Serum sRAGE Levels Research Articles

Abstract 9844: Endothelial Function is Impaired in Subjects With Increased Ratio of Serum Levels of AGEs to Soluble Form of RAGE

Introduction: Advanced glycation end products (AGEs) and their specific receptor, the receptor for AGEs (RAGE), play an important role in atherosclerosis. Recently, a soluble form of RAGE (sRAGE) has been identified in human serum. However, the role of sRAGE in cardiovascular disease is still controversial. There is no information on the association between simultaneous measurements of AGEs and sRAGE and vascular function. In this study, we evaluated the associations between serum levels of AGEs and sRAGE, ratio of AGEs to sRAGE and vascular function. Methods: We measured serum levels of AGEs and sRAGE and assessed vascular function by measurement of flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in 110 subjects who underwent health examinations. Multivariate regression analyses were performed to identify factors associated with vascular function. Results: Univariate regression analysis revealed that FMD correlated with age (ρ=-0.38, P<0.01), body mass index (ρ=-0.28, P<0.01), systolic blood pressure (ρ=-0.44, P<0.01), diastolic blood pressure (ρ=-0.46, P<0.01), heart rate (ρ=-0.29, P<0.01), triglycerides (ρ=-0.37, P<0.01), high-density lipoprotein cholesterol (ρ=0.19, P<0.05), glucose (ρ=-0.20, P<0.05), smoking pack-years (ρ=-0.32, P<0.01), nitroglycerine-induced vasodilation (ρ=0.40, P<0.01), serum levels of AGEs (ρ=-0.34, P<0.01) and sRAGE (ρ=0.20, P<0.05), and ratio of AGEs to sRAGE (ρ=-0.38, P<0.01). Multivariate analysis revealed that the ratio of AGEs to sRAGE remained an independent predictor of FMD (β=-0.22, P=0.03), while serum level of AGEs alone (β=-0.14, P=0.13) or sRAGE alone (β=0.13, P=0.15) was not associated with FMD. Conclusions: These findings suggest that sRAGE may have a counter-regulatory mechanism that is activated to counteract the vasotoxic effect of the AGEs-RAGE axis. The ratio of AGEs to sRAGE may be a new chemical biomarker of endothelial function.

Genetic polymorphisms of RAGE and risk of ulcerative colitis in a Chinese population

The receptor for advanced glycation end products (RAGE) and its proinflammatory ligands are critically implicated in the pathological progression of ulcerative colitis (UC). Functional polymorphisms in the regulatory elements and/or ligand-binding regions of the RAGE gene affect the expression and function of RAGE and thus may increase susceptibility to UC. In this study, a total of 266 unrelated UC patients and 247 control subjects were analyzed for 3 RAGE single nucleotide polymorphisms (SNPs) (−429 T/C, −374 T/A, and G82S) using an improved small-amplicon high resolution melting curve (HRM) analysis assay. Serum levels of soluble RAGE (sRAGE) were determined by a double sandwich ELISA system. The genotypes, alleles and haplotypes were analyzed and compared between UC patients and control subjects. Three pairs of genotyping primers for three RAGE polymorphism loci (−429 T/C, −374 T/A, and G82S) were developed based on HRM. Significant differences in the allele distribution of the G82S polymorphism was found among UC cases and controls from a Chinese population. Carriers of the RAGE G82S variant genotype were at higher risk of UC (OR=2.594, 95% CI: 1.778–3.784, P<0.001) than homozygous wild-type individuals. Further analyses revealed that the 82 (GS+SS) variant genotype was associated with patients who have extended UC (OR=1.924, 95% CI: 1.163–3.181, P=0.010), and a family history of inflammatory bowel disease (IBD) (OR=1.923, 95% CI: 1.049–3.521, P=0.032). The polymorphisms −374 T/A and −429 T/C did not demonstrate any association with UC, but an association was found between the −374(TA+AA) variant genotypes and the serum sRAGE level (P=0.002). Moreover, haplotypes T/A/A and T/A/G showed significantly different frequencies between UC patients and controls (OR=3.337, 95% CI: 1.892–6.091, P=0.026; OR=0.530, 95% CI: 0.351–0.801, P=0.002). The present study developed novel primers based on HRM to provide preliminary evidence in a Chinese population that the RAGE polymorphism is involved in genetic susceptibility to UC and that the 82(GS+SS) genotype of G82S is a risk factor for UC. Furthermore, RAGE polymorphisms may be related to the location of UC as well as a family history of IBD in a Chinese population.

Advanced glycation end products and soluble receptor as markers of oxidative stress in children on hemodialysis

Background: Advanced glycation end products (AGEs) have biological properties that may contribute to the mortality of children on hemodialysis (HD). This study examines the relationship of LMW fluorescence AGEs, oxidized LDL (ox-LDL), soluble receptor AGE (sRAGE) as markers of oxidative stress in children with end stage renal disease (ESRD) undergoing HD. Method: Thirty children with ESRD undergoing HD, and 30 healthy, age- and sex-matched children were included. Serum levels of LMW fluorescence AGEs, sRAGE, oxidized LDL (ox-LDL), pre- and post-dialysis urea, high-sensitivity C-reactive protein (hs-CRP), hemoglobin (Hb) and serum albumin (ALB), were measured. Results: Abnormal serum inflammatory changes: elevated levels of LMW AGEs, sRAGE, oxLDL, CRP and urea were exhibited in HD children compared with healthy controls; more so in anemic when compared to non-anemic patients. Significant positive correlation was found between serum levels of AGEs and sRAGE. Conclusion: The low molecular weight form of AGEs is associated with oxidative stress in children receiving chronic HD, and may be important in the mechanisms leading to atherosclerosis and inflammation in such patients. LMW AGEs levels showed a negative correlation with sRAGE and both exhibit a significant negative relation to seum urea.

Biomarkers of oxidation stress, inflammation, necrosis and apoptosis are associated with hepatitis B-related acute-on-chronic liver failure

Hepatitis B virus related acute-on-chronic liver failure is a serious condition with a high mortality. Oxidative stress, inflammation, necrosis and apoptosis may play an important role in it. This study is to investigate whether serum AOPP, S100A12, HMGB1 and sRAGE can provide diagnostic or prognostic information in HBV-related ACLF. We measured serum S100A12, HMGB1 and sRAGE levels in 50 patients with HBV-related ACLF, 35 patients with liver cirrhosis (LC), 35 patients with chronic hepatitis B (CHB) and 35 healthy controls by enzyme-linked immunosorbent assay. AOPP measured by spectrophotometry. Significantly higher AOPP, S100A12, HMGB1 and sRAGE levels on admission were found in patients with ACLF compared with LC, CHB and healthy controls (P<0.001). In ACLF patients, they were higher in nonsurvivors than survivors (P<0.001). They had a positive relationship with total bilirubin and MELD scores. AOPP, S100A12 and HMGB1 concentrations continually declined in survivors while increased in nonsurvivors, sRAGE concentrations did not change in survivors, but gradually increased in nonsurvivors during hospitalization. ROC curve analysis showed that the four biomarkers had a higher AUC than TBIL. Multivariate Cox regression analysis demonstrated that S100A12, AOPP and sRAGE were independent risk factors for poor prognosis. Serum AOPP, S100A12 and sRAGE maybe reflect the oxidation stress, inflammation levels in HBV-related acute-on-chronic liver failure. Increased AOPP, S100A12 and sRAGE may serve as important biological markers of worse outcome.

Correlation of the expressions of advanced glycation end products and its receptor in serum and placenta with the pathogenesis of preeclampsia

To investigate the correlation of the expressions of advanced glycation end products (AGE) and the receptor for advanced glycation end products (RAGE) in serum and placenta with the pathogenesis of preeclampsia. From December 2013 to June 2014, 32 women with severe preeclampsia who received cesarean section in the Affiliated Hospital of Qingdao University were recruited in the study, defined as the severe preeclampsia group. 30 healthy pregnant women who received cesarean section in the same hospital were recruited as the control group. ELISA was used to measure the maternal serum AGE, soluble receptor for advanced glycation end products (sRAGE) and tumor necrosis factor-α (TNF-α) in these women. Furthermore, ELISA was also used to measure AGE and TNF-α in the placenta. The localizations of AGE and RAGE protein in placentas were detected by immunohistochemical SP method. RAGE and TNF-α mRNA expression in placentas were measured by real-time quantitative PCR. AGE, RAGE and TNF-α protein expression in placentas were measured by western blot, respectively. (1) The serum levels of AGE, sRAGE and TNF-α in the severe preeclampsia group were (538 ± 75), (367 ± 86) and (322 ± 40) ng/L, respectively. They were significantly higher than those in the control group [(454 ± 50), (286 ± 35) and (270 ± 35) ng/L, respectively] (P < 0.05). The levels of AGE showed positive correlation with the levels of TNF-α (r = 0.588, P < 0.05), while the levels of sRAGE showed no correlation with TNF-α (r = -0.041, P > 0.05). (2) In the severe preeclampsia group, the levels of AGE and TNF-α in placentas were (500 ± 82) and (334 ± 57) ng/L, which were higher than those in the control group [(431 ± 74) and (263 ± 46) ng/L, respectively] (P < 0.05). The levels of AGE showed positive correlation with the levels of TNF-ɑ (r = 0.406, P < 0.05). (3) AGE and RAGE protein mainly located in the syncytiotrophoblasts, macrophages and vascular endothelial cells in the placentas of the two groups. AGE expressed mainly in the cytoplasm, and RAGE expressed in the cytoplasm and cell membranes. (4) RAGE and TNF-α mRNA expression in the placentas of the severe preeclampsia group were 12.6 ± 4.6 and 10.4 ± 2.4, which were significantly higher than those in the control group (0.9 ± 0.4 and 3.5 ± 0.9, P < 0.01). (5) The expressions of AGE, RAGE and TNF-α protein in placentas of the severe preeclampsia group were 0.68 ± 0.06, 0.82 ± 0.08 and 0.76 ± 0.08. All were significantly higher than those of the control group (0.46 ± 0.05, 0.42 ± 0.09 and 0.52 ± 0.07; P < 0.01). The levels of AGE and RAGE in serum and placentas elevated in the severe preeclampsia group, and the expression of TNF-α also elevated. These indicated that AGE and RAGE might be involved in the systemic inflammatory response and local inflammatory response in placentas, and then caused the preeclampsia.

SRage plasma level in association with multiple sclerosis risk in Slovak population

Receptor for advanced glycation end products (RAGE) triggers an intracellular signalling pathways of various proinflammatory ligands. Solubile form of RAGE (sRAGE) in human plasma can hinder the function of RAGE and can have the role in the pathogenesis of inflammatory diseases. In patients with multiple sclerosis (MS), altered level of sRAGE in plasma and cerebrospinal fluid has been found. In our study, we tried to identify possible association of sRAGE serum level with MS. Serum levels of sRAGE were detected by ELISA in 44 MS patients (22 patients with rapid progression of MS and 22 patients with slow progression of MS according to the MSSS score) and 32 healthy control subjects. We found significantly increased level of sRAGE in serum of MS patients when compared to controls. No significant differences in serum level of sRAGE where found between rapidly progressing and slow progressing subgroup of MS patients. Our results suggest for the role of sRAGE in MS ethiopathogenesis, but we did not find any association of sRAGE in serum with the rate of MS disability progression.

The clinical significance of circulating soluble RAGE in patients with severe sepsis.

The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor involved in the pathogenesis of inflammatory diseases. However, the significance of the soluble isoform of RAGE (sRAGE) has not been clarified in critical illness. We investigated circulating sRAGE in blood samples from septic patients. In this cross-sectional study, criteria for inclusion were patients with severe sepsis and age older than 18 years. Samples were collected within 24 hours after the diagnosis of sepsis and also from healthy volunteers. The levels of sRAGE and RAGE signaling pathway-associated biologic parameters were measured with an enzyme-linked immunosorbent assay kit. Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were calculated at the time of patient enrollment. We used the International Society of Thrombosis and Haemostasis (ISTH) overt disseminated intravascular coagulation (DIC) diagnostic criteria algorithm to assess coagulopathy. Included were 24 septic patients and 12 healthy volunteers. Serum sRAGE level was significantly increased in the patients compared with healthy controls. Significant correlations were found between sRAGE levels and APACHE II, SOFA, and ISTH DIC scores. The increase in sRAGE levels also correlated with the upregulation of interleukin-6, soluble vascular adhesion molecule 1, and plasminogen activator inhibitor 1 levels and a reduction in platelet count. The fraction of sRAGE other than the endogenous secreted form of RAGE (esRAGE) was augmented in the patients. We demonstrated for the first time that the serum level of sRAGE increased with the progression of DIC and the severity of sepsis, suggesting that circulating sRAGE reflects RAGE signaling pathway activity, which induces the excessive inflammatory response involved in endothelial injury and coagulopathy and that its measurement may be useful as a biomarker for sepis. Prognostic study, level IV.

Relationship between serum levels of endogenous secretory RAGE and blood pressure in male nondiabetic patients with obstructive sleep apnea.

The interaction of advanced glycation end products (AGE) and their specific cell-surface receptor (RAGE) has an important role in the pathogenesis of cardiovascular disease and diabetic complications. Two isoforms of C-truncated RAGE, soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE), may prevent activation of RAGE signaling by acting as decoys. This study investigated whether serum esRAGE and sRAGE levels are associated with blood pressure in nondiabetic patients with obstructive sleep apnea (OSA). Male nondiabetic patients (n=139) with OSA were enrolled. Serum esRAGE and sRAGE levels were examined using enzyme-linked immunosorbent assay. Three consecutive seated systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements were obtained at 5-min intervals in the morning. In univariate analysis, there was a significant correlation between serum esRAGE and SBP or DBP, but not between serum sRAGE and SBP or DBP. Multiple regression analysis showed that SBP was independently associated with waist circumference, HbA1c, minimum SaO2 and serum esRAGE, and that DBP was independently associated with low-density lipoprotein cholesterol, apnea-hypopnea index, serum AGE and body mass index, but not with serum esRAGE. These results indicated that serum esRAGE levels were inversely associated with blood pressure, especially SBP, in male nondiabetic patients with OSA. esRAGE may have a protective role against hypertension in patients with OSA, and it may be a novel biomarker for OSA patients at high risk of developing cardiovascular diseases.

Vitamin D Supplementation Increases Serum Levels of Soluble Receptor for Advanced Glycation End Products Among Women With Polycystic Ovary Syndrome [30

INTRODUCTION: To examine the effect of vitamin D3 supplementation on the changes in serum receptor for advanced glycation end products (sRAGE) and serum anti-Müllerian hormone (AMH) among vitamin D–deficient women with polycystic ovary syndrome (PCOS). METHODS: A total of 136 women with (n=68) or without (age-matched control; n=68) PCOS who were diagnosed with vitamin D deficiency were studied. All participants received supplemental oral vitamin D3 (50,000 international units/wk) for 8 weeks, followed by 1,000 international units vitamin D3 supplementation for 16 weeks. All women provided blood samples for the measurements of sRAGE, AMH, and other analytes at baseline and at the end of supplementation (24 weeks). RESULTS: In all participants, there was a negative correlation between body mass index and serum sRAGE levels (r=−0.46, P=.003). In women with PCOS, but not in those in the control group, vitamin D3 supplementation increased serum sRAGE (P<.001) and decreased serum AMH levels (P<.001). The increases in serum sRAGE were positively correlated with the increases in serum 25-hydroxyvitamin D after vitamin D3 supplementation in women with PCOS (r=0.72, P<.001). CONCLUSION: Vitamin D3 supplementation in women with PCOS showed a protective effect against the inflammatory action of advanced glycation end products by enhancing the circulating sRAGEs. The normalization in serum AMH induced by vitamin D3 therapy indicates a possible improvement in folliculogenesis.

New insights into the mechanisms of diastolic dysfunction in patients with type 2 diabetes

Background. Little is known about the role of advanced glycation end products (AGEs) and their receptor (RAGE) in diabetic cardiovascular complications. Therefore, we aimed to evaluate the association of serum soluble RAGE (sRAGE) levels and left ventricular (LV) diastolic dysfunction in patients with type 2 diabetes. Methods. Our study consisted of 40 patients with type 2 diabetes and 40 age- and sex-matched healthy control group. Subjects with age ≥ 50 years old and any cardiovascular risk factors or conditions were excluded from the study. Serum sRAGE levels determined by enzyme-linked immunosorbent assay and LV diastolic dysfunction were evaluated according to current American Society of Echocardiography guidelines. Results. Baseline characteristics were similar between groups except body mass index, waist–hip ratio, and fasting glucose levels. Serum sRAGE level was significantly lower in diabetic group compared with control group (676 ± 128 vs. 1044 ± 344, p < 0.05). Diastolic dysfunction was observed in 50% of diabetic patients (40% grade I and 10% grade II). Correlation analysis showed that serum sRAGE was negatively correlated with duration of diabetes, septal E’/A’, lateral E’/A’, and average E/E’. In multivariate regression analysis, serum sRAGE level was strongly associated with diastolic dysfunction in patients with type 2 diabetes. Conclusion. Our study showed that serum sRAGE level was significantly lower in type 2 diabetic patients aged < 50 years old. Also, sRAGE has negative correlation with the duration of diabetes and it was significantly associated with the presence of diastolic dysfunction in type 2 diabetes.

Soluble receptor for advanced glycation end products as a potential biomarker to predict weight loss and improvement of insulin sensitivity by a very low calorie diet of obese human subjects

IntroductionObesity is associated with low-grade systemic inflammation which is thought to trigger the development of comorbidities such as type 2 diabetes. The soluble receptor for advanced glycation end products (sRAGE) belongs to the innate immune system and has been linked to obesity, recently. The aim of the present study was to examine whether serum sRAGE concentrations are related to the grade of weight loss and improvement of insulin resistance due to a very low calorie diet (VLCD). Methods22 severe obese subjects (Median Body Mass Index (BMI): 44.5kg/m2) were included in a dietary intervention study of 6month, consisting of a very low calorie formula diet phase (VLCD: 800kcal/d) for 12weeks and a following 12week weight maintenance phase. Fasting glucose, fasting insulin, adiponectin, leptin and sRAGE were determined from sera. Insulin sensitivity was estimated by Homeostasis Model Assessment (HOMA) index and leptin-to-adiponectin-ratio (LAR). ResultsMean body weight reduction by VLCD accounted to 21.7kg with a significant improvement of insulin resistance. At baseline, sRAGE serum levels were significantly inversely related to BMI (rS=−0.642, p=0.001) and HOMA (rS=−0.419, p=0.041). Of interest, sRAGE serum levels at baseline were significantly lower in study subjects with greater reduction of BMI (p=0.017). In addition, a significantly greater HOMA reduction was observed in subjects with lower sRAGE serum levels at baseline (p=0.006). Finally, correlation analysis revealed, that changes of sRAGE serum levels were significantly correlated to changes of BMI (rS=−0.650, p=0.022) during intervention. ConclusionAnti-inflammatory sRAGE might be a potential future biomarker to predict weight loss and improvement of insulin resistance by a VLCD whereby lower baseline sRAGE serum levels indicate a better outcome of the dietary intervention.

The Circulating Level of Soluble Receptor for Advanced Glycation End Products Displays Different Patterns in Ulcerative Colitis and Crohn's Disease: A Cross-Sectional Study.

RAGE is a transmembrane receptor expressed on immune and endothelial cells, whose binding with its ligands, the S100 calgranulins, leads to chronic inflammation. Conversely, its soluble form (sRAGE) plays a protective role by acting as a decoy. We carried out a cross-sectional analysis of the sRAGE and S100A12 serum levels in patients with Crohn's disease (CD) and ulcerative colitis (UC) and searched for a correlation with clinical and biological markers of activity. We enrolled 60 CD, 67 UC patients, and 66 controls (all adults). Disease activity was scored through the clinical, endoscopic, and histologic indexes of severity, whilst disease location and behaviour were assessed according to the Montreal classification. In all cases, the levels of serum sRAGE, S100A12, C-reactive protein, and faecal calprotectin were measured. sRAGE levels were significantly lower in UC, both active and inactive, than in controls and CD (817.35, range 437.3-1449; 1211, range 843.7-1618; 1207.5, range 743.15-1875.75; P<0.05 for both), and inversely correlated with clinical and endoscopic indexes of activity in both IBD groups (P<0.05 for all) and with the histologic score in the CD group. Moreover, those CD patients with a penetrating behaviour showed a significant reduction in both sRAGE (P=0.006) and S100A12 (P=0.034) as compared to those with an inflammatory/stricturing pattern. Although S100A12 levels were not found up-regulated, a negative correlation appeared evident with the clinical (r=-0.38) and endoscopic (r=-0.32) indexes of activity in UC and CD, respectively. These data suggest a different role for RAGE in CD and UC, and a potential use of sRAGE as a new biomarker.

Relationship of Soluble RAGE with Insulin Resistance and Beta Cell Function during Development of Type 2 Diabetes Mellitus.

This study examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) alter in prediabetes and correlate with insulin resistance (IR) and beta cell function in prediabetes and newly diagnosed type 2 diabetes mellitus (T2DM). Subjects without previous history of diabetes were recruited and grouped as control, prediabetes, and newly diagnosed T2DM. The control subjects (n = 40) and people with prediabetes (n = 52) and diabetes (n = 66) were similar in terms of age, sex, BMI, systolic and diastolic BP, and fasting insulin level. HOMA-IR was found significantly higher in people with diabetes than control subjects (p < 0.001) and people with prediabetes (p = 0.005); and HOMA-%B was found significantly deteriorated in people with diabetes (p < 0.001) compared to control subjects and people with prediabetes. However, serum sRAGE levels did not show any significant alteration in people with prediabetes compared to control subjects. Moreover, univariate and multivariate analyses did not identify any significant correlation and statistical association of sRAGE with HOMA-IR and HOMA-%B in people with prediabetes and newly diagnosed T2DM. Our data suggest that serum sRAGE levels do not alter in people with prediabetes compared to control subjects and do not correlate or associate with IR and beta cell function during development of T2DM.

Role of Advanced Glycation End Products and Its Receptors in the Pathogenesis of Cigarette Smoke-Induced Cardiovascular Disease.

The interaction of advanced glycation end products (AGEs) with its cell-bound receptor RAGE increases gene expression and release of proinflammatory cytokines and increase generation of reactive oxygen species (ROS). Circulating receptors, soluble RAGE (sRAGE), and endosecretory RAGE (esRAGE) by binding with RAGE ligands have protective effects against AGE-RAGE interaction. Cigarette smoking is a risk factor for coronary artery disease, stroke, and peripheral vascular disease. This article reviews; if the AGE-RAGE axis is involved in the cigarette smoke-induced cardiovascular diseases. There are various sources of AGEs in smokers including, gas/tar of cigarette, activation of macrophages and polymorphonuclear leukocytes, uncoupling of endothelial isoform of nitric oxide synthase (eNOS) and xanthine oxidase. The levels of AGEs are elevated in smokers. Serum levels of sRAGE have been reported to be reduced, elevated, or unchanged in smokers. Mostly the levels are reduced. There is one article which shows an elevation of levels of sRAGE in smokers. Serum levels of esRAGE are unaltered in smokers. Mechanism of AGE-RAGE-induced atherosclerosis has been discussed. Atherosclerosis leads to the cardiovascular diseases. It has been suggested that ratio of AGE/sRAGE or AGE/esRAGE is useful in determining the deleterious effects of AGE-RAGE interaction in smokers. sRAGE alone is not a good marker for smoke-induced cardiovascular disease. In conclusion cigarette smoke induces formation of AGEs and reduces sRAGE resulting in the development of atherosclerosis and related coronary heart disease, stroke, and peripheral vascular disease. Ratio of AGEs/sRAGE is a better marker for cardiovascular disease than AGEs or sRAGE alone in smokers.

The presence of high mobility group box-1 and soluble receptor for advanced glycation end-products in juvenile idiopathic arthritis and juvenile systemic lupus erythematosus.

BackgroundThe involvement of high mobility group box-1 (HMGB1) in various inflammatory and autoimmune diseases has been documented but clinical trials on the contribution of this pro-inflammatory alarmin in children with juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE) are basically absent. To address the presence of HMGB1 and a soluble receptor for advanced glycation end products (sRAGE) in different subtypes of JIA and additionally in children with SLE, we enrolled a consecutive sample of children harvested peripheral blood as well as synovial fluids (SF) at diagnosis and correlated it with ordinary acute-phase reactants and clinical markers.MethodsSerum and synovial fluids levels of HMGB1 and sRAGE in total of 144 children (97 with JIA, 19 with SLE and 27 healthy controls) were determined by ELISA.ResultsThe children with JIA and those with SLE were characterised by significantly higher serum levels of HMGB1 and significantly lower sRAGE levels compared to the healthy controls. A positive correlation between serum HMGB1 and ESR, CRP, α2 globulin was found while serum sRAGE levels were inversely correlated with the same inflammatory markers in children with JIA. Additionally, high level of serum HMGB1 was related to hepatosplenomegaly or serositis in systemic onset JIA.ConclusionThe inverse relationship of the HMGB1 and its soluble receptor RAGE in the blood and SF indicates that inflammation triggered by alarmins may play a role in pathogenesis of JIA as well as SLE. HMGB1 may serve as an inflammatory marker and a potential target of biological therapy in these patients. Further studies need to show whether the determination of HMGB1 levels in patients with JIA can be a useful guideline for detecting disease activity.

Soluble receptor for advanced glycation end products in critically ill patients and its associations with other clinical markers and 28-day mortality.

PurposeTo investigate the possible associations between serum levels of soluble receptor for advanced glycation end products (sRAGE) and specific clinical markers and prognosis in critically ill patients diagnosed with stress hyperglycemia.Patients and methodsA total of 70 critically ill patients and 25 normal controls were recruited for this study. Serum levels of sRAGE and advanced glycation end products (AGEs) were determined using enzyme-linked immunosorbent assay. Additional data on other clinical markers were obtained from patient records in the intensive care unit. Comparisons of sRAGE and AGEs levels between groups were assessed by t-test. The relationships between sRAGE and other clinical markers were assessed by Pearson’s correlation analyses and multiple linear regression analyses. Risk factors for prognosis, such as 28-day mortality were analyzed using logistic regression analysis.ResultsSerum sRAGE and AGEs levels were significantly higher in critically ill patients, compared to normal controls (P<0.05). The increase in serum sRAGE levels was significantly correlated with AGEs levels, interleukin-6 levels, and the sequential organ failure assessment score (P<0.01). Using multiple linear regression analysis, the association between AGEs and sRAGE remained significant after adjustment of other clinical factors. However, there were no significant correlations between sRAGE levels and patient outcome in these critically ill patients.ConclusionSerum sRAGE levels were significantly elevated in critically ill patients and positively correlated with higher AGEs levels, but sRAGE levels were not associated with increased mortality, suggesting sRAGE levels are not a predictor of prognosis in critically ill patients.

Serum sRAGE as a potential biomarker for pediatric bronchiolitis: a pilot study.

Traditional inflammatory biomarkers are insufficient for the evaluation of bronchiolitis severity. Recent investigations have shown that the receptor for advanced glycation end product (RAGE) and its soluble isoforms (sRAGE) play a critical role in the pathogenesis of lung injury. Main objective was to assess the serum levels of sRAGE of children with severe bronchiolitis admitted to the pediatric intensive care unit (PICU). Secondary objective was to study sRAGE correlation with the evolution and traditional biomarkers. Prospective, observational and descriptive study, 43 healthy controls and 37 patients (December 2011-February 2012) were enrolled. sRAGE levels were assessed and compared. In patients, the relation between sRAGE levels and clinical evolution, respiratory assistance, white blood cell count, absolute neutrophils count, serum C-reactive protein, and serum procalcitonin was analyzed. A statistical difference was found in the mean value of sRAGE at PICU admission between patients and controls (1,215.7 ± 535 vs 849 ± 579 pg/ml). Also a significant inverse correlation was found between sRAGE and the Wood-Downes Score at admission (p = 0.02). Serum sRAGE could be elevated in children with bronchiolitis. Larger clinical studies are necessary to elucidate its role as a bronchiolitis inflammatory and/or lung injury biomarker.

Ratio of serum levels of AGEs to soluble form of RAGE is a predictor of endothelial function.

Advanced glycation end products (AGEs) and their specific receptor, the receptor for AGEs (RAGE), play an important role in atherosclerosis. Recently, a soluble form of RAGE (sRAGE) has been identified in human serum. However, the role of sRAGE in cardiovascular disease is still controversial. There is no information on the association between simultaneous measurements of AGEs and sRAGE and vascular function. In this study, we evaluated the associations between serum levels of AGEs and sRAGE, ratio of AGEs to sRAGE, and vascular function. We measured serum levels of AGEs and sRAGE and assessed vascular function by measurement of flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in 110 subjects who underwent health examinations. Multivariate regression analyses were performed to identify factors associated with vascular function. Univariate regression analysis revealed that FMD correlated with age, BMI, systolic blood pressure, diastolic blood pressure, heart rate, triglycerides, HDL cholesterol, glucose, smoking pack-years, nitroglycerine-induced vasodilation, serum levels of AGEs and sRAGE, and ratio of AGEs to sRAGE. Multivariate analysis revealed that the ratio of AGEs to sRAGE remained an independent predictor of FMD, while serum level of AGEs alone or sRAGE alone was not associated with FMD. These findings suggest that sRAGE may have a counterregulatory mechanism that is activated to counteract the vasotoxic effect of the AGE-RAGE axis. The ratio of AGEs to sRAGE may be a new chemical biomarker of endothelial function.

Two Soluble Isoforms of Receptors for Advanced Glycation End Products (RAGE) in Carotid Atherosclerosis: The Difference of Soluble and Endogenous Secretory RAGE

Advanced glycation end products (AGEs) promote atherosclerosis through binding to their receptor, RAGE. Since soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) may suppress AGEs-RAGE signaling, we examined the usefulness of sRAGE and esRAGE as biomarkers of early-stage atherosclerosis. Serum sRAGE and esRAGE levels were measured in 284 subjects with no history of atherothrombotic diseases. The subjects were divided into high-sRAGE and low-sRAGE groups and high-esRAGE and low-esRAGE groups based on respective median values. We investigated the relationships between these parameters and the following factors: number of metabolic components, maximum intima-media thickness of the common carotid artery (IMT Cmax), carotid plaque calcification, and asymptomatic cerebral white matter lesions. The low-sRAGE and low-esRAGE groups exhibited significantly more components of metabolic syndrome than the high-sRAGE and high-esRAGE groups, respectively. IMT Cmax was significantly higher in the low-sRAGE and low-esRAGE groups. Low-sRAGE levels were significantly associated with carotid plaque calcification. Multiple linear regression analysis identified body mass index (BMI), age, and high-sensitivity C-reactive protein as determinants of sRAGE, whereas only BMI was identified as a determinant of esRAGE. We demonstrated that sRAGE and esRAGE are associated with atherosclerotic risk factors in early-stage atherosclerosis, suggesting that their levels evolve in correlation with those of metabolic components and inflammation. Interestingly, low-sRAGE and esRAGE levels are associated with high IMT Cmax, but only low-sRAGE levels were associated with carotid plaque calcification. Thus, sRAGE and esRAGE may reflect different aspects of atherosclerosis in its early stage.

Elevation of soluble form of receptor for advanced glycation end products (sRAGE) in recurrent pregnancy losses (RPL): possible participation of RAGE in RPL

To determine whether the soluble receptor for advanced glycation end products (sRAGE) and immune inflammatory markers are associated with recurrent pregnancy losses (RPL). Prospective case-control study. University clinic. A total of 93 women (age 35.8±4.6 years) were enrolled including 63 women with three or more recurrent pregnancy losses (RPL), and age-matched fertile controls with a history of at least one live birth and no history of pregnancy losses (n=30). Peripheral blood collection. Assessment of anthropometric, metabolic, and inflammatory immune variables. Levels of sRAGE were statistically significantly higher in RPL patients than in control patients (1,528.9±704.5 vs. 1,149.9±447.4 pg/mL). In the multivariate analysis, the levels of insulin, plasminogen activator inhibitor-1, the resistance index of the uterine radial artery, and the ratio of tumor necrosis factor-α/interleukin-10 producing T helper cells were statistically significantly associated with the serum sRAGE level. Elevated levels of serum sRAGE are associated with RPL. The soluble receptor for advanced glycation end products might contribute to RPL by reducing uterine blood flow and subsequently causing ischemia in the fetus via inflammatory and thrombotic reactions.