The synergistic administration of sanguinarine and curcumin ameliorates indomethacin-induced small intestinal injury in rats through the modulation of Nrf2 and NF-κB signaling pathways.

The synergistic effects of natural compounds provide "multi-component, multi-target" advantages by optimizing efficacy-toxicity profiles. This study elucidates the protective mechanisms and optimal combination of sanguinarine (SA) and curcumin (Cur) in mitigating indomethacin-induced small intestinal injury. A rat model of indomethacin-induced intestinal injury was utilized to assess the therapeutic efficacy of various SA/Cur combinations, with the SA1+Cur40 mg/kg combination identified as optimal, using berberine (Ber) as a positive control. The SA1+Cur40 combination significantly alleviated intestinal injury, as evidenced by improved CMDI/TDI scores and reduced levels of key inflammatory markers, including TNF-α, IL-6, IL-1β, and LDH. Mechanistic investigations revealed that SA and Cur act synergistically through dual-pathway regulation: (1) SA enhances Nrf2 signaling, activating HO-1 and thereby augmenting antioxidant capacity; (2) Cur inhibits NF-κB activation, reducing pp65 and mitigating the inflammatory response. This synergy significantly enhances intestinal epithelial tight junction integrity by effectively inhibiting MMP2/9 activity and upregulating the expression of junctional proteins such as ZO-1, Claudin-1, and Occludin. CONCLUSION: The combination of SA and Cur, notably the SA1+Cur40 formulation, demonstrated significant efficacy in mitigating indomethacin-induced small intestinal injury. This effect was achieved through the synergistic activation of the Nrf2 antioxidant pathway and concurrent inhibition of the NF-κB inflammatory pathway.