Article Targeted therapies for regulating processes such as inflammation, apoptosis, and fibrogenesis might modulate human HCC development. Pirfenidone (PFD) has shown anti-fibrotic and anti-inflammatory functions in both clinical and experimental studies. The aim of this study was to evaluate PPARγ expression and localization in samples of primary human tumors and assess PFD-effect in early phases of hepatocarcinogenic process. Human HCC tissue samples were obtained by surgical resection. Experimental hepatocarcinogenesis was induced in male Fischer-344 rats. TGF-β1 and α-SMA expression was evaluated as fibrosis markers. NF-kB cascade, TNFα, IL-6, and COX-2 expression and localization were evaluated as inflammation indicators. Caspase-3, p53, and PARP-1 were used as apoptosis markers, PCNA for proliferation. Finally, PPARα and PPARγ expression were evaluated to understand the effect of PFD on the activation of such pathways. PPARγ expression was predominantly localized in cytoplasm in human HCC tissue. PFD was effective to prevent histopathological damage and TGF-β1 and α-SMA overexpression in the experimental model. Anti-inflammatory effects of PFD correlate with diminished IKK and decrease in both IkB-phosphorylation/NF-kB p65 expression and p65-translocation into the nucleus. Pro-apoptotic PFD-induced effects are related with p53 expression, Caspase-3 p17 activation, and PARP-1-cleavage. In conclusion, PFD acts as a tumor suppressor by preventing fibrosis, reducing inflammation, and promoting apoptosis in MRHM. MDPI 2021-10-21 /pmc/articles/PMC8583060/ /pubmed/34768791 http://dx.doi.org/10.3390/ijms222111360 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Silva-Gomez, Jorge Antonio
Galicia-Moreno, Marina
Sandoval-Rodriguez, Ana
Miranda-Roblero, Hipolito Otoniel
Lucano-Landeros, Silvia
Santos, Arturo
Monroy-Ramirez, Hugo Christian
Armendariz-Borunda, Juan
Hepatocarcinogenesis Prevention by Pirfenidone Is PPARγ Mediated and Involves Modification of Nuclear NF-kB p65/p50 Ratio
title Hepatocarcinogenesis Prevention by Pirfenidone Is PPARγ Mediated and Involves Modification of Nuclear NF-kB p65/p50 Ratio
title_full Hepatocarcinogenesis Prevention by Pirfenidone Is PPARγ Mediated and Involves Modification of Nuclear NF-kB p65/p50 Ratio
title_fullStr Hepatocarcinogenesis Prevention by Pirfenidone Is PPARγ Mediated and Involves Modification of Nuclear NF-kB p65/p50 Ratio
title_full_unstemmed Hepatocarcinogenesis Prevention by Pirfenidone Is PPARγ Mediated and Involves Modification of Nuclear NF-kB p65/p50 Ratio
title_short Hepatocarcinogenesis Prevention by Pirfenidone Is PPARγ Mediated and Involves Modification of Nuclear NF-kB p65/p50 Ratio
title_sort hepatocarcinogenesis prevention by pirfenidone is pparγ mediated and involves modification of nuclear nf-kb p65/p50 ratio
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583060/
https://www.ncbi.nlm.nih.gov/pubmed/34768791
http://dx.doi.org/10.3390/ijms222111360
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