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...
Published in: | PLOS Neglected Tropical Diseases |
---|---|
Main Authors: | , , , , , , |
Format: | Article in Journal/Newspaper |
Language: | English |
Published: |
Public Library of Science (PLoS)
2022
|
Subjects: | |
Online Access: | https://doi.org/10.1371/journal.pntd.0010989 https://doaj.org/article/08d43e58f63145449390345730a80040 |
id |
ftdoajarticles:oai:doaj.org/article:08d43e58f63145449390345730a80040 |
---|---|
record_format |
openpolar |
spelling |
ftdoajarticles:oai:doaj.org/article:08d43e58f63145449390345730a80040 2023-05-15T15:13:13+02:00 Natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera. Rattikarn Noitem Pawin Pongkorpsakol Chartchai Changsen Yaowapa Sukpondma Chittreeya Tansakul Vatcharin Rukachaisirikul Chatchai Muanprasat 2022-12-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0010989 https://doaj.org/article/08d43e58f63145449390345730a80040 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0010989 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010989 https://doaj.org/article/08d43e58f63145449390345730a80040 PLoS Neglected Tropical Diseases, Vol 16, Iss 12, p e0010989 (2022) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2022 ftdoajarticles https://doi.org/10.1371/journal.pntd.0010989 2022-12-30T19:26:58Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 16 12 e0010989 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 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. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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. |
format |
Article in Journal/Newspaper |
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 |
title |
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_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_sort |
natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2022 |
url |
https://doi.org/10.1371/journal.pntd.0010989 https://doaj.org/article/08d43e58f63145449390345730a80040 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 16, Iss 12, p e0010989 (2022) |
op_relation |
https://doi.org/10.1371/journal.pntd.0010989 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0010989 https://doaj.org/article/08d43e58f63145449390345730a80040 |
op_doi |
https://doi.org/10.1371/journal.pntd.0010989 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
16 |
container_issue |
12 |
container_start_page |
e0010989 |
_version_ |
1766343808896729088 |