Modulation of occludin, NF-κB, p-STAT3, and Th17 response by DJ-X-025 decreases inflammation and ameliorates experimental colitis - 20/03/25
Abstract |
Scope |
Inflammatory bowel disease (IBD) involves a range of immune-mediated disorders marked by systemic and local intestinal inflammation. We synthesized a novel compound DJ-X-025 and uncovered its anti-inflammatory properties using lipopolysaccharide (LPS)-induced RAW 264.7 macrophages in vitro and a dextran sodium sulfate (DSS)-induced model of colitis.
Methods and results |
We evaluated the alteration in cell morphology, cytoskeletal proteins, and inflammatory markers of DJ-X-025 treated LPS-stimulated RAW 264.7 macrophages. We administered DJ-X-025 by oral gavage in DSS-induced colitis, examined colon histology, and alterations of immune cells by flow cytometry, and performed molecular studies using RT-qPCR and western blot analysis. DJ-X-025 treatment markedly altered the morphology of LPS-treated RAW 264.7 macrophages from elongated to round shapes, modulated actin and tubulin, and reduced the level of inflammatory markers like TNF-α, IL-1β, IL-6, and iNOS. Further, we observed that DJ-X-025 steered to improve colon length, muscularis mucosa thickness, and colon inflammatory score compared to the DSS group alone. DJ-X-025 effectively inverted the increased population of activated T cells, Th17, and macrophages in lamina propria by DSS treatment, leading to a substantial reduction in the inflammatory response in the colon. Strikingly, DJ-X-025 treatment enhanced the expression of occludin and diminished the expression of NF-κB and phosphorylation of STAT3 in the colon of DSS-treated mice compared to DSS-alone. Additionally, DJ-X-025 induced the expression of Foxp3 in the colon and, reduced systemic inflammatory cytokine/chemokine levels further supporting its immunomodulatory effects. These results suggest that DJ-X-025 is linked to the induction of occludin expression and decreased expression of p-STAT3/NF-κB and Th17 response in the colon, which together suppresses systemic and colon inflammatory cytokines for effective amelioration of experimental colitis.
Conclusion |
These findings suggest that DJ-X-025 might be a promising therapeutic agent for the treatment of IBD.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Graphical abstract
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Highlights |
• | DJ-X-025 alters cell morphology, and cytoskeletal protein and attenuates inflammatory response of LPS-stimulated macrophages. |
• | DJ-X-025 ameliorates colitis via inhibiting pSTAT3/NF-κB signaling pathways and induces occludin expression in the colon. |
• | DJ-X-025 differentially modulates Th17/regulatory T cell response in the colon. |
• | DJ-X-025 might be developed as an alternative potential drug for IBD and other autoimmune diseases. |
Abbreviations : ADME, ANOVA, BBB, CD, CXCR3, DAPI, DCs, DMEM, DMSO, DSS, FBS, GI, H&E, HA, HBA, HBSS, HIA, IBD, IF, IFN-γ, IL, iNOS, LP, LPS, LIF, MLN, MLOGP, MT, MCP, MW, NF-κB, PBS, RB, RT-qPCR, RPMI medium, TJ, Tregs, RT, SEM, STAT, Th17 cell, TNF-α, UC, WB
Keywords : Macrophage, Colitis, Th17, NF-κB, Occludin, p-STAT3
Plan
Vol 185
Article 117939- avril 2025 Retour au numéro
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