Abstract

Background/Objectives: Ulcerative colitis (UC) is a relapsing colonic disorder in which persistent immune-mediated inflammation is accompanied by oxidative imbalance and deterioration of the protective intestinal mucosal barrier. Due to disease complexity and limitations of current therapies, alternative and adjunctive treatments are needed. This study investigated the phytochemical profiles and anti-UC activities of Commiphora gileadensis, Salsola incanescens, and Savignya parviflora. Methods: The methanolic extracts of aerial parts (AMEs) were characterized using LC-MS/MS and evaluated for their protective effects against acetic acid (AA)-induced UC in female Sprague Dawley rats. Animals were treated orally once daily for 14 days with extract doses of 250 and 500 mg/kg prior to colitis induction. In vitro anti-inflammatory and NO scavenging activities were also evaluated. Molecular docking was performed to explore the potential mechanisms of action by predicting the interactions of key compounds with COX-1 and 2 and the TLR4/MD-2 complex. Results: LC-MS/MS analysis revealed flavonoid-rich extracts with characteristic metabolites, including triterpenes in C. gileadensis, phenolic amides in S. incanescens, and amino acids in S. parviflora. C. gileadensis exhibited the strongest in vitro anti-inflammatory activity, showing marked suppression of interleukin-6 and tumor necrosis factor-α production in lipopolysaccharide (LPS)-induced RAW264.7 macrophages, selective COX-2 inhibition, and potent NO scavenging activity comparable to celecoxib. The extracts significantly attenuated AA-induced colonic injury in a dose-dependent manner. C. gileadensis at 500 mg/kg exhibited the highest protective efficacy by reducing disease activity index, colonic edema, oxidative stress, and inflammatory mediators, while restoring mucosal architecture. It downregulated TLR4 and attenuated NF-κB-dependent inflammatory and iNOS pathways. Histopathological examination and mucin expression results were consistent with these findings. Molecular docking was utilized as a hypothesis-generating tool to provide an in silico insight into the anti-inflammatory activity of C. gileadensis, suggesting potential multi-target interactions with COX-1, COX-2, and the TLR4/MD-2 complex, likely attributable to its unique triterpenoid and flavonoid constituents. Conclusions: C. gileadensis emerged as the most promising extract for UC management, exhibiting marked antioxidant and anti-inflammatory effects. Further mechanistic, pharmacokinetic, and clinical investigations are required to establish its translational potential for the treatment of UC.

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