Search Results (165)

Advanced glycation end-products (AGEs) are formed by the non-enzymatic glycation of proteins, lipids, and nucleic acids due to the consumption of high-carbohydrate diets; their production is also promoted by a sedentary lifestyle as well as cigarette smoking. Elevated levels of AGEs in the circulatory system and internal organs of the body are commonly observed in a number of cardiovascular diseases such as hypertension, diabetes, atherosclerosis, coronary artery disease, aortic aneurysm, atrial fibrillation, myocardial infarction, and heart failure, which are associated with the development of oxidative stress and myocardial inflammation. The adverse effects of AGEs on the cardiovascular system are elicited by both non-receptor mechanisms involving the cross-linking of extracellular and intracellular proteins, and by receptor-mediated mechanisms involving the binding of AGEs with advanced glycation end-product receptors (RAGEs) on the cell membrane. AGE–RAGE interactions along with the cross-linking of proteins promote the generation of oxidative stress, the production of inflammation, the occurrence of intracellular Ca²⁺-overload, and alterations in the extracellular matrix leading to the development of cardiovascular dysfunction. AGEs also bind with two other protein receptors in the circulatory system: soluble RAGEs (sRAGEs) are released upon the proteolysis of RAGEs due to the activation of matrix metalloproteinase, and endogenous secretory RAGEs (esRAGEs) are secreted as a spliced variant of endogenous RAGEs. While the AGE–RAGE signal transduction axis serves as a pathogenic mechanism, both sRAGEs and esRAGEs serve as cytoprotective interventions. The serum levels of sRAGEs are decreased in ischemic heart disease, vascular disease, and heart failure, as well as in other cardiovascular diseases, but are increased in chronic diabetes and renal disease. Several interventions which can reduce the formation of AGEs, block the AGE–RAGE axis, or increase the levels of circulating sRAGEs have been shown to exert beneficial effects in diverse cardiovascular diseases. These observations support the view that the AGE–RAGE axis not only plays a critical role in pathogenesis, but is also an excellent target for the treatment of cardiovascular disease. Full article

Dietary advanced glycation end-products (dAGEs) contained in high-sugar/fat and ultra-processed foods of the “Western diet” (WD) pattern predispose to several diseases by altering protein function or increasing oxidative stress and inflammation via RAGE (receptor for advanced glycation end-products). Although elevated endogenous AGEs are associated with loss of muscle mass and functionality (i.e., muscle wasting; MW), the impact of dAGEs on MW has not been elucidated. Here, we show that the most common dAGEs or their precursor, methylglyoxal (MGO), induce C2C12 myotube atrophy as endogenous AGE-derived BSA. ROS production, mitochondrial dysfunction, mitophagy, ubiquitin–proteasome activation, and inhibition of myogenic potential are common atrophying mechanisms used by MGO and AGE-BSA. Although of different origins, ROS are mainly responsible for AGE-induced myotube atrophy. However, while AGE-BSA activates the RAGE-myogenin axis, reduces anabolic mTOR, and causes mitochondrial damage, MGO induces glycolytic stress and STAT3 activation without affecting RAGE expression. Among thirty selected natural compounds, Vaccinium macrocarpon (VM), Camellia sinensis, and chlorophyll showed a surprising ability in counteracting in vitro AGE formation. However, only the standardized VM, containing anti-glycative metabolites as revealed by UHPLC-HRMS analysis, abrogates AGE-induced myotube atrophy. Collectively, our data suggest that WD-linked dAGE consumption predisposes to MW, which might be restricted by VM food supplements. Full article

Alzheimer’s disease (AD) and schizophrenia are traditionally considered distinct clinical entities, yet growing evidence highlights substantial overlap in their molecular and neuroinflammatory pathogenesis. This review explores current insights into the shared and divergent mechanisms underlying these disorders, with emphasis on neuroinflammation, autophagy dysfunction, blood–brain barrier (BBB) disruption, and cognitive impairment. We examine key signaling pathways, particularly spleen tyrosine kinase (SYK), the mechanistic (or mammalian) target of rapamycin (mTOR), and the S100 calcium-binding protein B (S100B)/receptor for advanced glycation end-products (RAGE) axis, that link glial activation, excitatory/inhibitory neurotransmitter imbalances, and impaired proteostasis across both disorders. Specific biomarkers such as S100B, matrix metalloproteinase 9 (MMP9), and soluble RAGE show promise for stratifying disease subtypes and predicting treatment response. Moreover, psychiatric symptoms frequently precede cognitive decline in both AD and schizophrenia, suggesting that mood and behavioral disturbances may serve as early diagnostic indicators. The roles of autophagic failure, cellular senescence, and impaired glymphatic clearance are also explored as contributors to chronic inflammation and neurodegeneration. Current treatments, including cholinesterase inhibitors and antipsychotics, primarily offer symptomatic relief, while emerging therapeutic approaches target upstream molecular drivers, such as mTOR inhibition and RAGE antagonism. Finally, we discuss the future potential of personalized medicine guided by genetic, neuroimaging, and biomarker profiles to optimize diagnosis and treatment strategies in both AD and schizophrenia. A greater understanding of the pathophysiological convergence between these disorders may pave the way for cross-diagnostic interventions and improved clinical outcomes. Full article

Stroke is still considered a predominant cause of morbidity and mortality, for which research on prevention and cure has been sought to prevent neuronal damage after a stroke incident. In this research, we evaluated the protective effects of virgin coconut oil (VCO) using behavioral, morphophysiological, and gene expression parameters using an ischemic stroke surgical rat model using Sprague Dawley (SD) rats. Eight-week-old SD rats were subjected to repeated oral administration (5 mL/kg/day) of either 1% Tween 80 or VCO. For behavioral and morphophysiological parameters, surgery was performed for each group, after which neurological scoring was performed at 4 h, 24 h, 48 h, 5 d, and 10 d. Further, hematological and brain morphology assessment was performed after euthanasia and necropsy of the animals. For gene expression studies, surgery was performed with animals sacrificed at different time points (baseline, before surgery, 4 h, 24 h, and 48 h after surgery) to collect the brain. Results of the study showed that there are differences in the neurological scores between the two treatments 24 h, 48 h, and 5 d after surgery. Brain morphology assessment also showed favorable results for VCO for infarct size, edema, and hypoxic neurons. Gene expression studies also showed positive results with an increase in the relative expression of angiogenin (Ang), angiopoietin (Angpt 1), Parkin, dynamin-related protein 1 (Drp 1), mitofusin 2 (Mfn 2), and mitochondrial rho (Miro) and decreased relative expression of caspase 3, receptor for advanced glycation end-product (Rage), and glyceraldehyde-3-phosphate dehydrogenase (Gapdh). In summary, the current study shows that VCO may have protective effects on the brain after stroke, which may be explained by the results of the gene expression studies. Full article

Background: Methylglyoxal (MGO), a reactive dicarbonyl compound, has been implicated in the formation of advanced glycation end-products (AGEs) and neuronal dysfunction. This study investigated the neuroprotective effects of the combination of trans-resveratrol and hesperidin (tRES-HESP) against MGO-induced neurotoxicity, focusing on memory dysfunction and depression-like behavior. Methods: Neuroblastoma 2a (N2a) cells were treated with MGO to induce neurotoxicity. The effects of tRES-HESP on cell viability, reactive oxygen species (ROS) production, apoptotic markers (BAX/Bcl 2 ratio, caspase 3 activity, and poly [ADP ribose] polymerase cleavage), and components of the glyoxalase system (glyoxalase-1, glyoxalase- 2, and receptors for AGEs) were assessed. The activation of the Kelch-like ECH-associated protein 1/Nuclear factor erythroid-2-related factor 2/Heme oxygenase-1 (Keap1/Nrf2/HO-1) pathway was also evaluated. In vivo, mice with MGO-induced depressive amnesia were treated with tRES-HESP (200 mg/kg) for eight weeks, and behavioral, biochemical, and histological assessments were performed. Results: tRES-HESP significantly reduced MGO-induced cytotoxicity, ROS production, and apoptosis in N2a cells. In addition, it restored the glyoxalase system and activated the Keap1/Nrf2/HO-1 pathway. In an in vivo model, tRES-HESP improved memory and depression-like behaviors, reduced cortisol and interleukin (IL)-6 levels, increased IL-10 levels, and lowered the expression of amyloid precursor protein and amyloid beta. Furthermore, tRES-HESP protected CA2/3 hippocampal subregions from MGO-induced damage. tRES-HESP exhibited neuroprotective effects through antioxidant, anti-apoptotic, and anti-inflammatory mechanisms. Conclusions: Our results suggest that tRES-HESP is a potential dietary supplement for preventing cognitive decline and depression, particularly in neurodegenerative conditions such as Alzheimer’s disease. Further studies are required to assess its clinical relevance and efficacy in the human population. Full article

Chronic obstructive pulmonary disease (COPD) is a chronic, debilitating condition that affects the lungs and airways. It is characterized by persistent bronchitis, a condition exemplified by the inflammation of the bronchial tubes, the hypersecretion of mucus, emphysema, and the destruction of the airway parenchyma. The combination of these conditions leads to persistent tissue damage, pulmonary fibrosis, and ongoing inflammation of the airways. The inflammatory response in COPD is a complex process that is orchestrated by a wide range of immune cells. These include lung epithelial cells, monocytes, macrophages, neutrophils, eosinophils, and T and B lymphocytes, among others. These cells work together to produce a wide range of inflammatory biomarkers that are involved in the pathogenesis of COPD. Some of the key inflammatory biomarkers that have been identified in COPD include a variety of cytokines, the C-reactive protein/serum albumin ratio, fibrinogen, soluble receptor for advanced glycation endproducts, club/clara cells in the lungs with a molecular weight of 16 kDa, surfactant protein D, adiponectin, reactive oxygen species, and proteases. This review aims to provide a comprehensive overview of the role of immune cells and key inflammatory biomarkers in the development and progression of COPD. It will delve into the intricacies of the inflammatory response in COPD, exploring the various cell types and biomarkers that are involved in this process. By understanding the underlying mechanisms that drive COPD, we can better develop targeted treatments that can help to alleviate the symptoms of COPD. Full article

The AGE (advanced glycation end-products)–RAGE (receptor for AGE) system is a pro-inflammatory pathway that contributes to the pathogenesis of obesity and obesity-related cardiovascular disorders (CVD). Circulating AGE and the soluble form of RAGE (sRAGE) has been suggested as a potential biomarker of CVD related to obesity. In this study, we aim to (1) summarize the current knowledge about the role of obesity in the onset and progression of CVD, (2) discuss the role of the AGE–RAGE system as a pathway promoting obesity and linking obesity to CVD, and (3) highlight available strategies for reducing AGE–RAGE system activation and the associated beneficial effects. Full article

Superoxide dismutase (SOD), a key antioxidant enzyme, plays a crucial role in neutralizing reactive oxygen species (ROS) and maintaining redox balance. However, SOD is highly susceptible to glycation, a non-enzymatic modification induced by reducing sugars and reactive carbonyl species such as methylglyoxal. This review aims to provide a comprehensive analysis of SOD glycation, examining its biochemical mechanisms, its impact on enzymatic function, and its role in the progression of oxidative stress-related diseases. Additionally, it explores potential therapeutic strategies to prevent SOD glycation and restore its activity, highlighting translational applications for disease management. The review examines research on SOD glycation and its pathological consequences in diabetes complications, neurodegenerative disorders, and cardiovascular diseases. Key therapeutic interventions, including advanced glycation end-product (AGE) inhibitors (aminoguanidine, pyridoxamine), antioxidants (N-acetylcysteine, alpha-lipoic acid), SOD mimetics (MnTBAP, Tempol), enzyme stabilizers (thymoquinone, alliin), and receptor for advanced glycation end-products (RAGE) blockade, are analyzed for their efficacy in mitigating oxidative stress. SOD glycation reduces enzymatic activity, leading to elevated ROS levels and inflammation. Glycated SOD interacts with RAGE, increasing oxidative stress biomarkers. AGE inhibitors reduce carbonyl stress, whereas antioxidants lower ROS levels. SOD mimetics restore up to 85% of enzymatic activity, and enzyme stabilizers protect SOD from structural degradation. Additionally, monoclonal antibodies targeting RAGE have been shown to reduce inflammatory cytokines and improve mitochondrial function. SOD glycation is a major contributor to oxidative stress-related diseases. Preventing glycation and restoring SOD function through a multifaceted therapeutic approach is crucial for mitigating disease progression. By elucidating the role of SOD in disease pathogenesis, this review contributes to the advancement of targeted therapies for oxidative stress-related conditions, including diabetes, neurodegeneration, and cardiovascular diseases. Full article

Resveratrol (RSV) improves metabolic functions, but its tissue-specific effects on diabetes remain unclear. This study investigated RSV’s impact on molecular pathways in an experimental model of diabetes in cardiac and skeletal muscles and adipose tissue. Wistar rats were assigned to control (C), control treated with RSV (RC), diabetic (D), and diabetic treated with RSV (RD). Diabetes was induced using streptozotocin and nicotinamide, and RSV was administered for six weeks. In diabetic rats, RSV treatment significantly reduced collagen accumulation in cardiac and skeletal muscle tissues compared to untreated diabetic controls, although it did not restore muscle mass. Adipose tissue in diabetic rats exhibited a significant reduction of 3.4 times in collagen levels following RSV treatment. However, this reduction was not associated with any measurable improvement in tissue function. In cardiac tissue, RSV downregulated phosphorylated protein kinase B (AKT)/AKT and phosphorylated ribosomal protein S6 (rpS6)/rpS6 while mammalian target of rapamycin (mTOR) activity remained unchanged. In skeletal muscle, RSV suppressed rpS6 phosphorylation without affecting (mTOR) signaling. RSV enhanced mTOR and Beclin-1 expression in adipose tissue, though metabolic dysfunction persisted. RSV reduced receptors for advanced glycation end-product expression in all tissues, indicating the modulation of hyperglycemia-driven pathways. RSV improved fibrosis and signaling pathways but failed to reverse abnormal tissue growth patterns, including cardiac hypertrophy, skeletal muscle atrophy, and adipose tissue atrophy. Full article

Oxidative stress levels are exacerbated in Alzheimer’s disease (AD). This phenomenon feeds back into the overactivation of oxidase enzymes, mitochondrial dysfunction, and the formation of advanced glycation end-products (AGEs), with the stimulation of their receptors (RAGE). These factors stimulate Aβ peptide aggregation and tau hyperphosphorylation through multiple pathways, which are addressed in this paper. The aim of this study was to evaluate the regulatory effect of N-acetyl cysteine (NAC) on oxidant/antioxidant balance as an adjuvant treatment in patients with AD. The results obtained showed that NAC supplementation produced improved cognitive performance, decreased levels of oxidative stress markers, lowered activities of oxidase enzymes, increased antioxidant responses, and attenuated inflammatory and apoptotic markers. Moreover, NAC reversed mitochondrial dysfunction, lowered AGEs-RAGE formation, attenuated Aβ peptide oligomerization, and reduced phosphorylation of tau, thereby halting the formation of neurofibrillary tangles and the progression of AD. Full article

Background and Objectives: Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury with high mortality, characterized by hypoxemic respiratory failure and diffuse lung damage. Despite advancements in care, no definitive biomarkers have been established for ARDS diagnosis and prognostic stratification. Soluble receptor for advanced glycation end-products (sRAGE), a marker of alveolar epithelial injury, has shown promise as a prognostic indicator in ARDS. This study evaluates sRAGE’s utility in predicting 28-day mortality. Materials and Methods: A retrospective cohort study was conducted at a tertiary care ICU in Serbia from January 2021 to June 2023. Adult patients meeting the Berlin definition of ARDS were included. Exclusion criteria included pre-existing chronic respiratory diseases and prolonged mechanical ventilation before diagnosis. Serum sRAGE levels were measured within 48 h of ARDS diagnosis using enzyme-linked immunosorbent assay (ELISA). Clinical severity scores, laboratory markers, and ventilatory parameters were recorded. Logistic regression and survival analyses were used to assess the prognostic value of sRAGE for 28-day mortality. Results: A cohort of 121 patients (mean age 55.5 years; 63.6% male) was analyzed. Non-survivors exhibited higher median sRAGE levels than survivors (5852 vs. 4479 pg/mL, p = 0.084). The optimal sRAGE cut-off for predicting mortality was >16,500 pg/mL (sensitivity 30.4%, specificity 86.9%). Elevated sRAGE levels were associated with greater disease severity and an increased risk of 28-day mortality in ARDS patients, highlighting its potential as a prognostic biomarker. The main findings, while indicative of a trend toward higher sRAGE levels in non-survivors, did not reach statistical significance. Conclusions: The main findings, while indicative of a trend toward higher sRAGE levels in non-survivors, did not reach statistical significance (p = 0.084). sRAGE demonstrates potential as a prognostic biomarker in ARDS and has moderate correlation with 28-day mortality. Integrating sRAGE with other biomarkers could enhance risk stratification and guide therapeutic decisions. The retrospective design limits the ability to establish causation, underscoring the need for multicenter prospective studies. Full article

The receptor for advanced glycation end-products (RAGE), a member of the immunoglobulin superfamily, is expressed in various cell types and mediates cellular responses to a wide range of ligands. The activation of RAGE triggers complex signaling pathways that drive inflammatory, oxidative, and proliferative responses, which are increasingly implicated in the pathogenesis of skin diseases. Despite its well-established roles in conditions such as diabetes, cancer, and chronic inflammation, the contribution of RAGE to skin pathologies remains underexplored. This review synthesizes current findings on RAGE’s involvement in the pathophysiology of skin diseases, including conditions such as psoriasis, atopic dermatitis, and lichen planus, focusing on its roles in inflammatory signaling, tissue remodeling, and skin cancer progression. Additionally, it examines RAGE-modulating treatments investigated in dermatological contexts, highlighting their potential as therapeutic options. Given RAGE’s significance in a variety of skin conditions, further research into its mediated pathways may uncover new opportunities for targeted interventions in skin-specific RAGE signaling. Full article

Advanced glycation end-products (AGEs) are products of a non-enzymatic reaction between amino acids and reducing sugars. Glycated human serum albumin (HSA) increases in diabetics as a consequence of elevated blood glucose levels and glycating metabolites like methylglyoxal (MGO). The impact of different types of glycation on the immunomodulatory properties of HSA is poorly understood and is studied here. HSA was glycated with D-glucose, MGO, or glyoxylic acid (CML). Glycation-related biochemical changes were characterized using various biochemical methods. The binding of differentially glycated HSA to AGE receptors was determined with inhibition ELISAs, and the impact on inflammatory markers in macrophage cell line THP-1 and adherent monocytes isolated from human peripheral blood mononuclear cells (PBMCs) was studied. All glycation methods led to unique AGE profiles and had a distinct impact on protein structure. Glycation resulted in increased binding of HSA to the AGE receptors, with MGO modification showing the highest binding, followed by glucose and, lastly, CML. Additionally, modification of HSA with MGO led to the increased expression of pro-inflammatory markers in THP-1 macrophages and enhanced phosphorylation of NF-κB p65. The same pattern, although less prominent, was observed for HSA glycated with glucose and CML, respectively. An increase in pro-inflammatory markers was also observed in PBMC-derived monocytes exposed to all glycated forms of HSA, although HSA–CML led to a significantly higher inflammatory response. In conclusion, the type of HSA glycation impacts immune functional readouts with potential relevance for diabetes. Full article

Diabetic retinopathy is a complex, microvascular disease that impacts millions of working adults each year. High blood glucose levels from Diabetes Mellitus lead to the accumulation of advanced glycation end-products (AGEs), which promote inflammation and the breakdown of the inner blood retinal barrier (iBRB), resulting in vision loss. This study used an in vitro model of hyperglycemia to examine how endothelial cells (ECs) and Müller glia (MG) collectively regulate molecular transport. Changes in cell morphology, the expression of junctional proteins, and the reactive oxygen species (ROS) of ECs and MG were examined when exposed to a hyperglycemic medium containing AGEs. Trans-endothelial resistance (TEER) assays were used to measure the changes in cell barrier resistance in response to hyperglycemic and inflammatory conditions, with and without an anti-VEGF compound. Both of the cell types responded to hyperglycemic conditions with significant changes in the cell area and morphology, the ROS, and the expression of the junctional proteins ZO-1, CX-43, and CD40, as well as the receptor for AGEs. The resistivities of the individual and dual ECs and MG barriers decreased within the hyperglycemia model but were restored to that of basal, normoglycemic levels when treated with anti-VEGF. This study illustrated significant phenotypic responses to an in vitro model of hyperglycemia, as well as significant changes in the expression of the key proteins used for cell–cell communication. The results highlight important, synergistic relationships between the ECs and MG and how they contribute to changes in barrier function in combination with conventional treatments. Full article

Endometrial cancer (EC) is the most common gynecological malignancy. EC is associated with metabolic disorders that may promote non-enzymatic glycation and activate the receptor for advanced glycation end-products (RAGE) signaling pathways. Thus, we assumed that RAGE and its ligands may contribute to EC. Of particular interest is the interaction between diaphanous-related formin 1 (Diaph1) and RAGE during the progression of human cancers. Diaph1 is engaged in the proper organization of actin cytoskeletal dynamics, which is crucial in cancer invasion, metastasis, angiogenesis, and axonogenesis. However, the detailed molecular role of RAGE in EC remains uncertain. In this review, we discuss epigenetic factors that may play a key role in the RAGE-dependent endometrial pathology. We propose that DNA methylation may regulate the activity of the RAGE pathway in the uterus. The accumulation of negative external factors, such as hyperglycemia, inflammation, and oxidative stress, may interfere with the DNA methylation process. Therefore, further research should take into account the role of epigenetic mechanisms in EC progression. Full article