Ulcerative Colitis (UC) is a form of Inflammatory Bowel Disease (IBD) characterized by chronic inflammation predominantly in the colon causing damage to intestinal walls. UC is a major cause of colon cancer which is among the top ten causes of death in USA. Anti-inflammatory and immune-suppressive drugs with negative side effects and/or repetitive surgeries are common treatments of IBD. IBD drugs also help prevent Colitis Associated Cancer (CAC). A thoroughly researched and FDA-regulated botanical therapy may offer a novel and well-tolerated alternative treatment option. However, consistent efficacy and mechanisms of action of botanicals are largely undetermined. The broad objective of this proposal is to establish Barbarea verna Seed Preparation (BSP), a standardized plant product, as a therapy for UC that will potentially reduce the risk of colon cancer in humans. Nuclear Factor kappa B (NFkB) is a key player in the transcriptional regulation of genes involved in the pathogenesis of IBD and is also known to control apoptosis. Phenethylisothiocyanate (PEITC) is an anti-carcinogenic, dietary bio-active compound present in BSP that inhibits NFkB in macrophages and colon cancer cells. Our studies show that BSP down-regulates several NFkB-controlled pro-inflammatory genes in induced macrophages in a similar way as synthetic PEITC and is effective in reducing inflammatory symptoms in vivo. BSP also demonstrated chemoprevention effects that resemble PEITC activities. This project will focus on characterizing the therapeutic mechanism of action, efficacy and the safety of BSP, specifically in context of UC and CAC. NFkB and other signaling pathway- focused detailed genetic profiles underlying the therapeutic activities of BSP will be investigated in mouse macrophages, human colon cancer cells and ex vivo rodent tissues. To test the efficacy of BSP, chemically induced mouse models of UC and CAC that mimic the human clinical condition will be used. Statistical significance of the responses of the diseased animals to oral treatments will be determined by comparing macroscopic and microscopic scorings with untreated control groups. Dose dependency, efficacy comparison with known drugs and bioavailability of BSP in blood and urine, will be assessed in the proposed mouse models. The knowledge gained from this work will provide the scientific basis for use of BSP in a clinical study and a general validation of alternative approaches in bio-medical research. ? ? ? ?
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