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.

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 Sitagliptin attenuates arterial calcification by downregulating oxidative stress-induced receptor for advanced glycation end products in LDLR knockout mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chih-Pei Lin ◽  
Po-Hsun Huang ◽  
Chi-Yu Chen ◽  
Meng-Yu Wu ◽  
Jia-Shiong Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Advanced Glycation End Products ◽  
Calcium Deposition ◽  
Arterial Calcification ◽  
Advanced Glycation ◽  
Tnf Α ◽  
Glycation End Products ◽  
End Products ◽  
Rage Expression

AbstractDiabetes is a complex disease characterized by hyperglycemia, dyslipidemia, and insulin resistance. Plasma advanced glycation end products (AGEs) activated the receptor for advanced glycation end products (RAGE) and the activation of RAGE is implicated to be the pathogenesis of type 2 diabetic mellitus (T2DM) patient vascular complications. Sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, is a new oral hypoglycemic agent for the treatment of T2DM. However, the beneficial effects on vascular calcification remain unclear. In this study, we used a high-fat diet (HFD)-fed low-density lipoprotein receptor deficiency (LDLR−/−) mice model to investigate the potential effects of sitagliptin on HFD-induced arterial calcification. Mice were randomly divided into 3 groups: (1) normal diet group, (2) HFD group and (3) HFD + sitagliptin group. After 24 weeks treatment, we collected the blood for chemistry parameters and DPP4 activity measurement, and harvested the aorta to evaluate calcification using immunohistochemistry and calcium content. To determine the effects of sitagliptin, tumor necrosis factor (TNF)-α combined with S100A12 was used to induce oxidative stress, activation of nicotinamide adenine dinucleotide phosphate (NADPH), up-regulation of bone markers and RAGE expression, and cell calcium deposition on human aortic smooth muscle cells (HASMCs). We found that sitagliptin effectively blunted the HFD-induced artery calcification and significantly lowered the levels of fasting serum glucose, triglyceride (TG), nitrotyrosine and TNF-α, decreased the calcium deposits, and reduced arterial calcification. In an in-vitro study, both S100A12 and TNF-α stimulated RAGE expression and cellular calcium deposits in HASMCs. The potency of S100A12 on HASMCs was amplified by the presence of TNF-α. Sitagliptin and Apocynin (APO), an NADPH oxidase inhibitor, inhibited the TNF-α + S100A12-induced NADPH oxidase and nuclear factor (NF)-κB activation, cellular oxidative stress, RAGE expression, osteo transcription factors expression and calcium deposition. In addition, treatment with sitagliptin, knockdown of RAGE or TNF-α receptor blunted the TNF-α + S100A12-induced RAGE expression. Our findings suggest that sitagliptin may suppress the initiation and progression of arterial calcification by inhibiting the activation of NADPH oxidase and NF-κB, followed by decreasing the expression of RAGE.

scholarly journals Evidence for Activation of Toll-Like Receptor and Receptor for Advanced Glycation End Products in Preterm Birth

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Taketoshi Noguchi ◽  
Toshiyuki Sado ◽  
Katsuhiko Naruse ◽  
Hiroshi Shigetomi ◽  
Akira Onogi ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Advanced Glycation End Products ◽  
Expression Profiles ◽  
Receptor Activation ◽  
Advanced Glycation ◽  
Specific Expression ◽  
Downstream Signaling ◽  
Glycation End Products ◽  
End Products ◽  
Rage Expression

Objective. Individuals with inflammation have a myriad of pregnancy aberrations including increasing their preterm birth risk. Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE) and their ligands were all found to play a key role in inflammation. In the present study, we reviewed TLR and RAGE expression, their ligands, and signaling in preterm birth.Research Design and Methods. A systematic search was performed in the electronic databases PubMed and ScienceDirect up to July 2010, combining the keywords “preterm birth,” “TLR”, “RAGE”, “danger signal”, “alarmin”, “genomewide,” “microarray,” and “proteomics” with specific expression profiles of genes and proteins.Results. This paper provides data on TLR and RAGE levels and critical downstream signaling events including NF-kappaB-dependent proinflammatory cytokine expression in preterm birth. About half of the genes and proteins specifically present in preterm birth have the properties of endogenous ligands “alarmin” for receptor activation. The interactions between the TLR-mediated acute inflammation and RAGE-mediated chronic inflammation have clear implications for preterm birth via the TLR and RAGE system, which may be acting collectively.Conclusions. TLR and RAGE expression and their ligands, signaling, and functional activation are increased in preterm birth and may contribute to the proinflammatory state.

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