Natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera
Issued Date
2022-12-10
Resource Type
ISSN
19352727
eISSN
19352735
Scopus ID
2-s2.0-85144593390
Pubmed ID
36490300
Journal Title
PLoS Neglected Tropical Diseases
Volume
16
Issue
12
Rights Holder(s)
SCOPUS
Bibliographic Citation
PLoS Neglected Tropical Diseases Vol.16 No.12 (2022)
Suggested Citation
Noitem R., Pongkorpsakol P., Changsen C., Sukpondma Y., Tansakul C., Rukachaisirikul V., Muanprasat C. Natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera. PLoS Neglected Tropical Diseases Vol.16 No.12 (2022). doi:10.1371/journal.pntd.0010989 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/85172
Title
Natural statin derivatives as potential therapy to reduce intestinal fluid loss in cholera
Other Contributor(s)
Abstract
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.