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Abstract
One of the main mechanisms carried out by the cells to counteract several forms of stress is the activation of the nuclear factor erythroid 2-related factor (Nrf2) signaling. Nrf2 signaling controls the expression of many genes through the binding of a specific cis-acting element known as the antioxidant response element (ARE). Activation of Nrf2/ARE signaling can mitigate several pathologic mechanisms associated with an autoimmune response, digestive and metabolic disorders, as well as respiratory, cardiovascular, and neurodegenerative diseases. Indeed, several studies have demonstrated that Nrf2 pathway plays a key role in inflammation and in cancer development in many organs, including the intestine. Nrf2 appears to be involved in inflammatory bowel disease (IBD), an immune-mediated chronic and disabling disease, with a high risk of developing intestinal fibrotic strictures and cancer. Currently, drugs able to increase cytoprotective Nrf2 function are in clinical trials or already being used in clinical practice to reduce the progression of some degenerative conditions. The role of Nrf2 in cancer development and progression is controversial, and drugs able to inhibit abnormal levels of Nrf2 are also under investigation. The goal of this review is to analyze and discuss Nrf2-dependent signals in the initiation and progression of intestinal fibrosis and cancers occurring in IBD.
Highlights
Inflammatory bowel disease (IBD) is a spectrum of diseases, including Crohn’s disease (CD) and ulcerative colitis (UC), that lead to numerous complications, among which the most common is represented by intestinal fibrosis and cancer
Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, represent a challenging clinical condition since they can lead to severe complications such as intestinal fibrosis and colorectal cancer which are currently manageable only through surgery
Identifying the main molecules responsible for the development of IBD-associated intestinal fibrosis and cancer is crucial for the prevention of such severe complications
Summary
Inflammatory bowel disease (IBD) is a spectrum of diseases, including Crohn’s disease (CD) and ulcerative colitis (UC), that lead to numerous complications, among which the most common is represented by intestinal fibrosis and cancer. Intestinal fibrosis is a process characterized by excessive deposition of extracellular matrix (ECM) proteins by activated myofibroblasts [1–3]. Perturbation of the delicate MMP/TIMP balance results in the excessive deposition of ECM proteins, which leads to fibrosis. A pivotal role in intestinal fibrosis, other than in many types of cancer, is certainly played by transforming growth factor β (TGF-β), through its canonical interaction with small mothers against decapentaplegic proteins (Smads) and by a complex network with other profibrotic and antifibrotic molecules [1,4–6]. Among the multiple aspects of Nrf, in this review, we discuss its role in intestinal fibrosis and in colorectal cancer occurring during IBD and the possibility that it may be a new and valid therapeutic target
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