sRAGE Concentrations Research Articles

Association of Acute Systemic Inflammation with Patient-Centric Postoperative Pulmonary Complications After Elective Cardiac Surgery.

Postoperative pulmonary complications (PPCs) occur frequently after cardiac surgery. Absolute postoperative values of biomarkers of inflammation (interleukin [IL]-6, IL-8, and tumor necrosis factor-alpha [TNF-α]) and alveolar epithelial injury (soluble receptor for advanced glycation end-products [sRAGE]) have been associated with hypoxia and prolonged ventilation. However, relationships between these biomarkers and PPCs, contextualized to preoperative inflammation and perioperative lung injury risk factors, are uncertain. We aimed to determine associations between perioperative increases in biomarkers of inflammation and alveolar epithelial injury with a patient-centric PPC definition in adult cardiac surgical patients, accounting for the influence of intraoperative risk factors for lung injury. Adults undergoing elective cardiac surgery were eligible for this observational cohort study. Blood concentrations of IL-6, IL-8, TNF-α, and sRAGE were collected after anesthesia induction (baseline) and on postoperative day 1 (POD 1). The primary outcome was the occurrence of moderate or severe PPCs, graded using a validated scale, in POD 0 to 7. We estimated the association between POD 1 IL-6, IL-8, TNF-α, and sRAGE concentrations and moderate/severe PPC presence using separate logistic regression models for each biomarker, adjusted for baseline biomarker values and risk factors for postoperative lung injury (age, baseline PaO2/FiO2, left ventricle ejection fraction [LVEF], procedural type, cardiopulmonary bypass duration, and transfusions). Covariables were chosen based on relevance to lung injury and unadjusted between-group differences among patients with versus without PPCs. The secondary outcome was postoperative ventilation duration, which was log-transformed and analyzed using linear regression, adjusted using the same variables as the primary outcome. We enrolled 204 patients from 2016 to 2018. Biomarkers were analyzed in 2023 among 175 patients with complete data. In adjusted analyses, POD 1 IL-8 and IL-6 were significantly associated with moderate/severe PPCs. The odds ratio (OR) for developing a PPC for every 50 pg/mL increase in POD 1 IL-8 was 7.19 (95% confidence interval [CI], 2.13-28.53, P = .003) and 1.42 (95% CI, 1.13-1.93, P = .01) for every 50 pg/mL increase in POD 1 IL-6. In adjusted analyses, postoperative ventilation duration was significantly associated with POD 1 sRAGE; each 50 pg/mL increase in sRAGE was associated with a 25% (95% CI, 2%-52%, P = .03) multiplicative increase in hours of ventilation. TNF-α was not significantly associated with PPCs or ventilation duration. Acute systemic inflammation is significantly associated with PPCs after elective cardiac surgery in adults when taking into consideration preoperative inflammatory burden and perioperative factors that may influence postoperative lung injury.

Plasma Concentrations of High Mobility Group Box 1 Proteins and Soluble Receptors for Advanced Glycation End-Products Are Relevant Biomarkers of Cognitive Impairment in Alcohol Use Disorder: A Pilot Study.

Alcohol use disorder (AUD) is a major component in the etiology of cognitive decline and dementia. Underlying mechanisms by which long-term alcohol abuse causes cognitive dysfunction include excessive oxidative stress and inflammation in the brain, activated by increased reactive oxygen/nitrogen species (ROS/RNS), advanced glycation end-products (AGEs) and high-mobility group box 1 protein (HMGB1). In a pilot study, we examine the potential clinical value of circulating biomarkers of oxidative stress including ROS/RNS, HMGB1, the soluble receptor for AGE (sRAGE), the brain biomarker of aging apolipoprotein D (ApoD), and the antioxidant regulator nuclear factor erythroid 2-related factor 2 (NRF2) as predictive indices for cognitive impairment (CI) in abstinent patients with AUD (n = 25) compared to patients with established Alzheimer's disease (AD, n = 26) and control subjects (n = 25). Plasma concentrations of sRAGE were evaluated with immunoblotting; ROS/RNS with a fluorometric kit; and HMGB1, ApoD, and NRF2 by ELISA. Abstinent AUD patients had higher sRAGE, ROS/RNS (p < 0.05), and ApoD (p < 0.01) concentrations, similar to those of AD patients, and lower NRF2 (p < 0.01) concentrations, compared to controls. These changes were remarkable in AUD patients with CI. HMGB1, and sRAGE correlated positively with duration of alcohol use (rho = 0.398, p = 0.022; rho = 0.404, p = 0.018), whereas sRAGE correlated negatively with periods of alcohol abstinence (rho = -0.340, p = 0.045). A predictive model including ROS/RNS, HMGB1, sRAGE, alcohol use duration, and alcohol abstinence periods was able to differentiate AUD patients with CI (92.3% of correct predictions, ROC-AUC= 0.90) from those without CI. In conclusion, we propose ROS/RNS, HMGB1, and sRAGE as stress biomarkers capable of predicting cognitive impairment in AUD patients.

Soluble receptor for advanced glycation end products (sRAGE) is associated with obesity rates: a systematic review and meta-analysis of cross-sectional study

BackgroundSeveral studies have highlighted the possible positive effects of soluble receptor for advanced glycation end products (sRAGE) against obesity. However, due to their inconsistent results, this systematic review and meta-analysis aimed to quantitatively evaluate and critically review the results of studies evaluating the relationship between sRAGE with obesity among adult population.MethodsIn the systematic search, the eligibility criteria were as follows: studies conducted with a cross-sectional design, included apparently healthy adults, adults with obesity, or obesity-related disorders, aged over 18 years, and evaluated the association between general or central obesity indices with sRAGE.ResultsOur systematic search in electronic databases, including PubMed, Scopus, and Embase up to 26 October, 2023 yielded a total of 21,612 articles. After removing duplicates, screening the titles and abstracts, and reading the full texts, 13 manuscripts were included in the final meta-analysis. According to our results, those at the highest category of circulating sRAGE concentration with median values of 934.92 pg/ml of sRAGE, had 1.9 kg/m2 lower body mass index (BMI) (WMD: -1.927; CI: -2.868, -0.986; P < 0.001) compared with those at the lowest category of sRAGE concentration with median values of 481.88 pg/ml. Also, being at the highest sRAGE category with the median values of 1302.3 pg/ml sRAGE, was accompanied with near 6 cm lower waist circumference (WC) (WMD: -5.602; CI: -8.820, -2.383; P < 0.001 with 86.4% heterogeneity of I2) compared with those at the lowest category of sRAGE concentration with median values of 500.525 pg/ml. Individuals with obesity had significantly lower circulating sRAGE concentrations (WMD: -135.105; CI: -256.491, -13.72; P = 0.029; with 79.5% heterogeneity of I2). According to the subgrouping and meta-regression results, country and baseline BMI were possible heterogeneity sources. According to Begg’s and Egger’s tests and funnel plots results, there was no publication bias.ConclusionAccording to our results, higher circulating sRAGE concentrations was associated with lower BMI and WC among apparently healthy adults. Further randomized clinical trials are warranted for possible identification of causal associations.

Serum-soluble receptor for advanced glycation end-products values might have diagnostic and prognostic significances in ulcerative colitis

Aims: There is evidence of anti-inflammatory qualities associated with a soluble receptor for advanced glycation end products (sRAGE). We aimed to evaluate whether serum sRAGE levels of patients with inflammatory bowel diseases (IBDs) could serve as a biomarker by utilizing several clinical and laboratory models of disease activity for these individuals.&#x0D; Methods: This case-control study included 77 ulcerative colitis (UC) patients (51 males and 26 females), 49 Crohn’s disease (CD) patients (33 males and 16 females) and 54 healthy controls (38 males and 16 females). In UC, the UC Mayo Clinical Scoring system (MCS) was used for the clinical and endoscopic features. The histological activity index (HAI) of UC patients was determined by Truelove and Richards method. The Crohn's disease activity index (CDAI) was utilized for CD patients.&#x0D; Results: In comparison to the control group, the median sRAGE concentrations in UC patients were significantly lower. [911.17 ng/L (322.91-1682.19 vs 1420.96 ng/L (816.68-2320.08), respectively, p=0.008)]. The patients with CD did not significantly differ from the other groups. The MCS and HAI values of UC patients negatively correlated to the serum sRAGE values (rho=-0,610, p

Association of plasma advanced glycation end-products and their soluble receptor with type 2 diabetes among Chinese adults.

Population-based evidence regarding circulating advanced glycation end-products (AGEs) and the risk of type 2 diabetes (T2D) is conflicting and insufficient. We aimed to examine the association of plasma AGEs and plasma soluble receptors for AGEs (sRAGE) with T2D. We conducted a hospital-based case-control study including 1072 pairs (53.9±9.7years, 56.0% male) of newly diagnosed T2D and age- and sex-matched controls. We further performed a nested case-control study within an ongoing prospective cohort consisting of 127 incident T2D cases and 381 well-matched controls (62.2±5.1years, 71.7% male). Plasma AGEs were detected using liquid chromatography-tandem mass spectrometry, and plasma sRAGE was measured by enzyme-linked immunosorbent assay. Conditional logistic regression was used to evaluate the association of plasma AGEs and sRAGE concentrations with T2D. Higher plasma AGEs and lower sRAGE concentrations were associated with higher odds of T2D. The multivariable-adjusted odds ratios of T2D comparing the highest with the lowest quartile levels were 3.28 (95% CI: 2.14, 5.02) for plasma AGEs and 0.25 (95% CI: 0.16, 0.39) for plasma sRAGE. Participants in the highest quartile of plasma AGEs and the lowest quartile of sRAGE concentrations had the greatest odds of T2D. The positive association of AGEs and inverse association of sRAGE with T2D risk was confirmed in the replication-nested case-control study. Increased circulating AGEs and decreased sRAGE concentrations were associated with elevated T2D risk. Our findings may have implications for the strategies of T2D prevention and management.

Increased AGE-RAGE axis stress in methamphetamine abuse and methamphetamine-induced psychosis: Associations with oxidative stress and increased atherogenicity.

Methamphetamine (MA)-induced psychosis (MIP) is associated with increased oxidative toxicity (especially lipid peroxidation) and lowered antioxidant defences. Advanced glycation end products (AGEs) cause oxidative stress upon ligand binding to AGE receptors (RAGEs). There is no data on whether MA use may cause AGE-RAGE stress or whether the latter is associated with MIP. This case-control study recruited 60 patients with MA use disorder and 30 normal controls and measured serum levels of oxidative stress toxicity (OSTOX, lipid peroxidation), antioxidant defences (ANTIOX), magnesium, copper, atherogenicity, AGE and soluble RAGE (sRAGE) and computed a composite reflecting AGE-RAGE axis activity. MA dependence and use were associated with elevated levels of AGE, sRAGE, OSTOX/ANTIOX, Castelli Risk Index 1 and atherogenic index of plasma. Increased sRAGE concentrations were strongly correlated with dependence severity and MA dose. Increased AGE-RAGE stress was correlated with OSTOX, OSTOX/ANTIOX and MA-induced intoxication symptoms, psychosis, hostility, excitement and formal thought disorders. The regression on AGE-RAGE, the OSTOX/ANTIOX ratio, decreased magnesium and increased copper explained 54.8% of the variance in MIP symptoms, and these biomarkers mediated the effects of increasing MA concentrations on MIP symptoms. OSTOX/ANTIOX, AGE-RAGE and insufficient magnesium were found to explain 36.0% of the variance in the atherogenicity indices. MA causes intertwined increases in AGE-RAGE axis stress and oxidative damage, which together predict the severity of MIP symptoms and increased atherogenicity.

Serum and follicular fluid levels of soluble receptor for advanced glycation end-products in women with and without polycystic ovary syndrome

BackgroundAdvanced glycation end products (AGEs) are known to associate with the pathogenesis of several chronic diseases via interaction with their corresponding receptor (RAGE). The soluble forms of RAGE (sRAGE) are considered as anti-inflammatory agents by inhibiting the consequent adverse effects of AGE. We aimed at comparing sRAGE levels in the follicular fluid (FF) and serum of women with or without Polycystic Ovary Syndrome (PCOS) who underwent controlled ovarian stimulation for in vitro fertilisation (IVF).MethodsA total of forty-five eligible women (26 non-PCOS (control) and 19 patients with PCOS (case)) were included the study. sRAGEs in FF and blood serum were measured using ELISA kit.ResultsNo statistically significant differences were found in FF and serum sRAGE between case and control groups. Correlation analysis showed a significant and positive relationship between serum levels of sRAGE and FF sRAGE in PCOS (r = 0.639; p = 0.004), in control participants (r = 0.481; p = 0.017), and in total participants (r = 0.552; p = 0.000). Data revealed a statistically significant difference in FF sRAGE concentration among all participants by body mass index (BMI) categories (p = 0.01) and in controls (p = 0.022). Significant differences were found for all the nutrients and AGEs consumption according to Food Frequency Questionnaire in both groups (p = 0.0001). A significant reverse relationship was found between FF levels of sRAGE and AGE in PCOS (r = -0.513; p = 0.025). The concentration of sRAGE in serum and FF is the same in PCOS and control.ConclusionThe present study revealed for the first time that there are no statistically significant differences between the concentration of serum sRAGE and FF sRAGE among Iranian women with and without PCOS. However, BMI and dietary intake of AGEs have more significant effects on sRAGE concentration in Iranian women. Future studies in developed and developing countries with larger sample sizes are required to determine the long-term consequences of chronic AGE over consumption and the optimal strategies for minimizing AGE-related pathology, specifically in low income and developing countries.

1092-P: sRAGE—A Biomarker of Kidney Disease in Youth-Onset Type 2 Diabetes (T2D)

The circulating soluble receptor for advanced glycation end products (sRAGE) has been proposed as a biomarker of diabetes complications in adults. In the TODAY study of youth with T2D, we measured sRAGE 3 times at: randomization (T1), glycemic failure (HbA1c≥8%) on randomized treatment or midpoint in study (T2), and end of follow-up (T3). Of TODAY subjects, 165 lost glycemic control with HbA1c ≥ 8% (G1) and 135 maintained HbA1c &amp;lt; 8% (G2)]. Controls [n=99, HbA1 5% (4.9, 5.2), with similar obesity, sex (60% female), race-ethnicity, median age 24 (21, 27) years as the TODAY cohort at T3] had sRAGE measured once. Multivariable models examined the relationship of sRAGE with nephropathy [urine albumin: creatinine (UACR) ≥30 mg/g, hyperfiltration (eGFR ≥135 ml/min/1.73m2)] and vascular measures [pulse wave velocity (PWV), augmentation index (AI)], adjusting for treatment, diabetes duration, HbA1c, BMI, age, sex, and race-ethnicity. At T1, the T2D youth groups had similar age (13.9 yrs), diabetes duration (0.7 yrs), and sex (60% female). sRAGE concentrations were lower in T2D vs. controls (752.8±308.3 vs. 954.4 ± 356.7 pg/ml, p&amp;lt;0.0001) at T3. By T3 (mean duration 7 yrs), sRAGE levels decreased compared with T1 and T2 in G1 vs. G2 (p&amp;lt;0.05). sRAGE concentrations were 711.9±294.1 vs. 802.7±318.9 pg/ml, p=0.0032 in G1 vs. G2 at T3, with no significant difference by treatment. HbA1c was inversely related with sRAGE. Higher sRAGE concentrations were associated with a lower risk of hyperfiltration (HR=0.93, 95% CI 0.86-0.99, p=0.03) and inversely related to eGFR (p&amp;lt;0.001); no relationships were observed with UACR, PWV, or AI. sRAGE levels decline overtime in youth with T2D, are inversely related to glycemia, and may serve as a biomarker of kidney function. Disclosure F.Bacha: Other Relationship; Takeda Pharmaceutical Co., Ltd., AstraZeneca. E.M.Urbina: Advisory Panel; Astellas Pharma Inc., Other Relationship; Targus Medical, Inc. S.Gidding: Consultant; ESPERION Therapeutics, Inc. V.M.Monnier: None. L.El ghormli: None. K.Drews: None. B.H.Braffett: None. Funding National Institutes of Health (5U01DK061230-16)

Serum levels of high mobility group box-1 protein (HMGB1) and soluble receptors of advanced glycation end-products (RAGE) in depressed patients treated with electroconvulsive therapy.

High mobility group box-1 (HMGB1) is one of the damage-associated molecular patterns produced by stress and induces inflammatory responses mediated by receptors of advanced glycation end-products (RAGE) on the cell surface. Meanwhile, soluble RAGE (sRAGE) exhibits an anti-inflammatory effect by capturing HMGB1. Animal models have shown upregulation of HMGB1 and RAGE in the brain or blood, suggesting the involvement of these proteins in depression pathophysiology. However, there have been no reports using blood from depressed patients, nor ones focusing on HMGB1 and sRAGE changes associated with treatment and their relationship to depressive symptoms. Serum HMGB1 and sRAGE concentrations were measured by enzyme-linked immunosorbent assay in a group of patients with severe major depressive disorder (MDD) (11 males and 14 females) who required treatment with electroconvulsive therapy (ECT), and also in a group of 25 age- and gender-matched healthy subjects. HMGB1 and sRAGE concentrations were also measured before and after a course of ECT. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAMD). There was no significant difference in HMGB1 and sRAGE concentrations in the MDD group compared to healthy subjects. Although ECT significantly improved depressive symptoms, there was no significant change in HMGB1 and sRAGE concentrations before and after treatment. There was also no significant correlation between HMGB1 and sRAGE concentrations and the HAMD total score or subitem scores. There were no changes in HMGB1 and sRAGE in the peripheral blood of severely depressed patients, and concentrations had no relationship with symptoms or ECT.

Protective effect of dexmedetomidine on Tourniquet induced lung injury in patients undergoing total knee arthroplasty: A randomized trial

Objective To investigate whether dexmedetomidine (Dex) can reduce the severity of tourniquet-induced lung injury. Methods 36 patients undergoing total knee arthroplasty with a tourniquet were randomly assigned to the control (ischemia/reperfusion [I/R]) group and Dex group. Patients in the Dex group received a loading dose of Dex (0.8 μg/kg over 10 min intravenously) followed by continuous infusion of Dex (0.5 μg/kg/h intravenously) until the end of the surgery. The I/R group received an equal amount of 0.9% saline instead of Dex. The serum concentrations of tumor necrosis factor-α (TNF-α), Clara cell protein (CC-16), soluble receptor for advanced glycation end products (sRAGE), and brain-derived neurotrophic factor (BDNF) were measured and arterial blood gas analysis was performed before anesthesia and 30 min, 6 h, and 24 h after tourniquet release. Results In the I/R group, compared with baseline, the TNF-α, CC-16, and sRAGE concentrations were higher ( p &lt; 0.05) and the BDNF concentration was lower ( p &lt; 0.05) at most time points. In the Dex group, the TNF-α, CC-16, and sRAGE concentrations were lower than those in the I/R group ( p &lt; 0.05), whereas the concentration of BDNF was higher ( p &lt; 0.05). In the arterial blood gas analysis, the Dex group showed a significantly higher partial pressure of oxygen and arterial/alveolar oxygen tension ratio ( p &lt; 0.05) and a significantly lower alveolar/arterial oxygen tension difference than the I/R group ( p &lt; 0.05). Conclusion Dex administration partly inhibits the release of proinflammatory cytokines, affording protection against tourniquet-induced lung injury.

Correlation of serum IGF-1, AGEs and their receptors with the risk of colorectal cancer in patients with type 2 diabetes mellitus.

According to epidemiological evidence, people with type 2 diabetes mellitus have a higher risk of developing colorectal cancer. To examine the relationship between colorectal cancer (CRC) and serum levels of IGF-1, IGF-1R, AGEs,RAGE and sRAGE in patients with type 2 diabetes. By using RNA-Seq data of CRC patients from The Cancer Genome Atlas (TCGA) database, we divided the patients into normal group(58 patients)and tumor group(446 patients), and analyzed the expression and prognostic value analysis of IGF-1,IGF1R and RAGE. Cox regression and the Kaplan-Meier method were used to determine the predictive value of target gene on clinical outcomes in CRC patients. In order to further combine CRC with diabetes research,one hundred forty-eight patients hospitalized in the Second Hospital of Harbin Medical University from July 2021 to July 2022 were enrolled and divided into CA and control groups. There were 106 patients in the CA group, including 75 patients with CRC and 31 patients with CRC+T2DM; the control group comprised 42 patients with T2DM. Circulating levels of IGF-1, IGF-1R, AGEs, RAGE, and sRAGE in the serum of the patients were measured using Enzyme-Linked Immunosorbnent Assay(ELISA) kits, and other clinical parameters were also measured during hospitalization. Statistical methods used were χ² test, independent samples t-test and Pearson correlation analysis were. Finally, we controlled for confounding factors and used logistic multi-factor regression analysis. Bioinformatics analysis showed that IGF-1, IGF1R and RAGE were highly expressed in CRC patients, and the patients with high expression also showed significantly lower overall survival rate. Through Cox regression analysis, IGF-1 can be used as an independent influencing factor of CRC. In the ELISA experiment, serum AGE, RAGE, IGF-1, and IGF-1R levels were higher in the CRC and CRC+T2DM groups than in the T2DM group, but the serum sRAGE concentrations in these groups were lower than those in the T2DM group (P < 0.05). Serum AGE, RAGE, sRAGE, IGF1, and IGF1R levels were higher in the CRC+T2DM group than in the CRC group (P < 0.05). In CRC+T2DM patients, serum AGEs were correlated with age (p = 0.027), and the serum AGE levels in these groups were positively correlated with RAGE and IGF-1 levels (p < 0.001) and negatively correlated with sRAGE and IGF-1R levels (p < 0.001). After correcting for confounding factors based on logistic multiple regression analysis, the effects of age, serum IGF-1 and IGF-1R on the development of CRC in patients with T2DM were statistically significant (p<0.05). Serum IGF-1 and IGF-1R levels independently influenced the development of CRC in patients with T2DM. Furthermore, IGF-1 and IGF-1R were correlated with AGEs in CRC patients who also had T2DM, suggesting that AGEs may influence the development of CRC in T2DM patients. These findings suggest that we may be able to lower the risk of CRC in the clinic by regulating AGEs through the regulation of blood glucose levels, which will affect IGF-1 and its receptors.

The Potential Influence of Advanced Glycation End Products and (s)RAGE in Rheumatic Diseases.

Advanced glycation end products (AGEs) are a class of compounds formed by nonenzymatic interactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs can alter the protein structure and activate one of their receptors, specifically the receptor for advanced glycation end products (RAGE). These phenomena impair the functions of cells, extracellular matrix, and tissues. RAGE is expressed by a variety of cells and has been linked to chronic inflammatory autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome. The soluble (s)RAGE cleavage product is a positively charged 48-kDa cleavage product that retains the ligand binding site but loses the transmembrane and signaling domains. By acting as a decoy, this soluble receptor inhibits the pro-inflammatory processes mediated by RAGE and its ligands. In the present review, we will give an overview of the role of AGEs, sRAGE, and RAGE polymorphisms in several rheumatic diseases. AGE overproduction may play a role in the pathogenesis and is linked to accelerated atherosclerosis. Low serum sRAGE concentrations are linked to an increased cardiovascular risk profile and a poor prognosis. Some RAGE polymorphisms may be associated with increased disease susceptibility. Finally, sRAGE levels can be used to track disease progression.

Alarmins and Related Molecules in Elective Surgery

Surgery is associated with alterations of alarmins’ and related molecules’ levels. The aim of this study was to investigate which biomarkers are most involved in surgery. The studied group consisted of 58 patients with inguinal or umbilical hernia or cholecystolithiasis and 21 healthy controls for compa­rison. We also added seven acute patients with appendicitis, cholecystitis and incarcerated hernia. Serum concentrations of soluble receptor of advanced glycation end-products (sRAGE), extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE), calprotectin, high mobility group box 1 (HMGB1) and interleukin 6 (IL-6) were analysed by ELISA before and after surgery. Preoperative concentrations of calprotectin were significantly decreased while concentrations of sRAGE were significantly increased in patients compared to controls; the concentrations of EN-RAGE and HMGB1 did not differ significantly. IL-6 levels were undetectable in elective patients preoperatively and in controls. Postoperatively, there was a significant increase of EN-RAGE, calprotectin, HMGB1, and IL-6 and a significant decrease of sRAGE compared to preoperative levels. In acute patients, all tested molecules except for sRAGE were significantly increased preoperatively, and sRAGE was significantly decreased. In contrast, after surgery, we could observe a further increase in IL-6; the other biomarkers did not differ significantly. We can conclude that the concentrations of all tested biomarkers are significantly influenced by elective surgery. The postoperative levels of all tested molecules increase except for sRAGE, whose level is significantly decreased after surgery. In acute states, these molecules are already increased, and the influence of surgery is, apart from IL-6, insignificant.

Concentrations of N6-Carboxymethyllysine (CML), N6-Carboxyethyllysine (CEL), and Soluble Receptor for Advanced Glycation End-Products (sRAGE) Are Increased in Psoriatic Patients.

Psoriasis is a chronic, recurrent, and often severe skin disease which is frequently associated with metabolic disorders and increased risk of cardiovascular complications. One of the postulated links is an intensified process of advanced protein glycation and/or glycoxidation. Therefore, the aim of the study was to assess concentrations of N6-carboxymethyllysine (CML), N6-carboxyethyllysine (CEL), and soluble form of receptor for advanced glycation end-products (sRAGE) in psoriasis patients at different phases of the disease activity, in comparison to healthy individuals. The study material consisted of sera from psoriasis patients in active phase, in the remission phase, and healthy controls. Concentrations of CML, CEL, and sRAGE were determined using ELISA technique. In the patients with psoriasis (in both phases of the disease), concentrations of CML, CEL and sRAGE were significantly higher than in healthy individuals but they did not correlate with psoriasis area severity index (PASI) values. The remission of the disease was followed by a significant decrease in CML, CEL, and sRAGE concentrations when compared to active patients; however, these concentrations were still significantly higher than in the controls. Our data suggest that psoriasis is accompanied by an intense glycoxidation process and that high sRAGE levels seem to reflect permanent RAGE overstimulation.

Genetically Modified Circulating Levels of Advanced Glycation End-Products and Their Soluble Receptor (AGEs-RAGE Axis) with Risk and Mortality of Breast Cancer.

The interaction of advanced glycation end-products (AGEs) with their receptor (RAGE) elicits oxidative stress and inflammation, which is involved in the development of breast cancer. However, large-scale population-based evidence exploring genetically modified circulating levels of AGEs-RAGE axis with risk and mortality of breast cancer is scarce. We recruited 1051 pairs of age-matched breast cancers and controls and measured plasma AGEs and sRAGE concentrations by enzyme-linked immunosorbent assay (ELISA). Multivariate logistic regression and Cox proportional hazard model were used to calculate the effects of plasma levels and genetic variants of the AGEs-RAGE axis and their combined effects on breast cancer risk and prognosis, respectively. Furthermore, linear regression was performed to assess the modifications in plasma AGEs/sRAGE levels by genetic predisposition. Higher levels of AGEs and AGEs/sRAGE-ratio were associated with an increased risk of breast cancer, but sRAGE levels were negatively associated with breast cancer risk, especially in women &lt;60 years. We also observed a positive association between AGEs and the bad prognosis of breast cancer. Although we did not observe a significant contribution of genetic variants to breast cancer risk, rs2070600 and rs1800624 in the AGER gene were dose-dependently correlated with sRAGE levels. Further, compared to the haplotype CT at the lowest quartile of AGEs, haplotypes TT and TA were prominently associated with breast cancer risk in the highest quartile of AGEs. This study depicted a significant association between circulating levels of AGEs-RAGE axis and breast cancer risk and mortality and revealed the potential of plasma AGEs, especially coupled with AGER polymorphism as biomarkers of breast cancer.

Time-varying parameters of glycemic control and glycation in relation to arterial stiffness in patients with type 1 diabetes.

A substantial proportion of type 1 diabetes (T1D) patients free from known cardiovascular disease (CVD) show premature arterial stiffening, with age, blood pressure, and HbA1c-as gold standard of glycemic control-as main predictors. However, the relationship of arterial stiffness with other time-varying parameters of glycemic control and glycation has been far less explored. This study investigated the relationship of arterial stiffness with several short- and long-term parameters of glycemic control and glycation in patients with T1D, such as advanced glycation end-products (AGEs) and continuous glucose monitoring (CGM)-derived parameters. Cross-sectional study at a tertiary care centre including 54 patients with T1D free from known CVD. Arterial stiffness was assessed with carotid-femoral pulse wave velocity (cf-PWV). Current level and 10-year history of HbA1c were evaluated, and skin AGEs, urinary AGEs, and serum soluble AGE-receptor (sRAGE) concentrations. CGM for 7days was used to determine time in range, time in hyper- and hypoglycemia, and glycemic variability. Cf-PWV was associated with current HbA1c (rs = + 0.28), mean 10-years HbA1c (rs = + 0.36), skin AGEs (rs = + 0.40) and the skin AGEs-to-sRAGE ratio (rs = + 0.40), but not with urinary AGE or serum sRAGE concentrations; and not with any of the CGM-parameters. Multiple linear regression for cf-PWV showed that the model with the best fit included age, T1D duration, 24-h mean arterial pressure and mean 10-years HbA1c (adjusted R2 = 0.645, p < 0.001). Longer-term glycemic exposure as reflected by current and mean 10-years HbA1c is a key predictor of arterial stiffness in patients with T1D, while no relationship was found with any of the short-term CGM parameters. Our findings stress the importance of early and sustained good glycemic control to prevent premature CVD in patients with T1D and suggest that HbA1c should continue to be used in the risk assessment for diabetic complications. The role of skin glycation, as a biomarker for vascular aging, in the risk assessment for CVD is an interesting avenue for further research.

Effects of AGEs, sRAGE and HMGB1 on Clinical Outcomes in Multiple Myeloma.

The receptor for advanced glycation end products (RAGE) upregulated during the onset and progression of cancer and bone-related pathologies. In this study, we aimed to investigate the role of serum advanced glycation end products (AGEs), soluble RAGE (sRAGE) and high mobility group box 1 (HMGB1), in multiple myeloma (MM). AGEs, sRAGE and HMGB1 concentrations of 54 newly diagnosed MM patients and 30 healthy volunteers were measured by ELISA. The estimations were done only once at diagnosis. The medical records of the patients were evaluated. There was no significant difference between the AGEs and sRAGE levels between the patient and control groups (p = 0.273, p = 0.313). In ROC analysis, a HMGB1 cutoff value of > 9170 pg/ml accurately discriminated MM patients (AUC = 0.672, 95% CI 0.561-0.77, p = 0.0034). AGEs level was found to be significantly higher in early-stage disease and HMGB1 in advanced disease (p = 0.022, p = 0.026). High HMGB1 levels were detected in patients whose with better first-line treatment response (p = 0.019). At 36 months, 54% of patients with low AGE were alive, compared to 79% of patients with high AGE (p = 0.055). Patients with high HMGB1 levels tended to have a longer PFS (median 43 mo [95% CI; 20.68-65.31] ) compared to patients with low HMGB1 levels (median 25 mo [95% CI; 12.39-37.6], p = 0.054). In this study, a significant elevation of serum HMGB1 level was found in MM patients. In addition, the positive effects of RAGE ligands on treatment response and prognosis were determined.

Soluble receptor for advanced glycation end products (sRAGE) correlates with obesity-related parameters, and it is not easy to be modified by moderate caloric restriction in obese humans.

Deficiency of a soluble form of the advanced glycation end products receptor (sRAGE) is implicated in obesity-induced complications. Serum sRAGE is inclined to be modified by changes in body weight. We analysed serum sRAGE concentrations in patients with obesity undergoing moderate calorie restriction, which mimics the real-life situation and is not harmful to obese humans. Serum sRAGE was measured by immunoassay in 50 patients with obesity who underwent calorie restriction by 300-500 kcal/day for 8 weeks. In effect calorie restriction resulted in an expected decrease in body weight (by 2.1 kg for an 8-week intervention, p<0.0001), as well as reduced systolic blood pressure, modified dyslipidemia (cholesterol, triglycerides), reduced obesity-related inflammation (tumor necrosis factor-alfa, interleukin-6, C-reactive protein), improved insulin sensitivity. However, it was not accompanied by any significant change in sRAGE concentration. There was a strong negative correlation between BMI and the sRAGE level. Accordingly, the levels of sRAGE were the highest in lean control. In conclusion: a modest weight reduction is unlikely to improve decreased sRAGE levels.

Advanced Glycation End Product (AGE) and Soluble Receptor of AGE (sRAGE) Levels in Relation to Periodontitis Severity and as Putative 3-Year Outcome Predictors in Patients Undergoing Coronary Artery Bypass Grafting (CABG).

Tissue concentrations of advanced glycation end product (AGE) and peripheral soluble receptor of AGE (sRAGE) levels may be associated with periodontitis severity. Both parameters and periodontitis might serve as outcome predictors for patients undergoing coronary artery bypass grafting (CABG). This study aimed to investigate possible associations between periodontitis and AGE/sRAGE. Ultimately, we wanted to examine whether AGE, sRAGE, and severe periodontitis are associated with the incidence of new cardiovascular events within 3 years of follow-up after CABG. Ninety-five patients with coronary vascular disease (CVD) (age 69 years, 88.3% males) needing CABG surgery were included. Periodontal diagnosis was made according to the guidelines of the “Centers for Disease Control and Prevention (CDC)” (2007) and staged according to the new classification of periodontal diseases (2018). AGE tissue concentrations were assessed as skin autofluorescence (sAF). sRAGE levels were determined by using a commercially available enzyme-linked immunoabsorbance assay (ELISA) kit. Univariate and multivariate baseline and survival analyses were carried out with Mann–Whitney U test, Chi² test, Kaplan–Meier curves with Log-Rank test, and logistic and Cox regression. sAF was identified as an independent risk indicator for severe periodontitis with respect to the cofactors age, gender, plaque index, and diabetes (adjusted odds ratio [OR] = 2.9, p = 0.028). The degree of subgingival inflammation assessed as a percentage of sites with bleeding on probing (BOP) was inversely correlated with sRAGE concentration (r = −0.189, p = 0.034). Both sAF (Hazard Ratio [HR] = 2.4, p = 0.004) and sRAGE (HR = 1.9, p = 0.031) increased the crude risk for new adverse events after CABG. The occurrence of severe periodontitis trends towards a higher risk for new cardiovascular events (HR = 1.8, p = 0.115). Applying multivariate Cox regression, only peripheral arterial disease (adjusted HR = 2.7, p = 0.006) and history of myocardial infarction (adjusted HR = 2.8, p = 0.010) proved to be independent risk factors for cardiovascular outcome. We conclude that sAF may represent a new, independent risk indicator for severe periodontitis. In contrast, sAF, sRAGE, and severe periodontitis were not independent prognostic factors for postoperative outcome in patients undergoing CABG.

The association between mediators of the receptor for advanced glycation end product (RAGE) axis and immune checkpoint inhibitor (ICI)–induced colitis in patients with melanoma.

9587 Background: Colitis and other gastrointestinal (GI) toxicity are a frequent and occasionally severe form of immune-related adverse events (irAEs) in patients treated with ICIs. To date, no definitive mechanism has been identified, and this area remains an active field of investigation. We hypothesized that activation of the RAGE axis, known to be implicated in inflammatory bowel disease through stimulation of signal transduction targeted by pro-inflammatory RAGE ligands, members of the S100 family and High Mobility Group Box 1 (HMGB1), might be associated with irAE- colitis. Methods: We examined sera from 111 advanced melanoma patients prospectively accrued and followed up at NYULH (treated with anti-PD-L1, n = 44; antiCTL4, n = 23; and combination, n = 44). 24 (22%) developed GI toxicity grade &gt;2. Serum biomarkers of the ligand-RAGE pathways, soluble (s)RAGE, endogenous secretory (es)RAGE, S100B, and HMGB1, were measured in the patients’ sera during ICI treatment. Multivariable ordinal logistic regression analyses with all grades of GI toxicity as the primary outcome for all the recorded covariates (including serum biomarkers, clinical covariates) were performed. We then used ordinal multivariable logistic regression with stepwise variable selection. Similar analyses with GI toxicity as a binary outcome ((≥grade 1 vs no toxicity) were also conducted. Only those variables that jointly contributed to the odds of developing toxicity were included in the final stepwise model. No adjustments for multiplicity were included. As sRAGE and esRAGE are highly correlated (r = 0.86), esRAGE concentrations were not used in the joint models. Results: A significant association between GI toxicity and concentrations of sRAGE and S100B was identified. The final stepwise multivariable logistic model includes only sRAGE and S100B. The odds of having a one level increase in GI toxicity grade increase 1.100 times (95% CI: 1.008, 1.199; p = 0.029) for each unit decrease of sRAGE ( = sRAGE/100). The odds of a one level increase in GI toxicity increase 1.059 times (95% CI: 1.004, 1.116; p = 0.035) for each unit increase of S100B ( = s100B/100). All other analyses yielded comparable results. In contrast, concentrations of HMGB1 and other clinical covariates, including response and treatment category, were not associated with GI toxicity. Conclusions: Mediators of the RAGE axis, specifically sRAGE and S100B, might have a role in GI toxicity in patients receiving ICIs. The ligand-RAGE axis may be a novel target for irAE therapies for patients receiving ICIs to mitigate the severity of GI toxicity.