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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Jorge Antonio Silva-Gomez, Marina Galicia-Moreno, Ana Sandoval-Rodriguez, Hipolito Otoniel Miranda-Roblero, Silvia Lucano-Landeros, Arturo Santos, Hugo Christian Monroy-Ramirez, Juan Armendariz-Borunda
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	HCC PPARγ inflammation apoptosis liver cancer Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/10fe863c657e484b924842c26900f114
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:10fe863c657e484b924842c26900f114
record_format	dspace
spelling	oai:doaj.org-article:10fe863c657e484b924842c26900f1142021-11-11T16:50:08ZHepatocarcinogenesis Prevention by Pirfenidone Is PPARγ Mediated and Involves Modification of Nuclear NF-kB p65/p50 Ratio10.3390/ijms2221113601422-00671661-6596https://doaj.org/article/10fe863c657e484b924842c26900f1142021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11360https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Targeted 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.Jorge Antonio Silva-GomezMarina Galicia-MorenoAna Sandoval-RodriguezHipolito Otoniel Miranda-RobleroSilvia Lucano-LanderosArturo SantosHugo Christian Monroy-RamirezJuan Armendariz-BorundaMDPI AGarticleHCCPPARγinflammationapoptosisliver cancerBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11360, p 11360 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	HCC PPARγ inflammation apoptosis liver cancer Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	HCC PPARγ inflammation apoptosis liver cancer Biology (General) QH301-705.5 Chemistry QD1-999 Jorge Antonio Silva-Gomez Marina Galicia-Moreno Ana Sandoval-Rodriguez Hipolito Otoniel Miranda-Roblero Silvia Lucano-Landeros Arturo Santos Hugo Christian Monroy-Ramirez Juan Armendariz-Borunda Hepatocarcinogenesis Prevention by Pirfenidone Is PPARγ Mediated and Involves Modification of Nuclear NF-kB p65/p50 Ratio
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.
format	article
author	Jorge Antonio Silva-Gomez Marina Galicia-Moreno Ana Sandoval-Rodriguez Hipolito Otoniel Miranda-Roblero Silvia Lucano-Landeros Arturo Santos Hugo Christian Monroy-Ramirez Juan Armendariz-Borunda
author_facet	Jorge Antonio Silva-Gomez Marina Galicia-Moreno Ana Sandoval-Rodriguez Hipolito Otoniel Miranda-Roblero Silvia Lucano-Landeros Arturo Santos Hugo Christian Monroy-Ramirez Juan Armendariz-Borunda
author_sort	Jorge Antonio Silva-Gomez
title	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_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_sort	hepatocarcinogenesis prevention by pirfenidone is pparγ mediated and involves modification of nuclear nf-kb p65/p50 ratio
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/10fe863c657e484b924842c26900f114
work_keys_str_mv	AT jorgeantoniosilvagomez hepatocarcinogenesispreventionbypirfenidoneisppargmediatedandinvolvesmodificationofnuclearnfkbp65p50ratio AT marinagaliciamoreno hepatocarcinogenesispreventionbypirfenidoneisppargmediatedandinvolvesmodificationofnuclearnfkbp65p50ratio AT anasandovalrodriguez hepatocarcinogenesispreventionbypirfenidoneisppargmediatedandinvolvesmodificationofnuclearnfkbp65p50ratio AT hipolitootonielmirandaroblero hepatocarcinogenesispreventionbypirfenidoneisppargmediatedandinvolvesmodificationofnuclearnfkbp65p50ratio AT silvialucanolanderos hepatocarcinogenesispreventionbypirfenidoneisppargmediatedandinvolvesmodificationofnuclearnfkbp65p50ratio AT arturosantos hepatocarcinogenesispreventionbypirfenidoneisppargmediatedandinvolvesmodificationofnuclearnfkbp65p50ratio AT hugochristianmonroyramirez hepatocarcinogenesispreventionbypirfenidoneisppargmediatedandinvolvesmodificationofnuclearnfkbp65p50ratio AT juanarmendarizborunda hepatocarcinogenesispreventionbypirfenidoneisppargmediatedandinvolvesmodificationofnuclearnfkbp65p50ratio
_version_	1718432222176870400

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

Ejemplares similares