Abstract
Interaction of intestinal barrier dysfunction and intestinal inflammation promotes the progression of Crohn's disease (CD). A more recent study has suggested that ruscogenins (RUS) can exert anti-inflammatory effects through activation of the Nrf2/NQO1 pathway. The current study is aimed at determining the functionalization of RUS on CD-like colitis. Wild-type (WT) mice induced with trinitrobenzene sulfonic acid (TNBS) exhibit a significant inflammation in their colon and are hence widely used for CD models. In the current study, the mice were treated with the Nrf-2 antagonist (ML385) or ruscogenin (RUS) whereas normal WT mice were kept as the negative control. Comparative analysis was then performed on the inflammation and barrier function of the colons. In vitro analysis of mouse colonic organoid systems revealed the influence of RUS on LPS-induced apoptosis, cytokine, and chemokine expressions in the intestinal epithelium. It was found that RUS ameliorates murine colitis through activation of the Nrf2/NQO1 pathway which was presented as a decrease in inflammation score and downregulated levels of cytokine and chemokine synthesis, as well as increased intestinal permeability. Further, it was noted that RUS alleviated LPS-induced apoptosis in the intestinal epithelium cells through upregulation of the Nrf2/NQO1 signaling pathway in the mouse colonic organoids. In addition, ruscogenin (RUS) attenuated the levels of Bax and C-caspase-3 through activation of the Nrf2/HO1 signaling pathway both in vivo and in vitro. Therefore, it was evident that RUS can be applied as a potential alternative therapeutic agent in CD based on its protective effects on the barrier function and anti-inflammatory activity.
Highlights
Crohn’s disease (CD) is an inflammatory bowel disease whose etiology is unknown and with lethal and lifelong recurrence tendency in patients [1]
Results showed that trinitrobenzene sulfonic acid (TNBS) treatment elicited compensatory protection in vivo by activating the nuclear factor E2-related factor 2 (Nrf2)/NQO1 signaling pathway
The expression of Nrf2 and NQO1 proteins was higher in mice treated with RUS than in those treated with LPS
Summary
Crohn’s disease (CD) is an inflammatory bowel disease whose etiology is unknown and with lethal and lifelong recurrence tendency in patients [1]. The dysfunction of mucosa barriers caused by abnormal immune response and infection plays a crucial role in the pathogenesis of CD whereas alteration of intestinal permeability is a major manifestation of barrier dysfunction [5, 6]. A series of physiological factors may contribute to induce intestinal hyperpermeability, and abnormal apoptosis of intestinal epithelial cells can lead to damage of the intestinal barrier as well as directly increase permeability [9]. The aberrant apoptosis of intestinal epithelial cells mainly results from aberrant activation of apoptotic pathways in response to inflammatory stimuli [10]. Upregulation of the antiapoptotic protein (B-cell lymphoma-2, Bcl-2) or downregulation of the proapoptotic protein (Bcl-2-associated X protein, Bax) may antagonize inflammation-induced apoptosis of intestinal epithelial cells and protect intestinal barrier function and this in turn ameliorates CD-like intestinal inflammation [11, 12]
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