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HuR (ELAVL1) is an RNA-binding protein that regulates cytokines and chemokines transcripts containing AU\/U-rich elements (AREs) and mediates the LPS-induced response. Here, we show that small-molecule tanshinone mimics (TMs) inhibiting HuR\u2013RNA interaction counteract LPS stimulus in macrophages. TMs exist in solution in keto-enolic tautomerism, and molecular dynamic calculations showed the ortho-quinone form inhibiting binding of HuR to mRNA targets. TM activity was lost in vitro by blocking the diphenolic reduced form as a diacetate, but resulted in prodrug-like activity in vivo. RNA and ribonucleoprotein immunoprecipitation sequencing revealed that LPS induces a strong coupling between differentially expressed genes and HuR-bound genes, and TMs reduced such interactions. TMs decreased the association of HuR with genes involved in chemotaxis and immune response, including Cxcl10, Il1b and Cd40, reducing their expression and protein secretion in primary murine bone marrow-derived macrophages and in an LPS-induced peritonitis model. Overall, TMs show anti-inflammatory properties in vivo and suggest HuR as a potential therapeutic target for inflammation-related diseases.<\/jats:p>","DOI":"10.1242\/dmm.050120","type":"journal-article","created":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T06:04:46Z","timestamp":1678687486000},"source":"Crossref","is-referenced-by-count":12,"title":["HuR modulation counteracts lipopolysaccharide response in murine macrophages"],"prefix":"10.1242","volume":"16","author":[{"given":"Isabelle","family":"Bonomo","sequence":"first","affiliation":[{"name":"University of Trento 1 Department of Cellular, Computational and Integrative Biology (CIBIO) , , Via Sommarive 9, 38123 Trento , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Assoni","sequence":"additional","affiliation":[{"name":"University of Trento 1 Department of Cellular, Computational and Integrative Biology (CIBIO) , , Via Sommarive 9, 38123 Trento , Italy"},{"name":"University of Milan \u2013 Statale 2 Department of Chemistry , , Via Golgi 19, 20133 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"La Pietra","sequence":"additional","affiliation":[{"name":"University of Napoli Federico II 3 Department of Pharmacy , , Via D. Montesano 49, 80131 Napoli , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Canarutto","sequence":"additional","affiliation":[{"name":"International Centre for Genetic Engineering and Biotechnology (ICGEB) 4 , Via Padriciano 99, 34149 Trieste , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Facen","sequence":"additional","affiliation":[{"name":"University of Trento 1 Department of Cellular, Computational and Integrative Biology (CIBIO) , , Via Sommarive 9, 38123 Trento , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greta","family":"Donati","sequence":"additional","affiliation":[{"name":"University of Napoli Federico II 3 Department of Pharmacy , , Via D. Montesano 49, 80131 Napoli , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Zucal","sequence":"additional","affiliation":[{"name":"University of Trento 1 Department of Cellular, Computational and Integrative Biology (CIBIO) , , Via Sommarive 9, 38123 Trento , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Genovese","sequence":"additional","affiliation":[{"name":"University of Milan \u2013 Statale 2 Department of Chemistry , , Via Golgi 19, 20133 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariachiara","family":"Micaelli","sequence":"additional","affiliation":[{"name":"University of Trento 1 Department of Cellular, Computational and Integrative Biology (CIBIO) , , Via Sommarive 9, 38123 Trento , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"P\u00e9rez-R\u00e0fols","sequence":"additional","affiliation":[{"name":"University of Florence 5 Department of Chemistry \u2018Ugo Schiff\u2019 , , Sesto Fiorentino 50019 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Robbiati","sequence":"additional","affiliation":[{"name":"University of Trento 1 Department of Cellular, Computational and Integrative Biology (CIBIO) , , Via Sommarive 9, 38123 Trento , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitris L.","family":"Kontoyannis","sequence":"additional","affiliation":[{"name":"Giotto Biotech, S.R.L 6 , Sesto Fiorentino, Florence 50019 , Italy"},{"name":"Biomedical Sciences Research Centre \u2018Alexander Fleming\u2019, Institute of Fundamental Biomedical Research 7 , Vari 16672 , Greece"},{"name":"School of Biology, Aristotle University of Thessaloniki 8 Division of Genetics, Development and Molecular Biology , , 54124 Thessaloniki , Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilenia","family":"De Matteo","sequence":"additional","affiliation":[{"name":"IRBM Promidis S.r.l. 9 , Pomezia, Rome 00071 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Fragai","sequence":"additional","affiliation":[{"name":"Centre for Magnetic Resonance (CERM) 10 , , via Sacconi 6, 50019 Sesto Fiorentino, Florence , Italy"},{"name":"University of Florence 10 , , via Sacconi 6, 50019 Sesto Fiorentino, Florence , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierfausto","family":"Seneci","sequence":"additional","affiliation":[{"name":"University of Milan \u2013 Statale 2 Department of Chemistry , , Via Golgi 19, 20133 Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Marinelli","sequence":"additional","affiliation":[{"name":"University of Napoli Federico II 3 Department of Pharmacy , , Via D. 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