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The receptor for advanced glycation end products (RAGE) is a non-specific multi-ligand pattern recognition receptor capable of binding to a range of structurally diverse ligands, expressed on a variety of cell types, and performing different functions. The ligand-RAGE axis can trigger a range of signaling events that are associated with diabetes and its complications, neurological disorders, cancer, inflammation and other diseases. Since RAGE is involved in the pathophysiological processes of many diseases, targeting RAGE may be an effective strategy to block RAGE signaling.

Numerous hypotheses including amyloid cascade, cholinergic, and oxidative have been proposed for pathogenesis of Alzheimer’s disease (AD). The data suggest that advanced glycation end products (AGEs) and its receptor RAGE (receptor for AGE) are involved in the pathogenesis of AD. AGE–RAGE stress, defined as a balance between stressors (AGE, RAGE) and anti-stressors (sRAGE, AGE degraders) in favor of stressors, has been implicated in pathogenesis of diseases. AGE and its interaction with RAGE-mediated increase in the reactive oxygen species (ROS) damage brain because of its increased vulnerability to ROS. AGE and ROS increase the synthesis of amyloid β (Aβ) leading to deposition of Aβ and phosphorylation of tau, culminating in formation of plaques and neurofibrillary tangles. ROS increase the synthesis of Aβ, high-mobility group box 1(HMGB1), and S100 that interacts with RAGE to produce additional ROS resulting in enhancement of AD pathology. Elevation of ROS precedes the Aβ plaques formation. Because of involvement of AGE and RAGE in AD pathology, the treatment should be targeted at lowering AGE levels through reduction in consumption and formation of AGE, and lowering expression of RAGE, blocking of RAGE ligand binding, increasing levels of soluble RAGE (sRAGE), and use of antioxidants. The above treatment aspect of AD is lacking. In conclusion, AGE–RAGE stress initiates, and Aβ, HMGB1, and S100 enhance the progression of AD. Reduction of levels of AGE and RAGE, elevation of sRAGE, and antioxidants would be beneficial therapeutic modalities in the prevention, regression, and slowing of progression of AD.

In this research, we examine customer rage-associated emotions, expressions, and behaviors following service failure. Three independent studies involving 656 respondents and multiple methods are employed to investigate customer rage. Scales for each form of rage emotion, expression, and behavior were developed and used to assess their interrelationships. Results suggest that different forms of customer rage emotions tend to be linked to different types of expressions and behaviors. For example, both Rancorous Rage and Retaliatory Rage emotions tend to increase Verbal expressions (such as raising one's voice, yelling, and making insulting remarks). In contrast, Retaliatory Rage emotion increases Physical expressions (tried to physically harm a service employee, tried to cause damage to property, and threatened to damage property) and Displaced expressions (took anger out on other people nearby, yelled at other people, and took their anger out on other people later on) whereas Rancorous Rage emotion decreases Physical and Displaced expressions. Interestingly, Verbal expressions are linked to passive-aggressive behaviors, such as switching service providers and spreading negative word of mouth while Physical expressions are linked to relatively aggressive behavior, such as a desire for revenge. Implications for scholarly research and retailers are discussed.

Advanced glycation end products (AGEs) are formed as a result of non-enzymatic reaction between the free reducing sugars and proteins, lipids, or nucleic acids. AGEs are predominantly synthesized during chronic hyperglycemic conditions or aging. AGEs interact with their receptor RAGE and activate various sets of genes and proteins of the signal transduction pathway. Accumulation of AGEs and upregulated expression of RAGE is associated with various pathological conditions including diabetes, cardiovascular diseases, neurodegenerative disorders, and cancer. The role of AGE-RAGE signaling has been demonstrated in the progression of various types of cancer and other pathological disorders. The expression of RAGE increases manifold during cancer progression. The activation of AGE-RAGE signaling also perturbs the cellular redox balance and modulates various cell death pathways. The programmed cell death signaling often altered during the progression of malignancies. The cellular reprogramming of AGE-RAGE signaling with cell death machinery during tumorigenesis is interesting to understand the complex signaling mechanism of cancer cells. The present review focus on multiple molecular paradigms relevant to cell death particularly Apoptosis, Autophagy, and Necroptosis that are considerably influenced by the AGE-RAGE signaling in the cancer cells. Furthermore, the review also attempts to shed light on the provenience of AGE-RAGE signaling on oxidative stress and consequences of cell survival mechanism of cancer cells.

Atherosclerosis is the most common type of cardiovascular disease, and it causes intima thickening, plaque development, and ultimate blockage of the artery lumen. Advanced glycation end products (AGEs) are thought to have a role in the development and progression of atherosclerosis. there is developing an enthusiasm for AGEs as a potential remedial target. AGES mainly induce arterial damage and exacerbate the development of atherosclerotic plaques by triggering cell receptor-dependent signalling. The interplay of AGEs with RAGE, a transmembrane signalling receptor present across all cells important to atherosclerosis, changes cell activity, boosts expression of genes, and increases the outflow of inflammatory compounds, resulting in arterial wall injury and plaque formation. Here in this review, function of AGEs in the genesis, progression, and instability of atherosclerosis is discussed. In endothelial and smooth muscle cells, as well as platelets, the interaction of AGEs with their transmembrane cell receptor, RAGE, triggers intracellular signalling, resulting in endothelial damage, vascular smooth muscle cell function modification, and changed platelet activity.

Objectives High glucose (HG)–mediated bone marrow mesenchymal stem cell (BMSC) dysfunction plays a key role in impaired bone formation induced by type 1 diabetes mellitus (T1DM). Morroniside is an iridoid glycoside derived from the Chinese herb Cornus officinalis, and it has abundant biological activities associated with cell metabolism and tissue regeneration. However, the effects and underlying mechanisms of morroniside on HG‐induced BMSC dysfunction remain poorly understood. Materials and methods Alkaline phosphatase (ALP) staining, ALP activity and Alizarin Red staining were performed to assess the osteogenesis of BMSCs. Quantitative real‐time PCR and Western blot (WB) were used to investigate the osteo‐specific markers, receptor for advanced glycation end product (RAGE) signalling and glyoxalase‐1 (Glo1). Additionally, a T1DM rat model was used to assess the protective effect of morroniside in vivo. Results Morroniside treatment reverses the HG‐impaired osteogenic differentiation of BMSCs in vitro. Morroniside suppressed advanced glycation end product (AGEs) formation and RAGE expression by triggering Glo1. Moreover, the enhanced osteogenesis due to morroniside treatment was partially blocked by the Glo1 inhibitor, BBGCP2. Furthermore, in vivo, morroniside attenuated bone loss and improved bone microarchitecture accompanied by Glo1 upregulation and RAGE downregulation. Conclusions These findings suggest that morroniside attenuates HG‐mediated BMSC dysfunction partly through the inhibition of AGE‐RAGE signalling and activation of Glo1 and may be a potential treatment for diabetic osteoporosis. Under pathological diabetic conditions, chronic hyperglycaemia leads to the increased accumulation of advanced glycation end products (AGEs) by methylglyoxal (MG) and activation of receptor for advanced glycation end product (RAGE) signalling. Subsequently, AGE‐RAGE activation induces bone marrow mesenchymal stem cell (BMSC) dysfunction due to a combination of decreased osteogenic differentiation of BMSCs and enhanced inflammation, reactive oxygen species generation and BMSC apoptosis. Finally, reduced osteogenesis of BMSCs causes impaired bone formation in type 1 diabetes. Morroniside triggers Glo1 to degrade MG, thus downregulating AGE‐RAGE signalling, rectifying these downstream detrimental effects and attenuating BMSC dysfunction induced by high glucose.

The receptor for advanced glycation end-products (RAGE) was initially characterized and named for its ability to bind to advanced glycation end-products (AGEs) that form upon the irreversible and non-enzymatic interaction between nucleophiles, such as lysine, and carbonyl compounds, such as reducing sugars. The concentrations of AGEs are known to increase in conditions such as diabetes, as well as during ageing. However, it is now widely accepted that RAGE binds with numerous ligands, many of which can be defined as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The interaction between RAGE and its ligands mainly results in a pro-inflammatory response, and can lead to stress events often favouring mitochondrial dysfunction or cellular senescence. Thus, RAGE should be considered as a pattern recognition receptor (PRR), similar to those that regulate innate immunity. Innate immunity itself plays a central role in inflammaging, the chronic low-grade and sterile inflammation that increases with age and is a potentially important contributory factor in ageing. Consequently, and in addition to the age-related accumulation of PAMPs and DAMPs and increases in pro-inflammatory cytokines from senescent cells and damaged cells, PRRs are therefore important in inflammaging. We suggest here that, through its interconnection with immunity, senescence, mitochondrial dysfunction and inflammasome activation, RAGE is a key contributor to inflammaging and that the pro-longevity effects seen upon blocking RAGE, or upon its deletion, are thus the result of reduced inflammaging.

Nonenzymatic reactions of reducing sugars with primary amino groups of amino acids, proteins, and nucleic acids, followed by oxidative degradations would lead to the formation of advanced glycation endproducts (AGEs). The AGEs exert multifactorial effects on cell damage leading to the onset of neurological disorders. The interaction of AGEs with the receptors for advanced glycation endproducts (RAGE) contribute to the activation of intracellular signaling and the expression of the pro-inflammatory transcription factors and various inflammatory cytokines. This inflammatory signaling cascade is associated with various neurological diseases, including Alzheimer’s disease (AD), secondary effects of traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and diabetic neuropathy, and other AGE-related diseases, including diabetes and atherosclerosis. Furthermore, the imbalance of gut microbiota and intestinal inflammation are also associated with endothelial dysfunction, disrupted blood–brain barrier (BBB) and thereby the onset and progression of AD and other neurological diseases. AGEs and RAGE play an important role in altering the gut microbiota composition and thereby increase the gut permeability and affect the modulation of the immune-related cytokines. The inhibition of the AGE–RAGE interactions, through small molecule-based therapeutics, prevents the inflammatory cascade of events associated with AGE–RAGE interactions, and thereby attenuates the disease progression. Some of the RAGE antagonists, such as Azeliragon, are currently in clinical development for treating neurological diseases, including AD, although currently there have been no FDA-approved therapeutics based on the RAGE antagonists. This review outlines the AGE–RAGE interactions as a leading cause of the onset of neurological diseases and the current efforts on developing therapeutics for neurological diseases based on the RAGE antagonists.

Background: Intestinal inflammation in Crohn’s disease (CD) and ulcerative colitis (UC) is characterised by an influx of neutrophils into the intestinal mucosa. S100A12 is a calcium binding protein with proinflammatory properties. It is secreted by activated neutrophils and interacts with the multiligand receptor for advanced glycation end products (RAGE). Promising anti-inflammatory effects of blocking agents for RAGE have been reported in murine models of colitis. Aims: To investigate expression and serum concentrations of S100A12 in inflammatory bowel disease (IBD). Methods: We performed immunohistochemical studies and immunofluorescence microscopy in biopsies from patients with CD and UC. S100A12 serum concentrations were analysed using a sandwich ELISA. Results: Immunohistochemical studies revealed profound expression of S100A12 in inflamed intestinal tissue from IBD patients whereas no expression was found in tissue from healthy controls. Staining for S100A12 during chronic active CD and UC was restricted to infiltrating neutrophils. Serum S100A12 levels were significantly elevated in patients with active CD (470 (125) ng/ml; p<0.001, n=30) as well as those with active UC (400 (120) ng/ml; p<0.01, n=15) compared with healthy controls (75 (15) ng/ml; n=30). Even in inactive disease, elevated serum concentrations were found, at least in CD. S100A12 levels were well correlated with disease activity in CD and UC. Conclusions: We demonstrated that neutrophil derived S100A12 is strongly upregulated during chronic active IBD, suggesting an important role during the pathogenesis of IBD. Serum S100A12 may serve as a useful marker for disease activity in patients with IBD.