Natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera.
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-12-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | https://doi.org/10.1371/journal.pntd.0010989 |
| _version_ | 1828085974646652928 |
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| author | Rattikarn Noitem Pawin Pongkorpsakol Chartchai Changsen Yaowapa Sukpondma Chittreeya Tansakul Vatcharin Rukachaisirikul Chatchai Muanprasat |
| author_facet | Rattikarn Noitem Pawin Pongkorpsakol Chartchai Changsen Yaowapa Sukpondma Chittreeya Tansakul Vatcharin Rukachaisirikul Chatchai Muanprasat |
| author_sort | Rattikarn Noitem |
| collection | DOAJ |
| description | 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 α,β-dehydrolovastatin (DHLV), α,β-dehydrodihydromonacolin K, lovastatin, mevastatin and simvastatin were found to inhibit the cAMP-dependent chloride secretion with IC50 values of 1.8, 8.9, 11.9, 11.4 and 5 μM, respectively. Being the most potent statin derivatives, DHLV was evaluated for its pharmacological properties including cellular toxicity, mechanism of action, target specificity and in vivo efficacy. DHLV at concentrations up to 20 μM 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+-K+ ATPase activities but inhibited Ca2+-dependent chloride secretion without affecting intracellular Ca2+ levels. Importantly, intraperitoneal (2 mg/kg) and intraluminal (20 μM) 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. |
| first_indexed | 2024-04-11T04:48:25Z |
| format | Article |
| id | doaj.art-08d43e58f63145449390345730a80040 |
| institution | Directory Open Access Journal |
| issn | 1935-2727 1935-2735 |
| language | English |
| last_indexed | 2024-04-11T04:48:25Z |
| publishDate | 2022-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj.art-08d43e58f63145449390345730a800402022-12-27T05:32:05ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352022-12-011612e001098910.1371/journal.pntd.0010989Natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera.Rattikarn NoitemPawin PongkorpsakolChartchai ChangsenYaowapa SukpondmaChittreeya TansakulVatcharin RukachaisirikulChatchai MuanprasatAs 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 α,β-dehydrolovastatin (DHLV), α,β-dehydrodihydromonacolin K, lovastatin, mevastatin and simvastatin were found to inhibit the cAMP-dependent chloride secretion with IC50 values of 1.8, 8.9, 11.9, 11.4 and 5 μM, respectively. Being the most potent statin derivatives, DHLV was evaluated for its pharmacological properties including cellular toxicity, mechanism of action, target specificity and in vivo efficacy. DHLV at concentrations up to 20 μM 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+-K+ ATPase activities but inhibited Ca2+-dependent chloride secretion without affecting intracellular Ca2+ levels. Importantly, intraperitoneal (2 mg/kg) and intraluminal (20 μM) 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.https://doi.org/10.1371/journal.pntd.0010989 |
| spellingShingle | Rattikarn Noitem Pawin Pongkorpsakol Chartchai Changsen Yaowapa Sukpondma Chittreeya Tansakul Vatcharin Rukachaisirikul Chatchai Muanprasat Natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera. PLoS Neglected Tropical Diseases |
| title | Natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera. |
| title_full | Natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera. |
| title_fullStr | Natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera. |
| title_full_unstemmed | Natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera. |
| title_short | Natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera. |
| title_sort | natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera |
| url | https://doi.org/10.1371/journal.pntd.0010989 |
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