Activation of AMP-Activated Protein Kinase by a Plant-Derived Dihydroisosteviol in Human Intestinal Epithelial Cell
Our previous study has shown that dihydroisosteviol (DHIS), a derivative of stevioside isolated from Stevia rebaudiana (Bertoni), inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated transepithelial chloride secretion across monolayers of human intestinal epithelial (T84) cel...
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| Veröffentlicht in: | Biological & pharmaceutical bulletin 2013/04/01, Vol.36(4), pp.522-528 |
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| creator | Muanprasat, Chatchai Sirianant, Lalida Sawasvirojwong, Sutthipong Homvisasevongsa, Sureeporn Suksamrarn, Apichart Chatsudthipong, Varanuj |
| description | Our previous study has shown that dihydroisosteviol (DHIS), a derivative of stevioside isolated from Stevia rebaudiana (Bertoni), inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated transepithelial chloride secretion across monolayers of human intestinal epithelial (T84) cells and prevents cholera toxin-induced intestinal fluid secretion in mouse closed loop models. In this study, we aimed to investigate a mechanism by which DHIS inhibits CFTR activity. Apical chloride current measurements in Fisher rat thyroid cells stably transfected with wild-type human CFTR (FRT-CFTR cells) and T84 cells were used to investigate mechanism of CFTR inhibition by DHIS. In addition, effect of DHIS on AMP-activated protein kinase (AMPK) activation was investigated using Western blot analysis. Surprisingly, it was found that DHIS failed to inhibit CFTR-mediated apical chloride current in FRT-CFTR cells. In contrast, DHIS effectively inhibited CFTR-mediated apical chloride current induced by a cell permeable cAMP analog CPT-cAMP and a direct CFTR activator genistein in T84 cell monolayers. Interestingly, this inhibitory effect of DHIS on CFTR was significantly (p |
| doi_str_mv | 10.1248/bpb.b12-00711 |
| format | Article |
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In this study, we aimed to investigate a mechanism by which DHIS inhibits CFTR activity. Apical chloride current measurements in Fisher rat thyroid cells stably transfected with wild-type human CFTR (FRT-CFTR cells) and T84 cells were used to investigate mechanism of CFTR inhibition by DHIS. In addition, effect of DHIS on AMP-activated protein kinase (AMPK) activation was investigated using Western blot analysis. Surprisingly, it was found that DHIS failed to inhibit CFTR-mediated apical chloride current in FRT-CFTR cells. In contrast, DHIS effectively inhibited CFTR-mediated apical chloride current induced by a cell permeable cAMP analog CPT-cAMP and a direct CFTR activator genistein in T84 cell monolayers. Interestingly, this inhibitory effect of DHIS on CFTR was significantly (p<0.05) reduced by pretreatment with compound C, an AMPK inhibitor. AICAR, a known AMPK activator, was able to inhibit CFTR activity in both FRT-CFTR and T84 cells. Western blot analysis showed that DHIS induced AMPK activation in T84 cells, but not in FRT-CFTR cells. Our results indicate that DHIS inhibits CFTR-mediated chloride secretion in T84 cells, in part, by activation of AMPK activity. DHIS therefore represents a novel candidate of AMPK activators.</description><identifier>ISSN: 0918-6158</identifier><identifier>EISSN: 1347-5215</identifier><identifier>DOI: 10.1248/bpb.b12-00711</identifier><identifier>PMID: 23343619</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>AMP-activated protein kinase ; AMP-Activated Protein Kinases - metabolism ; Animals ; Cell Line ; chloride channel ; Chlorides - metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator - antagonists & inhibitors ; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism ; dihydroisosteviol ; Diterpenes, Kaurane - pharmacology ; Enzyme Activators - pharmacology ; Epithelial Cells - drug effects ; Epithelial Cells - metabolism ; Humans ; Intestinal Mucosa - cytology ; Rats ; Stevia ; stevioside ; T84 cell</subject><ispartof>Biological and Pharmaceutical Bulletin, 2013/04/01, Vol.36(4), pp.522-528</ispartof><rights>2013 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c702t-9141382fcefd8c0dd3a923ec9a13cfa3b2a06e96a68d4658a6e0f20215d768983</citedby><cites>FETCH-LOGICAL-c702t-9141382fcefd8c0dd3a923ec9a13cfa3b2a06e96a68d4658a6e0f20215d768983</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1881,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23343619$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Muanprasat, Chatchai</creatorcontrib><creatorcontrib>Sirianant, Lalida</creatorcontrib><creatorcontrib>Sawasvirojwong, Sutthipong</creatorcontrib><creatorcontrib>Homvisasevongsa, Sureeporn</creatorcontrib><creatorcontrib>Suksamrarn, Apichart</creatorcontrib><creatorcontrib>Chatsudthipong, Varanuj</creatorcontrib><creatorcontrib>Ramkhamhaeng University</creatorcontrib><creatorcontrib>Faculty of Science and Technology</creatorcontrib><creatorcontrib>Division of Physical Science</creatorcontrib><creatorcontrib>Department of Chemistry and Center of Excellence for Innovation in Chemistry</creatorcontrib><creatorcontrib>Huachiew Chalermprakiet University</creatorcontrib><creatorcontrib>Graduate Program in Toxicology</creatorcontrib><creatorcontrib>Department of Physiology</creatorcontrib><creatorcontrib>Research Center of Transport Protein for Medical Innovation</creatorcontrib><creatorcontrib>Faculty of Science</creatorcontrib><creatorcontrib>Mahidol University</creatorcontrib><title>Activation of AMP-Activated Protein Kinase by a Plant-Derived Dihydroisosteviol in Human Intestinal Epithelial Cell</title><title>Biological & pharmaceutical bulletin</title><addtitle>Biol Pharm Bull</addtitle><description>Our previous study has shown that dihydroisosteviol (DHIS), a derivative of stevioside isolated from Stevia rebaudiana (Bertoni), inhibits cystic fibrosis transmembrane conductance regulator (CFTR)-mediated transepithelial chloride secretion across monolayers of human intestinal epithelial (T84) cells and prevents cholera toxin-induced intestinal fluid secretion in mouse closed loop models. In this study, we aimed to investigate a mechanism by which DHIS inhibits CFTR activity. Apical chloride current measurements in Fisher rat thyroid cells stably transfected with wild-type human CFTR (FRT-CFTR cells) and T84 cells were used to investigate mechanism of CFTR inhibition by DHIS. In addition, effect of DHIS on AMP-activated protein kinase (AMPK) activation was investigated using Western blot analysis. Surprisingly, it was found that DHIS failed to inhibit CFTR-mediated apical chloride current in FRT-CFTR cells. In contrast, DHIS effectively inhibited CFTR-mediated apical chloride current induced by a cell permeable cAMP analog CPT-cAMP and a direct CFTR activator genistein in T84 cell monolayers. Interestingly, this inhibitory effect of DHIS on CFTR was significantly (p<0.05) reduced by pretreatment with compound C, an AMPK inhibitor. AICAR, a known AMPK activator, was able to inhibit CFTR activity in both FRT-CFTR and T84 cells. Western blot analysis showed that DHIS induced AMPK activation in T84 cells, but not in FRT-CFTR cells. Our results indicate that DHIS inhibits CFTR-mediated chloride secretion in T84 cells, in part, by activation of AMPK activity. DHIS therefore represents a novel candidate of AMPK activators.</description><subject>AMP-activated protein kinase</subject><subject>AMP-Activated Protein Kinases - metabolism</subject><subject>Animals</subject><subject>Cell Line</subject><subject>chloride channel</subject><subject>Chlorides - metabolism</subject><subject>Cystic Fibrosis Transmembrane Conductance Regulator - antagonists & inhibitors</subject><subject>Cystic Fibrosis Transmembrane Conductance Regulator - metabolism</subject><subject>dihydroisosteviol</subject><subject>Diterpenes, Kaurane - pharmacology</subject><subject>Enzyme Activators - pharmacology</subject><subject>Epithelial Cells - drug effects</subject><subject>Epithelial Cells - metabolism</subject><subject>Humans</subject><subject>Intestinal Mucosa - cytology</subject><subject>Rats</subject><subject>Stevia</subject><subject>stevioside</subject><subject>T84 cell</subject><issn>0918-6158</issn><issn>1347-5215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU1vEzEQhi0EoqFw5IosceGyxR-7XvsYpaWtKCIHOFter5c4cuxgO5Hy75k0IUgcPGN5Hs-8M4PQe0puKGvl52E73AyUNYT0lL5AM8rbvukY7V6iGVFUNoJ28gq9KWVNgCGMv0ZXjPOWC6pmqMxt9XtTfYo4TXj-bdmcX9yIlzlV5yP-6qMpDg8HbPAymFibW5f9HohbvzqMOfmSSnV7nwIG_GG3MRE_xupKhZ8B3219Xbng4bpwIbxFryYTint39tfo55e7H4uH5un7_eNi_tRYkFkbRVvKJZusm0ZpyThyoxh3VhnK7WT4wAwRTgkj5NiKThrhyMQItD72QirJr9GnU95tTr93IEZvfLEgwESXdkVTzjjrJRcE0I__oeu0y6AdqLaXRAqlWqCaE2VzKiW7SW-z35h80JTo4zY0bEPDNvTzNoD_cM66GzZuvNB_xw_A_QmAqLcmpBh8dP9q29IPMNSkGaEckoLUFhycjrGjkVQpSeWx18Up07pU88tdSplcvQ3uWRgXuj2ai8BL1K5M1i7yP6jts38</recordid><startdate>20130401</startdate><enddate>20130401</enddate><creator>Muanprasat, Chatchai</creator><creator>Sirianant, Lalida</creator><creator>Sawasvirojwong, Sutthipong</creator><creator>Homvisasevongsa, Sureeporn</creator><creator>Suksamrarn, Apichart</creator><creator>Chatsudthipong, Varanuj</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20130401</creationdate><title>Activation of AMP-Activated Protein Kinase by a Plant-Derived Dihydroisosteviol in Human Intestinal Epithelial Cell</title><author>Muanprasat, Chatchai ; 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In this study, we aimed to investigate a mechanism by which DHIS inhibits CFTR activity. Apical chloride current measurements in Fisher rat thyroid cells stably transfected with wild-type human CFTR (FRT-CFTR cells) and T84 cells were used to investigate mechanism of CFTR inhibition by DHIS. In addition, effect of DHIS on AMP-activated protein kinase (AMPK) activation was investigated using Western blot analysis. Surprisingly, it was found that DHIS failed to inhibit CFTR-mediated apical chloride current in FRT-CFTR cells. In contrast, DHIS effectively inhibited CFTR-mediated apical chloride current induced by a cell permeable cAMP analog CPT-cAMP and a direct CFTR activator genistein in T84 cell monolayers. Interestingly, this inhibitory effect of DHIS on CFTR was significantly (p<0.05) reduced by pretreatment with compound C, an AMPK inhibitor. AICAR, a known AMPK activator, was able to inhibit CFTR activity in both FRT-CFTR and T84 cells. Western blot analysis showed that DHIS induced AMPK activation in T84 cells, but not in FRT-CFTR cells. Our results indicate that DHIS inhibits CFTR-mediated chloride secretion in T84 cells, in part, by activation of AMPK activity. DHIS therefore represents a novel candidate of AMPK activators.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>23343619</pmid><doi>10.1248/bpb.b12-00711</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | AMP-activated protein kinase AMP-Activated Protein Kinases - metabolism Animals Cell Line chloride channel Chlorides - metabolism Cystic Fibrosis Transmembrane Conductance Regulator - antagonists & inhibitors Cystic Fibrosis Transmembrane Conductance Regulator - metabolism dihydroisosteviol Diterpenes, Kaurane - pharmacology Enzyme Activators - pharmacology Epithelial Cells - drug effects Epithelial Cells - metabolism Humans Intestinal Mucosa - cytology Rats Stevia stevioside T84 cell |
| title | Activation of AMP-Activated Protein Kinase by a Plant-Derived Dihydroisosteviol in Human Intestinal Epithelial Cell |
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