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Mangalmurti, Nilam S., Jessica Friedman, Don L. Siegel, Janet Lee, and Steven M. Albelda. "Erythrocyte Advanced Glycation End-Products as Novel Mediators of Endothelial Dysfunction Following Transfusion." Blood 120, no. 21 (November 16, 2012): SCI—47—SCI—47. http://dx.doi.org/10.1182/blood.v120.21.sci-47.sci-47.
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Abstract Abstract SCI-47 Red cell transfusions are associated with the development of acute lung injury in critically ill patients, yet the mechanisms for this association remain unknown. We have previously shown that stored red blood cells (RBCs) express the advanced glycation end-product Nε-carboxymethyl lysine (Nε-CML) (1). Advanced glycation end-products (AGEs), a heterogeneous group of adducts formed during states of increased oxidative stress or hyperglycemia, are thought to exert their effects by binding to membrane receptors, including RAGE (the receptor for advanced glycation-end products). RAGE is a multiligand pattern-recognition receptor implicated in vascular disease whose function in lung endothelium remains unknown. Our previous data demonstrate that RAGE ligands on stored erythrocytes can induce reactive oxygen species in lung endothelial cells. We therefore hypothesized that RAGE ligands on the surface of stored RBCs exacerbate lung inflammation by interacting with the pulmonary endothelium, thus possibly participating in the pathogenesis of lung injury following transfusion. We first examined lung endothelial cells at baseline using multiple techniques and observed low basal expression of RAGE. Because RAGE ligands can induce the expression of RAGE, and stored red blood cells (RBCs) express the RAGE ligand Nε-carboxymethyl lysine (Nε-CML), we investigated whether RBC transfusion would augment RAGE expression on lung endothelium utilizing a syngeneic model of RBC transfusion. Increased lung endothelial RAGE expression and enhanced lung inflammation and endothelial activation was observed, as evidenced by increases in lung high mobility group box 1 (HMGB1) and vascular cell adhesion molecule (VCAM-1) expression following transfusion. These effects were mediated by RAGE, as endothelial activation was absent in RBC-transfused Rage knockout mice. Therefore, functional consequences of RBC transfusion are augmented RAGE expression, increased RAGE ligation, and endothelial activation, thus linking RAGE activation to lung inflammation following RBC transfusion. Disclosures: No relevant conflicts of interest to declare.
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Wautier, Jean-Luc, and Marie-Paule Wautier. "Cellular and Molecular Aspects of Blood Cell–Endothelium Interactions in Vascular Disorders." International Journal of Molecular Sciences 21, no. 15 (July 27, 2020): 5315. http://dx.doi.org/10.3390/ijms21155315.
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In physiology and pathophysiology the molecules involved in blood cell–blood cell and blood cell–endothelium interactions have been identified. Platelet aggregation and adhesion to the walls belonging to vessels involve glycoproteins (GP), GP llb and GP llla and the GP Ib–IX–V complex. Red blood cells (RBCs) in normal situations have little interaction with the endothelium. Abnormal adhesion of RBCs was first observed in sickle cell anemia involving vascular cell adhesion molecule (VCAM)-1, α4β1, Lu/BCAM, and intercellular adhesion molecule (ICAM)-4. More recently RBC adhesion was found to be increased in retinal-vein occlusion (RVO) and in polycythemia vera (PV). The molecules which participate in this process are phosphatidylserine and annexin V in RVO, and phosphorylated Lu/BCAM and α5 laminin chain in PV. The additional adhesion in diabetes mellitus occurs due to the glycated RBC band 3 and the advanced glycation end-product receptors. The multiligand receptor binds advanced glycation end products (AGEs) or S100 calgranulins, or β-amyloid peptide. This receptor for advanced glycation end products is known as RAGE. The binding to RAGE-activated endothelial cells leads to an inflammatory reaction and a prothrombotic state via NADPH activation and altered gene expression. RAGE blockade is a potential target for drugs preventing the deleterious consequences of RAGE activation.
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Kuzan, Aleksandra, Emilia Królewicz, Karolina Nowakowska, Kamilla Stach, Krzysztof Kaliszewski, Paweł Domosławski, Łukasz Kotyra, Andrzej Gamian, and Irena Kustrzeba-Wójcicka. "Contribution of Glycation and Oxidative Stress to Thyroid Gland Pathology—A Pilot Study." Biomolecules 11, no. 4 (April 10, 2021): 557. http://dx.doi.org/10.3390/biom11040557.
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The patho-mechanism of changes in the thyroid gland, including carcinogenesis, is a complex process, which involves oxidative stress. The goal of our investigation was to verify the extent of stress in the thyroid gland related to glycation. The study samples were comprised of blood sera, thyroid, and adipose tissue sections probed from 37 patients diagnosed with thyroid cancers and goiter. Using immuno-enzymatic and fluorometric assays we analyzed the content of advanced glycation end-products (AGEs), pentosidine, receptors for advanced glycation end-products (RAGE), scavenger receptor class (SR)-A, SR-B, glutathione, malondialdehyde and nitric oxide synthase. In addition to classic AGEs, a recent study detected the melibiose-derived glycation (MAGE) product. We demonstrated the presence of AGEs, MAGE and their receptors of the RAGE and SR-A. In addition, in the control samples of thyroid glands SR-B groups were detected as well as of pathological groups without noticeable tendency to antigen concentration in the area of carcinogenesis. Fluorescent AGEs correlate positively with glutathione, which supports the assumption that glycation stress leads to augmentation of oxidative stress and increase of the intensity of antioxidant mechanisms.
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Buckley, Stephen T., and Carsten Ehrhardt. "The Receptor for Advanced Glycation End Products (RAGE) and the Lung." Journal of Biomedicine and Biotechnology 2010 (2010): 1–11. http://dx.doi.org/10.1155/2010/917108.
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The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules. As a pattern-recognition receptor capable of binding a diverse range of ligands, it is typically expressed at low levels under normal physiological conditions in the majority of tissues. In contrast, the lung exhibits high basal level expression of RAGE localised primarily in alveolar type I (ATI) cells, suggesting a potentially important role for the receptor in maintaining lung homeostasis. Indeed, disruption of RAGE levels has been implicated in the pathogenesis of a variety of pulmonary disorders including cancer and fibrosis. Furthermore, its soluble isoforms, sRAGE, which act as decoy receptors, have been shown to be a useful marker of ATI cell injury. Whilst RAGE undoubtedly plays an important role in the biology of the lung, it remains unclear as to the exact nature of this contribution under both physiological and pathological conditions.
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Jensen, Louise J. N., Allan Flyvbjerg, and Mette Bjerre. "Soluble Receptor for Advanced Glycation End Product: A Biomarker for Acute Coronary Syndrome." BioMed Research International 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/815942.
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The receptor of advanced glycation end products (RAGE) and its ligands are linked to the pathogenesis of coronary artery disease (CAD), and circulating soluble receptor of advanced glycation end products (sRAGE), reflecting the RAGE activity, is suggested as a potential biomarker. Elevated sRAGE levels are reported in relation to acute ischemia and this review focuses on the role of sRAGE as a biomarker for the acute coronary syndrome (ACS). The current studies demonstrated that sRAGE levels are elevated in relation to ACS, however during a very narrow time period, indicating that the time of sampling needs attention. Interestingly, activation of RAGE may influence the pathogenesis and reflection in sRAGE levels in acute and stable CAD differently.
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Rouhiainen, Ari, Niko-Petteri Nykänen, Juha Kuja-Panula, Päivi Vanttola, Henri Huttunen, and Heikki Rauvala. "Inhibition of Homophilic Interactions and Ligand Binding of the Receptor for Advanced Glycation End Products by Heparin and Heparin-Related Carbohydrate Structures." Medicines 5, no. 3 (July 30, 2018): 79. http://dx.doi.org/10.3390/medicines5030079.
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Background: Heparin and heparin-related sulphated carbohydrates inhibit ligand binding of the receptor for advanced glycation end products (RAGE). Here, we have studied the ability of heparin to inhibit homophilic interactions of RAGE in living cells and studied how heparin related structures interfere with RAGE–ligand interactions. Methods: Homophilic interactions of RAGE were studied with bead aggregation and living cell protein-fragment complementation assays. Ligand binding was analyzed with microwell binding and chromatographic assays. Cell surface advanced glycation end product binding to RAGE was studied using PC3 cell adhesion assay. Results: Homophilic binding of RAGE was mediated by V1- and modulated by C2-domain in bead aggregation assay. Dimerisation of RAGE on the living cell surface was inhibited by heparin. Sulphated K5 carbohydrate fragments inhibited RAGE binding to amyloid β-peptide and HMGB1. The inhibition was dependent on the level of sulfation and the length of the carbohydrate backbone. α-d-Glucopyranosiduronic acid (glycyrrhizin) inhibited RAGE binding to advanced glycation end products in PC3 cell adhesion and protein binding assays. Further, glycyrrhizin inhibited HMGB1 and HMGB1 A-box binding to heparin. Conclusions: Our results show that K5 polysaccharides and glycyrrhizin are promising candidates for RAGE targeting drug development.
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Sotokawauchi, Ami, Takanori Matsui, Yuichiro Higashimoto, and Sho-ichi Yamagishi. "Fructose causes endothelial cell damage via activation of advanced glycation end products–receptor system." Diabetes and Vascular Disease Research 16, no. 6 (August 2, 2019): 556–61. http://dx.doi.org/10.1177/1479164119866390.
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Objective: Advanced glycation end products and their receptor – RAGE – in the adipose tissues contribute to metabolic derangements in fructose-fed rats. However, it remains unclear whether fructose could cause endothelial cell damage via the activation of AGE-RAGE. Methods: Intracellular advanced glycation end products were evaluated by dot blot analysis. Fructose-derived advanced glycation end products (Fruc-AGEs) were prepared by incubating bovine serum albumin with fructose for 8 weeks. Reactive oxygen species generation was measured using a fluorescent probe. Vascular cell adhesion molecule-1 gene expression was analysed by reverse transcription-polymerase chain reaction. Binding affinities of Fruc-AGEs to DNA-aptamer raised against Fruc-AGEs (Fruc-AGE-aptamer) or RAGE were measured with a quartz crystal microbalance. Results: Fructose increased the advanced glycation end product–specific fluorescence intensity in assay medium, while it stimulated intracellular formation of advanced glycation end products in human umbilical vein endothelial cells. Furthermore, 0.3 mM fructose for 4 days significantly increased reactive oxygen species generation and vascular cell adhesion molecule-1 gene expression in human umbilical vein endothelial cells. Fruc-AGE-aptamer, but not Control-aptamer, bound to Fruc-AGEs with Kd value of 5.60 × 10−6 M and dose-dependently inhibited the binding of Fruc-AGEs to RAGE. Moreover, Fruc-AGE-aptamer prevented the Fruc-AGE- and fructose-induced reactive oxygen species generation and vascular cell adhesion molecule-1 gene expression in human umbilical vein endothelial cells. Conclusion: This study suggests that fructose may elicit endothelial cell damage partly via the activation of AGE-RAGE axis.
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Zhou, Xiaoyan, Jie Weng, Jing Xu, Qiulin Xu, Weiju Wang, Weijin Zhang, Qiaobing Huang, and Xiaohua Guo. "Mdia1 is Crucial for Advanced Glycation End Product-Induced Endothelial Hyperpermeability." Cellular Physiology and Biochemistry 45, no. 4 (2018): 1717–30. http://dx.doi.org/10.1159/000487780.
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Background/Aims: Disruption of endothelial barrier integrity in response to advanced glycation end products (AEGs) stimulation contributes to vasculopathy associated with diabetes mellitus. Mammalian diaphanous-related formin (mDia1) has been reported to bind to the cytoplasmic domain of the receptor for advanced glycation end products (RAGE), which induces a series of cellular processes. This study directly evaluated the participation of mDia1 in AGE-induced hyperpermeability and revealed the precise intracellular signal transductions of this pathological process. Methods: Human umbilical vein endothelial cells (HUVECs) were used in the in vitro studies. Trans-endothelial electric resistance and permeability coefficient for dextran (Pd) were measured to analyze cell permeability. Western blotting, immunofluorescence staining and flow cytometry assay were performed to investigate the underlying mechanism. Dextran flux across the mesentery in mice was monitored to investigate in vivo microvascular permeability. Results: we found that AGEs evoked Nox4 membrane translocation, reactive oxygen species production, phosphorylation of Src and VE-cadherin, dissociation of adherens junctions and eventual endothelial hyperpermeability through RAGE-mDia1 binding. Cells overexpressing mDia1 by recombinant adenovirus infection showed stronger cellular responses induced by AGEs. Down-regulation of mDia1 by infection with an adenovirus encoding siRNA or blockade of RAGE-mDia1 binding by transfection with RAGE mutant plasmids into HUVECs abolished these AGE-induced effects. Furthermore, knockdown of mDia1 using an adenovirus or genetical knockout of RAGE in C57 mice rescued AGE-evoked microvascular hyperpermeability. Conclusion: Our study revealed that mDia1 plays a critical role in AGE-induced microvascular hyperpermeability through binding to RAGE.
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Bohlender, Jürgen M., Sybille Franke, Günter Stein, and Gunter Wolf. "Advanced glycation end products and the kidney." American Journal of Physiology-Renal Physiology 289, no. 4 (October 2005): F645—F659. http://dx.doi.org/10.1152/ajprenal.00398.2004.
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Advanced glycation end products (AGEs) are a heterogeneous group of protein and lipids to which sugar residues are covalently bound. AGE formation is increased in situations with hyperglycemia (e.g., diabetes mellitus) and is also stimulated by oxidative stress, for example in uremia. It appears that activation of the renin-angiotensin system may contribute to AGE formation through various mechanisms. Although AGEs could nonspecifically bind to basement membranes and modify their properties, they also induce specific cellular responses including the release of profibrogenic and proinflammatory cytokines by interacting with the receptor for AGE (RAGE). However, additional receptors could bind AGEs, adding to the complexity of this system. The kidney is both: culprit and target of AGEs. A decrease in renal function increases circulating AGE concentrations by reduced clearance as well as increased formation. On the other hand, AGEs are involved in the structural changes of progressive nephropathies such as glomerulosclerosis, interstitial fibrosis, and tubular atrophy. These effects are most prominent in diabetic nephropathy, but they also contribute to renal pathophysiology in other nondiabetic renal diseases. Interference with AGE formation has therapeutic potential for preventing the progression of chronic renal diseases, as shown from data of animal experiments and, more recently, the first clinical trials.
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Eichhorst, Alexandra, Christoph Daniel, Rita Rzepka, Bettina Sehnert, Falk Nimmerjahn, Reinhard E. Voll, and Nina Chevalier. "Relevance of Receptor for Advanced Glycation end Products (RAGE) in Murine Antibody-Mediated Autoimmune Diseases." International Journal of Molecular Sciences 20, no. 13 (July 1, 2019): 3234. http://dx.doi.org/10.3390/ijms20133234.
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It is incompletely understood how self-antigens become targets of humoral immunity in antibody-mediated autoimmune diseases. In this context, alarmins are discussed as an important level of regulation. Alarmins are recognized by various receptors, such as receptor for advanced glycation end products (RAGE). As RAGE is upregulated under inflammatory conditions, strongly binds nucleic acids and mediates pro-inflammatory responses upon alarmin recognition, our aim was to examine its contribution to immune complex-mediated autoimmune diseases. This question was addressed employing RAGE−/− animals in murine models of pristane-induced lupus, collagen-induced, and serum-transfer arthritis. Autoantibodies were assessed by enzyme-linked immunosorbent assay, renal disease by quantification of proteinuria and histology, arthritis by scoring joint inflammation. The associated immune status was determined by flow cytometry. In both disease entities, we detected tendentiously decreased autoantibody levels in RAGE−/− mice, however no differences in clinical outcome. In accordance with autoantibody levels, a subgroup of the RAGE−/− animals showed a decrease in plasma cells, and germinal center B cells and an increase in follicular B cells. Based on our results, we suggest that RAGE deficiency alone does not significantly affect antibody-mediated autoimmunity. RAGE may rather exert its effects along with other receptors linking environmental factors to auto-reactive immune responses.
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Miyazaki, Dai, Michiko Kandori-Inoue, Yumiko Shimizu, Fumie Ohtani, Ikuyo Chono, Yoshitsugu Inoue, and Satoru Yamagami. "Role Played by Receptors for Advanced Glycosylation End Products in Corneal Endothelial Cells after HSV-1 Infection." International Journal of Molecular Sciences 22, no. 11 (May 29, 2021): 5833. http://dx.doi.org/10.3390/ijms22115833.
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Senescence, sterile inflammation, and infection cause dysfunction of corneal endothelial cells, leading to visual morbidity that may require corneal transplantation. With increasing age, the extracellular matrix is modified by non-enzymatic glycation forming advanced glycation end products (AGEs). The modifications are primarily sensed by the receptors for the AGEs (RAGE) and are manifested as a type I interferon response. Interestingly, in our study, human corneal endothelial cells (HCEn) cells did not respond to the typical RAGE ligands, including the AGEs, high mobility group box 1 (HMGB1), and serum amyloid-A (SAA). Instead, HCEn cells responded exclusively to the CpG DNA, which is possessed by typical corneal pathogen, herpes simplex virus-1 (HSV-1). Upon HSV-1 infection, the surface expression of RAGE was increased, and endocytosed HSV-1 was associated with RAGE and CpG DNA receptor, TLR9. RAGE DNA transfection markedly increased interferon-β secretion by CpG DNA or HSV-1 infection. HSV-1 infection-induced interferon-β secretion was abolished by TLR9 inhibition and partially by RAGE inhibition. Global transcriptional response analysis confirmed that RAGE and TLR9 were both significantly involved in type I interferon responses. We conclude that RAGE is a sensor of HSV-1 infection and provokes a type I interferon response.
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Borriello, Iannuzzi, and Sirangelo. "Pinocembrin Protects from AGE-Induced Cytotoxicity and Inhibits Non-Enzymatic Glycation in Human Insulin." Cells 8, no. 5 (April 26, 2019): 385. http://dx.doi.org/10.3390/cells8050385.
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Advanced glycation end products (AGEs) are the end products of the glycation reaction and have a great importance in clinical science for their association with oxidative stress and inflammation, which play a major role in most chronic diseases, such as cardiovascular disease, neurodegenerative diseases, and diabetes. Their pathogenic effects are generally induced by the interaction between AGEs and the receptor for advanced glycation end product (RAGE) on the cell surface, which triggers reactive oxygen species production, nuclear factor kB (NF-kB) activation, and inflammation. Pinocembrin, the most abundant flavonoid in propolis, has been recently proven to interfere with RAGE activation in Aβ–RAGE-induced toxicity. In the present study, we investigated the ability of pinocembrin to interfere with RAGE signaling pathways activated by AGEs. Interestingly, pinocembrin was able to inhibit oxidative stress and NF-kB activation in cells exposed to AGEs. In addition, it was able to block caspase 3/7 and 9 activation, thus suggesting an active role of this molecule in counteracting AGE–RAGE-induced toxicity mediated by NF-kB signaling pathways. The ability of pinocembrin to affect the glycation reaction has been also tested. Our data suggest that pinocembrin might be a promising molecule in protecting from AGE-mediated pathogenesis.
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Uspenskaya, Yuliya Aleksandrovna, Yuliya Konstantinovna Komleva, Elena Anatol'evna Pozhilenkova, Vladimir Valer'evic Salmin, Ol'ga Leonidovna Lopatina, Aleksandr Anatol'evich Fursov, Pavel Vyacheslavovich Lavrent'ev, Ol'ga Anatol'evna Belova, and Alla Borisovna Salmina. "Ligands of RAGE-Proteins: Role in Intercellular Communication and Pathogenesis of Inflammation." Annals of the Russian academy of medical sciences 70, no. 6 (December 8, 2015): 694–703. http://dx.doi.org/10.15690/vramn566.
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The review contains data on the diversity of endogenous ligands of RAGE receptors (receptor for advanced glycation end products) that play an important role in the signal transduction in (patho) physiological conditions. RAGE takes part in various physiological processes like cell growth and survival, apoptosis and regeneration. They serve as regulators of inflammatory reactions due to their ability to induce secretion of cytokines and chemokines. In addition, they facilitate elimination of apoptotic cells and mediate innate immune response. We discuss mechanisms of soluble RAGE production as well as the role of membrane and soluble forms of the receptor in cell signaling. Several endogenous ligands of RAGE are well-known: advanced glycation end products (AGE), amyloid-beta (Аβ), nuclear high mobility group box 1 proteins (HMGB1), and calcium-binding proteins S100A4, S100A8/A9, S100A12 и S100B. The review is focused on the mechanisms of the ligands production, their secretion from the cells of various origin, interaction with RAGE, and associated intracellular signal transduction pathways. Special attention is paid to the role of RAGE in pathogenesis of inflammation, particularly, in brain injury and neurodegeneration.
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Prasad, Chandan, Kathleen E. Davis, Victorine Imrhan, Shanil Juma, and Parakat Vijayagopal. "Advanced Glycation End Products and Risks for Chronic Diseases: Intervening Through Lifestyle Modification." American Journal of Lifestyle Medicine 13, no. 4 (May 15, 2017): 384–404. http://dx.doi.org/10.1177/1559827617708991.
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Advanced glycation end products (AGEs) are a family of compounds of diverse chemical nature that are the products of nonenzymatic reactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs bind to one or more of their multiple receptors (RAGE) found on a variety of cell types and elicit an array of biologic responses. In this review, we have summarized the data on the nature of AGEs and issues associated with their measurements, their receptors, and changes in their expression under different physiologic and disease states. Last, we have used this information to prescribe lifestyle choices to modulate AGE-RAGE cycle for better health.
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Tesarova, P., M. Kalousova, M. Jachymova, O. Mestek, L. Petruzelka, and T. Zima. "Receptor for advanced glycation end-products (RAGE) - soluble form (sRAGE) and gene polymorphisms in patients with breast cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 21113. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.21113.
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21113 Background: Receptor for advanced glycation end products (RAGE) may be involved in the pathogenesis of the cancer progression and metastasis. Pathological effects mediated via RAGE are physiologically inhibited by soluble RAGE (sRAGE), so the higher sRAGE levels may confer the patients with cancer with better outcome.. Our aim was to study sRAGE and RAGE gene polymorphisms in patients with breast cancer. Methods: We studied sRAGE and RAGE polymorphisms in 120 patients with breast cancer (subdivided based on the clinical stage, histologic grading, expression of hormonal and C-erb B2 receptors) and in 92 healthy controls. Results: Despite higher serum concentrations of AGEs, serum concentrations of sRAGE were lower in patients with breast cancer compared to healthy controls (1581 ± 777 vs. 1803 ± 632 ng/ml, p < 0.05). Serum levels of sRAGE were higher in patients with advanced breast cancer (stage III), lower grade and positive estrogen receptors and intermediate positivity of C-erb B2 (Her-neu) receptors and were also influenced genetically (G82S and 2184 AG polymorphisms of the RAGE gene). Conclusions: Decreased sRAGE levels in patients with breast cancer may contribute to the progression of the disease. Patients with better outcome (with low grade and positive estrogen receptors) have higher sRAGE levels. Progression of the disease, may, however, increase sRAGE levels, possibly as a compensatory mechanism to counteract further progression. No significant financial relationships to disclose.
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Bakunina, Natalya Sergeyevna, Ruslan Ivanovich Glushakov, Natalya Igorevna Tapilskaya, and Petr Dmitriyevich Shabanov. "Pharmacology of polyprenols as adaptogens reducing glycation processes." Reviews on Clinical Pharmacology and Drug Therapy 11, no. 4 (December 15, 2013): 44–53. http://dx.doi.org/10.17816/rcf11444-53.
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Nowadays a significant attention is currently given to the process of glycation which plays an important role in the pathogenesis of vascular complications of diabetes and different neurodegenerative diseases. As a result of inconvertible transformation of early glycation products, stable compounds with different structure are produced - advanced glycation end-products (AGE), which have special patterns leading to pathological development. There are specific receptors of AGE which include phagocyte receptor, RAGE-receptor for advanced glycation end products, and galectin-3. It is necessary to find methods for prevention of development negative processes induced by glycation. It can be administration of glycation inhibitors or the use of compounds, leading to reduction of the level of glycation products, as well as intensification of metabolic processes, which also promotes reduction of glycation. It can also be inhibition of interlocking with receptor and/or post-receptor signaling pathways, which can theoretically reduce the risk of negative phenomena, induced by glycation products. Polyprenols are biologically highly functional active compounds taking part in the process of polysaccharides, glycoproteins, peptidoglycanes and carbohydrate-containing biopolymers biosynthesis. Polyprenols are perspective drugs that can be applied in various fields of experimental and clinical medicine.
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Serveaux-Dancer, Marine, Matthieu Jabaudon, Isabelle Creveaux, Corinne Belville, Raïko Blondonnet, Christelle Gross, Jean-Michel Constantin, Loïc Blanchon, and Vincent Sapin. "Pathological Implications of Receptor for Advanced Glycation End-Product (AGER) Gene Polymorphism." Disease Markers 2019 (February 4, 2019): 1–17. http://dx.doi.org/10.1155/2019/2067353.
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The receptor for advanced glycation end-products (RAGE) is a cell surface transmembrane multiligand receptor, encoded by the AGER gene. RAGE presents many transcripts, is expressed mainly in the lung, and involves multiple pathways (such as NFκB, Akt, p38, and MAP kinases) that initiate and perpetuate an unfavorable proinflammatory state. Due to these numerous functional activities, RAGE is implicated in multiple diseases. AGER is a highly polymorphic gene, with polymorphisms or SNP (single-nucleotide polymorphism) that could be responsible or co-responsible for disease development. This review was designed to shed light on the pathological implications of AGER polymorphisms. Five polymorphisms are described: rs2070600, rs1800624, rs1800625, rs184003, and a 63 bp deletion. The rs2070600 SNP may be associated with the development of human autoimmune disease, diabetes complications, cancer, and lung diseases such as chronic obstructive pulmonary disease and acute respiratory distress syndrome. The rs1800624 SNP involves AGER gene regulation and may be related to reduced risk of heart disease, cancer, Crohn’s disease, and type 1 diabetes complications. The rs1800625 SNP may be associated with the development of diabetic retinopathy, cancer, and lupus but may be protective against cardiovascular risk. The rs184003 SNP seems related to coronary artery disease, breast cancer, and diabetes. The 63 bp deletion may be associated with reduced survival from heart diseases during diabetic nephropathy. Here, these potential associations between AGER polymorphisms and the development of diseases are discussed, as there have been conflicting findings on the pathological impact of AGER SNPs in the literature. These contradictory results might be explained by distinct AGER SNP frequencies depending on ethnicity.
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Chen, Lixian, Yun Cui, Bingyu Li, Jie Weng, Weiju Wang, Shuangshuang Zhang, Xuliang Huang, Xiaohua Guo, and Qiaobing Huang. "Advanced glycation end products induce immature angiogenesis in in vivo and ex vivo mouse models." American Journal of Physiology-Heart and Circulatory Physiology 318, no. 3 (March 1, 2020): H519—H533. http://dx.doi.org/10.1152/ajpheart.00473.2019.
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Proliferative diabetic retinopathy (PDR) is a progressive disease predominantly involving pathological angiogenesis and is characterized by the development of immature, fragile, and easily hemorrhagic new vessels. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play important roles in the progression of diabetic retinopathy. Our previous studies demonstrated that AGEs promoted HUVEC angiogenesis by inducing moesin phosphorylation via RhoA/Rho-associated protein kinase (ROCK) pathway. The aim of this study was to further confirm AGE-induced angiogenesis in vivo and the involvement of RAGE, ROCK, and moesin phosphorylation in this process. We performed the study in an AGE-treated mouse model with various angiogenesis assays in multiple in vivo and ex vivo models. The results demonstrated that AGEs promoted significant neovascularization in whole mount retina and mouse aortic ring of adult and postnatal mice and in Matrigel plug as well, which were consistently accompanied by increased moesin phosphorylation. The increase of AGE-evoked neovascularization and moesin phosphorylation were both attenuated by RAGE knockout or ROCK inhibitor Y27632 administration in mice. We also revealed the pathological characteristics of AGE-promoted angiogenesis by demonstrating the decrease of pericyte coverage and the disarranged endothelial alignment in microvessels. In conclusion, this study provides in vivo evidences that AGEs induce immature angiogenesis by binding to RAGE, activating the RhoA/ROCK signal pathway and inducing moesin phosphorylation. NEW & NOTEWORTHY Advanced glycation end product (AGE)-induced formation of neovessels and phosphorylation of moesin in retina and aortic ring required AGE receptors. AGEs increased neovessels and the phosphorylation of moesin in retina and aortic ring via RhoA/ROCK pathway. AGE-induced immature angiogenesis in AGE-treated mouse retina and aortic ring. The AGE-RAGE axis and moesin could be candidate targets for overcoming relative diseases.
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Sourris, Karly C., Brooke E. Harcourt, Sally A. Penfold, Felicia Y. T. Yap, Amy L. Morley, Philip E. Morgan, Michael J. Davies, Scott T. Baker, George Jerums, and Josephine M. Forbes. "Modulation of the Cellular Expression of Circulating Advanced Glycation End-Product Receptors in Type 2 Diabetic Nephropathy." Experimental Diabetes Research 2010 (2010): 1–9. http://dx.doi.org/10.1155/2010/974681.
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Background. Advanced glycation end-products (AGEs) and their receptors are prominent contributors to diabetic kidney disease.Methods. Flow cytometry was used to measure the predictive capacity for kidney impairment of the AGE receptors RAGE, AGE-R1, and AGE-R3 on peripheral blood mononuclear cells (PBMCs) in experimental models of type 2 diabetes (T2DM) fed varied AGE containing diets and in obese type 2 diabetic and control human subjects.Results. Diets high in AGE content fed to diabetic mice decreased cell surface RAGE on PBMCs and in type 2 diabetic patients with renal impairment (RI). All diabetic mice had elevated Albumin excretion rates (AERs), and high AGE fed dbdb mice had declining Glomerular filtration rate (GFR). Cell surface AGE-R1 expression was also decreased by high AGE diets and with diabetes in dbdb mice and in humans with RI. PBMC expression of AGE R3 was decreased in diabetic dbdb mice or with a low AGE diet.Conclusions. The most predictive PBMC profile for renal disease associated with T2DM was an increase in the cell surface expression of AGE-R1, in the context of a decrease in membranous RAGE expression in humans, which warrants further investigation as a biomarker for progressive DN in larger patient cohorts.
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El-Far, Ali H., Grazyna Sroga, Soad K. Al Jaouni, and Shaker A. Mousa. "Role and Mechanisms of RAGE-Ligand Complexes and RAGE-Inhibitors in Cancer Progression." International Journal of Molecular Sciences 21, no. 10 (May 20, 2020): 3613. http://dx.doi.org/10.3390/ijms21103613.
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Interactions of the receptor for advanced glycation end product (RAGE) and its ligands in the context of their role in diabetes mellitus, inflammation, and carcinogenesis have been extensively investigated. This review focuses on the role of RAGE-ligands and anti-RAGE drugs capable of controlling cancer progression. Different studies have demonstrated interaction of RAGE with a diverse range of acidic (negatively charged) ligands such as advanced glycation end products (AGEs), high-mobility group box1 (HMGB1), and S100s, and their importance to cancer progression. Some RAGE-ligands displayed effects on anti- and pro-apoptotic proteins through upregulation of the phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), and nuclear factor kappa B (NF-κB) pathways, while downregulating p53 in cancer progression. In addition, RAGE may undergo ligand-driven multimodal dimerization or oligomerization mediated through self-association of some of its subunits. We conclude our review by proposing possible future lines of study that could result in control of cancer progression through RAGE inhibition.
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Deng, Quanwen, Can Bu, Liqian Mo, Bin Lv, Shaolian Song, Xiaoyan Xiao, Guo Dan, and Xixiao Yang. "Huang Gan Formula Eliminates the Oxidative Stress Effects of Advanced Oxidation Protein Products on the Divergent Regulation of the Expression of AGEs Receptors via the JAK2/STAT3 Pathway." Evidence-Based Complementary and Alternative Medicine 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/4520916.
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Chronic kidney disease (CKD) has a high prevalence and low cure rate and represents a significant health issue. Oxidative stress is common in CKD due to metabolic disorders, inflammation, and impaired renal function changing normal proteins into advanced oxidation protein products (AOPPs). Huang Gan formula (HGF) is a new type of traditional Chinese herbal medicine. Although we previously investigated the protective effects of HGF against oxidative stress, the mechanism of HGF in CKD is still not fully understood. In this study, we used western blotting, quantitative polymerase chain reaction, and biochemical assays to show that HGF significantly decreased AOPP-induced oxidative stress damage. Moreover, the protective effects of HGF might be associated with upregulation of the advanced glycation end product receptor 1 (AGE-R1) and downregulation of the receptor for advance glycation end products (RAGE). Treatment with HGF and the Janus kinase 2 (JAK2) inhibitor, AG4-90, significantly attenuated AOPP-induced JAK2/STAT3 protein levels. These findings indicate that HGF inhibits AOPP-mediated biological responses by inactivating the JAK2/STAT3 pathway. In conclusion, HGF eliminated AOPP-induced effects in human mesangial cells (HMCs) by interrupting JAK2/STAT3 signaling, which altered RAGE/AGE-R1 expression and reduced oxidative stress in CKD.
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Khanam, Afreen, Saheem Ahmad, Arbab Husain, Shahnawaz Rehman, Alvina Farooqui, and Mohd Aslam Yusuf. "Glycation and Antioxidants: Hand in the Glove of Antiglycation and Natural Antioxidants." Current Protein & Peptide Science 21, no. 9 (December 11, 2020): 899–915. http://dx.doi.org/10.2174/1389203721666200210103304.
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The non-enzymatic interaction of sugar and protein resulting in the formation of advanced glycation end products responsible for cell signaling alterations ultimately leads to the human chronic disorders such as diabetes mellitus, cardiovascular diseases, cancer, etc. Studies suggest that AGEs upon interaction with receptors for advanced glycation end products (RAGE) result in the production of pro-inflammatory molecules and free radicals that exert altered gene expression effect. To date, many studies unveiled the potent role of synthetic and natural agents in inhibiting the glycation reaction at a lesser or greater extent. This review focuses on the hazards of glycation reaction and its inhibition by natural antioxidants, including polyphenols.
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Kumar Pasupulati, Anil, P. Swathi Chitra, and G. Bhanuprakash Reddy. "Advanced glycation end products mediated cellular and molecular events in the pathology of diabetic nephropathy." Biomolecular Concepts 7, no. 5-6 (December 1, 2016): 293–309. http://dx.doi.org/10.1515/bmc-2016-0021.
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AbstractDiabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetic patients and a leading cause of end-stage renal disease (ESRD). Degenerative changes such as glomerular hypertrophy, hyperfiltration, widening of basement membranes, tubulointerstitial fibrosis, glomerulosclerosis and podocytopathy manifest in various degrees of proteinuria in DN. One of the key mechanisms implicated in the pathogenesis of DN is non-enzymatic glycation (NEG). NEG is the irreversible attachment of reducing sugars onto free amino groups of proteins by a series of events, which include the formation of Schiff’s base and an Amadori product to yield advanced glycation end products (AGEs). AGE modification of client proteins from the extracellular matrix induces crosslinking, which is often associated with thickening of the basement membrane. AGEs activate several intracellular signaling cascades upon interaction with receptor for AGEs (RAGE), which manifest in aberrant cellular responses such as inflammation, apoptosis and autophagy, whereas other receptors such as AGE-R1, AGE-R3 and scavenger receptors also bind to AGEs and ensue endocytosis and degradation of AGEs. Elevated levels of both serum and tissue AGEs are associated with adverse renal outcome. Increased evidence supports that attenuation of AGE formation and/or inhibition of RAGE activation manifest(s) in improving renal function. This review provides insights of NEG, discusses the cellular and molecular events triggered by AGEs, which manifest in the pathogenesis of DN including renal fibrosis, podocyte epithelial-mesenchymal transition and activation of renin-angiotensin system. Therapies designed to target AGEs, such as inhibitors of AGEs formation and crosslink breakers, are discussed.
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Asadipooya, Kamyar, and Edilfavia Mae Uy. "Advanced Glycation End Products (AGEs), Receptor for AGEs, Diabetes, and Bone: Review of the Literature." Journal of the Endocrine Society 3, no. 10 (July 10, 2019): 1799–818. http://dx.doi.org/10.1210/js.2019-00160.
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AbstractDiabetes compromises bone cell metabolism and function, resulting in increased risk of fragility fracture. Advanced glycation end products (AGEs) interact with the receptor for AGEs (RAGE) and can make a meaningful contribution to bone cell metabolism and/or alter function. Searches in PubMed using the key words “advanced glycation end-product,” “RAGE,” “sRAGE,” “bone,” and “diabetes” were made to explain some of the clinical outcomes of diabetes in bone metabolism through the AGE–RAGE signaling pathway. All published clinical studies were included in tables. The AGE–RAGE signaling pathway participates in diabetic complications, including diabetic osteopathy. Some clinical results in diabetic patients, such as reduced bone density, suppressed bone turnover markers, and bone quality impairment, could be potentially due to AGE–RAGE signaling consequences. However, the AGE–RAGE signaling pathway has some helpful roles in the bone, including an increase in osteogenic function. Soluble RAGE (sRAGE), as a ligand decoy, may increase in either conditions of RAGE production or destruction, and then it cannot always reflect the AGE–RAGE signaling. Recombinant sRAGE can block the AGE–RAGE signaling pathway but is associated with some limitations, such as accessibility to AGEs, an increase in other RAGE ligands, and a long half-life (24 hours), which is associated with losing the beneficial effect of AGE/RAGE. As a result, sRAGE is not a helpful marker to assess activity of the RAGE signaling pathway. The recombinant sRAGE cannot be translated into clinical practice due to its limitations.
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Sharma, Anil K., Var R. Sharma, Girish K. Gupta, Ghulam Md Ashraf, and Mohammad A. Kamal. "Advanced Glycation End Products (AGEs), Glutathione and Breast Cancer: Factors, Mechanism and Therapeutic Interventions." Current Drug Metabolism 20, no. 1 (March 11, 2019): 65–71. http://dx.doi.org/10.2174/1389200219666180912104342.
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Background: Advanced Glycation End products (AGEs) are basically the end result of glycation of proteins and/or lipids in the presence of sugars. Specific cases of hyperglycemia have been reported with increased propensity of generation of AGEs. Many chronic and deadly diseases such as diabetes, cancer and neurodegenerative disorders have been known to be caused as a result of generation of AGEs. The role of glutathione (GSH) metabolism and its intricate association with AGEs have also been well established in breast cancer prognosis and treatment. To understand the etiology, mechanism and production of AGEs along with clinical relevance of Receptors for Advanced Glycation End-products (RAGE) and RAGE ligands, their interplay with GSH is of paramount importance especially in relation to breast cancer. Methods: The available literature using PubMed, National Library of Medicine database, Web of Science and SCOPUS indexed, Science Direct and other prestigious journals have been systematically reviewed using the keywords: advanced glycation end-products, breast cancer, glutathione RAGE, and AGEs inhibitors. This narrative review of all the relevant papers with significant citations has led us to have greater insight into the action mechanism and potential therapeutic significance of AGEs inhibitors. Results: Targeting breast cancer with the specific immunoglobulins and with other therapeutic interventions is needed to inhibit the generation of AGEs and manage glutathione expression, thus having strong implications in the management of breast cancer. Many RAGE ligands such as HMGB1, S100P, S100A8, S100A9 etc. have been known to enhance RAGE expression which may further lead to increased proliferation, migration and metastatic nature of tumor cells. Hence, RAGE and RAGE ligands in a close linkup with GSH may prove to be effective therapeutic markers of severity of breast cancer and for angiogenesis of tumor. Conclusion: This review provides a strong platform to comprehend the etiology, mechanism and production of AGEs and glutathione along with the agents which can block their production, paving a way for the therapeutic intervention and an amicable solution to treat and manage breast cancer.
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Noguchi, Taketoshi, Toshiyuki Sado, Katsuhiko Naruse, Hiroshi Shigetomi, Akira Onogi, Shoji Haruta, Ryuji Kawaguchi, et al. "Evidence for Activation of Toll-Like Receptor and Receptor for Advanced Glycation End Products in Preterm Birth." Mediators of Inflammation 2010 (2010): 1–10. http://dx.doi.org/10.1155/2010/490406.
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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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Lee, Hee-Weon, Min Ji Gu, Yoonsook Kim, Jee-Young Lee, Seungju Lee, In-Wook Choi, and Sang Keun Ha. "Glyoxal-Lysine Dimer, an Advanced Glycation End Product, Induces Oxidative Damage and Inflammatory Response by Interacting with RAGE." Antioxidants 10, no. 9 (September 17, 2021): 1486. http://dx.doi.org/10.3390/antiox10091486.
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The glyoxal-lysine dimer (GOLD), which is a glyoxal (GO)-derived advanced glycation end product (AGE), is produced by the glycation reaction. In this study, we evaluated the effect of GOLD on the oxidative damage and inflammatory response in SV40 MES 13 mesangial cells. GOLD significantly increased the linkage with the V-type immunoglobulin domain of RAGE, a specific receptor of AGE. We found that GOLD treatment increased RAGE expression and reactive oxygen species (ROS) production in mesangial cells. GOLD remarkably regulated the protein and mRNA expression of nuclear factor erythroid 2-related factor 2 (NRF2) and glyoxalase 1 (GLO1). In addition, mitochondrial deterioration and inflammation occurred via GOLD-induced oxidative stress in mesangial cells. GOLD regulated the mitogen-activated protein kinase (MAPK) and the release of proinflammatory cytokines associated with the inflammatory mechanism of mesangial cells. Furthermore, oxidative stress and inflammatory responses triggered by GOLD were suppressed through RAGE inhibition using RAGE siRNA. These results demonstrate that the interaction of GOLD and RAGE plays an important role in the function of mesangial cells.
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Yang, Fan, Zhe Wang, John H. Zhang, Jiping Tang, Xin Liu, Liang Tan, Qing-Yuan Huang, and Hua Feng. "Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage." Stroke 46, no. 5 (May 2015): 1328–36. http://dx.doi.org/10.1161/strokeaha.114.008336.
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Background and Purpose— To determine whether the receptor for advanced glycation end-products (RAGE) plays a role in early brain injury from intracerebral hemorrhage (ICH), RAGE expression and activation after injury were examined in a rat model of ICH with or without administration of a RAGE-specific antagonist (FPS-ZM1). Methods— Autologous arterial blood was injected into the basal ganglia of rats to induce ICH. The motor function of the rats was examined, and water content was detected after euthanization. Blood–brain barrier permeability was determined by Evans blue staining and colloidal gold nanoparticle tracers. Nerve fiber injury in white matter was determined by diffusion tensor imaging analysis, and the expression of target genes was analyzed by Western blotting and quantitative reverse transcription polymerase chain reaction. FPS-ZM1 was administered by intraperitoneal injection. Results— Expression of RAGE and its ligand high-mobility group protein B1 were increased at 12 hours after ICH, along with blood–brain barrier permeability and perihematomal nerve fiber injury. RAGE and nuclear factor-κB p65 upregulation were also observed when FeCl 2 was infused into the basal ganglia at 24 hours. FPS-ZM1 administration resulted in significant improvements of blood–brain barrier damage, brain edema, motor dysfunction, and nerve fiber injury, and the expression of RAGE, nuclear factor-κB p65, proinflammatory mediators interleukin 1β, interleukin-6, interleukin-8R, cyclooxygenase-2, inducible nitric oxide synthase, and matrix metallopeptidase-9 was attenuated. Moreover, decreases in claudin-5 and occludin expression were partially recovered. FPS-ZM1 also reversed FeCl 2 -induced RAGE and nuclear factor-κB p65 upregulation. Conclusions— RAGE signaling is involved in blood–brain barrier and white matter fiber damage after ICH, the initiation of which is associated with iron. RAGE antagonists represent a novel therapeutic intervention to prevent early brain injury after ICH.
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Grimm, Stefanie, Christiane Ott, Melanie Hörlacher, Daniela Weber, Annika Höhn, and Tilman Grune. "Advanced-glycation-end-product-induced formation of immunoproteasomes: involvement of RAGE and Jak2/STAT1." Biochemical Journal 448, no. 1 (October 18, 2012): 127–39. http://dx.doi.org/10.1042/bj20120298.
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AGEs (advanced glycation-end products) accumulate during aging and several pathologies such as Alzheimer's disease and diabetes. These protein products are known to inhibit proteolytic pathways. Moreover, AGEs are known to be involved in the activation of immune responses. In the present study we demonstrate that AGEs induce the expression of immunoproteasomal subunits. To elucidate a molecular basis underlying the observed effects we were able to demonstrate an activation of the Jak2 (Janus kinase 2)/STAT1 (signal transducer and activator of transcription 1) pathway. Inhibition of Jak2 by AG-490 and STAT1 by specific siRNA (small interfering RNA) abolished AGEinduced expression of immunoproteasomal subunits. Furthermore, silencing of RAGE (receptor for AGEs) revealed that AGE-induced up-regulation of the immunoproteasome is mediated by a RAGE signalling process. Thus we have described for the first time that the signalling pathway of Jak2 and STAT1 activated by AGEs via RAGE is involved in the induction of the immunoproteasome.
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Reynolds, Paul R., Stephen D. Kasteler, Manuel G. Cosio, Anne Sturrock, Tom Huecksteadt, and John R. Hoidal. "RAGE: developmental expression and positive feedback regulation by Egr-1 during cigarette smoke exposure in pulmonary epithelial cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 294, no. 6 (June 2008): L1094—L1101. http://dx.doi.org/10.1152/ajplung.00318.2007.
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The receptor for advanced glycation end-products (RAGE) is a member of the immunoglobin superfamily of multiligand receptors. Following ligand binding, mechanisms associated with host defense, tissue remodeling, and inflammation are activated. RAGE is highly expressed in pulmonary epithelium transitioning from alveolar type (AT) II to ATI cells and is upregulated in the presence of ligand; however, the regulation and function of RAGE during development are less clear. Herein, immunohistochemistry demonstrated a temporal-spatial pattern of RAGE expression in pulmonary epithelial cells from embryonic day 17.5 to postnatal day 10. Cotransfection experiments revealed that the mouse RAGE promoter was activated by early growth response gene 1 (Egr-1) and inhibited by thyroid transcription factor-1 (TTF-1) via interaction with specific regulatory elements. A rat ATI cell line (R3/1) with endogenous RAGE expression also differentially regulated RAGE when transfected with TTF-1 or Egr-1. Because Egr-1 is markedly induced in pulmonary epithelial cells exposed to cigarette smoke extract (CSE; Reynolds PR, Hoidal JR. Am J Respir Cell Mol Biol 35: 314–319, 2006.), we sought to investigate RAGE induction by CSE. Employing RT-PCR and Western blotting, RAGE and common ligands (amphoterin and S100A12) were upregulated in epithelial (R3/1 and A549) and macrophage (RAW) cell lines following exposure to CSE. Immunostaining for RAGE in cells similarly exposed and in lungs from mice exposed to cigarette smoke for 6 mo revealed elevated RAGE expression in pulmonary epithelium. After the addition of glyoxylated BSA, an advanced glycation end-product that binds RAGE, real-time RT-PCR detected a 200-fold increase in Egr-1. These results indicate that Egr-1 regulates RAGE expression during development and the likelihood of positive feedback involving Egr-1 and RAGE in cigarette smoke-related disease.
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Sirois, Cherilyn M., Tengchuan Jin, Allison L. Miller, Damien Bertheloot, Hirotaka Nakamura, Gabor L. Horvath, Abubakar Mian, et al. "RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA." Journal of Experimental Medicine 210, no. 11 (September 30, 2013): 2447–63. http://dx.doi.org/10.1084/jem.20120201.
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Recognition of DNA and RNA molecules derived from pathogens or self-antigen is one way the mammalian immune system senses infection and tissue damage. Activation of immune signaling receptors by nucleic acids is controlled by limiting the access of DNA and RNA to intracellular receptors, but the mechanisms by which endosome-resident receptors encounter nucleic acids from the extracellular space are largely undefined. In this study, we show that the receptor for advanced glycation end-products (RAGE) promoted DNA uptake into endosomes and lowered the immune recognition threshold for the activation of Toll-like receptor 9, the principal DNA-recognizing transmembrane signaling receptor. Structural analysis of RAGE–DNA complexes indicated that DNA interacted with dimers of the outermost RAGE extracellular domains, and could induce formation of higher-order receptor complexes. Furthermore, mice deficient in RAGE were unable to mount a typical inflammatory response to DNA in the lung, indicating that RAGE is important for the detection of nucleic acids in vivo.
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Prasad, Kailash, Abdullah Sarkar, Mohammad Zafar, Ahmed Shoker, Hamdi Moselhi, Maryann Tranquilli, Bulat Ziganshin, and John Elefteriades. "Advanced Glycation End Products and its Soluble Receptors in the Pathogenesis of Thoracic Aortic Aneurysm." AORTA 04, no. 01 (February 2016): 1–10. http://dx.doi.org/10.12945/j.aorta.2015.15.018.
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Background: Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of thoracic aortic aneurysms (TAAs). Cytokines [Interleukin (IL)-Iβ, IL-2, IL-6, and TNF-α)] increase the expression of MMP-2 and -3. Advanced glycation end products (AGEs) interact with cell receptors to increase the release of cytokines. Circulating soluble receptors for AGEs (sRAGE) and endogenous secretory RAGE (esRAGE) compete with membrane bound RAGE for binding with AGEs and reduce the production of cytokines. It is hypothesized that low levels of serum sRAGE and esRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE would increase the levels of cytokines that would increase the levels MMPs, thus contributing to the formation of TAAs. Methods: The study population was composed of 17 control subjects and 20 patients with TAA. Blood samples were collected for measurement of serum sRAGE, esRAGE, AGEs, cytokines, and MMPs. AGEs, sRAGE, and esRAGE were measured using ELISA kits, whereas the remaining parameters were measured using the Luminex Multi-Analyte system. Results: The levels of sRAGE were lower, while the levels of AGEs, AGEs/sRAGE, AGEs/esRAGE, cytokines and MMPs were higher in patients with TAA compared to controls. The levels of sRAGE were inversely correlated with cytokines and MMPs, while AGEs, AGEs/sRAGE and AGEs/esRAGE were positively correlated with cytokines and MMPs. Cytokines were positively correlated with MMPs. Conclusions: The data suggest that the AGE-RAGE axis may be involved in the pathogenesis of TAA and that low levels of sRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE are risk factors for TAA.
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Tancharoen, Salunya, Tassanee Tengrungsun, Theeralaksna Suddhasthira, Kiyoshi Kikuchi, Nuttavun Vechvongvan, Masayuki Tokuda, and Ikuro Maruyama. "Overexpression of Receptor for Advanced Glycation End Products and High-Mobility Group Box 1 in Human Dental Pulp Inflammation." Mediators of Inflammation 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/754069.
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High mobility group box 1 (HMGB1), a nonhistone DNA-binding protein, is released into the extracellular space and promotes inflammation. HMGB1 binds to related cell signaling transduction receptors, including receptor for advanced glycation end products (RAGE), which actively participate in vascular and inflammatory diseases. The aim of this study was to examine whether RAGE and HMGB1 are involved in the pathogenesis of pulpitis and investigate the effect of Prevotella intermedia (P. intermedia) lipopolysaccharide (LPS) on RAGE and HMGB1 expression in odontoblast-like cells (OLC-1). RAGE and HMGB1 expression levels in clinically inflamed dental pulp were higher than those in healthy dental pulp. Upregulated expression of RAGE was observed in odontoblasts, stromal pulp fibroblasts-like cells, and endothelial-like cell lining human pulpitis tissue. Strong cytoplasmic HMGB1 immunoreactivity was noted in odontoblasts, whereas nuclear HMGB1 immunoreactivity was seen in stromal pulp fibroblasts-like cells in human pulpitis tissue. LPS stimulated OLC-1 cells produced HMGB1 in a dose-dependent manner through RAGE. HMGB1 translocation towards the cytoplasm and secretion from OLC-1 in response to LPS was inhibited by TPCA-1, an inhibitor of NF-κB activation. These findings suggest that RAGE and HMGB1 play an important role in the pulpal immune response to oral bacterial infection.
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Nelson, Michael B., Adam C. Swensen, Duane R. Winden, Jared S. Bodine, Benjamin T. Bikman, and Paul R. Reynolds. "Cardiomyocyte mitochondrial respiration is reduced by receptor for advanced glycation end-product signaling in a ceramide-dependent manner." American Journal of Physiology-Heart and Circulatory Physiology 309, no. 1 (July 1, 2015): H63—H69. http://dx.doi.org/10.1152/ajpheart.00043.2015.
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Cigarette smoke exposure is associated with an increased risk of cardiovascular complications. The role of advanced glycation end products (AGEs) is already well established in numerous comorbidities, including cardiomyopathy. Given the role of AGEs and their receptor, RAGE, in activating inflammatory pathways, we sought to determine whether ceramides could be a mediator of RAGE-induced altered heart mitochondrial function. Using an in vitro model, we treated H9C2 cardiomyocytes with the AGE carboxy-methyllysine before mitochondrial respiration assessment. We discovered that mitochondrial respiration was significantly impaired in AGE-treated cells, but not when cotreated with myriocin, an inhibitor of de novo ceramide biosynthesis. Moreover, we exposed wild-type and RAGE knockout mice to secondhand cigarette smoke and found reduced mitochondrial respiration in the left ventricular myocardium from wild-type mice, but RAGE knockout mice were protected from this effect. Finally, conditional overexpression of RAGE in the lungs of transgenic mice elicited a robust increase in left ventricular ceramides in the absence of smoke exposure. Taken together, these findings suggest a RAGE-ceramide axis as an important contributor to AGE-mediated disrupted cardiomyocyte mitochondrial function.
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Chhipa, Abu Sufiyan, Swapnil P. Borse, Ruma Baksi, Sunali Lalotra, and Manish Nivsarkar. "Targeting receptors of advanced glycation end products (RAGE): Preventing diabetes induced cancer and diabetic complications." Pathology - Research and Practice 215, no. 11 (November 2019): 152643. http://dx.doi.org/10.1016/j.prp.2019.152643.
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Brinkley, Tina E., Richard D. Semba, Stephen B. Kritchevsky, and Denise K. Houston. "Dietary protein intake and circulating advanced glycation end product/receptor for advanced glycation end product concentrations in the Health, Aging, and Body Composition Study." American Journal of Clinical Nutrition 112, no. 6 (September 21, 2020): 1558–65. http://dx.doi.org/10.1093/ajcn/nqaa241.
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ABSTRACT Background Advanced glycation end products (AGEs) promote adverse health effects and may contribute to the multi-system functional decline observed in aging. Diet is a major source of AGEs, and foods high in protein may increase circulating AGE concentrations. However, epidemiological evidence that high-protein diets increase AGEs is lacking. Objectives We examined whether dietary protein intake was associated with serum concentrations of the major AGE carboxymethyl-lysine (CML) and the soluble receptor for AGEs (sRAGE) in 2439 participants from the Health, Aging, and Body Composition study (mean age, 73.6 ± 2.9 y; 52% female; 37% black). Methods CML and sRAGE were measured by ELISA, and the CML/sRAGE ratio was calculated. Protein intake was estimated using an interviewer-administered FFQ and categorized based on current recommendations for older adults: &lt;0.8 g/kg/d (n = 1077), 0.8 to &lt;1.2 g/kg/d (n = 922), and ≥1.2 g/kg/d (n = 440). Associations between protein intake and AGE-RAGE biomarkers were examined using linear regression models adjusted for demographics, height, lifestyle behaviors, prevalent disease, cognitive function, inflammation, and other dietary factors. Results CML concentrations were higher in individuals with higher total protein intake (adjusted least squares mean ± SE: &lt;0.8 g/kg/d, 829 ± 17 ng/ml; 0.8 to &lt;1.2 g/kg/d, 860 ± 15 ng/ml; ≥1.2 g/kg/d, 919 ± 23 ng/ml; P for trend = 0.001), as were sRAGE concentrations (&lt;0.8 g/kg/d, 1412 ± 34 pg/ml; 0.8 to &lt;1.2 g/kg/d, 1479 ± 31 pg/ml; ≥1.2 g/kg/d, 1574 ± 47 pg/ml; P for trend &lt; 0.0001). Every 0.1 g/kg/d increment in total protein intake was associated with a 13.3 ± 3.0 ng/ml increment in CML and a 22.1 ± 6.0 pg/ml increment in sRAGE (P &lt; 0.0001 for both). Higher CML and sRAGE concentrations were also associated with higher intakes of both animal and vegetable protein (all P values ≤ 0.01). There were no significant associations with the CML/sRAGE ratio. Conclusions Higher dietary protein intake was associated with higher CML and sRAGE concentrations in older adults; however, the CML/sRAGE ratio remained similar across groups.
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Bronowicka-Szydełko, Agnieszka, Łukasz Kotyra, Łukasz Lewandowski, Andrzej Gamian, and Irena Kustrzeba-Wójcicka. "Role of Advanced Glycation End-Products and Other Ligands for AGE Receptors in Thyroid Cancer Progression." Journal of Clinical Medicine 10, no. 18 (September 10, 2021): 4084. http://dx.doi.org/10.3390/jcm10184084.
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To date, thyroid cancers (TCs) remain a clinical challenge owing to their heterogeneous nature. The etiopathology of TCs is associated not only with genetic mutations or chromosomal rearrangements, but also non-genetic factors, such as oxidative-, nitrosative-, and carbonyl stress-related alterations in tumor environment. These factors, through leading to the activation of intracellular signaling pathways, induce tumor tissue proliferation. Interestingly, the incidence of TCs is often coexistent with various simultaneous mutations. Advanced glycation end-products (AGEs), their precursors and receptors (RAGEs), and other ligands for RAGEs are reported to have significant influence on carcinogenesis and TCs progression, inducing gene mutations, disturbances in histone methylation, and disorders in important carcinogenesis-related pathways, such as PI3K/AKT/NF-kB, p21/MEK/MPAK, or JAK/STAT, RAS/ERK/p53, which induce synthesis of interleukins, growth factors, and cytokines, thus influencing metastasis, angiogenesis, and cancer proliferation. Precursors of AGE (such as methylglyoxal (MG)) and selected ligands for RAGEs: AS1004, AS1008, and HMGB1 may, in the future, become potential targets for TCs treatment, as low MG concentration is associated with less aggressive anaplastic thyroid cancer, whereas the administration of anti-RAGE antibodies inhibits the progression of papillary thyroid cancer and anaplastic thyroid cancer. This review is aimed at collecting the information on the role of compounds, engaged in glycation process, in the pathogenesis of TCs. Moreover, the utility of these compounds in the diagnosis and treatment of TCs is thoroughly discussed. Understanding the mechanism of action of these compounds on TCs pathogenesis and progression may potentially be the grounds for the development of new treatment strategies, aiming at quality-of-life improvements.
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Wu, Yidi, Wenwu Zhang, and Susan J. Gunst. "S100A4 is secreted by airway smooth muscle tissues and activates inflammatory signaling pathways via receptors for advanced glycation end products." American Journal of Physiology-Lung Cellular and Molecular Physiology 319, no. 1 (July 1, 2020): L185—L195. http://dx.doi.org/10.1152/ajplung.00347.2019.
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S100A4 is a low-molecular-mass (12 kDa) EF-hand Ca2+-binding S100 protein that is expressed in a broad range of normal tissue and cell types. S100A4 can be secreted from some cells to act in an autocrine or paracrine fashion on target cells and tissues. S100A4 has been reported in the extracellular fluids of subjects with several inflammatory diseases, including asthma. Airway smooth muscle plays a critical role in airway inflammation by synthesizing and secreting inflammatory cytokines. We hypothesized that S100A4 may play an immunomodulatory role in airway smooth muscle. Trachealis smooth muscle tissues were stimulated with recombinant His-S100A4, and the effects on inflammatory responses were evaluated. S100A4 induced the activation of Akt and NF-κB and stimulated eotaxin secretion. It also increased the expression of RAGE and endogenous S100A4 in airway tissues. Stimulation of airway smooth muscle tissues with IL-13 or TNF-α induced the secretion of S100A4 from the tissues and promoted the expression of endogenous receptors for advanced glycation end products (RAGE) and S100A4. The role of RAGE in mediating the responses to S100A4A was evaluated by expressing a mutant nonfunctional RAGE (RAGEΔcyto) in tracheal muscle tissues and by treating tissues with a RAGE inhibitor. S100A4 did not activate NF-κB or Akt in tissues that were expressing RAGEΔcyto or treated with a RAGE inhibitor, indicating that S100A4 mediates its effects by acting on RAGE. Our results demonstrate that inflammatory mediators stimulate the synthesis and secretion of S100A4 in airway smooth muscle tissues and that extracellular S100A4 acts via RAGE to mediate airway smooth muscle inflammation.
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Frank, Franziska, Veronika Bezold, Kaya Bork, Philip Rosenstock, Jonas Scheffler, and Rüdiger Horstkorte. "Advanced glycation endproducts and polysialylation affect the turnover of the neural cell adhesion molecule (NCAM) and the receptor for advanced glycation endproducts (RAGE)." Biological Chemistry 400, no. 2 (January 28, 2019): 219–26. http://dx.doi.org/10.1515/hsz-2018-0291.
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Abstract The balance between protein synthesis and degradation regulates the amount of expressed proteins. This protein turnover is usually quantified as the protein half-life time. Several studies suggest that protein degradation decreases with age and leads to increased deposits of damaged and non-functional proteins. Glycation is an age-dependent, non-enzymatic process leading to posttranslational modifications, so-called advanced glycation endproducts (AGE), which usually damage proteins and lead to protein aggregation. AGE are formed by the Maillard reaction, where carbonyls of carbohydrates or metabolites react with amino groups of proteins. In this study, we quantified the half-life time of two important receptors of the immunoglobulin superfamily, the neural cell adhesion molecule (NCAM) and the receptor for advanced glycation end products (RAGE) before and after glycation. We found, that in two rat PC12 cell lines glycation leads to increased turnover, meaning that glycated, AGE-modified proteins are degraded faster than non-glycated proteins. NCAM is the most prominent carrier of a unique enzymatic posttranslational modification, the polysialylation. Using two PC12 cell lines (a non-polysialylated and a polysialylated one), we could additionally demonstrate, that polysialylation of NCAM has an impact on its turnover and that it significantly increases its half-life time.
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TANJI, NOZOMU, GLEN S. MARKOWITZ, CAIFENG FU, THOMAS KISLINGER, AKIHIKO TAGUCHI, MONIKA PISCHETSRIEDER, DAVID STERN, ANN MARIE SCHMIDT, and VIVETTE D. D'AGATI. "Expression of Advanced Glycation End Products and Their Cellular Receptor RAGE in Diabetic Nephropathy and Nondiabetic Renal Disease." Journal of the American Society of Nephrology 11, no. 9 (September 2000): 1656–66. http://dx.doi.org/10.1681/asn.v1191656.
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Abstract.Advanced glycation end products (AGE) contribute to diabetic tissue injury by two major mechanisms,i.e., the alteration of extracellular matrix architecture through nonenzymatic glycation, with formation of protein crosslinks, and the modulation of cellular functions through interactions with specific cell surface receptors, the best characterized of which is the receptor for AGE (RAGE). Recent evidence suggests that the AGE-RAGE interaction may also be promoted by inflammatory processes and oxidative cellular injury. To characterize the distributions of AGE and RAGE in diabetic kidneys and to determine their specificity for diabetic nephropathy, an immunohistochemical analysis of renal biopsies from patients with diabetic nephropathy (n= 26), hypertensive nephrosclerosis (n= 7), idiopathic focal segmental glomerulosclerosis (n= 11), focal sclerosis secondary to obesity (n= 7), and lupus nephritis (n= 11) and from normal control subjects (n= 2) was performed, using affinity-purified antibodies raised to RAGE and two subclasses of AGE,i.e., Nϵ-(carboxymethyl)-lysine (CML) and pentosidine (PENT). AGE were detected equally in diffuse and nodular diabetic nephropathy. CML was the major AGE detected in diabetic mesangium (96%), glomerular basement membranes (GBM) (42%), tubular basement membranes (85%), and vessel walls (96%). In diabetic nephropathy, PENT was preferentially located in interstitial collagen (90%) and was less consistently observed in vessel walls (54%), mesangium (77%), GBM (4%), and tubular basement membranes (31%). RAGE was expressed on normal podocytes and was upregulated in diabetic nephropathy. The restriction of RAGE mRNA expression to glomeruli was confirmed by reverse transcription-PCR analysis of microdissected renal tissue compartments. The extent of mesangial and GBM immunoreactivity for CML, but not PENT, was correlated with the severity of diabetic glomerulosclerosis, as assessed pathologically. CML and PENT were also identified in areas of glomerulosclerosis and arteriosclerosis in idiopathic and secondary focal segmental glomerulosclerosis, hypertensive nephrosclerosis, and lupus nephritis. In active lupus nephritis, CML and PENT were detected in the proliferative glomerular tufts and crescents. In conclusion, CML is a major AGE in renal basement membranes in diabetic nephropathy, and its accumulation involves upregulation of RAGE on podocytes. AGE are also accumulated in acute inflammatory glomerulonephritis secondary to systemic lupus erythematosus, possibly via enzymatic oxidation of glomerular matrix proteins.
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Wilkinson, Kim, and Joseph El Khoury. "Microglial Scavenger Receptors and Their Roles in the Pathogenesis of Alzheimer's Disease." International Journal of Alzheimer's Disease 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/489456.
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Alzheimer’s disease (AD) is increasing in prevalence with the aging population. Deposition of amyloid-β(Aβ) in the brain of AD patients is a hallmark of the disease and is associated with increased microglial numbers and activation state. The interaction of microglia with Aβappears to play a dichotomous role in AD pathogenesis. On one hand, microglia can phagocytose and clear Aβ, but binding of microglia to Aβalso increases their ability to produce inflammatory cytokines, chemokines, and neurotoxic reactive oxygen species (ROS). Scavenger receptors, a group of evolutionally conserved proteins expressed on the surface of microglia act as receptors for Aβ. Of particular interest are SCARA-1 (scavenger receptor A-1), CD36, and RAGE (receptor for advanced glycation end products). SCARA-1 appears to be involved in the clearance of Aβ, while CD36 and RAGE are involved in activation of microglia by Aβ. In this review, we discuss the roles of various scavenger receptors in the interaction of microglia with Aβand propose that these receptors play complementary, nonredundant functions in the development of AD pathology. We also discuss potential therapeutic applications for these receptors in AD.
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Li, Jie, Haiyan Shangguan, Xiaoqian Chen, Xiao Ye, Bin Zhong, Pen Chen, Yamei Wang, Bin Xin, Yan Bi, and Dalong Zhu. "Advanced glycation end product levels were correlated with inflammation and carotid atherosclerosis in type 2 diabetes patients." Open Life Sciences 15, no. 1 (June 11, 2020): 364–72. http://dx.doi.org/10.1515/biol-2020-0042.
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AbstractDiabetes mellitus with atherosclerosis (AS) adds to the social burden. This study aimed to investigate whether advanced glycation end product (AGE) levels were correlated with inflammation and carotid AS (CAS) in type 2 diabetes mellitus (T2DM) patients. A total of 50 elderly T2DM patients and 50 age-matched senior healthy subjects were recruited in this study. T2DM patients were classified into two groups based on the intima–media thickness (IMT) of the carotid artery from color Doppler ultrasonography. Patients with IMT > 1 mm were classified into the T2DM + CAS group (n = 28), and patients with IMT < 1 mm were assigned as the T2DM + non-atherosclerosis (NAS) group (n = 22). The plasma levels of AGEs, receptor for AGE (RAGE), tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) of all subjects were measured by enzyme-linked immunosorbent assay. The T-lymphocyte subsets were analyzed by a flow detector. T2DM + CAS patients showed significantly higher concentrations of AGEs, RAGE, TNF-α, and IFN-γ in the peripheral blood. The highest levels of CD4+ T cells were observed in the T2DM + CAS group. The AGE level was positively correlated with the concentrations of RAGE, TNF-α, IFN-γ, and CD4+. In summary, the results showed that the levels of AGEs may be correlated with the inflammatory status in T2DM patients with CAS.
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Cheng, Cailan L., Ying Tang, Zhenda Zheng, Xun Liu, Zengchun C. Ye, Cheng Wang, and Tanqi Q. Lou. "Advanced glycation end-products activate the renin-angiotensin system through the RAGE/PI3-K signaling pathway in podocytes." Clinical & Investigative Medicine 35, no. 5 (October 6, 2012): 282. http://dx.doi.org/10.25011/cim.v35i5.18701.
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Purpose: The purpose of this study was to investigate the effects of advanced glycation end-products (AGEs) on the components of the renin-angiotensin system (RAS) in podocytes and to understand the mechanism of these effects. Methods: Immortalized mouse podocytes were exposed to various concentrations of AGEs for different time intervals. The expression levels of angiotensinogen (AGT), angiotensin II type 1 and 2 receptors (AT1R and AT2R) and renin were examined by real-time PCR and western blot; the receptor for AGEs (RAGE) and both Akt and phosphorylated Akt were examined by western blot; levels of angiotensin II (Ang II) were assayed by ELISA, and the activity of angiotensin-converting enzyme (ACE) was evaluated by measuring the production of hippuric acid in vitro. Results: Treatment with AGEs resulted in significant increases in the expression of AGT (62%, P=0.002) and AT1R (59%, P=0.01). Moreover, Ang II levels increased significantly in both cell lysates (70%, P=0.018) and conditioned media (65%, P=0.01). ACE activity was also significantly higher in cell lysates (68% , P= 0.035) and conditioned media (65%, P=0.023). There were no changes in renin or AT2R expression (P > 0.05). AGEs did increase the expression of RAGE by 50% (P=0.012) and the phosphorylation of Akt by 100% (P=0.001). When podocytes were pretreated with anti-RAGE antibody (50 µg/ml) or the phosphoinositide 3-kinase (PI3-K) inhibitor, LY294002 (10 µM), the AGEs-induced increases in AGT and AT1R expression were reduced. Likewise, Ang II levels and ACE activity decreased significantly. Conclusion: AGEs activate the RAS in podocytes through the RAGE-PI3-K/Akt-dependent pathway and lead to an increase in podocyte apoptosis.
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Ma, Ke, Yiming Xu, Chenchen Wang, Nan Li, Kexue Li, Yan Zhang, Xiaoyu Li, et al. "A cross talk between class a scavenger receptor and receptor for advanced glycation end-products contributes to diabetic retinopathy." American Journal of Physiology-Endocrinology and Metabolism 307, no. 12 (December 15, 2014): E1153—E1165. http://dx.doi.org/10.1152/ajpendo.00378.2014.
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In response to hyperglycemia in patients with diabetes, many signaling pathways contribute to the pathogenesis of diabetic complications, including diabetic retinopathy (DR). Excessive production of inflammatory mediators plays an important role in this process. Amadori-glycated albumin, one of the major forms of advanced glycated end-products, has been implicated in DR by inducing inflammatory responses in microglia/macrophages. Our goal was to delineate the potential cross talk between class A scavenger receptor (SR-A) and the receptor for advanced glycated end-product (RAGE) in the context of DR. We show here that SR-A ablation caused an exacerbated form of DR in streptozotocin-injected C57BL/6J mice as evidenced by fundus imaging and electroretinography. Immunohistochemical staining and RT-PCR assay indicated that there was augmented activation of proinflammatory macrophages with upregulated synthesis of proinflammatory mediators in the retina in Sr-a−/− mice. Overexpression of SR-A suppressed RAGE-induced mitogen-activated protein kinase (MAPK) signaling, whereas RAGE activation in macrophages favored a proinflammatory (M1) phenotype in the absence of SR-A. Mechanistic analysis on bone marrow-derived macrophages and HEK293 cell line revealed that SR-A interacted with and inhibited the phosphorylation of mitogen-activated protein kinase kinase 7, the major kinase in the RAGE-MAPK-NF-κB signaling, thereby leading to diminished secretion of proinflammatory cytokines. Our findings suggest that the antagonism between SR-A and RAGE contributes to the pathogenesis of DR by nurturing a disease-prone macrophage phenotype. Therefore, specific agonist that boosts SR-A signaling could potentially provide benefits in the prevention and/or intervention of DR.
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Dinarvand, Peyman, Seyed Mahdi Hassanian, Shabir H. Qureshi, Chandrashekhara Manithody, Joel C. Eissenberg, Likui Yang, and Alireza R. Rezaie. "Polyphosphate amplifies proinflammatory responses of nuclear proteins through interaction with receptor for advanced glycation end products and P2Y1 purinergic receptor." Blood 123, no. 6 (February 6, 2014): 935–45. http://dx.doi.org/10.1182/blood-2013-09-529602.
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Key Points Extracellular nuclear proteins H4 and HMGB1 are highly proinflammatory cytokines. Inorganic polyP dramatically amplifies proinflammatory responses of H4 and HMGB1 through the RAGE and P2Y1 receptors.
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Buchs, A. E., A. Kornberg, M. Zahavi, D. Aharoni, C. Zarfati, and M. J. Rapoport. "Increased Expression of Tissue Factor and Receptor for Advanced Glycation End Products in Peripheral Blood Mononuclear Cells of Patients With Type 2 Diabetes Mellitus with Vascular Complications." Experimental Diabesity Research 5, no. 2 (2004): 163–69. http://dx.doi.org/10.1080/15438600490424325.
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The aim of the study was to determine the correlation between the expression of tissue factor (TF) and the receptor for advanced glycation end products (RAGEs) and vascular complications in patients with longstanding uncontrolled type 2 diabetes (T2D). TF and RAGE mRNAs as well as TF antigen and activity were investigated in 21 T2D patients with and without vascular complications. mRNA expression was assessed by reverse transcriptase–polymerase chain reaction (RT-PCR) in nonstimulated and advanced glycation end product (AGE) albumin–stimulated peripheral blood mononuclear cells (PBMCs). TF antigen expression was determined by enzyme-linked immunosorbent assay (ELISA) and TF activity by a modified prothrombin time assay. Basal RAGE mRNA expression was 0.2 ± 0.06 in patients with complications and 0.05 ± 0.06 patients without complications (P= .004). Stimulation did not cause any further increase in either group. TF mRNA was 0.58 ± 0.29 in patients with complications and 0.21 ± 0.18 in patients without complications (P= .003). Stimulation resulted in a nonsignificant increase in both groups. Basal TF activity (U/106PBMCs) was 18.4 ± 13.2 in patients with complications and 6.96 ± 5.2 in patients without complications (P= .003). It increased 3-fold in both groups after stimulation (P= .001). TF antigen (pg/106PBMCs) was 33.7 ± 28.6 in patients with complications, 10.4 ± 7.8 in patients without complications (P= .02). Stimulation tripled TF antigen in both groups of patients (P= .001). The RAGE/TF axis is up-regulated inT2Dpatients with vascular complications as compared to patients without complications. This suggests a role for this axis in the pathogenesis of vascular complications in T2D.
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Ohira, Hideo, Atsuki Tsuruya, Daiki Oikawa, Wao Nakagawa, Rie Mamoto, Masahira Hattori, Toshiyuki Waki, Seiji Takahashi, Yoshio Fujioka, and Toru Nakayama. "Alteration of oxidative-stress and related marker levels in mouse colonic tissues and fecal microbiota structures with chronic ethanol administration: Implications for the pathogenesis of ethanol-related colorectal cancer." PLOS ONE 16, no. 2 (February 12, 2021): e0246580. http://dx.doi.org/10.1371/journal.pone.0246580.
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Chronic ethanol consumption is a risk factor for colorectal cancer, and ethanol-induced reactive oxygen species have been suggested to play important roles in the pathogenesis of ethanol-related colorectal cancer (ER-CRC). In this study, the effects of 10-week chronic administration of ethanol on the colonic levels of oxidative stress and advance glycation end product (AGE) levels, as well as fecal microbiota structures, were examined in a mouse model. Chronic oral administration of ethanol in mice (1.0 mL of 1.5% or 5.0% ethanol (v/v) per day per mouse, up to 10 weeks) resulted in the elevation of colonic levels of oxidative stress markers (such as 8-hydroxy-2’-deoxyguanosine and 4-hydroxynonenal) compared to control mice, and this was consistently accompanied by elevated levels of inflammation-associated cytokines and immune cells (Th17 and macrophages) and a decreased level of regulatory T (Treg) cells to produce colonic lesions. It also resulted in an alteration of mouse fecal microbiota structures, reminiscent of the alterations observed in human inflammatory bowel disease, and this appeared to be consistent with the proposed sustained generation of oxidative stress in the colonic environment during chronic ethanol consumption. Moreover, the first experimental evidence that chronic ethanol administration results in elevated levels of advanced glycation end products (AGEs) and their receptors (RAGE) in the colonic tissues in mice is also shown, implying enhanced RAGE-mediated signaling with chronic ethanol administration. The RAGE-mediated signaling pathway has thus far been implicated as a link between the accumulation of AGEs and the development of many types of chronic colitis and cancers. Thus, enhancement of this pathway likely exacerbates the ethanol-induced inflammatory states of colonic tissues and might at least partly contribute to the pathogenesis of ER-CRC.
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Park, Jong Sung, Fabia Gamboni-Robertson, Qianbin He, Daiva Svetkauskaite, Jae-Yeol Kim, Derek Strassheim, Jang-Won Sohn, et al. "High mobility group box 1 protein interacts with multiple Toll-like receptors." American Journal of Physiology-Cell Physiology 290, no. 3 (March 2006): C917—C924. http://dx.doi.org/10.1152/ajpcell.00401.2005.
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High mobility group box 1 (HMGB1), originally described as a DNA-binding protein, can also be released extracellularly and functions as a late mediator of inflammatory responses. Although recent reports have indicated that the receptor for advanced glycation end products (RAGE) as well as Toll-like receptor (TLR)2 and TLR4 are involved in cellular activation by HMGB1, there has been little evidence of direct association between HMGB1 and these receptors. To examine this issue, we used fluorescence resonance energy transfer (FRET) and immunoprecipitation to directly investigate cell surface interactions of HMGB1 with TLR2, TLR4, and RAGE. FRET images in RAW264.7 macrophages demonstrated association of HMGB1 with TLR2 and TLR4 but not RAGE. Transient transfections into human embryonic kidney-293 cells showed that HMGB1 induced cellular activation and NF-κB-dependent transcription through TLR2 or TLR4 but not RAGE. Coimmunoprecipitation also found interaction between HMGB1 and TLR2 as well as TLR4, but not with RAGE. These studies provide the first direct evidence that HMGB1 can interact with both TLR2 and TLR4 and also supply an explanation for the ability of HMGB1 to induce cellular activation and generate inflammatory responses that are similar to those initiated by LPS.
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Yuan, Gang, Guangyan Si, Qingchun Hou, Zhaonan Li, Kaiqiang Xu, Yuping Wang, Weiming Wang, et al. "Advanced Glycation End Products Induce Proliferation and Migration of Human Aortic Smooth Muscle Cells through PI3K/AKT Pathway." BioMed Research International 2020 (July 14, 2020): 1–11. http://dx.doi.org/10.1155/2020/8607418.
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Advanced glycation end products (AGEs) have been widely regarded as an important inducing factor in the pathogenesis of diabetic arteriosclerosis, and the proliferation and migration of vascular smooth muscle cells (VSMCs) are also involved in this process. However, it is not clear whether AGEs promote atherosclerosis by inducing the proliferation and migration of VSMCs. To figure out this question, this study investigated the effects of AGEs on the proliferation and migration of human aorta vascular smooth muscle cells (HASMCs) and the underlying mechanisms. This study evaluated the effects of different concentrations of AGEs on cell proliferation and migration. CCK8, transwell, and western blotting assays demonstrated that AGEs significantly increased cell proliferation and migration in a concentration-dependent manner and that the optimal proproliferative and promigratory concentrations of AGEs were 10 mg/L and 20 mg/L, respectively. AGE-induced cell proliferation, migration, and expression of filament actin (F-actin) were markedly attenuated by a PI3K inhibitor (LY2940002). Additionally, the phosphorylation of AKT was reduced when the receptor of advanced glycation end product (RAGE) gene was silenced by lentivirus transfection, which led to a concomitant reduction of the expression of proliferation and migration-related proteins. These data indicate that AGEs may activate the PI3K/AKT pathway through RAGE and thus facilitate the proliferation and migration of HASMCs.
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Olejarz, Wioletta, Dominika Łacheta, Alicja Głuszko, Ewa Migacz, Wojciech Kukwa, Mirosław J. Szczepański, Piotr Tomaszewski, and Grażyna Nowicka. "RAGE and TLRs as Key Targets for Antiatherosclerotic Therapy." BioMed Research International 2018 (August 26, 2018): 1–10. http://dx.doi.org/10.1155/2018/7675286.
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Receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) are the key factors indicating a danger to the organism. They recognize the microbial origin pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The primary response induced by PAMPs or DAMPs is inflammation. Excessive stimulation of the innate immune system occurs in arterial wall with the participation of effector cells. Persistent adaptive responses can also cause tissue damage and disease. However, inflammation mediated by the molecules innate responses is an important way in which the adaptive immune system protects us from infection. The specific detection of PAMPs and DAMPs by host receptors drives a cascade of signaling that converges at nuclear factor-κB (NF-κB) and interferon regulatory factors (IRFs) and induces the secretion of proinflammatory cytokines, type I interferon (IFN), and chemokines, which promote direct killing of the pathogen. Therefore, signaling of these receptors’ pathways also appear to present new avenue for the modulation of inflammatory responses and to serve as potential novel therapeutic targets for antiatherosclerotic therapy.