Advanced glycation end-products and its soluble receptor are not independent predictors of incident dysglycaemia or metabolic syndrome in women with polycystic ovary syndrome: a prospective observational study.

BACKGROUND: To evaluate the association of serum advanced glycation end-products (AGEs) and its soluble receptor of AGE (sRAGE) levels with dysglycaemia and metabolic syndrome in women with polycystic ovary syndrome (PCOS). METHODS: This was an analysis of a cohort of women with PCOS who were prospectively recruited for a longitudinal observational study on their endocrine and metabolic profile between January 2010 and December 2013. The association of serum AGEs and sRAGE levels with dysglycaemia and metabolic syndrome at the second-year visit (the index visit) and the sixth-year visit (the outcome visit) were determined. Comparisons of continuous variables between groups were made using the Mann-Whitney U-test. Spearman test was used for correlation analysis. Multivariate binary logistic regression analysis was employed to identify the factors independently associated with the outcome events. RESULTS: A total of 329 women were analysed at the index visit. Significantly lower serum levels of sRAGE (both p < 0.001), but no significant difference in AGEs, were observed in those with dysglycaemia or metabolic syndrome. At the outcome visit, those with incident metabolic syndrome had a significantly lower initial serum sRAGE levels (p = 0.008). The association of serum sRAGE with dysglycaemia and metabolic syndrome at the index visit was no longer significant in multivariate logistic regression after controlling for body mass index, free androgen index and homeostatic model assessment for insulin resistance (HOMA-IR). sRAGE was also not significantly associated with incident metabolic syndrome at the outcome visit on multivariate logistic regression. CONCLUSIONS: Serum sRAGE levels are significantly lower in women with PCOS who have dysglycaemia or metabolic syndrome, and in those developing incident metabolic syndrome in four years. However, it does not have a significant independent association with these outcome measures after adjusting for body mass index, free androgen index and HOMA-IR.

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.

Apolipoprotein E ε4 Allele is Associated With Plasma Amyloid Beta and Amyloid Beta Transporter Levels: A Cross-sectional Study in a Rural Area of Xi'an, China.

OBJECTIVE: The effects of the Apolipoprotein E (ApoE) genotype on peripheral amyloid beta (Aß) and Aß transporter levels are still unclear. Soluble low-density lipoprotein receptor-related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE) are the major transporter for Aß, which can prevent plasma Aß from flowing into brain. The aim of this study was to investigate the relationships between the ApoE genotype and plasma Aß, sLRP1, sRAGE levels. DESIGN: Cross-sectional study. SETTING: The committee office of the village. PARTICIPANTS: Residents lived in the village for more than 3 years, aged 40-85 years (n = 1,119, 63.5% women). MEASUREMENTS: Plasma biomarkers include ApoE genotype, Aß, sLRP1, sRAGE, fasting blood-glucose, and blood lipids. General information, medical history, living habits, and cognitive status (cognitive impairment or not) were also collected. RESULTS: After controlling for all possible covariates, multiple linear regression analysis showed that the plasma level of Aß42 was higher and log-transformed sLRP1 was lower in ApoE ε4 carriers than that in noncarriers (ßAß42 = 1.214, 95% confidence interval: 0.105-2.316, pAß42 = 0.031; ßsLRP1 = -0.075, 95% confidence interval: -0.129 to -0.021, psLRP1 = 0.006, respectively). Partial correlation analysis showed that plasma Aß40 was positively correlated with log-transformed sLRP1 and log-transformed sRAGE (rsLRP1 = 0.116, psLRP1 <0.001; rsRAGE = 0.078, psLRP1 = 0.009, respectively). Plasma Aß42 was positively correlated with log-transformed sRAGE (r = 0.072, p = 0.017). CONCLUSION: ApoE ε4 carriers had higher plasma Aß42 levels and lower sLRP1 levels. These data indicated that the ApoE ε4 allele may also contribute to the pathogenesis of Alzheimer's disease through its effects on peripheral Aß42 and sLRP1 levels, but it needs to be further elucidated.

Breath of fresh air: Investigating the link between AGEs, sRAGE, and lung diseases.

Advanced glycation end products (AGEs) are compounds formed via non-enzymatic reactions between reducing sugars and amino acids or proteins. AGEs can accumulate in various tissues and organs and have been implicated in the development and progression of various diseases, including lung diseases. The receptor of advanced glycation end products (RAGE) is a receptor that can bind to advanced AGEs and induce several cellular processes such as inflammation and oxidative stress. Several studies have shown that both AGEs and RAGE play a role in the pathogenesis of lung diseases, such as chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, and acute lung injury. Moreover, the soluble form of the receptor for advanced glycation end products (sRAGE) has demonstrated its ability to function as a decoy receptor, possessing beneficial characteristics such as anti-inflammatory, antioxidant, and anti-fibrotic properties. These qualities make it an encouraging focus for therapeutic intervention in managing pulmonary disorders. This review highlights the current understanding of the roles of AGEs and (s)RAGE in pulmonary diseases and their potential as biomarkers and therapeutic targets for preventing and treating these pathologies.

The role of sRAGE in cardiovascular diseases.

Advanced glycation end products (AGEs), by-products of glucose metabolism, have been linked to the emergence of cardiovascular disorders (CVD). AGEs can cause tissue damage in four different ways: (1) by altering protein function, (2) by crosslinking proteins, which makes tissue stiffer, (3) by causing the generation of free radicals, and (4) by activating an inflammatory response after binding particular AGE receptors, such as the receptor for advanced glycation end products (RAGE). It is suggested that the soluble form of RAGE (sRAGE) blocks ligand-mediated pro-inflammatory and oxidant activities by serving as a decoy. Therefore, several studies have investigated the possible anti-inflammatory and anti-oxidant characteristics of sRAGE, which may help lower the risk of CVD. According to the results of various studies, the relationship between circulating sRAGE, cRAGE, and esRAGE and CVD is inconsistent. To establish the potential function of sRAGE as a therapeutic target in the treatment of cardiovascular illnesses, additional studies are required to better understand the relationship between sRAGE and CVD. In this review, we explored the potential function of sRAGE in different CVD, highlighting unanswered concerns and outlining the possibilities for further investigation.

Effects of Simvastatin on Plasma Amyloid-ß Transport in Patients with Hyperlipidemia: A 12-Week Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Abnormal blood lipids are associated with cognitive impairment and amyloid-ß (Aß) deposition in the brain. However, the effects of statins on Alzheimer's disease (AD) have not been determined. OBJECTIVE: Considering that plasma Aß are related to Aß deposition in the brain, we investigated the effects of simvastatin on plasma Aß transport. METHODS: This was a randomized, double-blind, placebo-controlled trial. One hundred and twenty patients with hyperlipidemia were randomly assigned to receive 40 mg of simvastatin per day or matching placebo for 12 weeks (sixty patients per group). Plasma Aß, sLRP1, sRAGE, and lipid levels were measured at baseline and at the 6-week and 12-week visits. RESULTS: The ITT database ultimately included 108 participants (placebo group: n = 53; simvastatin group: n = 55) and 64 (59.3%) were women, ranging in age from 45 to 75 years (mean 57.2±6.9 years). Multiple linear regression analysis showed that, after 12 weeks of follow-up, compared with the placebo group, ΔAß42 levels (the change of Aß42 levels from baseline at week 12) increased more and ΔsRAGE levels decreased more in the simvastatin group (Aß42: ß= 5.823, p = 0.040; sRAGE: ß= -72.012, p = 0.031), and a significant negative association was found between ΔAß42 and ΔsRAGE levels (ß= -0.115, p = 0.045). In addition, generalized estimation equation analysis showed that triglycerides levels were negatively correlated with Aß40 (ß= -16.79, p = 0.023), Aß42 (ß= -6.10, p = 0.001), and sRAGE (ß= -51.16, p = 0.003). CONCLUSION: Daily oral simvastatin (40 mg/day) in patients with hyperlipidemia for 12 weeks can significantly increase plasma Aß42 levels compared with placebo, which was associated with reduced triglycerides and sRAGE levels, indicating that statins may affect plasma Aß transport.

Blood Triglyceride and High-Density Lipoprotein Levels Are Associated with Plasma Amyloid-ß Transport: A Population-Based Cross-Sectional Study.

BACKGROUND: Studies have found that blood lipids are associated with plasma amyloid-ß (Aß) levels, but the underlying mechanism is still unclear. Two Aß transporters, soluble form of low-density lipoprotein receptor related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE), are crucial in peripheral Aß transport. OBJECTIVE: The aim was to investigate the effects of lipids on the relationships between plasma Aß and transporter levels. METHODS: This study included 1,436 adults aged 40 to 88 years old. Blood Aß, sLRP1, sRAGE, and lipid levels were measured. Univariate and multivariate analyses were used to analyze the relationships between lipids and plasma Aß, sLRP1, and sRAGE. RESULTS: After adjusting for all possible covariates, high-density lipoprotein (HDL-c) was positively associated with plasma Aß42 and sRAGE (ß= 6.158, p = 0.049; ß= 121.156, p < 0.001, respectively), while triglyceride (TG) was negatively associated with plasma Aß40, Aß42, and sRAGE (ß= -48.389, p = 0.017; ß= -11.142, p = 0.020; ß= -147.937, p = 0.003, respectively). Additionally, positive correlations were found between plasma Aß and sRAGE in the normal TG (Aß40: ß= 0.034, p = 0.005; Aß42: ß= 0.010, p = 0.001) and HDL-c groups (Aß40: ß= 0.023, p = 0.033; Aß42: ß= 0.008, p = 0.002) but not in the high TG and low HDL-c groups. CONCLUSION: Abnormal levels of TG and HDL-c are associated with decreased Aß and sRAGE levels. Positive correlations between plasma Aß and sRAGE were only found in the normal TG and HDL-c groups but not in the high TG and low HDL-c groups. These results indicated that dyslipidemia contributing to plasma Aß levels might also be involved in peripheral Aß clearance.

Relationship Between Peripheral Transport Proteins and Plasma Amyloid-ß in Patients with Alzheimer's Disease Were Different from Cognitively Normal Controls: A Propensity Score Matching Analysis.

BACKGROUND: Transport proteins, soluble LRP1 (sLRP1) and soluble RAGE (sRAGE), play a pivotal role in the peripheral clearance of plasma amyloid-ß (Aß). However, their relationship is seldom discussed, especially in Alzheimer's disease (AD). OBJECTIVE: To explore whether their relationship in patients with AD varied from those in cognitively normal (CN) controls. METHODS: We initially recruited 70 patients with AD and 725 CN controls, then applied propensity score matching (PSM) analysis to balance the differences between two groups. Plasma levels of sLRP1, sRAGE, and Aß were measured using commercial ELISA kits and log transformed when skewed distributed. The relationship between sLRP1/sRAGE and plasma Aß were analyzed using Pearson's correlation analysis followed by multiple linear regression separately in the original population and matched participants. RESULTS: After PSM, 70 patients with AD and 140 matched controls were included for further analysis. Log sLRP1 was positively correlated with plasma Aß40 in matched CN controls (r = 0.222, p = 0.008) but not in patients with AD (r = 0.137, p = 0.260). After multivariable adjustment, Log sLRP1 remained significantly associated with plasma Aß40 in the CN group (ß= 7.347, p = 0.014) but not in the AD group (ß= 10.409, p = 0.105). In contrast, Log sLRP1 was not correlated with plasma Aß42 in patients with AD or CN controls, and Log sRAGE was consistently not associated with plasma Aß40 or Aß42 in either group. CONCLUSION: The significant correlation between sLRP1 and plasma Aß40 present in CN controls was not found in patients with AD, suggesting that their relationship was different in AD. However, the specific mechanisms and its influence on cerebral amyloid burden require further validation.

Evaluation of the AGE/sRAGE Axis in Patients with Multiple Myeloma.

Glycative stress influences tumor progression. The aim of the present study was to evaluate the advanced glycation end products/soluble receptor of advanced glycation end products (AGE/sRAGE) axis in patients with multiple myeloma (MM). Blood samples were taken from 19 patients affected by MM and from 16 sex-matched and age-matched healthy subjects. AGE and sRAGE axis were dosed in patients with MM and matched with controls. AGEs were measured by spectrofluorimetric methods. Blood samples for the determination of sRAGE were analyzed by ELISA. AGE levels were significantly reduced in patients with respect to controls. Instead, sRAGE was significantly elevated in patients affected by MM compared to healthy subjects. Moreover, we showed that there was a statistically significant difference in sRAGE according to the heavy and light chain. IgA lambda had significantly higher sRAGE values than IgA kappa, IgG kappa, and IgG Lambda MM patients. From our data emerges the role of the sRAGE/AGE axis in MM. Since AGE is a positive regulator of the activity of RAGE, circulating sRAGE concentrations may reflect RAGE expression and may be raised in parallel with serum AGE concentrations as a counter-system against AGE-caused tissue damage. Serum concentrations of AGE and sRAGE could therefore become potential therapeutic targets.

The impact of polytrauma on sRAGE levels: evidence and statistical analysis of temporal variations.

BACKGROUND: According to recently published findings, levels of the soluble receptor of advanced glycation end products (sRAGE) and its clearance from the blood may reflect the evolution of lung damage during hospitalization. Thus, the objective of this study was to reveal the course of sRAGE levels over the first three posttraumatic weeks, focusing on the severity of thoracic trauma and the development of acute respiratory distress syndrome (ARDS) and/or pneumonia. METHODS: Twenty-eight consecutive surviving polytraumatized patients suffering thoracic trauma, age ≥ 18 years, Injury Severity Score ≥ 16, and directly admitted to our level I trauma center were enrolled in this prospective study. Blood samples were taken initially and on days 1, 3, 5, 7, 10, 14, and 21 during hospitalization. Luminex multi-analyte-technology was used for biomarker analysis. RESULTS: Common to all our patients was an almost continuous decline of sRAGE levels within the first five posttraumatic days. Day 0 levels in polytrauma victims with severe thoracic trauma were more than twice as high than in those suffering mild thoracic trauma (p = 0.035), whereas the difference between the two groups did not reach significance from day 1. Neither the development of ARDS and/or pneumonia nor the necessity of secondary surgery did result in significant differences in sRAGE levels between the subgroups with and without the particular complication at any time point. CONCLUSIONS: sRAGE levels assessed immediately after hospital admission might serve as a diagnostic marker for the vehemence of impacts against the chest and thus might be applied as an additional tool in diagnosis, risk evaluation, and choice of the appropriate treatment strategy of polytraumatized patients in routine clinical practice.

The Level of Plasma Amyloid-ß40 Is Correlated with Peripheral Transport Proteins in Cognitively Normal Adults: A Population-Based Cross-Sectional Study.

BACKGROUND: Transport proteins, soluble low-density lipoprotein receptor-related protein-1 (sLRP1), and soluble receptor of advanced glycation end products (sRAGE), play an important role in the clearance of plasma amyloid-ß (Aß). However, their relationship is not clear. OBJECTIVE: The aim was to explore the relationship between plasma levels of sLRP1, sRAGE, and Aß in a cross-sectional study. METHODS: A total of 1,185 cognitively normal participants (age above 40) from a village in the suburbs of Xi'an, China were enrolled from October 8, 2014 to March 30, 2015. Plasma Aß40, Aß42, sLRP1, and sRAGE were tested using a commercial ELISA. Apolipoprotein E (APOE) genotyping was conducted using PCR and sequencing. The relationship between plasma levels of sLRP1, sRAGE, and Aß was analyzed using Pearson's correlation analysis and multiple linear regression. RESULTS: In the total population, Log sLRP1 and Log sRAGE were positively correlated with plasma Aß40 (r= 0.103, p < 0.001; r= 0.064, p = 0.027, respectively), but neither were associated with plasma Aß42. After multivariable adjustment in the regression model, Log sLRP1 and Log sRAGE were still positively related with plasma Aß40 (ß= 2.969, p < 0.001; ß= 1.936, p = 0.017, respectively) but not Aß42. Furthermore, the positive correlations between transport proteins and plasma Aß40 remained significant only in APOEɛ4 non-carriers after Pearson's analysis and multiple regression analysis after stratification by gene status. CONCLUSION: The concentrations of plasma sLRP1 and sRAGE had a significant impact on the level of plasma Aß40 in cognitively normal adults, especially in APOEɛ4 non-carriers. However, the mechanism by which the transport proteins are involved in peripheral Aß clearance and the relationship between transporters and amyloid burden in the brain needs further validation.

Soluble receptor for advanced glycation end products in male infertility.

BACKGROUND: Soluble receptor of advanced glycation end-products (sRAGE) is widely expressed in various organs including male genital tract and spermatozoa. Their regulation depends on many simultaneous conditions that may occur. Male fertility is a multifactorial condition which is influenced by various parameters, some of which are detrimental to the spermatozoa. The aim of this study was to detect possible differences in sRAGE concentrations between serum and seminal plasma of infertile men, compared to fertile men population. METHODS: Seventy-five men were included in the study and divided into three groups: a group of fertile controls (age 34.8 ± 4.6 years, n =12) and two groups of men from infertile couples (age 36.1 ± 5.2 years) with normal (NS, n =10) and abnormal (AS, n =53) semen parameters, respectively. sRAGE was measured by ELISA in serum, and seminal plasma samples of all participants and biochemical, hormonal examinations, as well as anthropometric characteristics, were co-evaluated. Data were statistically analyzed using the chi-square test and the independent samples t-test. A two-tailed p <0.05 was considered significant. RESULTS: Serum sRAGE levels of fertile men were higher than those of men of infertile couples with AS or NS semen parameters (2,061 ± 884 pg/ml vs 1,673 ± 613 pg/ml and 1,411 ± 405 pg/ml, respectively; p <0.058). Seminal plasma sRAGE levels in fertile men were similar to the ones measured in both groups of men from infertile couples AS and NS (327 ± 81 pg/ml vs 322 ± 162 - 413 ± 207 pg/ml; p =0.197). Interestingly, the seminal plasma sRAGE levels in those three groups were significantly lower than the corresponding serum sRAGE levels (p <0.001). CONCLUSION: Serum and seminal plasma sRAGE concentrations seem to show variations worth considering between fertile and infertile men. Moreover, further research is required to elucidate the role of the sRAGEs and oxidative stress in male infertility. HIPPOKRATIA 2017, 21(1): 19-24.

Dynamic changes in sRAGE levels and relationship with cardiac function in STEMI patients.

OBJECTIVES: Soluble receptor of advanced glycation end-products (sRAGE) may be a predictive biomarker in coronary artery disease (CAD). Patients with acute myocardial infarction (AMI) have higher sRAGE levels compared to healthy subjects. Accordingly, the aim of this study was to investigate the dynamic changes in sRAGE levels during AMI and relationship with cardiac dysfunction. DESIGN AND METHODS: We prospectively included 80 patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). sRAGE concentrations were measured before pPCI, immediately after pPCI and again on the first and second following days. Left ventricular ejection fraction (LVEF) was evaluated 1-3 days after the pPCI and again at a median of 7months by echocardiography, and infarct size was measured by cardiac magnetic resonance. RESULTS: sRAGE levels were high in the early phase of AMI; sRAGE levels significantly increased after pPCI compared with sRAGE before pPCI (median ratio: 1.25, 95% CI: 1.15-1.35, P<0.001), and the increase was observed prior to Troponin I (TnI). sRAGE levels decreased notably the first day after pPCI (median ratio: 0.34, 95% CI: 0.30-0.39, P<0.001). Peak sRAGE independently associated with long-term cardiac dysfunction estimated by LVEF (P=0.008). Furthermore, sRAGE measured after pPCI associated with infarct size (P=0.038). CONCLUSIONS: sRAGE levels were high in the early phase rather than in the days after AMI and pPCI. The increase in sRAGE was seen before detectable changes in TnI. In addition, sRAGE was independently associated with long-term cardiac dysfunction.