Advanced Glycation End Products Axis Research Articles

Contributions of the receptor for advanced glycation end products axis activation in gastric cancer.

Compelling shreds of evidence derived from both clinical and experimental research have demonstrated the crucial contribution of receptor for advanced glycation end products (RAGE) axis activation in the development of neoplasms, including gastric cancer (GC). This new actor in tumor biology plays an important role in the onset of a crucial and long-lasting inflammatory milieu, not only by supporting phenotypic changes favoring growth and dissemination of tumor cells, but also by functioning as a pattern-recognition receptor in the inflammatory response to Helicobacter pylori infection. In the present review, we aim to highlight how the overexpression and activation of the RAGE axis contributes to the proliferation and survival of GC cells as and their acquisition of more invasive phenotypes that promote dissemination and metastasis. Finally, the contribution of some single nucleotide polymorphisms in the RAGE gene as susceptibility or poor prognosis factors is also discussed.

Receptor of advanced glycation end-products axis and gallbladder cancer: A forgotten connection that we should reconsider.

Compelling evidence derived from clinical and experimental research has demonstrated the crucial contribution of chronic inflammation in the development of neoplasms, including gallbladder cancer. In this regard, data derived from clinical and experimental studies have demonstrated that the receptor of advanced glycation end-products (RAGE)/AGEs axis plays an important role in the onset of a crucial and long-lasting inflammatory milieu, thus supporting tumor growth and development. AGEs are formed in biological systems or foods, and food-derived AGEs, also known as dietary AGEs are known to contribute to the systemic pool of AGEs. Once they bind to RAGE, the activation of multiple and crucial signaling pathways are triggered, thus favoring the secretion of several proinflammatory cytokines also involved in the promotion of gallbladder cancer invasion and migration. In the present review, we aimed to highlight the relevance of the association between high dietary AGEs intakes and high risk for gallbladder cancer, and emerging data supporting that dietary intervention to reduce gallbladder cancer risk is a very attractive approach that deserves much more research efforts.

Receptor for advanced glycation end-products axis and coronavirus disease 2019 in inflammatory bowel diseases: A dangerous liaison?

Compelling evidence supports the crucial role of the receptor for advanced glycation end-products (RAGE) axis activation in many clinical entities. Since the beginning of the coronavirus disease 2019 pandemic, there is an increasing concern about the risk and handling of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in inflammatory gastrointestinal disorders, such as inflammatory bowel diseases (IBD). However, clinical data raised during pandemic suggests that IBD patients do not have an increased risk of contracting SARS-CoV-2 infection or develop a more severe course of infection. In the present review, we intend to highlight how two potentially important contributors to the inflammatory response to SARS-CoV-2 infection in IBD patients, the RAGE axis activation as well as the cross-talk with the renin-angiotensin system, are dampened by the high expression of soluble forms of both RAGE and the angiotensin-converting enzyme (ACE) 2. The soluble form of RAGE functions as a decoy for its ligands, and soluble ACE2 seems to be an additionally attenuating contributor to RAGE axis activation, particularly by avoiding the transactivation of the RAGE axis that can be produced by the virus-mediated imbalance of the ACE/angiotensin II/angiotensin II receptor type 1 pathway.

Exosomal HMGB1 Promoted Cancer Malignancy.

Simple SummaryIn addition to their role in hemostasis and thrombosis, platelets have been implicated in cancer malignancy and thrombocytosis in cancer patients and have been associated with an adverse prognosis. These phenomena indicate that antiplatelet drugs may be useful as an anticancer therapy. Using K562-differentiated megakaryocytes and murine platelets, conditioned medium and exosomes obtained from megakaryocytes and platelets contained high-mobility group box 1 (HMGB1) and promoted cancer cell survival, as well as protected cancer cells from doxorubicin cytotoxicity. Data of tumor-bearing mice established by Lewis lung carcinoma (LLC) cells and C57BL/6 mice revealed that antiplatelet drug dipyridamole and exosome release inhibitor GW4869 mitigated tumor growth and ameliorated concurrent alterations in blood circulation and tumor tissues, as well as platelet infiltration in tumor tissues. Therefore, exosomes and exosomal HMGB1 appear to have roles in platelet-driven cancer malignancy and represent targets of antiplatelet drugs in anticancer treatment.Reciprocal crosstalk between platelets and malignancies underscores the potential of antiplatelet therapy in cancer treatment. In this study, we found that human chronic myeloid leukemia K562 cell-differentiated megakaryocytes and murine platelets produced bioactive substances and these are released into the extracellular space, partly in their exosomal form. High-mobility group box 1 (HMGB1) is a type of exosomal cargo, and the antiplatelet drugs aspirin and dipyridamole interfered with its incorporation into the exosomes. Those released substances and exosomes, along with exogenous HMGB1, promoted cancer cell survival and protected cells from doxorubicin cytotoxicity. In a tumor-bearing model established using murine Lewis lung carcinoma (LLC) cells and C57BL/6 mice, the tumor suppressive effect of dipyridamole correlated well with decreased circulating white blood cells, soluble P-selectin, TGF-β1 (Transforming Growth Factor-β1), exosomes, and exosomal HMGB1, as well as tumor platelet infiltration. Exosome release inhibitor GW4869 exhibited suppressive effects as well. The suppressive effect of dipyridamole on cancer cell survival was paralleled by a reduction of HMGB1/receptor for advanced glycation end-products axis, and proliferation- and migration-related β-catenin, Yes-associated protein 1, Runt-related transcription factor 2, and TGF- β1/Smad signals. Therefore, exosomes and exosomal HMGB1 appear to have roles in platelet-driven cancer malignancy and represent targets of antiplatelet drugs in anticancer treatment.

Inflammation Meets Metabolism: Roles for the Receptor for Advanced Glycation End Products Axis in Cardiovascular Disease.

Fundamental modulation of energy metabolism in immune cells is increasingly being recognized for the ability to impart important changes in cellular properties. In homeostasis, cells of the innate immune system, such as monocytes, macrophages and dendritic cells (DCs), are enabled to respond rapidly to various forms of acute cellular and environmental stress, such as pathogens. In chronic stress milieus, these cells may undergo a re-programming, thereby triggering processes that may instigate tissue damage and failure of resolution. In settings of metabolic dysfunction, moieties such as excess sugars (glucose, fructose and sucrose) accumulate in the tissues and may form advanced glycation end products (AGEs), which are signaling ligands for the receptor for advanced glycation end products (RAGE). In addition, cellular accumulation of cholesterol species such as that occurring upon macrophage engulfment of dead/dying cells, presents these cells with a major challenge to metabolize/efflux excess cholesterol. RAGE contributes to reduced expression and activities of molecules mediating cholesterol efflux. This Review chronicles examples of the roles that sugars and cholesterol, via RAGE, play in immune cells in instigation of maladaptive cellular signaling and the mediation of chronic cellular stress. At this time, emerging roles for the ligand-RAGE axis in metabolism-mediated modulation of inflammatory signaling in immune cells are being unearthed and add to the growing body of factors underlying pathological immunometabolism.

Ethyl Pyruvate Alleviates Pulmonary Hypertension through the Suppression of Pulmonary Artery Smooth Muscle Cell Proliferation via the High Mobility Group Protein B1/Receptor for Advanced Glycation End-Products Axis.

Purpose: Pulmonary arterial hypertension (PAH) is a formidable disease with no effective treatment at present. With the goal of developing potential therapies, we attempted to determine whether ethyl pyruvate (EP) could alleviate PAH and its mechanism.Methods: Pulmonary smooth muscle cells were cultured in conventional low-oxygen environments, and cellular proliferation was monitored after treatment with either EP or phosphate-balanced solution (PBS). Expression of high mobility group protein B1 (HMGB1) and receptor for advanced glycation end-products (RAGE) protein were detected by western blot. After hyperkinetic PAH rat models were treated with EP, hemodynamic data were collected. Right ventricular hypertrophy and pulmonary vascular remodeling were evaluated. Expression of HMGB1 and RAGE protein was also detected.Results: In vitro, proliferative activity increased in low-oxygen environments, but was inhibited by EP treatment. Furthermore, Western blotting showed the decreased expression of HMGB1 and RAGE protein after EP treatment. In vivo, pulmonary artery pressures were attenuated with EP. Right ventricular hypertrophy and pulmonary vascular remodeling were also reversed. Additionally, the expression levels of HMGB1 and RAGE were reduced in lung tissues.Conclusions: EP can alleviate PAH by suppressing the proliferation of pulmonary artery smooth muscle cells via inhibition of HMGB1/RAGE expression.

Bone mineral density and mortality in end-stage renal disease patients.

Osteoporosis characterized by low bone mineral density (BMD) as assessed by dual-energy X-ray absorptiometry (DXA) is common among end-stage renal disease (ESRD) patients and associates with high fracture incidence and high all-cause mortality. This is because chronic kidney disease-mineral bone disorders (CKD-MBDs) promote not only bone disease (osteoporosis and renal dystrophy) but also vascular calcification and cardiovascular disease. The disturbed bone metabolism in ESRD leads to ‘loss of cortical bone’ with increased cortical porosity and thinning of cortical bone rather than to loss of trabecular bone. Low BMD, especially at cortical-rich bone sites, is closely linked to CKD-MBD, vascular calcification and poor cardiovascular outcomes. These effects appear to be largely mediated by shared mechanistic pathways via the ‘bone–vascular axis’ through which impaired bone status associates with changes in the vascular wall. Thus, bone is more than just the scaffolding that holds the body together and protects organs from external forces but is—in addition to its physical supportive function—also an active endocrine organ that interacts with the vasculature by paracrine and endocrine factors through pathways including Wnt signalling, osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/RANK ligand system and the Galectin-3/receptor of advanced glycation end products axis. The insight that osteogenesis and vascular calcification share many similarities—and the knowledge that vascular calcification is a cell-mediated active rather than a passive mineralization process—suggest that low BMD and vascular calcification (‘vascular ossification’) to a large extent represent two sides of the same coin. Here, we briefly review changes of BMD in ESRD as observed using different DXA methods (central and whole-body DXA) at different bone sites for BMD measurements, and summarize recent knowledge regarding the relationships between ‘low BMD’ and ‘fracture incidence, vascular calcification and increased mortality’ in ESRD patients, as well as potential ‘molecular mechanisms’ underlying these associations.

The different roles for the advanced glycation end products axis in heart failure and acute coronary syndrome settings

AimsThis work aimed to compare the behavior of the advanced glycation end products (AGEs) and their soluble receptor (sRAGE) in two cohorts of patients: those with heart failure (HF) and acute coronary syndrome (ACS). Methods and resultsA unicentric observational clinical study was performed in 102 patients with ACS and 102 patients with chronic HF matched by age and gender. At inclusion, fluorescent AGEs were measured by quantitative fluorescence spectroscopy of plasma, and total sRAGE and endogenous secretory RAGE (esRAGE) levels were determined by enzyme-linked immunosorbent assay kits. A 5-year follow-up period was established for recording cardiac death (primary endpoint) and the incidence of non-fatal myocardial infarction or HF readmission (secondary endpoints). Higher glycation parameters were observed in HF patients, whereas no differences in sRAGE forms were found between HF and ACS cohorts, except for cRAGE, which was higher in HF. Associations between glycation parameters and sRAGE forms were observed in HF, but not in ACS. Differences were also evidenced in the long-term prognosis of each cohort: esRAGE showed an independent prognostic value for cardiac death or non-fatal cardiovascular events in HF, but none of the AGE–RAGE variables were predictors in ACS. ConclusionsA different role for the AGE–RAGE axis was observed in HF and ACS. All the sRAGE forms were directly related with glycation parameters in HF, but not in ACS. The independent value of the sRAGE forms on each cardiovascular disease was supported by esRAGE being an independent predictor of bad long-term prognosis only for HF.

Advanced Glycation End Products:Receptors for Advanced Glycation End Products Axis in Coronary Stent Restenosis: A Prospective Study.

This study was aimed to correlate the pre- and 6-month postpercutaneous coronary intervention (PCI) serum concentrations of advanced glycation end products (AGE), soluble receptors for advanced glycation end products (sRAGE), AGE/sRAGE ratio, and serum malondialdehyde (MDA) levels with in-stent restenosis (ISR) among patients receiving either a drug-eluting stent (DES) or a bare-metal stent (BMS).In-stent restenosis remains as an adverse outcome following PCI. Sixty consecutive nondiabetic, Caucasian male patients, diagnosed with a non-ST-elevation myocardial infarction who received either a DES or BMS via PCI, were enrolled. Baseline levels of serum AGE, sRAGE, AGE/sRAGE ratios, MDA, and angiographic parameters were determined at stenting and at 6 months. Patients with and without ISR at 6 months were compared on both baseline and 6-month biomarker levels and within stent types.The pre-PCI serum AGE levels and AGE/sRAGE ratios were higher in ISR patients compared with non-ISR patients, while the pre-PCI and post-PCI serum sRAGE levels were lower in ISR patients compared with non-ISR patients. The pre and post-PCI levels of MDA were also higher in ISR patients. Comparing stent types, relative levels of MDA between those with and without ISR at the respective time points were similar, although changes between time points appeared type specific.Post-PCI ISR correlates with low serum values of sRAGE and high serum values of AGE, MDA, and AGE/sRAGE ratio which are present at stenting. The associations of baseline AGE, sRAGE, AGE/sRAGE, and MDA levels with ISR appear consistent between stent types.

P5673The different role of the advanced glycation end products axis in heart failure and in acute coronary syndrome settings

P5673The different role of the advanced glycation end products axis in heart failure and in acute coronary syndrome settings

From Human Megakaryocytes to Platelets: Effects of Aspirin on High-Mobility Group Box 1/Receptor for Advanced Glycation End Products Axis.

Platelets (PLTs) are the major source of high-mobility group box 1 (HMGB1), a protein that is involved in sterile inflammation of blood vessels and thrombosis. Megakaryocytes (MKs) synthesize HMGB1 and transfer both protein and mRNA into PLTs and PLT-derived microvesicles (MV). Free HMGB1 found in supernatants of in vitro differentiated MKs and in a megakaryoblastic cell line (DAMI cells). Aspirin “in vivo” and “in vitro” not only reduces HMGB1 and receptor for advanced glycation end products expression on MKs and PLTs but also drives the movement of HMGB1 from MKs into PLTs and PLT-derived MV. These findings suggest that consumption of low doses of aspirin reduces the risk of atherosclerosis complications as well as reducing PLT aggregation by the inhibition of COX-1.

Members of the receptor for advanced glycation end products axis as potential therapeutic targets in patients with lupus nephritis.

The relationship of inflammation and the expression of full-length receptor for advanced glycation end products (flRAGE) on monocytes, plasma levels of RAGE ligand high mobility group box protein 1 (HMGB1), soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) was assessed to elucidate the effect of HMGB1/DNA/RAGE-mediated innate inflammatory responses in patients with lupus nephritis. Cell surface expression of flRAGE was elevated on the monocytes of lupus patients, correlated with plasma HMGB1 levels. Plasma sRAGE level negatively correlated with systemic lupus erythematosus (SLE) disease activity index. Plasma esRAGE level was significantly lower in SLE patients with flare while esRAGE/sRAGE ratio negatively correlated with complement C3 level. HMGB1 alone could moderately induce ex vivo IL-6 production from monocytes, resulting in activation of intracellular p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase and nuclear factor (NF)-κB. Moreover, toll-like receptor-9 ligand together with HMGB1 exhibited a synergistic effect on IL-6 and IL-12p70 secretions and the phosphorylation of p38 MAPK and NF-κB. Therefore, over-expression of flRAGE in lupus may lead to the amplification of RAGE ligands-mediated inflammatory responses through the activation of p38 MAPK and NF-κB. Plasma sRAGE may serve as a potential biomarker for disease activity and a future therapeutic target in SLE.

Impact of diet-induced obesity in male mouse reproductive system: The role of advanced glycation end product-receptor for advanced glycation end product axis.

Obesity represents a route to broad physiological dysfunction affecting major organs including male urogenital system. Hyperglycemia, hyperlipidemia, and oxidative stress associated with obesity augment the formation of reactive metabolic by-products, namely advanced glycation end products (AGEs), leading to increased tissue deposition and damage. The exogenous intake and the endogenous accumulation of AGEs contribute to metabolic and reproductive abnormalities in both women and men. The present study assessed the effects of a diet high in saturated fatty acids (SAFA) on the lipid and metabolic profile (AGE levels, oxidative stress) as well as pathogenic (AGE, receptor for AGEs [RAGE] expression, apoptosis) and morphometric parameters of male reproductive system invivo. Effects of switching to a diet rich in monounsaturated fatty acids (MUFA) or equal in the proportion MUFA to SAFA were further investigated. SAFA-fed animals were characterized by increased serum lipid concentrations (p < .05) compared to controls, but AGEs and peroxide levels were not significantly different across the different experimental groups. Elevated AGE deposition was detected for the first time in germ cells with a higher staining intensity in animals on the SAFA diet, compared to MUFA or MUFA-SAFA-fed animals or the control samples (p = .018). In Leydig cells, AGE localization was higher in the entire cohort of high-fat-fed animals compared to controls (p < .05). High-fat-fed mice displayed enhanced apoptosis compared to controls (p < .005). Furthermore, prostatic tissue demonstrated reduction in epithelial folding, an effect which was significantly reversed after MUFA diet administration. Our findings provide the basis for further investigation of AGE-RAGE axis in testicular and prostatic disturbances associated with diet-induced obesity. Simple dietetic intervention has beneficial effects on metabolic dysfunction of reproductive system before overt manifestations, indicating glycation as a promising therapeutic target.

Nε-(carboxymethyl)lysine-receptor for advanced glycation end product axis is a key modulator of obesity-induced dysregulation of adipokine expression and insulin resistance.

Dysregulation of inflammatory adipokines by the adipose tissue plays an important role in obesity-associated insulin resistance. Pathways leading to this dysregulation remain largely unknown. We hypothesized that the receptor for advanced glycation end products (RAGE) and the ligand N(ε)-(carboxymethyl)lysine (CML) are increased in adipose tissue and, moreover, that activation of the CML-RAGE axis plays an important role in obesity-associated inflammation and insulin resistance. In this study, we observed a strong CML accumulation and increased expression of RAGE in adipose tissue in obesity. We confirmed in cultured human preadipocytes that adipogenesis is associated with increased levels of CML and RAGE. Moreover, CML induced a dysregulation of inflammatory adipokines in adipocytes via a RAGE-dependent pathway. To test the role of RAGE in obesity-associated inflammation further, we constructed an obese mouse model that is deficient for RAGE (ie, RAGE(-/-)/Leptr(Db-/-) mice). RAGE(-/-)/Leptr(Db-/-) mice displayed an improved inflammatory profile and glucose homeostasis when compared with RAGE(+/+)/Leptr(Db-/-) mice. In addition, CML was trapped in adipose tissue in RAGE(+/+)/Leptr(Db-/-) mice but not in RAGE(-/-)/Leptr(Db-/-). RAGE-mediated trapping in adipose tissue provides a mechanism underlying CML accumulation in adipose tissue and explaining decreased CML plasma levels in obese subjects. Decreased CML plasma levels in obese individuals were strongly associated with insulin resistance. RAGE-mediated CML accumulation in adipose tissue and the activation of the CML-RAGE axis are important mechanisms involved in the dysregulation of adipokines in obesity, thereby contributing to the development of obesity-associated insulin resistance.

Receptor for advanced glycation end products axis in critically ill patients

Systemic inflammation caused by infection or trauma often leads to adverse outcome in critically ill patients. Binding of ligands to the receptor for advanced glycation end products (RAGE) activates several pathways, including the nuclear factor-kappa B pathway, which generates inflammatory cytokines, proteases and oxidative stress. RAGE activation has been suggested to link amplification and perpetuation of inflammation to subsequent organ damage and adverse outcome in sepsis, acute lung injury and myocardial dysfunction [1]. The soluble receptor, sRAGE, is thought to act as a decoy, thus protecting against further RAGE activation. High mobility group box 1 (HMGB1) is a nuclear protein that is released during cellular stress and damage. S100A12 is a neutrophil-derived protein that acts as a proinflammatory danger signal. Both are ligands for RAGE. We hypothesized that excessive RAGE activation is linked to adverse outcome in critically ill patients and that a different pattern of RAGE activation and inflammation may be present in patients according to underlying pathology.

DAMP signaling in fungal infections and diseases

Fungal infections and diseases predominantly affect patients with deregulated immunity. Compelling experimental and clinical evidence indicate that severe fungal diseases belong to the spectrum of fungus-related inflammatory diseases. Some degree of inflammation is required for protection during the transitional response occurring temporally between the rapid innate and slower adaptive response. However, progressive inflammation worsens disease and ultimately prevents pathogen eradication. The challenge now is to elucidate cellular and molecular pathways distinguishing protective vs. pathogenic inflammation to fungi. In addition to fungal ligands of pattern recognition receptors (pathogen-associated molecular patterns, PAMPs), several host-encoded proteins, the damage-associated molecular patterns (DAMPs), are released during tissue injury and activate innate recognition receptors. DAMPs have been shown to regulate inflammation in fungal diseases. The DAMP/receptor for advanced glycation end-products axis integrated with the PAMP/Toll-like receptors axis in the generation of the inflammatory response in experimental and clinical fungal pneumonia. These emerging themes better accommodate fungal pathogenesis in the face of high-level inflammation seen in several clinical settings and point to DAMP targeting as a novel immunomodulatory strategy in fungal diseases.

Suppression of high-mobility group box-1 and receptor for advanced glycation end-product axis by polymyxin B–immobilized fiber hemoperfusion in septic shock patients

Purpose Endotoxin plays a role in organ failure in septic shock patients. High-mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) axis is also involved in septic shock. We investigated here the effects of endotoxin removal by polymyxin B–immobilized polystyrene fiber (PMX-F) treatment on circulating levels of HMGB1, soluble RAGE (sRAGE), and interleukin-6 (IL-6) in septic shock patients. Materials and Methods Fifteen septic shock patients (70.1 ± 8.5 years) and 15 age- and sex-matched healthy volunteers were included in this study. Polymyxin B–immobilized polystyrene fiber treatment was repeated twice, separated by an interval of 24 hours. Blood samples were collected before and immediately after the second PMX-F treatment for determinations of biochemical variables. Results Systolic and diastolic blood pressures were significantly lower, and endotoxin, IL-6, HMGB1, and sRAGE levels were higher in septic shock patients compared with healthy volunteers. These parameters were significantly improved by PMX-F treatment. The changes in endotoxin obtained by PMX-F treatment were correlated with those in HMGB1, sRAGE, and IL-6. Multiple stepwise regression analysis revealed that IL-6 was a sole independent correlate of endotoxin. Conclusions Our present study suggests that PMX-F treatment could block the HMGB1-RAGE axis in patients with septic shock via removal of endotoxin-induced inflammatory reactions.