Inflammation in the colon can trigger clinical disorders such as Inflammatory bowel disease (IBD), in the form of ulcerative colitis (UC) and Crohn's disease (CD). These are debilitating disorders that significantly affect life-style, and can lead to development of colon cancer. The precise mechanisms that trigger inflammation which leads to the development of IBD are not clear. We have made exciting observations, leading to several publications, indicating that that American ginseng (AG, Panax quinquefolius), can suppress inflammation and is highly effective in the prevention and treatment of colitis. We have also identified the mechanisms of action of AG. Together, our studies indicated that (a) AG is an anti-oxidant that prevents and treats mouse colitis;(b) AG prevents colon cancer associated with colitis in mice;(c) AG drives apoptosis of CD4+/CD25- effector T cells through a p53-mediated pathway in vitro and in vivo;(d) a Hexane Fraction of AG (AG Fraction V) is more potent than the whole AG extract in preventing colitis and colon cancer;and (e) both AG and AG Fraction V target the Nrf2 signaling pathway as a means to suppress inflammation. Our long-term goal is to understand the epigenetic molecular and cellular pathways through which AG mediates its anti-inflammatory effects so that AG and/or one or more of its ingredients can be used as a viable treatment for IBD and prevention of colon cancer in humans. The overall objectives of this application, which is the next step toward attainment of our long-term goal, are to further delineate the ingredients in AG that have the strongest anti-inflammatory properties, as well as examine the mechanisms;focusing on the epigenetic regulation of Nrf2 and its targets. We have demonstrated that AG Fraction V attenuates UC and found that only this fraction V activates Nrf2. Thus, our central hypothesis is that Nrf2 is a critical mediator of AG-induced suppression of colonic inflammation and AG-Fraction V contains the most effective components driving Nrf2-mediated efficacy in IBD treatment. Mechanistically, we propose that the putative bio-effective components of AG mediate epigenetic regulation of Nrf2 thereby providing efficacy in IBD treatment. The rationale that underlies the proposed research is that Nrf2 signaling is a key mechanism toward suppressing inflammation, that inflammation underlies the devastating effects of colitis and eventually colon cancer, and AG/AG Fraction V target Nrf2. Therefore, it is reasonable to investigate the effects and mechanisms of AG/AG Fraction V on Nrf2 signaling. Overall, these studies will demonstrate a central role for Nrf2 in AG-induced suppression of colonic inflammation and prevention of colon cancer through an influence of AG and specific ingredients such as polyacetylenes on the Keap1:Nrf2 interface, miRNAs, and epigenetic regulation. Identifying mechanisms of action of AG will have important implications in understanding the colonic inflammation and approaches to effectively treat IBD.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Program Projects (P01)
Project #
2P01AT003961-06A1
Application #
8739825
Study Section
Special Emphasis Panel (ZAT1)
Project Start
Project End
Budget Start
2014-09-30
Budget End
2015-08-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of South Carolina at Columbia
Department
Type
DUNS #
City
Columbia
State
SC
Country
United States
Zip Code
29208
Bam, Marpe; Yang, Xiaoming; Sen, Souvik et al. (2017) Characterization of Dysregulated miRNA in Peripheral Blood Mononuclear Cells from Ischemic Stroke Patients. Mol Neurobiol :
Sagar, Divya; Singh, Narendra P; Ginwala, Rashida et al. (2017) Antibody blockade of CLEC12A delays EAE onset and attenuates disease severity by impairing myeloid cell CNS infiltration and restoring positive immunity. Sci Rep 7:2707
Finnell, Julie E; Lombard, Calliandra M; Melson, Michael N et al. (2017) The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior. Brain Behav Immun 59:147-157
Shamran, Haidar; Singh, Narendra P; Zumbrun, Elizabeth E et al. (2017) Fatty acid amide hydrolase (FAAH) blockade ameliorates experimental colitis by altering microRNA expression and suppressing inflammation. Brain Behav Immun 59:10-20
Shivappa, Nitin; H├ębert, James R; Steck, Susan E et al. (2017) Dietary inflammatory index and odds of colorectal cancer in a case-control study from Jordan. Appl Physiol Nutr Metab 42:744-749
Bam, M; Yang, X; Zumbrun, E E et al. (2017) Decreased AGO2 and DCR1 in PBMCs from War Veterans with PTSD leads to diminished miRNA resulting in elevated inflammation. Transl Psychiatry 7:e1222
Alhasson, Firas; Das, Suvarthi; Seth, Ratanesh et al. (2017) Altered gut microbiome in a mouse model of Gulf War Illness causes neuroinflammation and intestinal injury via leaky gut and TLR4 activation. PLoS One 12:e0172914
Chitrala, Kumaraswamy Naidu; Guan, Hongbing; Singh, Narendra P et al. (2017) CD44 deletion leading to attenuation of experimental autoimmune encephalomyelitis results from alterations in gut microbiome in mice. Eur J Immunol 47:1188-1199
Harmon, Brook E; Wirth, Michael D; Boushey, Carol J et al. (2017) The Dietary Inflammatory Index Is Associated with Colorectal Cancer Risk in the Multiethnic Cohort. J Nutr 147:430-438
Chumanevich, Anastasiya A; Chaparala, Anusha; Witalison, Erin E et al. (2017) Looking for the best anti-colitis medicine: A comparative analysis of current and prospective compounds. Oncotarget 8:228-237

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