| Hydroxyxanthone as an inhibitor of cAMP-activated apical chloride channel in human intestinal epithelial cell. | |
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MedLine Citation:
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PMID: 22634581 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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AIMS: Previous investigation showed that polyphenols abundantly found in many plants could inhibit Cl(-) secretion. The present study was aimed to investigate the effect of phenol containing xanthone derivatives on cAMP-activated intestinal Cl(-) secretion and evaluate potential benefits of these compounds in the treatment of cholera. MAIN METHODS: Four hydroxy xanthones were synthesized via oxidative coupling reaction of the corresponding ortho-hydroxybenzoic acids and hydroxyphenols. Short-current current and apical Cl(-) current measurements across monolayers of human intestinal epithelial (T84) cell and Fisher rat thyroid cells transfected with human CFTR (FRT-CFTR cell) were performed to determine effect of hydroxy xanthones on cAMP-activated Cl(-) secretion. Intracellular cAMP was measured by immunoassay methods. Anti-diarrheal efficacy was evaluated using closed loop model of cholera. KEY FINDINGS: Among the tested xanthones, 1,3,6-trihydroxyxanthone (THX-001) was found to be the most potent derivative in the inhibition of cAMP-activated Cl(-) secretion across T84 cell monolayers (IC(50) ~100 μM). Electrophysiological analysis of T84 cells and FRT-CFTR cells revealed that THX-001 targeted two distinct cAMP-activated Cl(-) channels in the apical membrane of T84 cells, namely, CFTR and inward rectifying Cl(-) channel (IRC). In contrast, THX-001 had no effect on intracellular cAMP levels in these cells. Importantly, THX-001 completely abolished cholera toxin-induced Cl(-) secretion across T84 cell monolayers and significantly inhibited cholera toxin-induced intestinal fluid secretion in mouse closed loop models. SIGNIFICANCE: This study revealed that hydroxyxanthone represents another chemical class of polyphenolic compounds that may hold a promise as anti-secretory therapy of cholera. |
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Authors:
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Wachiraporn Luerang; Thongchai Khammee; Watinee Kumpum; Sunit Suksamrarn; Varanuj Chatsudthipong; Chatchai Muanprasat |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-5-24 |
Journal Detail:
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Title: Life sciences Volume: - ISSN: 1879-0631 ISO Abbreviation: - Publication Date: 2012 May |
Date Detail:
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Created Date: 2012-5-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0375521 Medline TA: Life Sci Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012. Published by Elsevier Inc. |
Affiliation:
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Research Center of Transport Proteins for Medical Innovation (TMED), Mahidol University, Bangkok, Thailand; Graduate Program in Toxicology, Faculty of Science, Mahidol University, Bangkok, Thailand. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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