蝙蝠葛碱通过TLR4/NLRP3/GSDMD焦亡和Nrf2通路改善DSS诱导结肠炎

Abstract

Dauricine (DAU), a natural bisbenzyltetrahydroisoquinoline alkaloid extracted from the medicinal herb Menispermi rhizoma, has therapeutic potential in ulcerative colitis (UC). This investigation was conducted to confirm the therapeutic effect of DAU against UC and elucidate its underlying mechanisms. Dextran sulfate sodium (DSS) was applied to develop the UC model in vivo. The therapeutic efficacy of DAU on UC was assessed through analyzing body weight, colon index, disease activity index (DAI), histopathology, inflammatory cytokines, and oxidative stress markers levels. The potential mechanisms of DAU on UC were evaluated by analyzing the TLR4/NLRP3/GSDMD-mediated pyroptosis and Nrf2 pathway. DAU treatment exerted therapeutic efficacy on UC via inhibiting weight loss, restoring colon index, alleviating DAI score, ameliorating pathological damage, and normalizing the levels of inflammatory cytokines and oxidative stress markers. Mechanistically, DAU inhibited intestinal inflammation through suppressing the TLR4/MyD88/NF-κB pathway, preventing the NLRP3/Caspase-1/GSDMD-mediated pyroptosis. Moreover, DAU reduced oxidative stress via activating the Nrf2 pathway. These findings demonstrated that DAU exhibited appreciable therapeutic efficacy on UC, which is achieved by mediating intestinal inflammation and oxidative stress via TLR4/NF-κB/NLRP3/GSDMD-mediated pyroptosis and the Nrf2 pathway. Graphical