The Experts below are selected from a list of 8538 Experts worldwide ranked by ideXlab platform
Ann Marie Schmidt - One of the best experts on this subject based on the ideXlab platform.
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activation of the rock1 branch of the transforming growth factor β pathway contributes to RAGE dependent acceleration of atherosclerosis in diabetic apoe null mice
Circulation Research, 2010Co-Authors: Vivek Rai, Shi Fang Yan, Xiaoping Shen, Rosa Rosario, Vivette D Dagati, Richard A Friedman, Edem Nuglozeh, Ann Marie SchmidtAbstract:Rationale: The multiligand RAGE (Receptor for advanced glycation end products) contributes to atherosclerosis in apolipoprotein (Apo)E-null mice. Objective: To delineate the specific mechanisms by which RAGE accelerated atherosclerosis, we performed Affymetrix gene expression arrays on aortas of nondiabetic and diabetic ApoE-null mice expressing RAGE or devoid of RAGE at nine weeks of age, as this reflected a time point at which frank atherosclerotic lesions were not yet present, but that we would be able to identify the genes likely involved in diabetes- and RAGE-dependent atherogenesis. Methods and Results: We report that there is very little overlap of the genes that are differentially expressed both in the onset of diabetes in ApoE-null mice, and in the effect of RAGE deletion in diabetic ApoE-null mice. Pathway-Express analysis revealed that the transforming growth factor-β pathway and focal adhesion pathways might be expected to play a significant role in both the mechanism by which diabetes facilit...
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the RAGE axis a fundamental mechanism signaling danger to the vulnerable vasculature
Circulation Research, 2010Co-Authors: Ravichandran Ramasamy, Ann Marie SchmidtAbstract:Abstract: The immunoglobulin superfamily molecule RAGE (Receptor for advanced glycation end product) transduces the effects of multiple ligands, including AGEs (advanced glycation end products), advanced oxidation protein products, S100/calgranulins, high-mobility group box-1, amyloid-β peptide, and β-sheet fibrils. In diabetes, hyperglycemia likely stimulates the initial burst of production of ligands that interact with RAGE and activate signaling mechanisms. Consequently, increased generation of proinflammatory and prothrombotic molecules and reactive oxygen species trigger further cycles of oxidative stress via RAGE, thus setting the stage for augmented damage to diabetic tissues in the face of further insults. Many of the ligand families of RAGE have been identified in atherosclerotic plaques and in the infarcted heart. Together with increased expression of RAGE in diabetic settings, we propose that release and accumulation of RAGE ligands contribute to exaggerated cellular damage. Stopping the viciou...
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The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature.
Circulation research, 2010Co-Authors: Shi Fang Yan, Ravichandran Ramasamy, Ann Marie SchmidtAbstract:The immunoglobulin superfamily molecule RAGE (Receptor for advanced glycation end product) transduces the effects of multiple ligands, including AGEs (advanced glycation end products), advanced oxidation protein products, S100/calgranulins, high-mobility group box-1, amyloid-beta peptide, and beta-sheet fibrils. In diabetes, hyperglycemia likely stimulates the initial burst of production of ligands that interact with RAGE and activate signaling mechanisms. Consequently, increased generation of proinflammatory and prothrombotic molecules and reactive oxygen species trigger further cycles of oxidative stress via RAGE, thus setting the stage for augmented damage to diabetic tissues in the face of further insults. Many of the ligand families of RAGE have been identified in atherosclerotic plaques and in the infarcted heart. Together with increased expression of RAGE in diabetic settings, we propose that release and accumulation of RAGE ligands contribute to exaggerated cellular damage. Stopping the vicious cycle of AGE-RAGE and RAGE axis signaling in the vulnerable heart and great vessels may be essential in controlling and preventing the consequences of diabetes.
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RAGE a novel biological and genetic marker for vascular disease
Clinical Science, 2009Co-Authors: Anastasia Z Kalea, Ann Marie Schmidt, Barry I HudsonAbstract:RAGE [Receptor for AGEs (advanced glycation end-products)] plays an important role in the development and progression of vascular disease. Studies in cultured cells and small animal models of disease have clearly demonstrated that RAGE is central to the pathogenesis of vascular disease of the macro- and micro-vessels in both the diabetic and non-diabetic state. Emerging results from human clinical studies have revealed that levels of circulating soluble RAGE in the plasma may reflect the presence and/or extent of vascular disease state. Additionally, genetic variants of the RAGE gene (AGER in HUGO nomenclature) have been associated with vascular disease risk. Combining RAGE circulating protein levels and the presence of particular RAGE polymorphisms may be a useful clinical tool for the prediction of individuals at risk for vascular disease. Therapeutic intervention targeted at the RAGE gene may therefore be a useful means of treating pathologies of the vasculature.
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Tempering the wrath of RAGE: an emerging therapeutic strategy against diabetic complications, neurodegeneration, and inflammation.
Annals of medicine, 2009Co-Authors: Shi Fang Yan, Ravichandran Ramasamy, Shi Du Yan, Ann Marie SchmidtAbstract:The multiligand Receptor RAGE (Receptor for advanced glycation end-products) is emerging as a central mediator in the immune/inflammatory response. Epidemiological evidence accruing in the human suggests upregulation of RAGE's ligands (AGEs, S100/calgranulins, high mobility group box-1 (HMGB1), and amyloid β-peptide and β-sheet fibrils) and the Receptor itself at sites of inflammation and in chronic diseases such as diabetes and neurodegeneration. The consequences of ligand-RAGE interaction include upregulation of molecules implicated in inflammatory responses and tissue damage, such as cytokines, adhesion molecules, and matrix metalloproteinases. In this review, we discuss the localization of RAGE and its ligand families and the biological impact of this axis in multiple cell types implicated in chronic diseases. Lastly, we consider findings from animal model studies suggesting that although tissue-damaging effects ensue from recruitment of the ligand-RAGE interaction, in distinct settings, adaptive and ...
Rosario Donato - One of the best experts on this subject based on the ideXlab platform.
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Levels of S100B protein drive the reparative process in acute muscle injury and muscular dystrophy
Scientific reports, 2017Co-Authors: Francesca Riuzzi, Guglielmo Sorci, Ileana Giambanco, Sara Beccafico, Roberta Sagheddu, Sara Chiappalupi, Oxana Bereshchenko, Carlo Riccardi, Rosario DonatoAbstract:Regeneration of injured skeletal muscles relies on a tightly controlled chain of cellular and molecular events. We show that appropriate levels of S100B protein are required for timely muscle regeneration after acute injury. S100B released from damaged myofibers and infiltrating macrophages expands the myoblast population, attracts macrophages and promotes their polarization into M2 (pro-regenerative) phenotype, and modulates collagen deposition, by interacting with RAGE (Receptor for advanced glycation end-products) or FGFR1 (fibroblast growth factor Receptor 1) depending on the muscle repair phase and local conditions. However, persistence of high S100B levels compromises the regeneration process prolonging myoblast proliferation and macrophage infiltration, delaying M1/M2 macrophage transition, and promoting deposition of fibrotic tissue via RAGE engagement. Interestingly, S100B is released in high abundance from degenerating muscles of mdx mice, an animal model of Duchenne muscular dystrophy (DMD), and blocking S100B ameliorates histopathology. Thus, levels of S100B differentially affect skeletal muscle repair upon acute injury and in the context of muscular dystrophy, and S100B might be regarded as a potential molecular target in DMD.
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S100A6 protein: functional roles
Cellular and Molecular Life Sciences, 2017Co-Authors: Rosario Donato, Guglielmo Sorci, Ileana GiambancoAbstract:S100A6 protein belongs to the A group of the S100 protein family of Ca^2+-binding proteins. It is expressed in a limited number of cell types in adult normal tissues and in several tumor cell types. As an intracellular protein, S100A6 has been implicated in the regulation of several cellular functions, such as proliferation, apoptosis, the cytoskeleton dynamics, and the cellular response to different stress factors. S100A6 can be secreted/released by certain cell types which points to extracellular effects of the protein. RAGE (Receptor for advanced glycation endproducts) and integrin β1 transduce some extracellular S100A6’s effects. Dosage of serum S100A6 might aid in diagnosis in oncology.
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RAGE in tissue homeostasis, repair and regeneration
Biochimica et biophysica acta, 2012Co-Authors: Guglielmo Sorci, Francesca Riuzzi, Ileana Giambanco, Rosario DonatoAbstract:RAGE (Receptor for advanced glycation end-products) is a multiligand Receptor of the immunoglobulin superfamily involved in inflammation, diabetes, atherosclerosis, nephropathy, neurodegeneration, and cancer. Advanced glycation end-products, high mobility group box-1 (amphoterin), β-amyloid fibrils, certain S100 proteins, and DNA and RNA are RAGE ligands. Upon RAGE ligation, adaptor proteins (i.e., diaphanous-1, TIRAP, MyD88 and/or other as yet unidentified adaptors) associate with RAGE cytoplasmic domain resulting in signaling. However, RAGE activation may not be restricted to pathological statuses, the Receptor being involved in tissue homeostasis and regeneration/repair upon acute injury, and in resolution of inflammation. RAGE effects are strongly dependent on the cell type and the context, which may condition therapeutic strategies aimed at reducing RAGE signaling.
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S100B's double life: Intracellular regulator and extracellular signal
Biochimica et biophysica acta, 2008Co-Authors: Rosario Donato, Guglielmo Sorci, Francesca Riuzzi, Cataldo Arcuri, Roberta Bianchi, Flora Brozzi, Claudia Tubaro, Ileana GiambancoAbstract:The Ca2+-binding protein of the EF-hand type, S100B, exerts both intracellular and extracellular functions. Recent studies have provided more detailed information concerning the mechanism(s) of action of S100B as an intracellular regulator and an extracellular signal. Indeed, intracellular S100B acts as a stimulator of cell proliferation and migration and an inhibitor of apoptosis and differentiation, which might have important implications during brain, cartilage and skeletal muscle development and repair, activation of astrocytes in the course of brain damage and neurodegenerative processes, and of cardiomyocyte remodeling after infarction, as well as in melanomagenesis and gliomagenesis. As an extracellular factor, S100B engages RAGE (Receptor for advanced glycation end products) in a variety of cell types with different outcomes (i.e. beneficial or detrimental, pro-proliferative or pro-differentiative) depending on the concentration attained by the protein, the cell type and the microenvironment. Yet, RAGE might not be the sole S100B Receptor, and S100B's ability to engage RAGE might be regulated by its interaction with other extracellular factors. Future studies using S100B transgenic and S100B null mice might shed more light on the functional role(s) of the protein.
P F Alewood - One of the best experts on this subject based on the ideXlab platform.
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Total chemical synthesis and chemotactic activity of human S100A12 (EN-RAGE).
FEBS letters, 2001Co-Authors: L P Miranda, T Tao, A Jones, I Chernushevich, K G Standing, C L Geczy, P F AlewoodAbstract:Human S100A12 (extracellular newly identified RAGE (Receptor for advanced glycosylation end products)-binding protein), a new member of the S100 family of EF-hand calcium-binding proteins, was chemically synthesised using highly optimised 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate/tert-butoxycarbonyl in situ neutralisation solid-phase chemistry. Circular dichroism studies indicated that CaCl(2) decreased the helical content by 27% whereas helicity was marginally increased by ZnCl(2). The propensity of S100A12 to dimerise was examined by electrospray ionisation time-of-flight mass spectrometry which clearly demonstrated the prevalence of the non-covalent homodimer (20890 Da). Importantly, synthetic human S100A12 in the nanomolar range was chemotactic for neutrophils and macrophages in vitro.
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Total chemical synthesis and chemotactic activity of human S100A12 (EN-RAGE)
FEBS Letters, 2001Co-Authors: L P Miranda, T Tao, A Jones, I Chernushevich, K G Standing, C L Geczy, P F AlewoodAbstract:Human S100A12 (extracellular newly identified RAGE (Receptor for advanced glycosylation end products)binding protein), a new member of the S100 family of EF-hand calcium-binding proteins, was chemically synthesised using highly optimised 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate/tert-butoxycarbonyl in situ neutralisation solid-phase chemistry. Circular dichroism studies indicated that CaCl2 decreased the helical content by 27% whereas helicity was marginally increased by ZnCl2. The propensity of S100A12 to dimerise was examined by electrospray ionisation time-of-flight mass spectrometry which clearly demonstrated the prevalence of the non-covalent homodimer (20 890 Da). Importantly, synthetic human S100A12 in the nanomolar range was chemotactic for neutrophils and macrophages in vitro. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.
Ileana Giambanco - One of the best experts on this subject based on the ideXlab platform.
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Levels of S100B protein drive the reparative process in acute muscle injury and muscular dystrophy
Scientific reports, 2017Co-Authors: Francesca Riuzzi, Guglielmo Sorci, Ileana Giambanco, Sara Beccafico, Roberta Sagheddu, Sara Chiappalupi, Oxana Bereshchenko, Carlo Riccardi, Rosario DonatoAbstract:Regeneration of injured skeletal muscles relies on a tightly controlled chain of cellular and molecular events. We show that appropriate levels of S100B protein are required for timely muscle regeneration after acute injury. S100B released from damaged myofibers and infiltrating macrophages expands the myoblast population, attracts macrophages and promotes their polarization into M2 (pro-regenerative) phenotype, and modulates collagen deposition, by interacting with RAGE (Receptor for advanced glycation end-products) or FGFR1 (fibroblast growth factor Receptor 1) depending on the muscle repair phase and local conditions. However, persistence of high S100B levels compromises the regeneration process prolonging myoblast proliferation and macrophage infiltration, delaying M1/M2 macrophage transition, and promoting deposition of fibrotic tissue via RAGE engagement. Interestingly, S100B is released in high abundance from degenerating muscles of mdx mice, an animal model of Duchenne muscular dystrophy (DMD), and blocking S100B ameliorates histopathology. Thus, levels of S100B differentially affect skeletal muscle repair upon acute injury and in the context of muscular dystrophy, and S100B might be regarded as a potential molecular target in DMD.
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S100A6 protein: functional roles
Cellular and Molecular Life Sciences, 2017Co-Authors: Rosario Donato, Guglielmo Sorci, Ileana GiambancoAbstract:S100A6 protein belongs to the A group of the S100 protein family of Ca^2+-binding proteins. It is expressed in a limited number of cell types in adult normal tissues and in several tumor cell types. As an intracellular protein, S100A6 has been implicated in the regulation of several cellular functions, such as proliferation, apoptosis, the cytoskeleton dynamics, and the cellular response to different stress factors. S100A6 can be secreted/released by certain cell types which points to extracellular effects of the protein. RAGE (Receptor for advanced glycation endproducts) and integrin β1 transduce some extracellular S100A6’s effects. Dosage of serum S100A6 might aid in diagnosis in oncology.
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RAGE in tissue homeostasis, repair and regeneration
Biochimica et biophysica acta, 2012Co-Authors: Guglielmo Sorci, Francesca Riuzzi, Ileana Giambanco, Rosario DonatoAbstract:RAGE (Receptor for advanced glycation end-products) is a multiligand Receptor of the immunoglobulin superfamily involved in inflammation, diabetes, atherosclerosis, nephropathy, neurodegeneration, and cancer. Advanced glycation end-products, high mobility group box-1 (amphoterin), β-amyloid fibrils, certain S100 proteins, and DNA and RNA are RAGE ligands. Upon RAGE ligation, adaptor proteins (i.e., diaphanous-1, TIRAP, MyD88 and/or other as yet unidentified adaptors) associate with RAGE cytoplasmic domain resulting in signaling. However, RAGE activation may not be restricted to pathological statuses, the Receptor being involved in tissue homeostasis and regeneration/repair upon acute injury, and in resolution of inflammation. RAGE effects are strongly dependent on the cell type and the context, which may condition therapeutic strategies aimed at reducing RAGE signaling.
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S100B's double life: Intracellular regulator and extracellular signal
Biochimica et biophysica acta, 2008Co-Authors: Rosario Donato, Guglielmo Sorci, Francesca Riuzzi, Cataldo Arcuri, Roberta Bianchi, Flora Brozzi, Claudia Tubaro, Ileana GiambancoAbstract:The Ca2+-binding protein of the EF-hand type, S100B, exerts both intracellular and extracellular functions. Recent studies have provided more detailed information concerning the mechanism(s) of action of S100B as an intracellular regulator and an extracellular signal. Indeed, intracellular S100B acts as a stimulator of cell proliferation and migration and an inhibitor of apoptosis and differentiation, which might have important implications during brain, cartilage and skeletal muscle development and repair, activation of astrocytes in the course of brain damage and neurodegenerative processes, and of cardiomyocyte remodeling after infarction, as well as in melanomagenesis and gliomagenesis. As an extracellular factor, S100B engages RAGE (Receptor for advanced glycation end products) in a variety of cell types with different outcomes (i.e. beneficial or detrimental, pro-proliferative or pro-differentiative) depending on the concentration attained by the protein, the cell type and the microenvironment. Yet, RAGE might not be the sole S100B Receptor, and S100B's ability to engage RAGE might be regulated by its interaction with other extracellular factors. Future studies using S100B transgenic and S100B null mice might shed more light on the functional role(s) of the protein.
Claus W. Heizmann - One of the best experts on this subject based on the ideXlab platform.
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Calcium-regulated intramembrane proteolysis of the RAGE Receptor.
Biochemical and biophysical research communications, 2008Co-Authors: Arnaud Galichet, Mirjam Weibel, Claus W. HeizmannAbstract:The Receptor for advanced glycation endproducts (RAGE) interacts with several ligands and is involved in various human diseases. RAGE_v1 or sRAGE, a RAGE splice variant, is secreted and contributes to the removal of RAGE ligands. Because RAGE blockade by specific antibodies directed against RAGE extracellular domains and the use of sRAGE have been proven to be beneficial in the context of pathological settings, both RAGE and sRAGE are considered as therapeutic target. Here, we show that sRAGE is also produced through regulated intramembrane proteolysis of the RAGE Receptor, which is catalyzed by ADAM10 and the γ-secretase and that calcium is an essential regulator of RAGE processing. Furthermore, RAGE intracellular domain localizes both in the cytoplasm and the nucleus and induces apoptosis when expressed in cells. These findings reveal new aspects of RAGE regulation and signaling and also provide a new interaction between RAGE and human pathologies.
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s100b and s100a6 differentially modulate cell survival by interacting with distinct RAGE Receptor for advanced glycation end products immunoglobulin domains
Journal of Biological Chemistry, 2007Co-Authors: Estelle Leclerc, Claus W. Heizmann, Mirjam Weibel, Gunter Fritz, Arnaud GalichetAbstract:Abstract S100 proteins are EF-hand calcium-binding proteins with various intracellular functions including cell proliferation, differentiation, migration, and apoptosis. Some S100 proteins are also secreted and exert extracellular paracrine and autocrine functions. Experimental results suggest that the Receptor for advanced glycation end products (RAGE) plays important roles in mediating S100 protein-induced cellular signaling. Here we compared the interaction of two S100 proteins, S100B and S100A6, with RAGE by in vitro assay and in culture of human SH-SY5Y neuroblastoma cells. Our in vitro binding data showed that S100B and S100A6, although structurally very similar, interact with different RAGE extracellular domains. Our cell assay data demonstrated that S100B and S100A6 differentially modulate cell survival. At micromolar concentration, S100B increased cellular proliferation, whereas at the same concentration, S100A6 triggered apoptosis. Although both S100 proteins induced the formation of reactive oxygen species, S100B recruited phosphatidylinositol 3-kinase/AKT and NF-κB, whereas S100A6 activated JNK. More importantly, we showed that S100B and S100A6 modulate cell survival in a RAGE-dependent manner; S100B specifically interacted with the RAGE V and C1 domains and S100A6 specifically interacted with the C1 and C2 RAGE domains. Altogether these results highlight the complexity of S100/RAGE cellular signaling.
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Expression analysis of S100 proteins and RAGE in human tumors using tissue microarrays
Biochemical and biophysical research communications, 2003Co-Authors: Hsiao-ling Hsieh, Beat W. Schäfer, Nobuyuki Sasaki, Claus W. HeizmannAbstract:Microarray technology provides important information for diagnostic, prognostic, and even therapeutic applications. Several S100 proteins have been proposed to play important roles in tumor progression and are recognized as potential tumor markers. To substantiate these limited earlier findings, we screened hundreds of tumor specimens from patients of eight different tumor types using tissue microarrays. The results validated the expression of S100A4, S100A6, and S100B in specific tumor types. A significant S100A2 expression was observed in lymphoma biopsies, which implies a possible link between this S100 protein and lymphoma development. In contrast, S100A5 and S100A12 were not significantly expressed in any of the tumor tissues tested. Interestingly, expression of RAGE (Receptor for advanced glycation end products) was found in breast and lung tumor tissues where abundant S100A4 and S100A6 expression was also observed. This suggests a possible role of RAGE-mediated signal transduction in the development of these particular cancers.
