Pathophysiology of RAGE in inflammatory diseases.
Ontology highlight
ABSTRACT:
SUBMITTER: Dong H
PROVIDER: S-EPMC9373849 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Pathophysiology of RAGE in inflammatory diseases.
Dong Hanbing H Zhang Yue Y Huang Yu Y Deng Hui H
Frontiers in immunology 20220729
The receptor for advanced glycation end products (RAGE) is a non-specific multi-ligand pattern recognition receptor capable of binding to a range of structurally diverse ligands, expressed on a variety of cell types, and performing different functions. The ligand-RAGE axis can trigger a range of signaling events that are associated with diabetes and its complications, neurological disorders, cancer, inflammation and other diseases. Since RAGE is involved in the pathophysiological processes of ma ...[more]
Similar Datasets
Project description:High mobility group box 1 (HMGB1) is a nuclear protein that can interact with a receptor for advanced glycation end-products (RAGE; a multi-ligand immunoglobulin receptor) and mediates the inflammatory pathways that lead to various pathological conditions, such as cancer, diabetes, neurodegenerative disorders, and cardiovascular diseases. Blocking the HMGB1/RAGE axis could be an effective therapeutic approach to treat these inflammatory conditions, which has been successfully employed by various research groups recently. In this article, we critically review the structural insights and functional mechanism of HMGB1 and RAGE to mediate inflammatory processes. More importantly, current perspectives of recent therapeutic approaches utilized to inhibit the communication between HMGB1 and RAGE using small molecules are also summarized along with their clinical progression to treat various inflammatory disorders. Encouraging results are reported by investigators focusing on HMGB1/RAGE signaling leading to the identification of compounds that could be useful in further clinical studies. We highlight the current gaps in our knowledge and future directions for the therapeutic potential of targeting key molecules in HMGB1/RAGE signaling in the pathophysiology of inflammatory diseases.
| S-EPMC9658169 | biostudies-literature
Project description:Inflammatory bowel diseases are considered immune disorders with a complex genetic architecture involving constantly changing endogenous and exogenous factors. The rapid evolution of genomic technologies and the emergence of newly discovered molecular actors are compelling the research community to reevaluate the knowledge and molecular processes. The human intestinal tract contains intestinal human microbiota consisting of commensal, pathogenic, and symbiotic strains leading to immune responses that can contribute and lead to both systemic and intestinal disorders including IBD. In this review, we attempted to highlight some updates of the new IBD features related to genomics, microbiota, new emerging therapies and some major established IBD risk factors.
| S-EPMC9481278 | biostudies-literature
Project description:Nonenzymatic reactions of reducing sugars with primary amino groups of amino acids, proteins, and nucleic acids, followed by oxidative degradations would lead to the formation of advanced glycation endproducts (AGEs). The AGEs exert multifactorial effects on cell damage leading to the onset of neurological disorders. The interaction of AGEs with the receptors for advanced glycation endproducts (RAGE) contribute to the activation of intracellular signaling and the expression of the pro-inflammatory transcription factors and various inflammatory cytokines. This inflammatory signaling cascade is associated with various neurological diseases, including Alzheimer's disease (AD), secondary effects of traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), and diabetic neuropathy, and other AGE-related diseases, including diabetes and atherosclerosis. Furthermore, the imbalance of gut microbiota and intestinal inflammation are also associated with endothelial dysfunction, disrupted blood-brain barrier (BBB) and thereby the onset and progression of AD and other neurological diseases. AGEs and RAGE play an important role in altering the gut microbiota composition and thereby increase the gut permeability and affect the modulation of the immune-related cytokines. The inhibition of the AGE-RAGE interactions, through small molecule-based therapeutics, prevents the inflammatory cascade of events associated with AGE-RAGE interactions, and thereby attenuates the disease progression. Some of the RAGE antagonists, such as Azeliragon, are currently in clinical development for treating neurological diseases, including AD, although currently there have been no FDA-approved therapeutics based on the RAGE antagonists. This review outlines the AGE-RAGE interactions as a leading cause of the onset of neurological diseases and the current efforts on developing therapeutics for neurological diseases based on the RAGE antagonists.
| S-EPMC10136230 | biostudies-literature
Project description:While the primary pathology of Alzheimer's disease (AD) is defined by brain deposition of amyloid-β (Aβ) plaques and tau neurofibrillary tangles, chronic inflammation has emerged as an important factor in AD etiology. Upregulated cell surface expression of the receptor for advanced glycation end-products (RAGE), a key receptor of innate immune response, is reported in AD. In parallel, RAGE ligands, including Aβ aggregates, HMGB1, and S100B, are elevated in AD brain. Activation of RAGE by these ligands triggers release of inflammatory cytokines and upregulates cell surface RAGE. Despite such observation, there are currently no therapeutics that target RAGE for treatment of AD-associated neuroinflammation. Peptoids, a novel class of potential AD therapeutics, display low toxicity, facile blood-brain barrier permeability, and resistance to proteolytic degradation. In the current study, peptoids were designed to mimic Aβ, a ligand that binds the V-domain of RAGE, and curtail RAGE inflammatory activation. We reveal the nanomolar binding capability of peptoids JPT1 and JPT1a to RAGE and demonstrate their ability to attenuate lipopolysaccharide-induced pro-inflammatory cytokine production as well as upregulation of RAGE cell surface expression. These results support RAGE antagonist peptoid-based mimics as a prospective therapeutic strategy to counter neuroinflammation in AD and other neurodegenerative diseases.
| S-EPMC10711691 | biostudies-literature
Project description:Chronic obstructive pulmonary disease (COPD) is a disease of the airways and lungs due to an enhanced inflammatory response, commonly caused by cigarette smoking. Patients with COPD are often multimorbid, as they commonly suffer from multiple chronic (inflammatory) conditions. This intensifies the burden of individual diseases, negatively affects quality of life, and complicates disease management. COPD and comorbidities share genetic and lifestyle-related risk factors and pathobiological mechanisms, including chronic inflammation and oxidative stress. The receptor for advanced glycation end products (RAGE) is an important driver of chronic inflammation. Advanced glycation end products (AGEs) are RAGE ligands that accumulate due to aging, inflammation, oxidative stress, and carbohydrate metabolism. AGEs cause further inflammation and oxidative stress through RAGE, but also through RAGE-independent mechanisms. This review describes the complexity of RAGE signaling and the causes of AGE accumulation, followed by a comprehensive overview of alterations reported on AGEs and RAGE in COPD and in important co-morbidities. Furthermore, it describes the mechanisms by which AGEs and RAGE contribute to the pathophysiology of individual disease conditions and how they execute crosstalk between organ systems. A section on therapeutic strategies that target AGEs and RAGE and could alleviate patients from multimorbid conditions using single therapeutics concludes this review.
| S-EPMC10219583 | biostudies-literature
Project description:Early or primary injury due to brain aggression, such as mechanical trauma, hemorrhage or is-chemia, triggers the release of damage-associated molecular patterns (DAMPs) in the extracellular space. Some DAMPs, such as S100B, participate in the regulation of cell growth and survival but may also trigger cellular damage as their concentration increases in the extracellular space. When DAMPs bind to pattern-recognition receptors, such as the receptor of advanced glycation end-products (RAGE), they lead to non-infectious inflammation that will contribute to necrotic cell clearance but may also worsen brain injury. In this narrative review, we describe the role and ki-netics of DAMPs and RAGE at the acute phase of brain injury. We searched the MEDLINE database for "DAMPs" or "RAGE" or "S100B" and "traumatic brain injury" or "subarachnoid hemorrhage" or "stroke". We selected original articles reporting data on acute brain injury pathophysiology, from which we describe DAMPs release and clearance upon acute brain injury, and the implication of RAGE in the development of brain injury. We will also discuss the clinical strategies that emerge from this overview in terms of biomarkers and therapeutic perspectives.
| S-EPMC7957733 | biostudies-literature
Project description:Non-specific orbital inflammation (NSOI) and IgG4-related orbital disease (IgG4-ROD) are currently treated with non-specific immunosuppressive agents based on non-randomized, uncontrolled studies. Therefore, relapses and prolongated courses are common and remain challenging. For a more specific therapy, a better understanding of the underlying pathophysiology is crucial. Therefore, we aimed to analyze signaling pathways to expand the knowledge on the pathophysiology and possibly identify specific targets in the future, as occurred recently in Graves’ orbitopathy with the IGF-1 receptor. Furthermore, we analyzed potential mechanisms for the described potential progression to orbital MALT (mucosa-associated lymphoid tissue) lymphoma. The investigation cohort for this screening study comprised of 12 patients with either typical NSOI (n = 6), IgG4-ROD or MALT lymphoma (n = 3 each). Mean age was 56.4 ± 17 years. MALT samples, in contrast with IgG4-ROD and NSOI, showed overall upregulation for extracellular matrix receptor interaction (ECM) and adipocytokine signaling. Investigating signaling compounds for MALT samples, differentially expressed genes were re-identified as targets with relevant expression. Even though pathway analysis showed differentially altered products when comparing IgG4-ROD with MALT, main conductors of differentiation in B- and T-cell signaling were commonly altered when observing the microenvironment of examined tissues. Our data reveal the characteristic differences and similarities in genetic-expression-based pathway profiles between MALT lymphoma, IgG4-ROD and NSOI, which may be useful for elucidating the associated pathogenic mechanisms and developing specific treatments for these orbital diseases.
| S-EPMC9605068 | biostudies-literature
Project description:We hypothesized that patients with sarcoidosis have characteristic mRNA profiles. Microarray analysis of gene expression was done on peripheral blood. Comparing peripheral blood from patients with sarcoidosis to controls, 872 transcripts were upregulated and 1039 were downregulated at >1.5-fold change and a significant q value. Several transcripts associated with interferon and STAT1 were upregulated. Lung and lymph node analyses also showed dramatic increases in STAT1 and STAT1-regulated chemokines. Granulomas in lymph nodes of patients with sarcoidosis expressed abundant STAT1 and phosphorylated STAT1. STAT1 might play an important role in sarcoidosis. This novel hypothesis unites seemingly disparate observations with regard to sarcoidosis including implication of a casual role for interferons, a suspected infectious trigger, TH1 predominating lymphocytes in bronchoalveolar lavage, and the association with hypercalcemia. This study tested the hypothesis that SpA is characterized by a distinct pattern of gene expression in peripheral blood of affected individuals compared with healthy controls. High-density, human GeneChip probe arrays were used to profile mRNA of peripheral blood cells from 18 subjects with SpA and 25 normal individuals. Samples were processed as two separate sets at different times. Blood samples were taken at a time when patients were not receiving systemic immunomodulatory therapy. Differential expression was defined as a 1.5-fold change with a q value <5%. Gene ontology and pathway information were also studied. Signals from 134 probe sets (representing 95 known and 12 unknown gene transcripts) were consistently different from controls in both Sets 1 and 2. Included among these were transcripts for a group of 20 genes, such as interleukin-1 receptors 1 and 2, NLRP2, SLPI, SPARC, and TREM-1 that are clearly related to the immune or inflammatory response and a group of 4 transcripts that have a strong role in bone remodeling. Our observations are the first to implicate SPARC, SLPI, and NLRP2, a component of the innate immune system, in the pathogenesis of SpA. Our results also indicate a possible role for interleukin-1 and its receptors in SpA. In accord with the bone pathology component of SpA, we also found that expression levels of transcripts reflecting bone remodeling factors are also distinguishable in peripheral blood from patients with SpA versus controls. These results confirm some previously identified biomarkers implicated in the pathogenesis of SpA and also point to novel mediators in this disease. Peripheral blood was collected from diseased and control subjects. The sarcoidosis portion of the study included 12 patients and 12 control subjects. The spondyloarthropathy study was done in two independent sets. The first set included 11 patients and the same 12 control subjects used for the sarcoidosis study. The second set included 7 patients and 13 control subjects. For each sample, total RNA was isolated and analyzed by hybridization on Affymetrix arrays.
2009-11-04 | E-GEOD-18781 | biostudies-arrayexpress
Project description:Cytosolic lipid droplets (LDs) are present in most cell types, and consist of a core comprising neutral lipids, mainly triglycerides and sterol esters, surrounded by a monolayer of phospholipids. LDs are heterogeneous in their structure, chemical composition, and tissue distribution. LDs are coated by several proteins, including perilipins and other structural proteins, lipogenic enzymes, lipases and membrane-trafficking proteins. Five proteins of the perilipin (PLIN) family (PLIN1 (perilipin), PLIN2 (adipose differentiation-related protein), PLIN3 (tail-interacting protein of 47kDa), PLIN4 (S3-12), and PLIN5 (myocardial lipid droplet protein)), are associated with LD formation. More recently, the CIDE family of proteins, hypoxia-inducible protein 2 (HIG2), and patanin-like phospholipase domain-containing 3 (PNPLA3) have also gained attention in hepatic LD biology. Evidence suggests that LD proteins are involved in the pathophysiology of fatty liver diseases characterized by excessive lipid accumulation in hepatocytes. This review article will focus on how hepatic LDs and their associated proteins are involved in the pathogenesis of three chronic liver conditions: hepatitis C virus infection, non-alcoholic fatty liver disease, and alcoholic liver disease.
| S-EPMC4744586 | biostudies-literature
Project description:Mitochondria are the source of cellular energy production and are present in different types of cells. However, their function is especially important for the heart due to the high demands in energy which is achieved through oxidative phosphorylation. Mitochondria form large networks which regulate metabolism and the optimal function is achieved through the balance between mitochondrial fusion and mitochondrial fission. Moreover, mitochondrial function is upon quality control via the process of mitophagy which removes the damaged organelles. Mitochondrial dysfunction is associated with the development of numerous cardiac diseases such as atherosclerosis, ischemia-reperfusion (I/R) injury, hypertension, diabetes, cardiac hypertrophy and heart failure (HF), due to the uncontrolled production of reactive oxygen species (ROS). Therefore, early control of mitochondrial dysfunction is a crucial step in the therapy of cardiac diseases. A number of anti-oxidant molecules and medications have been used but the results are inconsistent among the studies. Eventually, the aim of future research is to design molecules which selectively target mitochondrial dysfunction and restore the capacity of cellular anti-oxidant enzymes.
| S-EPMC6046286 | biostudies-literature