BACKGROUND: This study sought to explore the clinical relevance of the associations of serum levels of advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), and thioredoxin-interacting protein (TXNIP) with the renal fat fraction (RFF) in individuals with type 2 diabetes mellitus (T2DM).
METHODS: A total of 133 patients with T2DM were enrolled in the study. RFF, which represents the renal fat level, was determined utilizing Dixon magnetic resonance imaging (MRI). Serum levels of AGEs, sRAGE, TXNIP, and other biochemical parameters were measured in patients who fasted.
RESULTS: RFF in T2DM patients was positively correlated with the fasting levels of C-peptide (CP), triglycerides (TG), AGEs, TXNIP, and sRAGE (P < 0.05) and negatively correlated with the high-density lipoprotein cholesterol (HDL-c) level (P < 0.05). Pearson\'s correlation analysis indicated that the serum levels of AGEs, sRAGE, and TXNIP were interrelated and positively correlated (P < 0.05). Then, all patients were assigned to four groups according to the RFF quartile. The HC, CP, TG, AGEs, sRAGE, TXNIP, and DKD percentages tended to increase as the RFF quartiles increased, while the HDL-c level tended to decrease (p for trend < 0.05). Next, multiple linear regression analysis was performed using RFF as the dependent variable. After controlling for covariates related to RFF, the results showed that the serum levels of AGEs and TXNIP were still significantly correlated with RFF.
CONCLUSIONS: These results suggest that circulating AGEs and TXNIP levels may be associated with ectopic fat accumulation in the kidneys of T2DM patients and may serve as indicators of the severity of renal fat deposition.

BACKGROUND: Diabetic nephropathy (DN) is a common complication of type 2 diabetes. Okra (Abelmoschus esculentus L) is reported to have anti-diabetic effects. The present study aimed to investigate the effects of dried okra extract (DOE) supplementation on lipid profile, renal function indices, and expression of inflammatory genes, as well as serum level of soluble Receptor for Advanced glycation end products (sRAGE) in patients with DN.
METHODS: In this triple-blind randomized placebo-controlled clinical trial, 64 eligible patients with DN received either 125 mg of DOE or placebo daily along with DN-related nutritional recommendations for 10 weeks. Changes in kidney indices including proteinuria and estimated glomerular filtration rate (eGFR), lipid profile, serum SRAGE, as well as the expression of RAGE, ICAM-1, and IL-1 genes were measured over 10 weeks.
RESULTS: After adjustment for the potential confounders, between-group analyses showed no significant differences in terms of lipid profile, kidney function indices, sRAGE, and RAGE-related inflammatory genes expression after 10 weeks.
CONCLUSIONS: Daily 125 mg DOE along with nutritional recommendations on top of usual care did not lead to significant changes in renal function indices, lipid profile, and inflammatory genes expression in patients with DN.

UNASSIGNED: The formation and accumulation of advanced glycation end products (AGEs) are enhanced with increased oxidative stress and inflammatory conditions. A hyperthyroid and hypothyroid state is associated with oxidative stress. This study aimed to evaluate skin AGE deposition, serum carboxymethyl-lysine (CML), and serum soluble receptor for AGEs (sRAGE) levels in hypothyroid and hyperthyroid patients.
UNASSIGNED: A total of 203 subjects were included in this cross-sectional study. After excluding diabetes mellitus, 103 newly diagnosed hypothyroid patients, 50 newly diagnosed hyperthyroid patients, and 50 control (euthyroid) subjects were enrolled. All tests were done before beginning the appropriate treatment. Accumulated AGEs in the skin collagen were measured by skin autofluorescence (SAF) using an AGE Reader.
UNASSIGNED: SAF measurements were 1.82 ± 0.04, 1.80 ± 0.40, and 1.63 ± 0.30 arbitrary units for the hypothyroid, hyperthyroid, and euthyroid groups, respectively (p = 0.04). Serum CML levels were 8.2 ± 2.8, 10.2 ± 2.0, and 8.0 ± 3.3 ng/mL for the hypothyroid, hyperthyroid, and euthyroid groups, respectively (p = 0.01). sRAGE levels were similar between the groups. Serum thyroid-stimulating hormone and SAF measurements were positively correlated (r = 0.25, p = 0.02) in the hypothyroid group and negatively correlated in the hyperthyroid group (r = -0.36, p = 0.04). There was no correlation between CML and sRAGE levels.
UNASSIGNED: SAF measurements are increased in both hypo- and hyperthyroid normoglycemic patients. Serum CML levels are increased in hyperthyroid patients. Hypo and hyperthyroid states might be associated with acceleration of AGE accumulation and may have a long term effect on metabolic memory.

OBJECTIVE: Advanced glycation end products (AGEs) are responsible for the complications in type 2 diabetes mellitus (T2DM) patients by acting via its receptor (RAGE). The soluble form of RAGE (sRAGE) prevents the harmful effects of AGE-RAGE signalling. The sRAGE is produced either by alternate splicing (esRAGE) or proteolytic RAGE cleavage by a disintegrin and metalloproteinase 10 (ADAM10). Hence, the study aimed to compare the expression of ADAM10 in peripheral blood mononuclear cell (PBMC), serum sRAGE and esRAGE levels in T2DM patients with and without acute coronary syndrome (ACS).
METHODS: Forty-five T2DM patients with ACS and 45 age, gender and duration of DM-matched T2DM patients without ACS were recruited. Serum sRAGE and esRAGE levels were measured by enzyme-linked immunosorbent assay. The expression of ADAM10 in PBMC was determined by quantitative reverse transcription-polymerase chain reaction.
RESULTS: The expression of ADAM10 in PBMC and serum sRAGE levels were significantly lower in T2DM patients with ACS than in T2DM patients without ACS (p < 0.001). Serum sRAGE levels and expression of ADAM10 in PBMC were positively correlated with each other and negatively correlated with markers of cardiac injury and glycaemic status (p < 0.05). Simple logistic regression showed that the models containing the expression of ADAM10 and serum sRAGE level could predict the ACS risk among T2DM patients. ROC analysis showed that both might be used for ACS diagnosis in T2DM patients.
CONCLUSIONS: Reduced expression of ADAM10 in PBMC might be responsible for lower serum sRAGE levels, predisposing T2DM patients to high ACS risk.

BACKGROUND: Dietary fat seems to affect advanced glycation end products (AGEs) and their receptors. This systematic review assesses studies that evaluated the effect of dietary fat on markers of glycation.
OBJECTIVE: The aim of this systematic review was to analyze the effect of dietary fat on markers of glycation and to explore the mechanisms involved.
METHODS: This study was conducted according to PRISMA guidelines. PubMed, Cochrane, and Scopus databases were searched, using descriptors related to dietary fat, AGEs, and the receptors for AGEs.
METHODS: Studies were selected independently by the 3 authors. Divergent decisions were resolved by consensus. All studies that evaluated the effects of the quantity and quality of dietary fat on circulating concentrations of AGEs and their receptors in adults and elderly adults with or without chronic diseases were included. Initially, 9 studies met the selection criteria.
METHODS: Three authors performed data extraction independently. Six studies were included.
RESULTS: Consumption of a Mediterranean diet rich in monounsaturated fatty acids (MUFAs) and low in dietary AGEs reduced serum concentrations of AGEs, reduced expression of the receptor for AGE (RAGE), and increased expression of the AGE receptor 1 (AGER1) when compared with consumption of a Western diet rich in saturated fatty acids and dietary AGEs. Supplementation with omega-3 polyunsaturated fatty acids (PUFAs) resulted in decreased concentrations of fluorescent AGEs and decreased expression of RAGE as well as increased expression of AGER1.
CONCLUSIONS: Increased consumption of MUFAs and omega-3 PUFAs and reduced consumption of saturated fatty acids seem to be effective strategies to beneficially affect glycation markers, which in turn may prevent and control chronic diseases.
UNASSIGNED: PROSPERO registration number CRD42021220489.

BACKGROUND: Arteriovenous fistula (AVF) failure due to thrombosis is a major cause of morbidity in patients undergoing regular hemodialysis (HD). Advanced glycation end products (AGEs) and their receptor (RAGE) might contribute to inflammation, neointimal hyperplasia, and thrombosis. RAGE has a C-truncated secretory receptor form, called soluble RAGE (sRAGE). In this study, we aimed to evaluate the association of serum sRAGE with AVF failure due to thrombosis in HD patients.
METHODS: Eighty-eight prevalent HD patients with functional AVF were included in the study. The presence of stenosis, clinical and laboratory data, and serum sRAGE was evaluated at inclusion. sRAGE concentration was measured by a competitive enzyme-linked immunosorbent assay, and stenosis was detected by ultrasound. Patients were prospectively followed up for 36 months. During this period, AVF failure (defined as the absence of blast or palpable thrill and impossible cannulation with 2 needles because of complete thrombosis) was noted and thrombosis was certified by ultrasound examination.
RESULTS: During follow-up, 16 (18.18%) patients lost their vascular access due to thrombosis. In multivariate Cox regression analysis, sRAGE was a significant predictor of vascular access thrombosis (hazard ratio = 1.15, 95% confidence interval: 1.03-1.25, p = 0.012). Kaplan-Meier analysis showed a significantly lower AVF patency time in patients with sRAGE >16.78 ng/mL than those with sRAGE <16.78 ng/mL (p = 0.02). In the subgroup of patients with stenosis at baseline, sRAGE, serum albumin, obesity, and ischemic heart disease were associated with thrombosis.
CONCLUSIONS: In our study, baseline, systemic sRAGE is associated with the occurrence of thrombosis of AVF, and this marker has a significant impact on AVF survival.

Advanced glycation end products (AGEs) are involved in the development of several age-related complications. The protective role of soluble receptors for AGEs (sRAGE) against deleterious effects of AGEs has been indicated in several studies. However, findings on the association of AGEs or sRAGE with mortality are equivocal. In this meta-analysis we aimed to present a quantitative estimation of the association between circulating AGEs or sRAGE and all-cause or cardiovascular disease (CVD) mortality. A comprehensive literature search was performed to determine relevant publications through the online databases including PubMed, Scopus, and Web of Science up to 29 November 2020. Prospective observational studies assessing the association between circulating AGEs or sRAGE and all-cause or CVD mortality were included. Seven studies with a total of 3718 participants and 733 mortality cases (345 CVD deaths) were included in the meta-analysis for assessing the association between circulating AGEs and mortality. Our results showed that higher circulating AGEs were associated with increased risk of all-cause (pooled effect measure: 1.05; 95% CI: 1.01, 1.09; P = 0.018, I2 = 77.7%) and CVD mortality (pooled effect measure: 1.08; 95% CI: 1.01, 1.14; P = 0.015, I2 = 80.2%), respectively. The association between sRAGE and mortality was assessed in 14 studies with a total of 16,335 participants and 2844 mortality cases (419 CVD deaths). Serum concentrations of sRAGE were not associated with the risk of all-cause mortality (pooled effect measure: 1.01; 95% CI: 1.00, 1.01; P = 0.205, I2 = 75.5%), whereas there was a significant link between sRAGE and the risk of CVD mortality (pooled effect measure: 1.02; 95% CI: 1.00, 1.04; P = 0.02, I2 = 78.9%). Our findings showed that a higher serum AGE concentration was associated with increased risk of all-cause and CVD mortality. In addition, higher circulating sRAGE was related to increased risk of CVD mortality. This review was registered at PROSPERO as CRD42021236559.

BACKGROUND: The established cardiovascular risk factors cannot explain the overall risk of coronary artery disease (CAD), especially in women. Therefore, there is a growing need for the assessment of novel biomarkers to identify women at risk. The receptor for advanced glycation end products (RAGE) and its interaction with the advanced glycation end product (AGE) ligand have been associated with atherogenesis. The soluble fraction of RAGE (sRAGE) antagonizes RAGE signaling and exerts an antiatherogenic effect.
OBJECTIVE: The study aim was to explore the association between plasma levels of sRAGE and CAD in nondiabetic postmenopausal women.
METHODS: This case-control study included 110 nondiabetic postmenopausal women who were enrolled in two groups. Group I included 55 angiographically proven CAD subjects with > 50% stenosis in at least one of the major coronary arteries and Group II included 55 healthy control women who did not have CAD or had < 50% stenosis of the coronary arteries. Stenosis was confirmed by invasive angiography. Plasma sRAGE was determined by an enzyme-linked immunosorbent assay.
RESULTS: We observed significantly lower plasma sRAGE concentrations in subjects with CAD vs healthy controls (P < 0.05). Univariate and multivariate logistic regression analysis also revealed a significant correlation between plasma sRAGE levels and CAD (P = 0.01). Multivariate odds ratios for CAD revealed that subjects with sRAGE concentrations below 225 pg/mL (lowest quartile) had a 6-fold increase in CAD prevalence independent of other risk factors.
CONCLUSIONS: Our findings indicated that low sRAGE levels were independently associated with CAD in nondiabetic postmenopausal women. Risk assessment of CAD in postmenopausal women can be improved by including sRAGE along with other risk factors.

The soluble receptor for advanced glycation end-products (sRAGE) has been classically considered a sink for pro-inflammatory RAGE ligands and as such has been associated with protection from inflammatory stress and disease. An alternative, though not mutually exclusive view is that high levels of sRAGE in circulation reflect the overstimulation of cell surface RAGE which if persistent, lead to the amplification of pro-inflammatory processes and the exacerbation of pathological states. With these two scenarios in mind this review focuses on the potential role of sRAGE as a prospective biomarker of disease risk and adverse outcomes.

The evidence that blood levels of the soluble receptor for advanced glycation end products (sRAGE) predict mortality in people with cardiovascular diseases (CVD) is inconsistent. To clarify this matter, we investigated if frailty status influences this association.
We analysed data of 1,016 individuals (median age, 75 years) from 3 population-based European cohorts, enrolled in the FRAILOMIC project. Participants were stratified by history of CVD and frailty status. Mortality was recorded during 8 years of follow-up.
In adjusted Cox regression models, baseline serum sRAGE was positively associated with an increased risk of mortality in participants with CVD (HR 1.64, 95% CI 1.09-2.49, p = 0.019) but not in non-CVD. Within the CVD group, the risk of death was markedly enhanced in the frail subgroup (CVD-F, HR 1.97, 95% CI 1.18-3.29, p = 0.009), compared to the non-frail subgroup (CVD-NF, HR 1.50, 95% CI 0.71-3.15, p = 0.287). Kaplan-Meier analysis showed that the median survival time of CVD-F with high sRAGE (>1,554 pg/mL) was 2.9 years shorter than that of CVD-F with low sRAGE, whereas no survival difference was seen for CVD-NF. Area under the ROC curve analysis demonstrated that for CVD-F, addition of sRAGE to the prediction model increased its prognostic value.
Frailty status influences the relationship between sRAGE and mortality in older adults with CVD. sRAGE could be used as a prognostic marker of mortality for these individuals, particularly if they are also frail.