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The Methyl Ester of 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid Reduces Endometrial Lesions Development by Modulating the NFkB and Nrf2 Pathways

Endometriosis is a common gynecological disease. Here, we aimed to investigate the anti-fibrotic, anti-inflammatory, and anti-oxidative role of the methyl ester of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) on endometriosis. An endometriosis rat model was constructed by intraperitoneall...

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Autores principales: Siracusa, Rosalba, D’Amico, Ramona, Cordaro, Marika, Peritore, Alessio Filippo, Genovese, Tiziana, Gugliandolo, Enrico, Crupi, Rosalia, Impellizzeri, Daniela, Cuzzocrea, Salvatore, Fusco, Roberta, Di Paola, Rosanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069675/
https://www.ncbi.nlm.nih.gov/pubmed/33924360
http://dx.doi.org/10.3390/ijms22083991
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author Siracusa, Rosalba
D’Amico, Ramona
Cordaro, Marika
Peritore, Alessio Filippo
Genovese, Tiziana
Gugliandolo, Enrico
Crupi, Rosalia
Impellizzeri, Daniela
Cuzzocrea, Salvatore
Fusco, Roberta
Di Paola, Rosanna
author_facet Siracusa, Rosalba
D’Amico, Ramona
Cordaro, Marika
Peritore, Alessio Filippo
Genovese, Tiziana
Gugliandolo, Enrico
Crupi, Rosalia
Impellizzeri, Daniela
Cuzzocrea, Salvatore
Fusco, Roberta
Di Paola, Rosanna
author_sort Siracusa, Rosalba
collection PubMed
description Endometriosis is a common gynecological disease. Here, we aimed to investigate the anti-fibrotic, anti-inflammatory, and anti-oxidative role of the methyl ester of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) on endometriosis. An endometriosis rat model was constructed by intraperitoneally injecting recipient rats with an equivalent of tissue from the uterus of a donor animal. Endometriosis was allowed to develop for seven days. CDDO-Me was administered on the 7th day and for the next 7 days. On day 14, rats were sacrificed, and peritoneal fluid and endometriotic implants were collected. CDDO-Me displayed antioxidant activity by activating the Nfr2 pathway and the expression of antioxidant mediators such as NQO-1 and HO-1. Moreover, it reduced lipid peroxidation and increased glutathione (GSH) levels and superoxide dismutase (SOD) activity. CDDO-Me also showed anti-inflammatory activity by decreasing the expression of pro-inflammatory cytokines in peritoneal fluids and NFkB activation. It, in turn, reduced cyclooxygenase-2 (COX-2) expression in the endometriotic loci and prostaglandin E2 (PGE2) levels in the peritoneal fluids, leading to increased apoptosis and reduced angiogenesis. The reduced oxidative stress and pro-inflammatory microenvironment decreased implants diameter, area, and volume. In particular, CDDO-Me administration reduced the histopathological signs of endometriosis and inflammatory cells recruitment into the lesions, as shown by toluidine blue staining and myeloperoxidase (MPO) activity. CDDO-Me strongly suppressed α-SMA and fibronectin expression and collagen deposition, reducing endometriosis-associated fibrosis. In conclusion, CDDO-Me treatment resulted in a coordinated and effective suppression of endometriosis by modulating the Nrf2 and NFkB pathways.
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spelling pubmed-80696752021-04-26 The Methyl Ester of 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid Reduces Endometrial Lesions Development by Modulating the NFkB and Nrf2 Pathways Siracusa, Rosalba D’Amico, Ramona Cordaro, Marika Peritore, Alessio Filippo Genovese, Tiziana Gugliandolo, Enrico Crupi, Rosalia Impellizzeri, Daniela Cuzzocrea, Salvatore Fusco, Roberta Di Paola, Rosanna Int J Mol Sci Article Endometriosis is a common gynecological disease. Here, we aimed to investigate the anti-fibrotic, anti-inflammatory, and anti-oxidative role of the methyl ester of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) on endometriosis. An endometriosis rat model was constructed by intraperitoneally injecting recipient rats with an equivalent of tissue from the uterus of a donor animal. Endometriosis was allowed to develop for seven days. CDDO-Me was administered on the 7th day and for the next 7 days. On day 14, rats were sacrificed, and peritoneal fluid and endometriotic implants were collected. CDDO-Me displayed antioxidant activity by activating the Nfr2 pathway and the expression of antioxidant mediators such as NQO-1 and HO-1. Moreover, it reduced lipid peroxidation and increased glutathione (GSH) levels and superoxide dismutase (SOD) activity. CDDO-Me also showed anti-inflammatory activity by decreasing the expression of pro-inflammatory cytokines in peritoneal fluids and NFkB activation. It, in turn, reduced cyclooxygenase-2 (COX-2) expression in the endometriotic loci and prostaglandin E2 (PGE2) levels in the peritoneal fluids, leading to increased apoptosis and reduced angiogenesis. The reduced oxidative stress and pro-inflammatory microenvironment decreased implants diameter, area, and volume. In particular, CDDO-Me administration reduced the histopathological signs of endometriosis and inflammatory cells recruitment into the lesions, as shown by toluidine blue staining and myeloperoxidase (MPO) activity. CDDO-Me strongly suppressed α-SMA and fibronectin expression and collagen deposition, reducing endometriosis-associated fibrosis. In conclusion, CDDO-Me treatment resulted in a coordinated and effective suppression of endometriosis by modulating the Nrf2 and NFkB pathways. MDPI 2021-04-13 /pmc/articles/PMC8069675/ /pubmed/33924360 http://dx.doi.org/10.3390/ijms22083991 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
Siracusa, Rosalba
D’Amico, Ramona
Cordaro, Marika
Peritore, Alessio Filippo
Genovese, Tiziana
Gugliandolo, Enrico
Crupi, Rosalia
Impellizzeri, Daniela
Cuzzocrea, Salvatore
Fusco, Roberta
Di Paola, Rosanna
The Methyl Ester of 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid Reduces Endometrial Lesions Development by Modulating the NFkB and Nrf2 Pathways
title The Methyl Ester of 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid Reduces Endometrial Lesions Development by Modulating the NFkB and Nrf2 Pathways
title_full The Methyl Ester of 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid Reduces Endometrial Lesions Development by Modulating the NFkB and Nrf2 Pathways
title_fullStr The Methyl Ester of 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid Reduces Endometrial Lesions Development by Modulating the NFkB and Nrf2 Pathways
title_full_unstemmed The Methyl Ester of 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid Reduces Endometrial Lesions Development by Modulating the NFkB and Nrf2 Pathways
title_short The Methyl Ester of 2-Cyano-3,12-Dioxooleana-1,9-Dien-28-Oic Acid Reduces Endometrial Lesions Development by Modulating the NFkB and Nrf2 Pathways
title_sort methyl ester of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid reduces endometrial lesions development by modulating the nfkb and nrf2 pathways
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069675/
https://www.ncbi.nlm.nih.gov/pubmed/33924360
http://dx.doi.org/10.3390/ijms22083991
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