The natural statin α,β-dehydromonacolin K exerts anti-secretory effect in human intestinal epithelial cells via a nonsense-mediated mRNA decay-dependent mechanism
Context cAMP-induced intestinal chloride secretion plays a pivotal role in the pathogenesis of secretory diarrheas.Objective In this study, we investigated the antisecretory effects of α,β-dehydromonacolin K, a derivative of lovastatin from Aspergillus sclerotiorum, on cAMP-induced chloride secretio...
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Taylor & Francis Group
2025-12-01
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| Series: | Pharmaceutical Biology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/13880209.2025.2544930 |
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| author | Saravut Satitsri Rungtiwa Khumjiang Chittreeya Tansakul Wararat Chiangjong Nuttapon Apichaiyarat Taya Kitiyakara Yanisa Purintrapibal Vatcharin Rukachaisirikul Chatchai Muanprasat |
| author_facet | Saravut Satitsri Rungtiwa Khumjiang Chittreeya Tansakul Wararat Chiangjong Nuttapon Apichaiyarat Taya Kitiyakara Yanisa Purintrapibal Vatcharin Rukachaisirikul Chatchai Muanprasat |
| author_sort | Saravut Satitsri |
| collection | DOAJ |
| description | Context cAMP-induced intestinal chloride secretion plays a pivotal role in the pathogenesis of secretory diarrheas.Objective In this study, we investigated the antisecretory effects of α,β-dehydromonacolin K, a derivative of lovastatin from Aspergillus sclerotiorum, on cAMP-induced chloride secretion in human T84 cells and fluid secretion in human colonoids.Materials and Methods Short-circuit current analyses and swelling assays were used to investigate the effects of α,β-dehydromonacolin K on chloride transport and fluid secretion, respectively. Proteomic analyses were performed to determine the potential anti-diarrheal mechanisms of α,β-dehydromonacolin K.Results In T84 cells, α,β-dehydromonacolin K inhibited cAMP-induced chloride secretion with an IC50 of ∼ 6.32 μM. Apical chloride current analyses demonstrated that α,β-dehydromonacolin K inhibited CFTR chloride channels stimulated by cAMP agonists with an IC50 of ∼ 1 μM. Basolateral potassium current analyses indicated that α,β-dehydromonacolin K had no effect on basolateral potassium channel activities. In a three-dimensional (3D) model of human colonoids, α,β-dehydromonacolin K (20 µM) suppressed both cAMP-induced and calcium-induced fluid secretion by ∼ 70%. Proteomic analyses of human colonoids revealed that α,β-dehydromonacolin K interacted with 33 proteins, including those associated with non-sense-mediated mRNA decay (NMD). Notably, the inhibitory effects of α,β-dehydromonacolin K on cAMP-induced chloride and fluid secretion were significantly diminished in the presence of SMG1i, an inhibitor of serine/threonine-protein kinase SMG1 involved in NMD, suggesting that α,β-dehydromonacolin K inhibits cAMP-induced chloride-driven fluid secretion in human intestinal epithelial cells by mechanisms involving SMG1-dependent NMD pathways.Discussion and conclusions α, β-Dehydromonacolin K represents a promising class of natural compounds that exert antisecretory effects in human intestinal epithelia via a novel mechanism of action involving SMG1 in NMD pathways. |
| format | Article |
| id | doaj-art-8ab88fa7b67846beb1e4b0124feb6d70 |
| institution | Kabale University |
| issn | 1388-0209 1744-5116 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Pharmaceutical Biology |
| spelling | doaj-art-8ab88fa7b67846beb1e4b0124feb6d702025-08-23T05:43:52ZengTaylor & Francis GroupPharmaceutical Biology1388-02091744-51162025-12-0163164566210.1080/13880209.2025.2544930The natural statin α,β-dehydromonacolin K exerts anti-secretory effect in human intestinal epithelial cells via a nonsense-mediated mRNA decay-dependent mechanismSaravut Satitsri0Rungtiwa Khumjiang1Chittreeya Tansakul2Wararat Chiangjong3Nuttapon Apichaiyarat4Taya Kitiyakara5Yanisa Purintrapibal6Vatcharin Rukachaisirikul7Chatchai Muanprasat8Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakarn, ThailandChakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakarn, ThailandDivision of Physical Science and Center of Excellence for Innovation in Chemistry, Faculty of Science, Prince of Songkla University, Songkhla, ThailandPediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, ThailandPediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, ThailandDivision of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, ThailandChakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakarn, ThailandDivision of Physical Science and Center of Excellence for Innovation in Chemistry, Faculty of Science, Prince of Songkla University, Songkhla, ThailandChakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakarn, ThailandContext cAMP-induced intestinal chloride secretion plays a pivotal role in the pathogenesis of secretory diarrheas.Objective In this study, we investigated the antisecretory effects of α,β-dehydromonacolin K, a derivative of lovastatin from Aspergillus sclerotiorum, on cAMP-induced chloride secretion in human T84 cells and fluid secretion in human colonoids.Materials and Methods Short-circuit current analyses and swelling assays were used to investigate the effects of α,β-dehydromonacolin K on chloride transport and fluid secretion, respectively. Proteomic analyses were performed to determine the potential anti-diarrheal mechanisms of α,β-dehydromonacolin K.Results In T84 cells, α,β-dehydromonacolin K inhibited cAMP-induced chloride secretion with an IC50 of ∼ 6.32 μM. Apical chloride current analyses demonstrated that α,β-dehydromonacolin K inhibited CFTR chloride channels stimulated by cAMP agonists with an IC50 of ∼ 1 μM. Basolateral potassium current analyses indicated that α,β-dehydromonacolin K had no effect on basolateral potassium channel activities. In a three-dimensional (3D) model of human colonoids, α,β-dehydromonacolin K (20 µM) suppressed both cAMP-induced and calcium-induced fluid secretion by ∼ 70%. Proteomic analyses of human colonoids revealed that α,β-dehydromonacolin K interacted with 33 proteins, including those associated with non-sense-mediated mRNA decay (NMD). Notably, the inhibitory effects of α,β-dehydromonacolin K on cAMP-induced chloride and fluid secretion were significantly diminished in the presence of SMG1i, an inhibitor of serine/threonine-protein kinase SMG1 involved in NMD, suggesting that α,β-dehydromonacolin K inhibits cAMP-induced chloride-driven fluid secretion in human intestinal epithelial cells by mechanisms involving SMG1-dependent NMD pathways.Discussion and conclusions α, β-Dehydromonacolin K represents a promising class of natural compounds that exert antisecretory effects in human intestinal epithelia via a novel mechanism of action involving SMG1 in NMD pathways.https://www.tandfonline.com/doi/10.1080/13880209.2025.2544930α,β-Dehydromonacolin KdiarrheaCFTRhuman colonoidNMD |
| spellingShingle | Saravut Satitsri Rungtiwa Khumjiang Chittreeya Tansakul Wararat Chiangjong Nuttapon Apichaiyarat Taya Kitiyakara Yanisa Purintrapibal Vatcharin Rukachaisirikul Chatchai Muanprasat The natural statin α,β-dehydromonacolin K exerts anti-secretory effect in human intestinal epithelial cells via a nonsense-mediated mRNA decay-dependent mechanism Pharmaceutical Biology α,β-Dehydromonacolin K diarrhea CFTR human colonoid NMD |
| title | The natural statin α,β-dehydromonacolin K exerts anti-secretory effect in human intestinal epithelial cells via a nonsense-mediated mRNA decay-dependent mechanism |
| title_full | The natural statin α,β-dehydromonacolin K exerts anti-secretory effect in human intestinal epithelial cells via a nonsense-mediated mRNA decay-dependent mechanism |
| title_fullStr | The natural statin α,β-dehydromonacolin K exerts anti-secretory effect in human intestinal epithelial cells via a nonsense-mediated mRNA decay-dependent mechanism |
| title_full_unstemmed | The natural statin α,β-dehydromonacolin K exerts anti-secretory effect in human intestinal epithelial cells via a nonsense-mediated mRNA decay-dependent mechanism |
| title_short | The natural statin α,β-dehydromonacolin K exerts anti-secretory effect in human intestinal epithelial cells via a nonsense-mediated mRNA decay-dependent mechanism |
| title_sort | natural statin α β dehydromonacolin k exerts anti secretory effect in human intestinal epithelial cells via a nonsense mediated mrna decay dependent mechanism |
| topic | α,β-Dehydromonacolin K diarrhea CFTR human colonoid NMD |
| url | https://www.tandfonline.com/doi/10.1080/13880209.2025.2544930 |
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