Epoxymicheliolide prevents dextran sulfate sodium-induced colitis in mice by inhibiting TAK1-NF-κB pathway and activating Keap1-NRF2 signaling in macrophages.
Int Immunopharmacol
; 113(Pt A): 109404, 2022 Dec.
Article
in En
| MEDLINE
| ID: mdl-36461599
ABSTRACT
Ulcerative colitis (UC) is an unspecific colorectal inflammation associated with macrophages overactivation. Therefore, macrophage-targeted treatment has been considered a promising strategy for UC therapy. Epoxymicheliolide (EMCL) is a compound from Aucklandia lappa Decne, a TCM for treating gastrointestinal inflammatory diseases. The purpose of this study is to investigate the therapeutic effect of EMCL on DSS-induced mice colitis through the anti-inflammatory activity on macrophages and its underlying mechanisms. We found that EMCL inhibited the release of NO and PGE2 by down-regulating the expression of iNOS and COX2, while suppressed the expression of IL-1ß, IL-6, and TNF-α in LPS-stimulated RAW264.7 macrophages. EMCL also inhibited NO production in LPS-activated peritoneal macrophages and TNFα-stimulated RAW264.7 cells. Moreover, EMCL blocked the phosphorylation of TAK1, IKKα/ß, and IκBα, as well as IκBα degradation, thereby inhibiting the NF-κB pro-inflammatory signaling. Furthermore, EMCL decreased the intracellular ROS, by activating the NRF2 antioxidant pathway. CETSA and molecular docking showed that EMCL might form a covalent bond with Cys174 of TAK1 or Cya151 of Keap1, which may contribute to EMCL-mediated actions. Additionally, a thiol donor ß-mercaptoethanol obviously abolished EMCL-mediated actions in vitro, suggesting the crucial role of the α, γ-unsaturated lactone of EMCL on its anti-inflammatory effects. Furthermore, EMCL not only ameliorated symptoms of colitis and colon barrier injury, but also decreased the levels of pro-inflammatory cytokines, MPO, NO, and MDA in DSS-challenged mice. Thus, our study demonstrated that EMCL ameliorated UC by targeting NF-κB and Nrf2 pathways, indicating it may server as a promising drug candidate for UC therapy.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colitis, Ulcerative
/
Colitis
Limits:
Animals
Language:
En
Journal:
Int Immunopharmacol
Journal subject:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Year:
2022
Document type:
Article
Affiliation country:
China