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Since the NF-\u03baB 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-\u03baB pathway represents an interesting therapeutic strategy. Through preliminary EMSA experiments, we identified several new TMA derivatives able to inhibit the NF-\u03baB\/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\u2032-dimethyl-angelicin) and GY964 (4-phenyl-6,4\u2032-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-\u03baB pathway, as well as the starting lead compound TMA, but without side effects.<\/jats:p>","DOI":"10.3390\/ijms232214483","type":"journal-article","created":{"date-parts":[[2022,11,22]],"date-time":"2022-11-22T02:59:22Z","timestamp":1669085962000},"page":"14483","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["New TMA (4,6,4\u2032-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease"],"prefix":"10.3390","volume":"23","author":[{"given":"Chiara","family":"Tupini","sequence":"first","affiliation":[{"name":"Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 74, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2038-1299","authenticated-orcid":false,"given":"Adriana","family":"Chilin","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy"},{"name":"Center of Innovative Therapies for Cystic Fibrosis (InnThera4CF), University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Rossi","sequence":"additional","affiliation":[{"name":"Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"De Fino","sequence":"additional","affiliation":[{"name":"Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Bragonzi","sequence":"additional","affiliation":[{"name":"Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"D\u2019Aversa","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 74, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia Carmela","family":"Cosenza","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 74, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Vaccarin","sequence":"additional","affiliation":[{"name":"Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherzer Institute, 5232 Villigen, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6833-1477","authenticated-orcid":false,"given":"Gianni","family":"Sacchetti","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 74, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8470-2496","authenticated-orcid":false,"given":"Monica","family":"Borgatti","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 74, 44121 Ferrara, Italy"},{"name":"Center of Innovative Therapies for Cystic Fibrosis (InnThera4CF), University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Tamanini","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement, Section of Clinical Biochemistry, University of Verona, Piazzale Stefani 1, 37126 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7357-2104","authenticated-orcid":false,"given":"Maria Cristina","family":"Dechecchi","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Biomedicine and Movement, Section of Clinical Biochemistry, University of Verona, Piazzale Stefani 1, 37126 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4046-8420","authenticated-orcid":false,"given":"Francesca","family":"Sanvito","sequence":"additional","affiliation":[{"name":"Pathology Unit, Division of Experimental 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1972-7766","authenticated-orcid":false,"given":"Ilaria","family":"Lampronti","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Biotechnology, University of Ferrara, Via Fossato di Mortara 74, 44121 Ferrara, Italy"},{"name":"Center of Innovative Therapies for Cystic Fibrosis (InnThera4CF), University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1126\/science.2475911","article-title":"Identification of the Cystic Fibrosis Gene: Cloning and Characterization of Complementary 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