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)
Type
Research Program Projects (P01)
Project #
2P01AT003961-06A1
Application #
8739825
Study Section
Special Emphasis Panel (ZAT1)
Project Start
Project End
Budget Start
Budget End
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
Monsanto, Stephany P; Edwards, Andrew K; Zhou, Juhua et al. (2016) Surgical removal of endometriotic lesions alters local and systemic proinflammatory cytokines in endometriosis patients. Fertil Steril 105:968-977.e5
Dattaroy, Diptadip; Seth, Ratanesh Kumar; Das, Suvarthi et al. (2016) Sparstolonin B attenuates early liver inflammation in experimental NASH by modulating TLR4 trafficking in lipid rafts via NADPH oxidase activation. Am J Physiol Gastrointest Liver Physiol 310:G510-25
Bam, Marpe; Yang, Xiaoming; Zhou, Juhua et al. (2016) Evidence for Epigenetic Regulation of Pro-Inflammatory Cytokines, Interleukin-12 and Interferon Gamma, in Peripheral Blood Mononuclear Cells from PTSD Patients. J Neuroimmune Pharmacol 11:168-81
Iwanowycz, Stephen; Wang, Junfeng; Hodge, Johnie et al. (2016) Emodin Inhibits Breast Cancer Growth by Blocking the Tumor-Promoting Feedforward Loop between Cancer Cells and Macrophages. Mol Cancer Ther 15:1931-42
Cranford, T L; Enos, R T; Velázquez, K T et al. (2016) Role of MCP-1 on inflammatory processes and metabolic dysfunction following high-fat feedings in the FVB/N strain. Int J Obes (Lond) 40:844-51
Ginwala, Rashida; McTish, Emily; Raman, Chander et al. (2016) Apigenin, a Natural Flavonoid, Attenuates EAE Severity Through the Modulation of Dendritic Cell and Other Immune Cell Functions. J Neuroimmune Pharmacol 11:36-47
Iwanowycz, Stephen; Wang, Junfeng; Altomare, Diego et al. (2016) Emodin Bidirectionally Modulates Macrophage Polarization and Epigenetically Regulates Macrophage Memory. J Biol Chem 291:11491-503
Enos, Reilly T; Velázquez, Kandy T; McClellan, Jamie L et al. (2016) High-fat diets rich in saturated fat protect against azoxymethane/dextran sulfate sodium-induced colon cancer. Am J Physiol Gastrointest Liver Physiol 310:G906-19
Yang, Xiaoming; Bam, Marpe; Nagarkatti, Prakash S et al. (2016) RNA-seq Analysis of δ9-Tetrahydrocannabinol-treated T Cells Reveals Altered Gene Expression Profiles That Regulate Immune Response and Cell Proliferation. J Biol Chem 291:15460-72
Bam, Marpe; Yang, Xiaoming; Zumbrun, Elizabeth E et al. (2016) Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation. Sci Rep 6:31209

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