Protective effect of a novel nonsteroidal organoselenium compound SLL-1-43 on ulcerative colitis through down-regulating NOX2 signaling pathway in vitro and in vivo

Background

Inflammatory bowel disease (IBD), including ulcerative colitis (UC), is a global health concern characterized by chronic inflammation and oxidative stress. These factors play pivotal roles in its pathogenesis, highlighting the need for novel therapeutic strategies. In this study, we synthesized and screened nine non-steroidal organicselenium compounds to evaluate their potential efficacy against UC, identifying SLL-1–43 and SLL-1–44 as the most promising candidates.

Purpose

To investigate the therapeutic potential of SLL-1–43 and SLL-1–44 in UC and elucidate the underlying molecular mechanisms.

Study design

We conducted in vitro experiments using LPS-induced RAW264.7 macrophages and in vivo studies on DSS-induced acute and chronic UC mouse models.

Methods

The expression levels of inflammatory and oxidative stress-related genes (iNOS, IL-1β, IL-18, and p47phox) were analyzed using quantitative PCR. Molecular docking and molecular dynamics simulations were performed to assess the interactions between SLL-1–43, SLL-1–44, and NOX2/p47phox. Western blot analysis was employed to examine protein expression, while clinical symptoms in DSS-induced UC mice were evaluated.

Results

Treatment with SLL-1–43 or SLL-1–44 significantly suppressed the mRNA expression of pro-inflammatory mediators in LPS-stimulated RAW264.7 macrophages. Molecular docking and dynamics simulations confirmed stable interactions between these compounds and NOX2/p47phox. Additionally, SLL-1–43 downregulated NOX2/p47phox expression and its downstream signaling pathways. In DSS-induced UC mice, SLL-1–43 improved clinical symptoms by modulating key molecular targets, including gp91phox, p47phox, NLRP3, Nrf2, and tight junction proteins, thereby alleviating inflammation and oxidative stress.

Conclusion

SLL-1–43 exhibits potent anti-inflammatory and protective effects against UC in vitro and in vivo by suppressing the NOX2 signaling pathway. These findings suggest that SLL-1–43 may serve as a promising candidate for UC therapy and new drug development.