A novel triazole derivative ameliorates ulcerative colitis by targeting PPAR gamma

Area of Science:

• Gastroenterology
• Immunology
• Pharmacology

Background:

• Ulcerative colitis (UC) is a chronic, incurable inflammatory bowel disease with significant unmet treatment needs.
• Current UC therapies face challenges including side effects and drug resistance, necessitating novel therapeutic strategies.
• Development of new drugs targeting underlying disease mechanisms is crucial for effective UC management.

Purpose of the Study:

• To investigate the therapeutic potential of a novel 1,2,3-triazole derivative, 5-phenyl-1-(p-tolyl)-1H-1,2,3-triazole (PPTT), for ulcerative colitis (UC).
• To identify the molecular targets and mechanisms of action of PPTT in alleviating UC symptoms.
• To evaluate PPTT's efficacy in a preclinical model of UC.

Main Methods:

• Dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis.
• Machine learning and multi-omics analyses to identify therapeutic targets.
• Molecular docking, molecular dynamics simulations, SPR, CETSA, and DARTS to confirm drug-target interaction.
• RT-qPCR, Western blotting, and ELISA to assess gene/protein expression and cytokine levels.

Main Results:

• PPTT significantly ameliorated disease symptoms in a DSS-induced UC mouse model.
• Peroxisome proliferator-activated receptor gamma (PPARG) was identified as a key therapeutic target for PPTT.
• PPTT modulated macrophage polarization (M1 to M2 phenotype) and regulated fatty acid metabolism via PPAR and PI3K/Akt signaling pathways.
• Direct interaction between PPTT and PPARG was confirmed through various biophysical and biochemical assays.

Conclusions:

• PPTT demonstrates significant therapeutic efficacy against ulcerative colitis by targeting PPARG.
• The mechanism involves suppression of PPAR and PI3K/Akt signaling pathways, promoting M2 macrophage polarization.
• PPTT represents a promising novel therapeutic candidate for ulcerative colitis treatment.