wedelolactone and Colitis

The incidence of inflammatory bowel disease (IBD) has markedly increased. Our research findings during the past showed that medicinal plant extracts and the derived phytochemical components from Wedelia chinensis (WC) can have strong anti-colitis activities. Here, we further identified the key component phytochemicals from active fractions of different WC preparations (WCHA) that are responsible for the protective effect of WCHA in colitis mice. Of the 3 major compounds (wedelolactone, luteolin and apigenin) in this fraction, luteolin had the highest anti-inflammatory effect in vivo. Using a next-generation sequencing (NGS) (e.g., RNA-seq) system to analyze the transcriptome of colorectal cells/tissues in mice with dextran sulfate sodium (DSS)-induced colitis with/without phytochemicals treatment, luteolin was found to strongly suppress the DSS-activated IL-17 pathway in colon tissue. In addition, co-treatment with wedelolactone and luteolin had a synergistic effect on the expression level of some IL-17 pathway-related genes. Interestingly, our NGS analyses also indicated that luteolin and wedelolactone can specifically suppress the expression of NLRP3 and NLRP1. Using a 3-dimensional cell co-culture system, we further demonstrated that luteolin could efficiently suppress NLRP3 expression via disruption of IL-17A signaling in inflamed colon tissue, which also indicates the pharmacological potential of luteolin and wedelolactone in treating IBD.

Topics: 3T3 Cells; Acute Disease; Alternative Splicing; Animals; Colitis; Colon; Coumarins; Dextran Sulfate; Feedback, Physiological; Gene Expression Profiling; Inflammasomes; Interleukin-17; Lipid Metabolism; Luteolin; Male; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Phytochemicals; Plant Extracts; Wedelia

It has been reported that the ethanol extract of Wedelia chinensis attenuates murine colitis. Wedelolactone (WEL), a coumestane-type compound with many pharmacological activities, was isolated from W. chinensis. The present study aims to investigate the beneficial effects and underlying mechanisms of WEL on ulcerative colitis. In a dextran sodium sulfate (DSS)-induced mouse model, oral administration of WEL (50mg/kg) significantly attenuated pathological colonic damage and inhibited inflammatory infiltration, myeloperoxidase and alkaline phosphatase activities through MAPKs and NF-κB signaling pathways, while activating AMPK in colons treated with DSS. Further study revealed that WEL treatment dramatically inhibited NLRP3 inflammasome activation and caspase-1 phosphorylation to decrease IL-1β release in colons treated with DSS. In addition, WEL effectively regulates the disorder of skeleton proteins in colonic epithelial cells NCM460 exposed to TNF-α and protects the intestinal barrier function by activating AMPK in vivo. In summary, the AMPK-NLRP3-IL-1β signaling axis plays an important role in colitis following WEL treatments. These findings provide new insights into the pharmacological actions of WEL as a potential therapeutic agent for colitis.

Topics: Adenylate Kinase; Animals; Cell Line; Colitis; Coumarins; Cytokines; Dextran Sulfate; Down-Regulation; Female; Humans; Inflammasomes; Intestinal Mucosa; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Protective Agents; Signal Transduction