{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T18:01:13Z","timestamp":1767895273935,"version":"3.49.0"},"update-to":[{"DOI":"10.1371\/journal.pntd.0010989","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T00:00:00Z","timestamp":1671580800000}}],"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T00:00:00Z","timestamp":1670544000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Crown Property Bureau and the National Science and Technology Development Agency"},{"DOI":"10.13039\/501100004156","name":"Mahidol University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004156","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Program Management Unit for Human Resources & Institutional Development, Research and Innovation","award":["B05F640169"],"award-info":[{"award-number":["B05F640169"]}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>As a leading cause of death in children under 5 years old, secretory diarrheas including cholera are characterized by excessive intestinal fluid secretion driven by enterotoxin-induced cAMP-dependent intestinal chloride transport. This study aimed to identify fungal bioactive metabolites possessing anti-secretory effects against cAMP-dependent chloride secretion in intestinal epithelial cells. Using electrophysiological analyses in human intestinal epithelial (T84) cells, five fungus-derived statin derivatives including \u03b1,\u03b2-dehydrolovastatin (DHLV), \u03b1,\u03b2-dehydrodihydromonacolin K, lovastatin, mevastatin and simvastatin were found to inhibit the cAMP-dependent chloride secretion with IC<jats:sub>50<\/jats:sub> values of 1.8, 8.9, 11.9, 11.4 and 5 \u03bcM, respectively. Being the most potent statin derivatives, DHLV was evaluated for its pharmacological properties including cellular toxicity, mechanism of action, target specificity and <jats:italic>in vivo<\/jats:italic> efficacy. DHLV at concentrations up to 20 \u03bcM did not affect cell viability and barrier integrity of T84 cells. Electrophysiological analyses indicated that DHLV inhibited cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent apical chloride channel, via mechanisms not involving alteration of intracellular cAMP levels or its negative regulators including AMP-activated protein kinases and protein phosphatases. DHLV had no effect on Na<jats:sup>+<\/jats:sup>-K<jats:sup>+<\/jats:sup> ATPase activities but inhibited Ca<jats:sup>2+<\/jats:sup>-dependent chloride secretion without affecting intracellular Ca<jats:sup>2+<\/jats:sup> levels. Importantly, intraperitoneal (2 mg\/kg) and intraluminal (20 \u03bcM) injections of DHLV reduced cholera toxin-induced intestinal fluid secretion in mice by 59% and 65%, respectively without affecting baseline intestinal fluid transport. This study identifies natural statin derivatives as novel natural product-derived CFTR inhibitors, which may be beneficial in the treatment of enterotoxin-induced secretory diarrheas including cholera.<\/jats:p>","DOI":"10.1371\/journal.pntd.0010989","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T18:35:58Z","timestamp":1670610958000},"page":"e0010989","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera"],"prefix":"10.1371","volume":"16","author":[{"given":"Rattikarn","family":"Noitem","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pawin","family":"Pongkorpsakol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chartchai","family":"Changsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaowapa","family":"Sukpondma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chittreeya","family":"Tansakul","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vatcharin","family":"Rukachaisirikul","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chatchai","family":"Muanprasat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"key":"pntd.0010989.ref001","author":"B Dadonaite","year":"2018","journal-title":"Diarrheal diseases: Our World in Data"},{"issue":"7","key":"pntd.0010989.ref002","doi-asserted-by":"crossref","first-page":"781","DOI":"10.4155\/fmc.13.42","article-title":"Cholera: pathophysiology and emerging therapeutic targets.","volume":"5","author":"C Muanprasat","year":"2013","journal-title":"Future Med Chem"},{"key":"pntd.0010989.ref003","first-page":"1","volume-title":"The treatment of diarrhoea: a mannual for physicians and other senior health workers","author":"World Health Organization","year":"2005"},{"issue":"1","key":"pntd.0010989.ref004","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.jcmgh.2018.02.009","article-title":"The Role of Ion Transporters in the Pathophysiology of Infectious Diarrhea","volume":"6","author":"S Das","year":"2018","journal-title":"Cell Mol Gastroenterol Hepatol"},{"issue":"8","key":"pntd.0010989.ref005","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/nrgastro.2015.111","article-title":"Secretory diarrhoea: mechanisms and emerging therapies.","volume":"12","author":"JR Thiagarajah","year":"2015","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"7","key":"pntd.0010989.ref006","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1172\/JCI200318326","article-title":"Intestinal ion transport and the pathophysiology of diarrhea","volume":"111","author":"M. 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