Abstract
Ribosome-inactivating (ribotoxic) xenobiotics are capable of using cleavage and modification to damage 28S ribosomal RNA, which leads to translational arrest. The blockage of global protein synthesis predisposes rapidly dividing tissues, including gut epithelia, to damage from various pathogenic processes, including epithelial inflammation and carcinogenesis. In particular, mucosal exposure to ribotoxic stress triggers integrated processes that are important for barrier regulation and re-constitution to maintain gut homeostasis. In the present study, various experimental models of the mucosal barrier were evaluated for their response to acute and chronic exposure to ribotoxic agents. Specifically, this review focuses on the regulation of epithelial junctions, epithelial transporting systems, epithelial cytotoxicity, and compensatory responses to mucosal insults. The primary aim is to characterize the mechanisms associated with the intestinal epithelial responses induced by ribotoxic stress and to discuss the implications of ribotoxic stressors as chemical modulators of mucosa-associated diseases such as ulcerative colitis and epithelial cancers.
Highlights
The mucosal epithelium constitutes a physical and functional barrier between the host and components of the external environment, including nutrients, microbes, and toxicants [1,2]
Different modulations of intestinal epithelial integrity by ribotoxic xenobiotics have been suggested in terms of human intestinal epithelial diseases, including ulcerative colitis and epithelial tumors (Figure 1). (1) Primarily, the epithelial barrier is important for mucosal defense and homeostasis
Ribotoxic xenobiotics modulate nutrient transporting by interfering with various nutrient transporter systems, which might account for the malnutrition and weight loss in exposed mammals
Summary
The mucosal epithelium constitutes a physical and functional barrier between the host and components of the external environment, including nutrients, microbes, and toxicants [1,2]. Various dysfunctions of the epithelial barrier have been identified in human intestinal mucosal diseases, including inflammatory bowel disease (IBD) and epithelial cancers [2,7,8]. Ribotoxic xenobiotics alter intestinal integrity, and this leads to blunting of intestinal villi, swelling of interepithelial spaces, mucous secretion, dysregulation of nutrient absorption, and mucosal immune hyper-activation, all of which are associated with diarrhea, weight loss, and ulcerative colitis (UC) in experimental animals [22,23,24,25,26]. The purpose of this review is to provide a deep understanding of the key roles played by intestinal epithelial cells within the epithelial barrier system in both healthy subjects and those exposed to ribotoxic stress. This review focuses on the modulation of epithelial junction regulation, epithelial transporting system, epithelial cytotoxicity, and compensatory responses to the mucosal insults associated with IBD and epithelial cancers
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