Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease that affects millions of people worldwide and increases the risk of colorectal cancer (CRC) development. We have previously shown that American ginseng (AG) can treat colitis and prevent colon cancer in mice. We further fractionated AG and identified the most potent fraction, hexane fraction (HAG), and the most potent compound in this fraction, panaxynol (PA). Because (1) oxidative stress plays a significant role in the pathogenesis of colitis and associated CRC and (2) nuclear factor erythroid-2-related factor 2 (Nrf2) is the master regulator of antioxidant responses, we examined the role of Nrf2 as a mechanism by which AG suppresses colitis. Through a series of in vitro and in vivo Nrf2 knockout mouse experiments, we found that AG and its components activate the Nrf2 pathway and decrease the oxidative stress in macrophages (mΦ) and colon epithelial cells in vitro. Consistent with these in vitro results, the Nrf2 pathway is activated by AG and its components in vivo, and Nrf2-/- mice are resistant to the suppressive effects of AG, HAG and PA on colitis. Results from this study establish Nrf2 as a mediator of AG and its components in the treatment of colitis.
Highlights
Inflammatory bowel disease (IBD), which includes Ulcerative colitis (UC) and Crohn’s disease (CD), debilitates approximately 2.6 million people in North America, and this number is on the rise [1].In particular, the relative risk for colorectal cancer (CRC) in patients with UC is tenfold greater than the general population [2]
Data are expressed as a mean ± standard error of the mean
Mean differences between the groups were compared by one-way analysis of variance (ANOVA), followed by Dunnett’s multiple comparison tests
Summary
The relative risk for colorectal cancer (CRC) in patients with UC is tenfold greater than the general population [2]. The etiology of UC remains to be fully elucidated but involves interactions among genetic, environmental, and immune factors, leading to uncontrolled abnormal immune responses in the intestinal mucosa [3]. Treatment strategies for UC (and the prevention of CRC) reduce periods of active disease and maintain remission, but patients become refractory, and there are dangerous side effects like cancer, infection, sepsis, hepatitis, and death [11,12,13,14]. Identifying new treatments that have minimal toxicity to treat the disease and prevent colon cancer, remains a high priority
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