Lycopene in Combination with Insulin Triggers Antioxidant Defenses and Increases the Expression of Components That Detoxify Advanced Glycation Products in Kidneys of Diabetic Rats.

BACKGROUND: Biochemical events provoked by oxidative stress and advanced glycation may be inhibited by combining natural bioactives with classic therapeutic agents, which arise as strategies to mitigate diabetic complications. The aim of this study was to investigate whether lycopene combined with a reduced insulin dose is able to control glycemia and to oppose glycoxidative stress in kidneys of diabetic rats. METHODS: Streptozotocin-induced diabetic rats were treated with 45 mg/kg lycopene + 1 U/day insulin for 30 days. The study assessed glycemia, insulin sensitivity, lipid profile and paraoxonase 1 (PON-1) activity in plasma. Superoxide dismutase (SOD) and catalase (CAT) activities and the protein levels of advanced glycation end-product receptor 1 (AGE-R1) and glyoxalase-1 (GLO-1) in the kidneys were also investigated. RESULTS: An effective glycemic control was achieved with lycopene plus insulin, which may be attributed to improvements in insulin sensitivity. The combined therapy decreased the dyslipidemia and increased the PON-1 activity. In the kidneys, lycopene plus insulin increased the activities of SOD and CAT and the levels of AGE-R1 and GLO-1, which may be contributing to the antialbuminuric effect. CONCLUSIONS: These findings demonstrate that lycopene may aggregate favorable effects to insulin against diabetic complications resulting from glycoxidative stress.

The RAGE Axis: A Relevant Inflammatory Hub in Human Diseases.

In 1992, a transcendental report suggested that the receptor of advanced glycation end-products (RAGE) functions as a cell surface receptor for a wide and diverse group of compounds, commonly referred to as advanced glycation end-products (AGEs), resulting from the non-enzymatic glycation of lipids and proteins in response to hyperglycemia. The interaction of these compounds with RAGE represents an essential element in triggering the cellular response to proteins or lipids that become glycated. Although initially demonstrated for diabetes complications, a growing body of evidence clearly supports RAGE's role in human diseases. Moreover, the recognizing capacities of this receptor have been extended to a plethora of structurally diverse ligands. As a result, it has been acknowledged as a pattern recognition receptor (PRR) and functionally categorized as the RAGE axis. The ligation to RAGE leads the initiation of a complex signaling cascade and thus triggering crucial cellular events in the pathophysiology of many human diseases. In the present review, we intend to summarize basic features of the RAGE axis biology as well as its contribution to some relevant human diseases such as metabolic diseases, neurodegenerative, cardiovascular, autoimmune, and chronic airways diseases, and cancer as a result of exposure to AGEs, as well as many other ligands.

Spinal HMGB1 participates in the early stages of paclitaxel-induced neuropathic pain via microglial TLR4 and RAGE activation.

Introduction: Chemotherapy-induced neuropathic pain (CINP) is one of the main adverse effects of chemotherapy treatment. At the spinal level, CINP modulation involves glial cells that upregulate Toll-like receptor 4 (TLR4) and signaling pathways, which can be activated by pro-inflammatory mediators as the high mobility group box-1 (HMGB1). Objective: To evaluate the spinal role of HMGB1 in the paclitaxel-induced neuropathic pain via receptor for advanced glycation end products (RAGE) and TLR4 activation expressed in glial cells. Methods: Male C57BL/6 Wild type and TLR4 deficient mice were used in the paclitaxel-induced neuropathic pain model. The nociceptive threshold was measured using the von Frey filament test. In addition, recombinant HMGB1 was intrathecally (i.t.) injected to confirm its nociceptive potential. To evaluate the spinal participation of RAGE, TLR4, NF-kB, microglia, astrocytes, and MAPK p38 in HMGB1-mediated nociceptive effect during neuropathic pain and recombinant HMGB1-induced nociception, the drugs FPS-ZM1, LPS-RS, PDTC, minocycline, fluorocitrate, and SML0543 were respectively administrated by i.t. rout. Microglia, astrocytes, glial cells, RAGE, and TLR4 protein expression were analyzed by Western blot. ELISA immunoassay was also used to assess HMGB1, IL-1ß, and TNF-α spinal levels. Results: The pharmacological experiments demonstrated that spinal RAGE, TLR4, microglia, astrocytes, as well as MAPK p38 and NF-kB signaling are involved with HMGB1-induced nociception and paclitaxel-induced neuropathic pain. Furthermore, HMGB1 spinal levels were increased during the early stages of neuropathic pain and associated with RAGE, TLR4 and microglial activation. RAGE and TLR4 blockade decreased spinal levels of pro-inflammatory cytokines during neuropathic pain. Conclusion: Taken together, our findings indicate that HMGB1 may be released during the early stages of paclitaxel-induced neuropathic pain. This molecule activates RAGE and TLR4 receptors in spinal microglia, upregulating pro-inflammatory cytokines that may contribute to neuropathic pain.

Loss of Direct Vascular Contact to Astrocytes in the Hippocampus as an Initial Event in Alzheimer's Disease. Evidence from Patients, In Vivo and In Vitro Experimental Models.

Alzheimer's disease (AD) is characterized by the accumulation of aggregated amyloid peptides in the brain parenchyma and within the walls of cerebral vessels. The hippocampus-a complex brain structure with a pivotal role in learning and memory-is implicated in this disease. However, there is limited data on vascular changes during AD pathological degeneration in this susceptible structure, which has distinctive vascular traits. Our aim was to evaluate vascular alterations in the hippocampus of AD patients and PDAPP-J20 mice-a model of AD-and to determine the impact of Aß40 and Aß42 on endothelial cell activation. We found a loss of physical astrocyte-endothelium interaction in the hippocampus of individuals with AD as compared to non-AD donors, along with reduced vascular density. Astrocyte-endothelial interactions and levels of the tight junction protein occludin were altered early in PDAPP-J20 mice, preceding any signs of morphological changes or disruption of the blood-brain barrier in these mice. At later stages, PDAPP-J20 mice exhibited decreased vascular density in the hippocampus and leakage of fluorescent tracers, indicating dysfunction of the vasculature and the BBB. In vitro studies showed that soluble Aß40 exposure in human brain microvascular endothelial cells (HBMEC) was sufficient to induce NFκB translocation to the nucleus, which may be linked with an observed reduction in occludin levels. The inhibition of the membrane receptor for advanced glycation end products (RAGE) prevented these changes in HBMEC. Additional results suggest that Aß42 indirectly affects the endothelium by inducing astrocytic factors. Furthermore, our results from human and mouse brain samples provide evidence for the crucial involvement of the hippocampal vasculature in Alzheimer's disease.

Assessing Pulmonary Epithelial Damage in Hantavirus Cardiopulmonary Syndrome: Challenging the Predominant Role of Vascular Endothelium through sRAGE as a Potential Biomarker.

Hantavirus cardiopulmonary syndrome (HCPS) is a severe respiratory illness primarily associated with microvascular endothelial changes, particularly in the lungs. However, the role of the pulmonary epithelium in HCPS pathogenesis remains unclear. This study explores the potential of soluble Receptors for Advanced Glycation End-products (sRAGE) as a biomarker for assessing pulmonary epithelial damage in severe HCPS, challenging the prevailing view that endothelial dysfunction is the sole driver of this syndrome. We conducted a cross-sectional study on critically ill HCPS patients, categorizing them into mild HCPS, severe HCPS, and negative control groups. Plasma sRAGE levels were measured, revealing significant differences between the severe HCPS group and controls. Our findings suggest that sRAGE holds promise as an indicator of pulmonary epithelial injury in HCPS and may aid in tracking disease progression and guiding therapeutic strategies. This study brings clarity on the importance of investigating the pulmonary epithelium's role in HCPS pathogenesis, offering potential avenues for enhanced diagnostic precision and support in this critical public health concern.

Evidence that methylglyoxal and receptor for advanced glycation end products are implicated in bladder dysfunction of obese diabetic ob/ob mice.

Glycolytic overload in diabetes causes large accumulation of the highly reactive dicarbonyl compound methylglyoxal (MGO) and overproduction of advanced glycation end products (AGEs), which interact with their receptors (RAGE), leading to diabetes-associated macrovascular complications. The bladder is an organ that stays most in contact with dicarbonyl species, but little is known about the importance of the MGO-AGEs-RAGE pathway to diabetes-associated bladder dysfunction. Here, we aimed to investigate the role of the MGO-AGEs-RAGE pathway in bladder dysfunction of diabetic male and female ob/ob mice compared with wild-type (WT) lean mice. Diabetic ob/ob mice were treated with the AGE breaker alagebrium (ALT-711, 1 mg/kg) for 8 wk in drinking water. Compared with WT animals, male and female ob/ob mice showed marked hyperglycemia and insulin resistance, whereas fluid intake remained unaltered. Levels of total AGEs, MGO-derived hydroimidazolone 1, and RAGE in bladder tissues, as well as fluorescent AGEs in serum, were significantly elevated in ob/ob mice of either sex. Collagen content was also markedly elevated in the bladders of ob/ob mice. Void spot assays in filter paper in conscious mice revealed significant increases in total void volume and volume per void in ob/ob mice with no alterations of spot number. Treatment with ALT-711 significantly reduced the levels of MGO, AGEs, RAGE, and collagen content in ob/ob mice. In addition, ALT-711 treatment normalized the volume per void and increased the number of spots in ob/ob mice. Activation of AGEs-RAGE pathways by MGO in the bladder wall may contribute to the pathogenesis of diabetes-associated bladder dysfunction.NEW & NOTEWORTHY The involvement of methylglyoxal (MGO) and advanced glycation end products (AGEs) in bladder dysfunction of diabetic ob/ob mice treated with the AGE breaker ALT-711 was investigated here. Diabetic mice exhibited high levels of MGO, AGEs, receptor for AGEs (RAGE), and collagen in serum and/or bladder tissues along with increased volume per void, all of which were reduced by ALT-711. Activation of the MGO-AGEs-RAGE pathway in the bladder wall contributes to the pathogenesis of diabetes-associated bladder dysfunction.

RAGE Against the Glycation Machine in Synucleinopathies: Time to Explore New Questions.

Oligomerization and aggregation of misfolded forms of α-synuclein are believed to be key molecular mechanisms in Parkinson's disease (PD) and other synucleinopathies, so extensive research has attempted to understand these processes. Among diverse post-translational modifications that impact α-synuclein aggregation, glycation may take place at several lysine sites and modify α-synuclein oligomerization, toxicity, and clearance. The receptor for advanced glycation end products (RAGE) is considered a key regulator of chronic neuroinflammation through microglial activation in response to advanced glycation end products, such as carboxy-ethyl-lysine, or carboxy-methyl-lysine. The presence of RAGE in the midbrain of PD patients has been reported in the last decades and this receptor was proposed to have a role in sustaining PD neuroinflammation. However, different PD animal models demonstrated that RAGE is preferentially expressed in neurons and astrocytes, while recent evidence demonstrated that fibrillar, non-glycated α-synuclein binds to RAGE. Here, we summarize the available data on α-synuclein glycation and RAGE in the context of PD, and discuss about the questions yet to be answered that may increase our understanding of the molecular bases of PD and synucleinopathies.

Metformin Counteracts the Deleterious Effects of Methylglyoxal on Ovalbumin-Induced Airway Eosinophilic Inflammation and Remodeling.

Exposure to methylglyoxal (MGO) increases the levels of receptor for advanced glycation end products (RAGE) and reactive-oxygen species (ROS) in mouse airways, exacerbating the inflammatory responses. Metformin scavenges MGO in plasma of diabetic individuals. We investigated if amelioration by metformin of eosinophilic inflammation reflects its ability to inactivate MGO. Male mice received 0.5% MGO for 12 weeks together or not with 2-week treatment with metformin. Inflammatory and remodeling markers were evaluated in bronchoalveolar lavage fluid (BALF) and/or lung tissues of ovalbumin (OVA)-challenged mice. MGO intake elevated serum MGO levels and MGO immunostaining in airways, which were reduced by metformin. The infiltration of inflammatory cells and eosinophils and levels of IL-4, IL-5 and eotaxin significantly increased in BALF and/or lung sections of MGO-exposed mice, which were reversed by metformin. The increased mucus production and collagen deposition by MGO exposure were also significantly decreased by metformin. In MGO group, the increases of RAGE and ROS levels were fully counteracted by metformin. Superoxide anion (SOD) expression was enhanced by metformin. In conclusion, metformin counteracts OVA-induced airway eosinophilic inflammation and remodeling, and suppresses the RAGE-ROS activation. Metformin may be an option of adjuvant therapy to improve asthma in individuals with high levels of MGO.

Soluble receptor for advanced glycation end products and lipid profile ratio as cardiovascular risk markers in children with obesity.

INTRODUCTION: Obesity has been shown to be associated with low levels of soluble receptor for advanced glycation end products (sRAGE). OBJECTIVE: To evaluate the levels of sRAGE and its association with the lipid index in children with obesity. METHODS: Cross-sectional study of children with obesity aged between six and 11 years. Anthropometric measurements, glucose, lipid profile, insulin and sRAGE were evaluated; body mass index, total cholesterol/high-density cholesterol (TC/HDL-C), triglycerides/glucose (TG/glucose), and triglycerides/HDL-C (TG-HDL-C) ratios and HOMA-IR were also calculated. RESULTS: Eighty children were studied, among which 50% were males and 50% females. Females had higher values for waist circumference, HOMA-IR, and TG/HDL-C and TG/glucose ratios. No significant differences were found for sRAGE. When the variables were compared according to TG/HDL-C ratio tertiles, higher TC/HDL, TG/glucose, and sRAGE values were found at upper tertile. A significant correlation was observed between sRAGE and HOMA-IR (p < 0.03) in males, and between sRAGE and TG/HDL-C (p < 0.01) and TG/glucose ratios (p < 0.008) in females. CONCLUSIONS: The female gender showed more cardiovascular risk factors and higher sRAGE at TG/HDL-C upper tertile. Further studies are required to test the possible predictive effect of higher risk for developing metabolic and cardiovascular complications.

INTRODUCCIÓN: Se ha mostrado que la obesidad está asociada a niveles bajos de la forma soluble del receptor para productos finales de glicación avanzada (sRAGE). OBJETIVO: Evaluar los niveles de sRAGE y su asociación con el índice lipídico en niños con obesidad. MÉTODOS: Estudio transversal de niños de seis a 11 años de edad con obesidad. Se evaluaron medidas antropométricas, glucosa, perfil lipídico, insulina y sRAGE; también se calculó índice de masa corporal, colesterol total/C-HDL, triglicéridos/glucosa, triglicéridos/C-HDL y HOMA-IR. RESULTADOS: Se estudiaron 80 niños, 50 % hombres y 50 % mujeres. Las mujeres presentaron mayor perímetro de cintura, HOMA-IR, triglicéridos/C-HDL y triglicéridos/glucosa. No se encontraron diferencias significativas en sRAGE. Al comparar las variables conforme a los terciles de la relación triglicéridos/C-HDL, en el tercil superior se encontraron mayores valores de colesterol total/HDL, triglicéridos/glucosa y sRAGE. Se observó correlación significativa entre sRAGE y HOMA-IR (p < 0.03) en los hombres y entre sRAGE, triglicéridos/C-HDL (p < 0.01) y triglicéridos/glucosa (p < 0.008) en las mujeres. CONCLUSIONES: El sexo femenino mostró más factores de riesgo cardiovascular y mayor sRAGE en el tercil superior de triglicéridos/C-HDL. Se requieren más estudios para probar el posible efecto predictor de mayor riesgo para desarrollar complicaciones metabólicas y cardiovasculares.

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

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

Receptors for Advanced Glycation End Products (RAGE): Promising Targets Aiming at the Treatment of Neurodegenerative Conditions.

Advanced glycation end products (AGEs) are compounds formed after the non-enzymatic addition of reducing sugars to lipids, proteins, and nucleic acids. They are associated with the development of various clinical complications observed in diabetes and cardiovascular diseases, such as retinopathy, nephropathy, diabetic neuropathy, and others. In addition, compelling evidence indicates that these molecules participate in the progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Multiple cellular and molecular alterations triggered by AGEs that could alter homeostasis have been identified. One of the main targets for AGE signaling is the receptor for advanced glycation end-products (RAGE). Importantly, this receptor is the target of not only AGEs, but also amyloid ß peptides, HMGB1 (high-mobility group box-1), members of the S100 protein family, and glycosaminoglycans. The activation of this receptor induces intracellular signaling cascades that are involved in pathological processes and cell death. Therefore, RAGE represents a key target for pharmacological interventions in neurodegenerative diseases. This review will discuss the various effects of AGEs and RAGE activation in the pathophysiology of neurodegenerative diseases, as well as the currently available pharmacological tools and promising drug candidates.

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

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

Relationship of advanced glycation end-products in hypertension in diabetic patients: a systematic review.

Diabetes mellitus and arterial hypertension are among the five risk factors that increase mortality in the world. Both are chronic, non-communicable diseases (NCDs), that have a pathophysiological association. Advanced glycation end products (AGEs), produced by the lack of glycemic control in diabetic patients, interact with their AGE receptors (AGER) resulting in increased arterial stiffness, inflammation and endothelial changes - which increases the risk of developing hypertension and other complications. We ran a systematic review in Pubmed, SciELO, Cochrane Library and Web of Science databases using keywords and Boolean operators to optimize the search, with the objective of assessing the mechanism of non-enzymatic glycation of proteins present in patients with diabetes and its correlation with the onset of hypertension, exposing all the endothelial and cellular damage caused by AGEs. We found 719 papers, of which 99 were read in full, and 26 met the eligibility criteria and were included in the present review. AGEs should be considered one of the main cardiometabolic risk factors. Reducing the AGE-AGER interaction will result in cardiovascular protection and increased life expectancy.

Acute Methylglyoxal-Induced Damage in Blood-Brain Barrier and Hippocampal Tissue.

Methylglyoxal (MG) is a reactive dicarbonyl compound formed mostly via the glycolytic pathway. Elevated blood glucose levels can cause MG accumulation in plasma and cerebrospinal fluid in patients with diabetes mellitus and Alzheimer's disease. Under these disease conditions, the high reactivity of MG leads to modification of proteins and other biomolecules, generating advanced glycation end products (AGEs), which are considered mediators in neurodegenerative diseases. We investigated the integrity of the blood-brain barrier (BBB) and astrocyte response in the hippocampus to acute insult induced by MG when it was intracerebroventricularly administered to rats. Seventy-two hours later, BBB integrity was lost, as assessed by the entry of Evans dye into the brain tissue and albumin in the cerebrospinal fluid, and a decrease in aquaporin-4 and connexin-43 in the hippocampal tissue. MG did not induce changes in the hippocampal contents of RAGE in this short interval, but decreased the expression of S100B, an astrocyte-secreted protein that binds RAGE. The expression of two important transcription factors of the antioxidant response, NF-κB and Nrf2, was unchanged. However, hemeoxigenase-1 was upregulated in the MG-treated group. These data corroborate the idea that hippocampal cells are targets of MG toxicity and that BBB dysfunction and specific glial alterations induced by this compound may contribute to the behavioral and cognitive alterations observed in these animals.

Polymorphisms in risk genes of type 2 diabetes mellitus could be also markers of susceptibility to periodontitis.

OBJECTIVES: This study aimed to investigate polymorphisms in genes considered molecular biomarkers of type 2 diabetes mellitus (T2DM) to assess whether they are associated with periodontitis, and relating them to the periodontal status, glycemic and lipid profile of the subjects. DESIGN: We investigated individuals who underwent complete periodontal examination and biochemical evaluation. We categorized them into three groups: (i) periodontitis with T2DM (Periodontitis+T2DM group, n = 206); (ii) periodontitis without T2DM (Periodontitis group, n = 346); and (iii) healthy individuals without Periodontitis or T2DM (Healthy group, n = 345). We investigated three single nucleotide polymorphisms (SNPs) for AGER, RBMS1 and VEGFA genes. We applied multivariate logistic and multiple linear regression models for all groups and stratified the subjects by sex and smoking habits. RESULTS: Compared with RBMS1-rs7593730-CC+CT genotype carriers, RBMS1-rs7593730-TT carriers were more susceptible to periodontitis [odds ratio (OR) = 2.29; 95% confidence interval (CI) = 1.04-5.01; P-value = 0.033]. Among AGER-rs184003-CC carriers, never smokers had reduced risks of periodontitis and Periodontitis+T2DM than ever smokers. For either RBMS1-rs7593730-CC or VEGFA-rs9472138-CC carriers, never smokers had less susceptibility to develop periodontitis than ever smokers. Compared with AGER-rs184003-CC carriers, AGER-rs184003-AA carriers presented fewer remaining teeth. VEGFA-rs9472138-TT carriers showed a lower percentage of sites with characteristics of active periodontal disease (bleeding on pocket probing and interproximal clinical attachment level) compared with VEGFA-rs9472138-CC carriers. CONCLUSIONS: In the studied population, AGER rs184003, RBMS1 rs7593730, and VEGFA rs9472138, which are considered genetic markers for T2DM, were associated with periodontitis without T2DM or periodontitis together with T2DM.

The RAGE/multiligand axis: a new actor in tumor biology.

The receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein which actively participates in several chronic inflammation-related diseases. RAGE, in addition to AGEs, has a wide repertoire of ligands, including several damage-associated molecular pattern molecules or alarmins such as HMGB1 and members of the S100 family proteins. Over the last years, a large and compelling body of evidence has revealed the active participation of the RAGE axis in tumor biology based on its active involvement in several crucial mechanisms involved in tumor growth, immune evasion, dissemination, as well as by sculpturing of the tumor microenvironment as a tumor-supportive niche. In the present review, we will detail the consequences of the RAGE axis activation to fuel essential mechanisms to guarantee tumor growth and spreading.

Endothelial expression of the receptor for advanced glycation end products in experimental diabetes / Expresión endotelial del receptor para productos finales de glicación avanzada en diabetes experimental

The receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of several chronic diseases including diabetes. The interaction between RAGE and advanced glycation end products (AGEs) promotes gene expression, enhances the release of proinflammatory molecules and causes the generation of oxidative stress in numerous cell types. The aim of this investigation was to evaluate the effect of enalapril and losartan on RAGE expression in abdominal aortic endothelium of rats with experimentally induced diabetes. Male Sprague-Dawley rats, weighing approximately 150 - 200 g, were used. Diabetes was induced in 30 rats by intravenous administration of a single dose of 55 mg/kg body weight of streptozotocin (ETZ). The following groups were studied: control (n=10), diabetic (n=10), losartan-treated diabetic (n=10) and enalapril-treated diabetic (n=10) rats. RAGE expression in aortic endothelium was determined by indirect immunofluorescence. A significant increase in RAGE expression was observed in diabetic animals versus controls (p<0.001), there was a decrease in RAGE expression, in animals treated with losartan versus controls (p<0.01) and in those treated with enalapril (p<0.05) versus control and versus diabetes + vehicle. In conclusion, in the experimental model of ETZ-induced diabetes, there is an increase in RAGE expression at the level of the abdominal aortic endothelium, which can be reversed by treatment with losartan and/or enalapril, two drugs that block the renin-angiotensin system, suggesting its involvement in the molecular events related to vascular damage during diabetes.

El receptor para productos finales de glicación avanzada (RAGE) está implicado en la patogénesis de varias enfermedades crónicas incluyendo la diabetes. La interacción entre RAGE y los productos finales de glicación avanzada (AGEs), promueve la expresión génica, potencia la liberación de moléculas proinflamatorias y provoca la generación de estrés oxidativo en numerosos tipos de células. El objetivo de esta investigación fue evaluar el efecto del enalapril y el losartán sobre la expresión de RAGE en el endotelio de la aorta abdominal de ratas con diabetes inducida experimentalmente. Se utilizaron ratas Sprague-Dawley machos, con un peso aproximado de entre 150 - 200 g. La diabetes se indujo en 30 ratas mediante la administración intravenosa de una sola dosis de 55 mg/Kg de peso corporal de estreptozotocina (ETZ). Se estudiaron los siguientes grupos: ratas control (n=10), diabéticas (n=10), diabéticas tratadas con losartán (n=10) y diabéticas tratadas con enalapril (n=10). La expresión de RAGE en el endotelio aórtico se determinó por inmunofluorescencia indirecta. Se observó un incremento significativo en la expresión de RAGE en los animales diabéticos versus los controles (p<0.001), hubo una disminución en la expresión de RAGE, en los animales tratados con losartán versus los controles (p<0.01) y en los tratados con enalapril (p<0.05) versus control y versus diabetes + vehículo. En conclusión, en el modelo experimental de diabetes inducida por ETZ, existe un incremento en la expresión de RAGE a nivel del endotelio de la aorta abdominal, la cual puede revertirse mediante el tratamiento con losartán y/o enalapril, dos fármacos bloqueadores del sistema renina-angiotensina, lo cual sugiere la participación del mismo en los acontecimientos moleculares relacionados con el daño vascular durante la diabetes.

Advanced Glycation End Products: A Sweet Flavor That Embitters Cardiovascular Disease.

Epidemiological studies demonstrate the role of early and intensive glycemic control in the prevention of micro and macrovascular disease in both type 1 and type 2 diabetes mellitus (DM). Hyperglycemia elicits several pathways related to the etiopathogenesis of cardiovascular disease (CVD), including the generation of advanced glycation end products (AGEs). In this review, we revisit the role played by AGEs in CVD based in clinical trials and experimental evidence. Mechanistic aspects concerning the recognition of AGEs by the advanced glycosylation end product-specific receptor (AGER) and its counterpart, the dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST) and soluble AGER are discussed. A special focus is offered to the AGE-elicited pathways that promote cholesterol accumulation in the arterial wall by enhanced oxidative stress, inflammation, endoplasmic reticulum stress and impairment in the reverse cholesterol transport (RCT).

Plasma advanced glycation end products and soluble receptor for advanced glycation end products as indicators of sterol content in human carotid atherosclerotic plaques.

Advanced glycation end products (AGEs) are independently related to cardiovascular disease (CVD) and favor cholesterol and oxysterol accumulation in macrophage foam cells. Soluble RAGE (sRAGE) impairs cellular AGE signaling alleviating the deleterious effects of AGE in atherogenesis. The association between plasma AGEs and sRAGE with the content of cholesterol, markers of cholesterol synthesis and absorption, and oxysterols in atherosclerotic plaques was evaluated in subjects undergoing carotid endarterectomy.Plasma and carotid plaques were obtained from symptomatic (n = 23) and asymptomatic subjects (n = 40). Lipids from plaques were extracted and sterols (oxysterols, cholesterol, desmosterol, lathosterol, sitosterol, and campesterol) were determined by using gas chromatography/mass spectrometry. Plasma total AGEs and pentosidine were measured by using fluorimetry and sRAGE by using ELISA.In symptomatic subjects´ atherosclerotic plaques, an increased amount of cholesterol (3x) and oxysterols [7 α-hydroxycholesterol (1.4x); 7 ß-hydroxycholesterol (1.2x); 25-hydroxycholesterol (1.3x); 24-hydroxycholesterol (2.7x), and 27-hydroxycholesterol, (1.15x)], with exception to 7 ketocholesterol, were found in comparison to asymptomatic individuals. Plasma total AGEs and pentosidine significantly and positively correlated to sterols accumulated in the atherosclerotic lesion, including cholesterol, desmosterol, campesterol, sitosterol, and oxysterols. On the other hand, sRAGE inversely correlated to total AGEs and pentosidine in plasma, and with major species of oxysterols, cholesterol, and markers of cholesterol synthesis and absorption in the atherosclerotic lesion. In multiple regression analyses, it was observed a significant inverse correlation between sRAGE and 24-hydroxycholesterol and desmosterol, and a positive significant correlation between pentosidine and 24-hydroxycholesterol, 27-hydroxycholesterol, and campesterol.In conclusion, the plasma concentration of AGEs and sRAGE is a tool to predict the accumulation of sterols in atherosclerotic lesions in symptomatic and asymptomatic individuals, helping to prevent and improve the management of acute cardiovascular complications.

The Methylglyoxal/RAGE/NOX-2 Pathway is Persistently Activated in the Hippocampus of Rats with STZ-Induced Sporadic Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia in humans, with a high social and economic cost. AD is predominantly a sporadic disease, and the intracerebroventricular (ICV) administration of streptozotocin (STZ) has been widely used as an AD-like model of dementia. While the etiology of AD remains unknown, changes such as glucose metabolism and activation of receptors for advanced glycation end products (RAGE) seem to underlie its pathogenesis. We hypothesized that methylglyoxal, an endogenous toxin derived from the glycolytic pathway, could be the precursor of advanced glycated end products that activates RAGE and that, consequently, may activate membrane NADPH oxidase (NOX), contributing to the inflammatory status of the model and the disease. We administered ICV-STZ to Wistar rats and evaluated several neurochemical parameters in the hippocampus, particularly glyoxalase 1 (GLO-1) activity, which serves as an index of high levels of methylglyoxal, and the contents of RAGE and NOX-2, the most abundant brain NOX isoform. At the times evaluated (4 and 24 weeks after STZ), we observed cognitive deficit, increased beta-amyloid content, and increased tau phosphorylation. A persistent increase in GLO-1 activity was found, as well as increases in RAGE and NOX-2 contents, suggesting astroglial and microglial commitment. The increase in NOX-2 may reflect elevated microglial activity (confirmed by IBA-1 marker), which may contribute to the synaptic dysfunction and pruning described in the literature, both in this model and AD patients. Furthermore, reinforcing this possibility, we found a reduction in cholinergic communication in the hippocampus (as shown by decreased choline acetyltransferase), a reduction in BDNF, and an increase in TGF-ß, the combination of which may result in synaptic deterioration.