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Mesua Assamica (Kingprain) Kosterm. (MA) is an evergreen endemic medicinal tree available in Assam in India and other parts of south Asia. The bark of the plant is traditionally used for ant-malarial activity and treating fevers. It was reported to have anti-oxidant, anti-inflammatory, anti-diabetic, anti-cancer and anti-malarial properties, but no research findings have been reported about its protective activity on intestinal inflammatory disorders like ulcerative colitis (UC) yet.The aim of the current study is to evaluate the anti-ulcerative property of ethanolic extract of MA (MAE) in-vitro on GloResponse™ NF-кB-RE-luc2P HEK 293 cells for its anti-oxidant and anti-inflammatory activities and in-vivo chronic restraint stress aggravated dextran sodium sulfate (DSS)-induced UC model.The chemical constituents of MAE were identified by LC-MS/MS. The in-vitro effects of MAE on GloResponse™ NF-кB-RE-luc2P HEK 293 cells stimulated with TNF-α 30 ng/ml were investigated for its potential therapeutic effects. Parameters such as body weights, behavioural, colonoscopy, colon lengths and spleen weights were measured and recorded in chronic restraint stress aggravated DSS-induced UC model in C57BL/6 mice. Histological, cytokines and immunoblotting analysis in the colon tissues were determined to prove its anti-inflammatory and anti-oxidant activities.MAE poses significant anti-oxidant and anti-inflammatory activity in-vitro in GloResponse™ NF-кB-RE-luc2P HEK 293 cells evidenced by DCFDA and immunoflourescence assay. MAE treatment at 100 mg/kg and 200 mg/kg for 14 consecutive days has reduced Disease activity Index (DAI), splenomegaly and improved the shortened colon length and sucrose preference in mice. MAE treatment has increased the levels of anti-oxidants like GSH and reduced the levels of MDA, MPO and nitrite levels in colon tissues. Moreover, MAE has ameliorated neutrophil accumulation, mucosal and submucosal inflammation and crypt density evidenced by histopathology. Furthermore, MAE treatment significantly reduced the increased pro-inflammatory cytokines like IL-6, IL-1β and TNF-α. we found from immunoblotting that there is a concomitant decrease in protein expression of NF-κB, STAT3 signalling cascades and phosphorylation of IKBα with an increase in Nrf2, SOD2, HO-1 and SIRT1 in colon tissues. In addition, we have performed molecular docking studies confirming that phytochemicals present in the MAE have a stronger binding ability and druggability to the NF-κB, Nrf2 and SIRT1 proteins.MAE exhibited significant anti-colitis activity on chronic restraint stress aggravated DSS-induced ulcerative colitis via regulating NF-κB/STAT3 and HO-1/Nrf2/SIRT1 signaling pathways.