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Mol. Life Sci."],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background and aims<\/jats:title>\n                <jats:p>Thiopurine-induced acute pancreatitis (TIP) is one of the most common adverse events among inflammatory bowel disease patients treated with azathioprine (AZA), representing a significant clinical burden. Previous studies focused on immune-mediated processes, however, the exact pathomechanism of TIP is essentially unclear.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>To model TIP in vivo, we triggered cerulein-induced experimental pancreatitis in mice receiving a daily oral dose of 1.5\u00a0mg\/kg AZA. Also, freshly isolated mouse pancreatic cells were exposed to AZA ex vivo<jats:italic>,<\/jats:italic> and acinar cell viability, ductal and acinar Ca<jats:sup>2+<\/jats:sup> signaling, ductal Cl<jats:sup>\u2013<\/jats:sup> and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2013<\/jats:sup> secretion, as well as cystic fibrosis transmembrane conductance regulator (CFTR) expression were assessed using microscopy techniques. Ras-related C3 botulinum toxin substrate (RAC1) activity was measured with a G-LISA assay. Super-resolution microscopy was used to determine protein colocalization.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We demonstrated that AZA treatment increases tissue damage in the early phase of cerulein-induced pancreatitis in vivo. Also, both <jats:italic>per os<\/jats:italic> and ex vivo AZA exposure impaired pancreatic fluid and ductal HCO<jats:sub>3<\/jats:sub><jats:sup>\u2013<\/jats:sup> and Cl<jats:sup>\u2013<\/jats:sup> secretion, but did not affect acinar cells. Furthermore, ex vivo AZA exposure also inhibited RAC1 activity in ductal cells leading to decreased co-localization of CFTR and the anchor protein ezrin, resulting in impaired plasma membrane localization of CFTR.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>AZA impaired the ductal HCO<jats:sub>3<\/jats:sub><jats:sup>\u2013<\/jats:sup> and Cl<jats:sup>\u2013<\/jats:sup> secretion through the inhibition of RAC1 activity leading to diminished ezrin-CFTR interaction and disturbed apical plasma membrane expression of CFTR. We report a novel direct toxic effect of AZA on pancreatic ductal cells and suggest that the restoration of ductal function might help to prevent TIP in the future.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00018-022-04662-y","type":"journal-article","created":{"date-parts":[[2023,1,7]],"date-time":"2023-01-07T06:04:01Z","timestamp":1673071441000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Thiopurines impair the apical plasma membrane expression of CFTR in pancreatic ductal cells via RAC1 inhibition"],"prefix":"10.1007","volume":"80","author":[{"given":"B\u00e1lint","family":"T\u00e9l","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"No\u00e9mi","family":"Papp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1rp\u00e1d","family":"Varga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vikt\u00f3ria","family":"Szab\u00f3","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marietta","family":"G\u00f6r\u00f6g","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Sus\u00e1nszki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Crul","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aletta","family":"Kis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingrid H.","family":"Sendstad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00e1ria","family":"Bagy\u00e1nszki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolett","family":"B\u00f3di","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P\u00e9ter","family":"Hegyi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5768-3090","authenticated-orcid":false,"given":"J\u00f3zsef","family":"Mal\u00e9th","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8906-0840","authenticated-orcid":false,"given":"Petra","family":"Pallagi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,1,7]]},"reference":[{"issue":"1","key":"4662_CR1","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1053\/j.gastro.2018.08.063","volume":"156","author":"AF Peery","year":"2019","unstructured":"Peery AF, Crockett SD, Murphy CC, Lund JL, Dellon ES, Williams JL, Jensen ET, Shaheen NJ, Barritt AS, Lieber SR, Kochar B, Barnes EL, Fan YC, Pate V, Galanko J, Baron TH, Sandler RS (2019) Burden and cost of gastrointestinal, liver, and pancreatic diseases in the United States: update 2018. 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