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New TMA (4,6,4′-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease
A series of new-generation TMA (4,6,4′-trimethyl angelicin) analogues was projected and synthetized in order to ameliorate anti-inflammatory activity, with reduced or absent toxicity. Since the NF-κB transcription factor (TF) plays a critical role in the expression of IL-8 (Interluekin 8), a typical...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699093/ https://www.ncbi.nlm.nih.gov/pubmed/36430961 http://dx.doi.org/10.3390/ijms232214483 |
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author | Tupini, Chiara Chilin, Adriana Rossi, Alice De Fino, Ida Bragonzi, Alessandra D’Aversa, Elisabetta Cosenza, Lucia Carmela Vaccarin, Christian Sacchetti, Gianni Borgatti, Monica Tamanini, Anna Dechecchi, Maria Cristina Sanvito, Francesca Gambari, Roberto Cabrini, Giulio Lampronti, Ilaria |
author_facet | Tupini, Chiara Chilin, Adriana Rossi, Alice De Fino, Ida Bragonzi, Alessandra D’Aversa, Elisabetta Cosenza, Lucia Carmela Vaccarin, Christian Sacchetti, Gianni Borgatti, Monica Tamanini, Anna Dechecchi, Maria Cristina Sanvito, Francesca Gambari, Roberto Cabrini, Giulio Lampronti, Ilaria |
author_sort | Tupini, Chiara |
collection | PubMed |
description | A series of new-generation TMA (4,6,4′-trimethyl angelicin) analogues was projected and synthetized in order to ameliorate anti-inflammatory activity, with reduced or absent toxicity. Since the NF-κB transcription factor (TF) plays a critical role in the expression of IL-8 (Interluekin 8), a typical marker of lung inflammation in Cystic Fibrosis (CF), the use of agents able to interfere with the NF-κB pathway represents an interesting therapeutic strategy. Through preliminary EMSA experiments, we identified several new TMA derivatives able to inhibit the NF-κB/DNA complex. The selected active molecules were then analyzed to evaluate the anti-inflammatory effect using both Pseudomonas aeruginosa (PAO1) infection and TNF-alpha stimulus on the CF IB3-1 cell line. It was demonstrated that mainly two TMA analogues, GY971a mesylate salt (6-p-minophenyl-4,4′-dimethyl-angelicin) and GY964 (4-phenyl-6,4′-dimethyl-angelicin), were able to decrease the IL-8 gene expression. At the same time, these molecules were found to have no pro-apoptotic, mutagenic and phototoxic effects, facilitating our decision to test the efficacy in vivo by using a mouse model of acute P. aeruginosa lung infection. The anti-inflammatory effect of GY971a was confirmed in vivo; this derivative was able to deeply decrease the total number of inflammatory cells, the neutrophil count and the cytokine/chemokine profile in the P. aeruginosa acute infection model, without evident toxicity. Considering all the obtained and reported in vitro and in vivo pre-clinical results, GY971a seems to have interesting anti-inflammatory effects, modulating the NF-κB pathway, as well as the starting lead compound TMA, but without side effects. |
format | Online Article Text |
id | pubmed-9699093 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-96990932022-11-26 New TMA (4,6,4′-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease Tupini, Chiara Chilin, Adriana Rossi, Alice De Fino, Ida Bragonzi, Alessandra D’Aversa, Elisabetta Cosenza, Lucia Carmela Vaccarin, Christian Sacchetti, Gianni Borgatti, Monica Tamanini, Anna Dechecchi, Maria Cristina Sanvito, Francesca Gambari, Roberto Cabrini, Giulio Lampronti, Ilaria Int J Mol Sci Article A series of new-generation TMA (4,6,4′-trimethyl angelicin) analogues was projected and synthetized in order to ameliorate anti-inflammatory activity, with reduced or absent toxicity. Since the NF-κB transcription factor (TF) plays a critical role in the expression of IL-8 (Interluekin 8), a typical marker of lung inflammation in Cystic Fibrosis (CF), the use of agents able to interfere with the NF-κB pathway represents an interesting therapeutic strategy. Through preliminary EMSA experiments, we identified several new TMA derivatives able to inhibit the NF-κB/DNA complex. The selected active molecules were then analyzed to evaluate the anti-inflammatory effect using both Pseudomonas aeruginosa (PAO1) infection and TNF-alpha stimulus on the CF IB3-1 cell line. It was demonstrated that mainly two TMA analogues, GY971a mesylate salt (6-p-minophenyl-4,4′-dimethyl-angelicin) and GY964 (4-phenyl-6,4′-dimethyl-angelicin), were able to decrease the IL-8 gene expression. At the same time, these molecules were found to have no pro-apoptotic, mutagenic and phototoxic effects, facilitating our decision to test the efficacy in vivo by using a mouse model of acute P. aeruginosa lung infection. The anti-inflammatory effect of GY971a was confirmed in vivo; this derivative was able to deeply decrease the total number of inflammatory cells, the neutrophil count and the cytokine/chemokine profile in the P. aeruginosa acute infection model, without evident toxicity. Considering all the obtained and reported in vitro and in vivo pre-clinical results, GY971a seems to have interesting anti-inflammatory effects, modulating the NF-κB pathway, as well as the starting lead compound TMA, but without side effects. MDPI 2022-11-21 /pmc/articles/PMC9699093/ /pubmed/36430961 http://dx.doi.org/10.3390/ijms232214483 Text en © 2022 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 Tupini, Chiara Chilin, Adriana Rossi, Alice De Fino, Ida Bragonzi, Alessandra D’Aversa, Elisabetta Cosenza, Lucia Carmela Vaccarin, Christian Sacchetti, Gianni Borgatti, Monica Tamanini, Anna Dechecchi, Maria Cristina Sanvito, Francesca Gambari, Roberto Cabrini, Giulio Lampronti, Ilaria New TMA (4,6,4′-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease |
title | New TMA (4,6,4′-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease |
title_full | New TMA (4,6,4′-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease |
title_fullStr | New TMA (4,6,4′-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease |
title_full_unstemmed | New TMA (4,6,4′-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease |
title_short | New TMA (4,6,4′-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease |
title_sort | new tma (4,6,4′-trimethyl angelicin) analogues as anti-inflammatory agents in the treatment of cystic fibrosis lung disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699093/ https://www.ncbi.nlm.nih.gov/pubmed/36430961 http://dx.doi.org/10.3390/ijms232214483 |
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