The Close Interplay of Nitro-Oxidative Stress, Advanced Glycation end Products and Inflammation in Inflammatory Bowel Diseases

2020 ◽  
Vol 27 (13) ◽  
pp. 2059-2076 ◽  
Author(s):  
Fabiana Andréa Moura ◽  
Marília Oliveira Fonseca Goulart ◽  
Samara Bonfim Gomes Campos ◽  
Amylly Sanuelly da Paz Martins
Keyword(s):  
Oxidative Stress ◽  
Advanced Glycation End Products ◽  
Bowel Disease ◽  
Antioxidant Systems ◽  
Related Factor ◽  
Advanced Glycation ◽  
Nuclear Expression ◽  
Glycation End Products ◽  
End Products ◽  
Inflammatory Bowel

Background: Inflammatory Bowel Disease (IBD) exhibits no defined aetiology. However, factors such as genetic and nitro-oxidative stress are associated with chronic inflammation and IBD progression to Colorectal Cancer (CRC). The present review discusses the association of nitro-oxidative stress, inflammation and Advanced Glycation End products (AGE) and their corresponding receptor (RAGE) in IBD and examines the connection between these factors and nuclear factors, such as Nuclear Factor Kappa B (NF-κB), factorerythroid 2-related factor-2 (Nrf2), and p53 Mutant (p53M). Methods: We searched the PubMed, ScienceDirect and Web of Science databases using a combination of the following terms: IBD, CRC, oxidative stress, inflammation, NF-κB, Nrf2, p53M, AGE and RAGE. Results: Oxidative stress and inflammation activated two cellular pathways, the nuclear expression of pro-inflammatory, pro-oxidant and pro-oncogenic genes based on NF-κB and p53M, which is associated with NF-κB activation, Deoxyribonucleic acid (DNA) damage and the expression of pro-oncogenic genes. Nrf2 stimulates the nuclear expression of enzymatic and non-enzymatic antioxidant systems and anti-inflammatory genes, and is inhibited by chronic oxidative stress, NF-κB and p53M. AGE/RAGE are involved in inflammation progression because RAGE polymorphisms and increased RAGE levels are found in IBD patients. Alterations of these pathways in combination with oxidative damage are responsible for IBD symptoms and the progression to CRC. Conclusion: IBD is an inflammatory and nitro-oxidative stress-based bowel disease. Achieving a molecular understanding of the biochemical events and their complicated interactions will impact basic and applied research, animal models, and clinical trials.

scholarly journals The Taming of Nuclear Factor Erythroid-2-Related Factor-2 (Nrf2) Deglycation by Fructosamine-3-Kinase (FN3K)-Inhibitors-A Novel Strategy to Combat Cancers

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 281
Author(s):  
Narasimha M. Beeraka ◽  
Venugopal R. Bovilla ◽  
Shalini H. Doreswamy ◽  
Sujatha Puttalingaiah ◽  
Asha Srinivasan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cancer Cell ◽  
Advanced Glycation End Products ◽  
Signaling Cascades ◽  
Related Factor ◽  
Nuclear Factor ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products

Glycated stress is mediated by the advanced glycation end products (AGE) and the binding of AGEs to the receptors for advanced glycation end products (RAGEs) in cancer cells. RAGEs are involved in mediating tumorigenesis of multiple cancers through the modulation of several downstream signaling cascades. Glycated stress modulates various signaling pathways that include p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa–B (NF-κB), tumor necrosis factor (TNF)-α, etc., which further foster the uncontrolled proliferation, growth, metastasis, angiogenesis, drug resistance, and evasion of apoptosis in several cancers. In this review, a balanced overview on the role of glycation and deglycation in modulating several signaling cascades that are involved in the progression of cancers was discussed. Further, we have highlighted the functional role of deglycating enzyme fructosamine-3-kinase (FN3K) on Nrf2-driven cancers. The activity of FN3K is attributed to its ability to deglycate Nrf2, a master regulator of oxidative stress in cells. FN3K is a unique protein that mediates deglycation by phosphorylating basic amino acids lysine and arginine in various proteins such as Nrf2. Deglycated Nrf2 is stable and binds to small musculoaponeurotic fibrosarcoma (sMAF) proteins, thereby activating cellular antioxidant mechanisms to protect cells from oxidative stress. This cellular protection offered by Nrf2 activation, in one way, prevents the transformation of a normal cell into a cancer cell; however, in the other way, it helps a cancer cell not only to survive under hypoxic conditions but also, to stay protected from various chemo- and radio-therapeutic treatments. Therefore, the activation of Nrf2 is similar to a double-edged sword and, if not controlled properly, can lead to the development of many solid tumors. Hence, there is a need to develop novel small molecule modulators/phytochemicals that can regulate FN3K activity, thereby maintaining Nrf2 in a controlled activation state.

scholarly journals DYSREGULATION OF GASTROINTESTINAL RAGE (RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS) EXPRESSION IN A SPONTANEOUS ANIMAL MODEL OF INFLAMMATORY BOWEL DISEASE

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S3-S3
Author(s):  
Angela Isabel Cabrera-García ◽  
Martina Protschka ◽  
Stefanie Kather ◽  
Franziska Dengler ◽  
Gottfried Alber ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Advanced Glycation End Products ◽  
Bowel Disease ◽  
Advanced Glycation ◽  
Protein Loss ◽  
Glycation End Products ◽  
End Products ◽  
Inflammatory Bowel ◽  
Gastrointestinal Inflammation ◽  
Rage Expression

Abstract The receptor for advanced glycation end products (RAGE), a pattern recognition receptor, plays a role in chronic inflammation. Abrogation of proinflammatory RAGE signaling by ligand binding (e.g., S100/calgranulins) to soluble RAGE decoy (sRAGE) is a promising novel therapeutic avenue for chronic inflammatory diseases, such as inflammatory bowel disease (IBD). However, the opportunities for studying S100/calgranulin-RAGE pathways in conventional animal models are limited due to species differences in the expression and function of S100/calgranulins (e.g., lack of the S100A12 protein in rodents). The pathogenesis of IBD in dogs involves dysregulated innate immune responses, and serum sRAGE levels are decreased in canine IBD and normalize only with clinical remission. Thus, canine IBD may serve as a spontaneous model of IBD for such studies. This study evaluated gastrointestinal mucosal RAGE expression in dogs with IBD and the binding of RAGE to canine S100/calgranulin ligands. Epithelial RAGE expression was quantified in endoscopic gastrointestinal (i.e., gastric, duodenal, ileal, and colonic) biopsies from 12 dogs with IBD and 9 healthy control dogs by laser scanning microscopy. RAGE expression was compared between both groups of dogs and was tested for an association with patient characteristics, clinical variables, histologic lesion severity, and biomarkers of extra-gastrointestinal disease, systemic or gastrointestinal inflammation, function, or protein loss. Statistical significance (non-parametric tests) was set at p<0.05. RAGE:S100/calgranulin binding was investigated by immunoassay and electrophoretic techniques. RAGE expression was detected in all biopsies evaluated. Epithelial RAGE expression in the duodenum and colon was significantly higher in dogs with IBD than in healthy controls (p<0.04), with a trend for overexpression in the ileum, underexpression in the stomach, and a general shift towards more basal than apical epithelial RAGE expression. Serum sRAGE was correlated with duodenal RAGE expression. Several histologic (structural and inflammatory) lesion criteria and markers of gastrointestinal inflammation or protein loss were related to segmental RAGE expression (all p<0.04). In vitro, canine RAGE:S100A12 binding appeared more pronounced than RAGE:S100A8/A9 binding. Alterations in the epithelial expression of RAGE along the gastrointestinal tract provide evidence for a dysregulated sRAGE/RAGE axis as a characteristic of canine IBD. S100/calgranulin (S100A8/A9 and S100A12) proteins are ligands for RAGE in dogs. The role of RAGE signaling in IBD pathogenesis and its potential for developing novel targeted therapeutics warrants further exploration. Furthermore, canine IBD is a suitable spontaneous model for human IBD that may benefit further research into pathway-specific IBD treatment options that target the sRAGE/RAGE axis.

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