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Pharmacol."],"abstract":"<jats:p>Kaempferol is a flavonol identified as the most potent activator of chloride (Cl<jats:sup>\u2212<\/jats:sup>) secretion among other flavonoids in airway epithelial cells. This study aimed to investigate the cellular mechanisms by which kaempferol stimulates Cl<jats:sup>\u2212<\/jats:sup> secretion in the T84 human colon carcinoma cell line by Ussing chambers and voltage clamp technique. Bilateral addition of kaempferol (1\u2013100\u00a0\u00b5M) increased short-circuit current (<jats:italic>I<\/jats:italic><jats:sub><jats:italic>sc<\/jats:italic><\/jats:sub>) in a concentration-dependent manner. Ion substitution of Cl<jats:sup>\u2212<\/jats:sup> or CFTR inhibitors NPPB and glibenclamide or a Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\/2Cl<jats:sup>\u2212<\/jats:sup> cotransporter inhibitor bumetanide attenuated kaempferol-induced <jats:italic>I<\/jats:italic><jats:sub><jats:italic>sc<\/jats:italic><\/jats:sub> response. In permeabilized monolayers, selective channel inhibitors CFTRinh-172 and CaCCinh-A01 inhibited kaempferol-induced apical Cl<jats:sup>\u2212<\/jats:sup> current (<jats:italic>I<\/jats:italic><jats:sub><jats:italic>Cl<\/jats:italic><\/jats:sub>), and K<jats:sup>+<\/jats:sup> blockers BaCl<jats:sub>2<\/jats:sub> and clotrimazole inhibited basolateral K<jats:sup>+<\/jats:sup> current (<jats:italic>I<\/jats:italic><jats:sub><jats:italic>Kb<\/jats:italic><\/jats:sub>). The kaempferol-induced <jats:italic>I<\/jats:italic><jats:sub><jats:italic>Cl<\/jats:italic><\/jats:sub> showed no additive effects with forskolin or 8cpt-cAMP. The kaempferol-induced <jats:italic>I<\/jats:italic><jats:sub><jats:italic>Cl<\/jats:italic><\/jats:sub> was mostly abolished by protein kinase A inhibitor H89, but not by tyrosine kinase inhibitors, AG490 and tyrphostin A23, or tyrosine phosphatase inhibitor vanadate. Treatment with kaempferol for 24\u00a0h increased the expression of CFTR protein as determined by the Western blot analysis. These results demonstrated that kaempferol activates Cl<jats:sup>\u2212<\/jats:sup> secretion across T84 cells by activating the apical Cl<jats:sup>\u2212<\/jats:sup> current and basolateral K<jats:sup>+<\/jats:sup> current. The mechanisms may involve the cAMP\/PKA pathway and CFTR expression. Taken together, these findings reveal the beneficial effects of kaempferol to increase fluid secretion which can be used to treat constipation.<\/jats:p>","DOI":"10.3389\/fphar.2024.1401273","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T08:28:59Z","timestamp":1726043339000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Kaempferol activates chloride secretion via the cAMP\/PKA signaling pathway and expression of CFTR in T84 cells"],"prefix":"10.3389","volume":"15","author":[{"given":"Janjira","family":"Thaweewattanodom","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chatsri","family":"Deachapunya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sutthasinee","family":"Poonyachoti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4073","DOI":"10.3390\/molecules25184073","article-title":"Kaempferol as a dietary anti-inflammatory agent: current therapeutic standing","volume":"25","author":"Alam","year":"2020","journal-title":"Molecules"},{"key":"B2","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1038\/s41467-019-08831-9","article-title":"An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics","volume":"10","author":"Angelidis","year":"2019","journal-title":"Nat. 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