Honokiol targeting ankyrin repeat domain of TRPV4 ameliorates endothelial permeability in mice inflammatory bowel disease induced by DSS.
J Ethnopharmacol
; 325: 117825, 2024 May 10.
Article
en En
| MEDLINE
| ID: mdl-38296175
ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE As a classic traditional Chinese medicine, Magnolia officinalis (M. officinalis) is widely used in digestive diseases. It has rich gastrointestinal activity including inflammatory bowel disease (IBD) treatment, but the mechanism is not clear. AIM OF THE STUDY In recent years, there has been a growing interest in investigating the regulatory effects of herbal compounds on transient receptor potential (TRP) channel proteins. Transient receptor potential vanilloid 4 (TRPV4), a subtype involved in endothelial permeability regulation, was discussed as the target of M. officinalis in the treatment of IBD in the study. Based on the targeting effect of TRPV4, this study investigated the active ingredients and mechanism of M. officinalis extract in treating IBD. MATERIALS AND METHODS:
To reveal the connection between the active ingredients in M. officinalis and TRPV4, a bioactivity-guided high performance liquid chromatography system coupled with mass spectrometry identification was utilized to screen for TRPV4 antagonists. TRPV4 siRNA knockdown experiment was employed to validate the significance of TRPV4 as a crucial target in regulating endothelial permeability by honokiol (HON). The interaction of the active ingredient representing HON with TRPV4 was confirmed by molecular docking, fluorescence-based thermal shift and live cell calcium imaging experiments. The potential binding sites and inhibitory mechanisms of HON in TRPV4 were analyzed by molecular dynamics simulation and microscale thermophoresis. The therapeutic effect of HON based on TRPV4 was discussed in DSS-IBD mice.RESULTS:
Our finding elucidated that the inhibitory activity of M. officinalis against TRPV4 is primarily attributed to HON analogues. The knockdown of TRPV4 expression significantly impaired the calcium regulation and permeability protection in endothelial cells. The mechanism study revealed that HON specifically targets the Q239 residue located in the ankyrin repeat domain of TRPV4, and competitively inhibits channel opening with adenosine triphosphate (ATP) binding. The immunofluorescence assay demonstrated that the administration of HON enhances the expression and location of VE-Cadherin to protect the endothelial barrier and attenuates immune cell infiltration.CONCLUSIONS:
The finding suggested that HON alleviates IBD by improving endothelial permeability through TRPV4. The discovery provides valuable insights into the potential therapeutic strategy of active natural products for alleviating IBD.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fenoles
/
Compuestos de Bifenilo
/
Enfermedades Inflamatorias del Intestino
/
Repetición de Anquirina
/
Compuestos Alílicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Ethnopharmacol
Año:
2024
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Irlanda