Integrinß3 mediates the protective effects of soluble receptor for advanced glycation end-products during myocardial ischemia/reperfusion through AKT/STAT3 signaling pathway.

Soluble receptor for advanced glycation end-product (sRAGE) was reported to protect myocardial ischemia/reperfusion (I/R) injuries via directly interacting with cardiomyocytes besides competing with RAGE for AGEs. However, the specific molecule for the interaction between sRAGE and cardiomyocytes are not clearly defined. Integrins which were reported to interact with RAGE on leukocytes were also expressed on myocardial cells, therefore it was supposed that sRAGE might interact with integrins on cardiomyocytes to protect hearts from ischemia/reperfusion injuries. The results showed that sRAGE increased the expression of integrinß3 but not integrinß1, ß2, ß4 or ß5 in cardiomyocytes during I/R injuries. Meanwhile, the suppressive effects of sRAGE on cardiac function, cardiac infraction size and apoptosis in mice were cancelled by inhibition of integrinß3 with cilengitide (CLG, 75 mg/kg). The results from cultured cardiomyocytes also proved that sRAGE attenuated myocardial apoptosis and autophagy through interacting with integrinß3 to activate Akt and STAT3 pathway during oxygen and glucose deprivation/reperfusion (OGD/R) treatment. Furthermore, the phosphorylation of STAT3 was significantly downregulated by the inhibition of Akt (LY294002, 10 µM) in OGD/R and sRAGE treated cardiomyocytes, which suggested that STAT3 pathway was induced by Akt in I/R and sRAGE treated cardiomyocytes. The present study contributes to the understanding of myocardial I/R pathogenesis and provided a novel integrinß3-dependent therapy strategy for sRAGE ameliorating I/R injuries.

The role of soluble receptor for advanced glycation end-products (sRAGE) in the general population and patients with diabetes mellitus with a focus on renal function and overall outcome.

Isoforms of the receptor for advanced glycation end-product (RAGE) protein, which lack the transmembrane and the signaling (soluble RAGE or sRAGE) domains are hypothesized to counteract the detrimental action of the full-length receptor by acting as a decoy, and they provide a potential tool to treat RAGE-associated diseases. Multiple studies have explored the relationship between sRAGE and endogenous secretory RAGE and its polymorphism and obesity, metabolic syndrome, atherosclerosis, kidney function, and increased mortality in the general population. In addition, sRAGE may be a key player in the pathogenesis of diabetes mellitus and its microvascular (e.g. kidney disease) as well as macrovascular (e.g. cardiovascular disease) complications. In this review, we focus on the role of sRAGE as a biomarker in these specific areas. As there is a lack of an underlying unifying hypothesis about how sRAGE changes according to the disease condition or risk factor, there is a call to incorporate all three players of the AGE-RAGE axis into a new universal biomarker/risk marker: (AGE + RAGE)/sRAGE. However, the measurement of RAGE in humans is not practical as it is a cell-bound receptor for which tissue is required for analysis. A high AGE/sRAGE ratio may be a valuable alternative and practical universal biomarker/risk marker for diseases associated with the AGE-RAGE axis, irrespective of low or high serum sRAGE concentrations.

Elevated level of the soluble receptor for advanced glycation end-products involved in sarcopenia: an observational study.

BACKGROUND: The soluble receptor for advanced glycation end products (sRAGE) has been proposed to serve as a marker for disease severity, but its role in sarcopenia, an age-related progressive loss of muscle mass and function, remains elusive. This study examines the association between sRAGE and sarcopenia. METHODS: A total of 314 community-dwelling elderly adults who had their health examination at Tri-Service General Hospital from 2017 to 2019 underwent protein analysis with enzyme-linked immunosorbent assay. The relationship with sarcopenia and its detailed information, including components and diagnosis status, were examined using linear and logistic regressions. RESULTS: As for sarcopenia components, low muscle mass (ß = 162.8, p = 0.012) and strength (ß = 181.31, p = 0.011) were significantly correlated with sRAGE, but not low gait speed (p = 0.066). With regard to disease status, confirmed sarcopenia (ß = 436.93, p < 0.001), but not probable (p = 0.448) or severe sarcopenia (p = 0.488), was significantly correlated with sRAGE. In addition, females revealed a stronger association with sRAGE level by showing significant correlations with low muscle mass (ß = 221.72, p = 0.014) and low muscle strength (ß = 208.68, p = 0.043). CONCLUSIONS: sRAGE level showed a positive association with sarcopenia, illustrating its involvement in the evolution of sarcopenia. This association is more evident in female groups, which may be attributed to the loss of protection from estrogen in postmenopausal women. Utilizing sRAGE level as a prospective marker for sarcopenia deserves further investigation in future studies.

Soluble receptor for advanced glycation end-products promotes angiogenesis through activation of STAT3 in myocardial ischemia/reperfusion injury.

Soluble receptor for advanced glycation end-products (sRAGE), which exerts cardioprotective effect through inhibiting cardiomyocyte apoptosis and autophagy during ischemia/reperfusion (I/R) injury, is also known to enhance angiogenesis in post-ischemic reperfusion injury-critical limb ischemia (PIRI-CLI) mice. However, whether sRAGE protects the heart from myocardial I/R injury via promoting angiogenesis remains unclear. Myocardial model of I/R injury was conducted by left anterior descending (LAD) ligation for 30 min and reperfusion for 2 weeks in C57BL/6 mice. And I/R injury in cardiac microvascular endothelial cells (CMECs) was duplicated by oxygen and glucose deprivation. The results showed that I/R-induced cardiac dysfunction, inflammation and myocardial fibrosis were all reversed by sRAGE. CD31 immunohistochemistry staining showed that sRAGE increased the density of vessels after I/R injury. The results from cultured CMECs showed that sRAGE inhibited apoptosis and increased proliferation, migration, angiogenesis after exposure to I/R. These effects were dependent on signal transducer and activator of transcription 3 (STAT3) pathway. Together, the present study demonstrated that activation of STAT3 contributed to the protective effects of sRAGE on myocardial I/R injury via promoting angiogenesis.

Circulating soluble receptor for advanced glycation end products and other factors in type 2 diabetes patients with colorectal cancer.

BACKGROUND: Recent study showed that individuals with type 2 diabetes have a high risk of developing colorectal cancer (CRC), in which Receptor for Advanced Glycation End Products (RAGE) plays a pivotal role. We conducted a cross-sectional study to examine the relationships of circulating sRAGE, CRC and other clinical factors in type2 diabetes patients. METHODS: A total of 150 type 2 diabetes patients aged 50 years and older were enrolled, including 50 patients with CRC and 100 patients without CRC. We measured Serum levels of sRAGE and interleukin-6(IL-6) using an enzyme-linked immunosorbent assay (ELISA). In addition, other clinical parameters were also measured during hospitalization. RESULTS: Type 2 diabetes patients with CRC had higher triglyceride, total cholesterol, IL-6, and circulating sRAGE levels and lower use of medicines than type 2 diabetes patients without CRC. Circulating sRAGE was associated with an increased risk for CRC (OR = 2.289 for each SD increase in sRAGE, 95% CI = 1.037-5.051; P = 0.04) among Type 2 diabetes patients after adjustment for confounders. Furthermore, circulating sRAGE levels among type 2 diabetes patients were positively correlated with triglyceride (r = 0.377, P < 0.001), total cholesterol (r = 0.491, P < 0.001), and low-density lipoprotein cholesterol (LDL-c)(r = 0.330, P < 0.001) levels; the homeostatic model assessment for insulin resistance(HOMA-IR)score (r = 0.194, P = 0.017); and fasting serum insulin (r = 0.167, P = 0.041) and IL-6 (r = 0.311, P < 0.001) concentrations. CONCLUSIONS: Our results suggested that circulating sRAGE is independently risk factor for CRC, and also closely related to inflammation, dyslipidemia in type 2 diabetes patients.

Soluble receptor for AGE in diabetic nephropathy and its progression in Finnish individuals with type 1 diabetes.

AIMS/HYPOTHESIS: Activation of the receptor for AGE (RAGE) has been shown to be associated with diabetic nephropathy. The soluble isoform of RAGE (sRAGE) is considered to function as a decoy receptor for RAGE ligands and thereby protects against diabetic complications. A possible association between sRAGE and diabetic nephropathy is still, however, controversial and a more comprehensive analysis of sRAGE with respect to diabetic nephropathy in type 1 diabetes is therefore warranted. METHODS: sRAGE was measured in baseline serum samples from 3647 participants with type 1 diabetes from the nationwide multicentre Finnish Diabetic Nephropathy (FinnDiane) Study. Associations between sRAGE and diabetic nephropathy, as well as sRAGE and diabetic nephropathy progression, were evaluated by regression, competing risks and receiver operating characteristic curve analyses. The non-synonymous SNP rs2070600 (G82S) was used to test causality in the Mendelian randomisation analysis. RESULTS: Baseline sRAGE concentrations were highest in participants with diabetic nephropathy, compared with participants with a normal AER or those with microalbuminuria. Baseline sRAGE was associated with progression from macroalbuminuria to end-stage renal disease (ESRD) in the competing risks analyses, but this association disappeared when eGFR was entered into the model. The SNP rs2070600 was strongly associated with sRAGE concentrations and with progression from macroalbuminuria to ESRD. However, Mendelian randomisation analysis did not support a causal role for sRAGE in progression to ESRD. CONCLUSIONS/INTERPRETATION: sRAGE is associated with progression from macroalbuminuria to ESRD, but does not add predictive value on top of conventional risk factors. Although sRAGE is a biomarker of diabetic nephropathy, in light of the Mendelian randomisation analysis it does not seem to be causally related to progression from macroalbuminuria to ESRD.

Increased levels of soluble Receptor for Advanced Glycation End-products (RAGE) are associated with a higher risk of mortality in frail older adults.

OBJECTIVE: to evaluate the relationship between serum levels of the soluble Receptor for Advanced Glycation End-products (sRAGE) and mortality in frail and non-frail older adults. METHODS: we studied 691 subjects (141 frail and 550 non-frail) with a median age of 75 years from two population-based cohorts, the Toledo Study of Healthy Aging and the AMI study, who were enrolled to the FRAILOMIC initiative. Multivariate Cox proportional hazards regression and Kaplan-Meier survival analysis were used to assess the relationship between baseline sRAGE and mortality. RESULTS: during 6 years of follow-up 101 participants died (50 frail and 51 non-frail). Frail individuals who died had significantly higher sRAGE levels than those who survived (median [IQR]: 1563 [1015-2248] vs 1184 [870-1657] pg/ml, P = 0.006), whilst no differences were observed in the non-frail group (1262 [1056-1554] vs 1186 [919-1551] pg/ml, P = 0.19). Among frail individuals higher sRAGE levels were associated with an increased risk of death after adjustment for relevant covariates (HR = 2.72 per unit increment in ln-sRAGE, 95%CI 1.48-4.99, P = 0.001). In contrast, in non-frail individuals sRAGE showed no association with mortality. Survival curves demonstrated that among frail individuals the incidence of death was significantly higher in the top sRAGE quartile compared to the three lower quartiles (P = 0.002). Area under the ROC curve analysis demonstrated that for frail individuals, inclusion of sRAGE in the hazard model increased its predictive accuracy by ~3%. CONCLUSIONS: sRAGE is an independent predictor of mortality among frail individuals. Determination of sRAGE in frail subjects could be useful for prognostic assessment and treatment stratification.

High intake of dietary advanced glycation end-products is associated with increased arterial stiffness and inflammation in subjects with type 2 diabetes.

BACKGROUND AND AIMS: Modern diets are high in advanced glycation end-products (dAGEs), derived from processing methods, exerting a pivotal role in promoting atherosclerotic risk. In this cross-sectional study we investigate the relationship between dAGE intake, arterial stiffness, inflammatory profile and macronutrient composition, in subjects with type 2 diabetes without overt cardiovascular disease. METHODS AND RESULTS: Arterial stiffness, carboxy-methyl-lysine, endogenous secretory receptor for AGEs (esRAGE), high sensitivity C reactive protein (hs-CRP), S100A12 and macronutrient intake were evaluated in 85 subjects with type 2 diabetes. The subjects were stratified into two groups according to dAGE consumption: high and low dAGE intake (≥ or <15.000 kU/day, respectively). Subjects with high dAGE intake (n = 45) showed a higher augmentation, augmentation index and pulse wave velocity (PWV) compared with those subjects with low dAGE intake (18 ± 5.4 vs 12.2 ± 6.3 mmHg, P < 0.05; 38.3 ± 5.4 vs 29.3 ± 10%; 9.2 ± 1.4 m/sec vs 7.9 ± 1.7, P < 0.05, respectively). hs-CRP were higher in subjects with high dAGE intake [0.42 (0.18-0.54) vs 0.21 (0.14-0.52) mg/dL, P < 0.05] whereas esRAGE plasma levels were lower [0.16 (0.23-0.81) vs 0.2 (0.14-0.54) ng/dL, P < 0.05]. Simple regression analysis showed a correlation between dAGEs and fat intake. Multivariate analysis showed an independent association between augmentation, systolic blood pressure (BP) and dAGE consumption; BMI and esRAGE were the major determinants of PWV. CONCLUSIONS: Our data suggests that a chronic high dAGE diet could lead to a vascular dysfunction and inflammatory activation, contributing to the development of vascular complications in subjects with type 2 diabetes. Testing this hypothesis may represent a direction of future research.

Interaction of extracellular S100A4 with RAGE prompts prometastatic activation of A375 melanoma cells.

S100A4, a member of the S100 protein family of EF-hand calcium-binding proteins, is overexpressed in various tumour entities, including melanoma, and plays an important role in tumour progression. Several studies in epithelial and mesenchymal tumours revealed a correlation between extracellular S100A4 and metastasis. However, exact mechanisms how S100A4 stimulates metastasis in melanoma are still unknown. From a pilot experiment on baseline synthesis and secretion of S100A4 in human melanoma cell lines, which are in broad laboratory use, A375 wild-type cells and, additionally, newly generated A375 cell lines stably transfected with human S100A4 (A375-hS100A4) or human receptor for advanced glycation endproducts (A375-hRAGE), were selected to investigate the influence of extracellular S100A4 on cell motility, adhesion, migration and invasion in more detail. We demonstrated that A375 cells actively secrete S100A4 in the extracellular space via an endoplasmic reticulum-Golgi-dependent pathway. S100A4 overexpression and secretion resulted in prometastatic activation of A375 cells. Moreover, we determined the influence of S100A4-RAGE interaction and its blockade on A375, A375-hS100A4, A375-hRAGE cells, and showed that interaction of RAGE with extracellular S100A4 contributes to the observed activation of A375 cells. This investigation reveals additional molecular targets for therapeutic approaches aiming at blockade of ligand binding to RAGE or RAGE signalling to inhibit melanoma metastasis.

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 <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.

Advanced Glycation End-Products (AGEs) and Their Soluble Receptor (sRAGE) in Women Suffering from Systemic Lupus Erythematosus (SLE).

Systemic lupus erythematosus (SLE) is characterized by abnormal action of the immune system and a state of chronic inflammation. The disease can cause life-threatening complications. Neoepitopes arising from interdependent glycation and oxidation processes might be an element of SLE pathology. The groups included in the study were 31 female SLE patients and 26 healthy female volunteers (the control group). Blood serum samples were obtained to evaluate concentrations of advanced glycation end-products (AGEs), carboxymethyllysine (CML), carboxyethyllysine (CEL), pentosidine, and a soluble form of the receptor for advanced glycation end-products (sRAGE). Compared to a healthy control group, the SLE patients exhibited a higher concentration of AGEs and a lower concentration of sRAGE in serum. There were no statistically significant differences in serum CML, CEL, and pentosidine concentrations between the groups. Therefore, SLE patients could be at risk of intensified glycation process and activation of the proinflammatory receptor for advanced glycation end-products (RAGE), which could potentially worsen the disease course; however, it is not clear which compounds contribute to the increased concentration of AGEs in the blood. Additionally, information about the cigarette smoking and alcohol consumption of the study participants was obtained.

Soluble Receptor for Glycation End-products Concentration Increases Following the Treatment of Severe Diabetic Ketoacidosis

Objective: To determine the time relationships of soluble receptor for glycation end-products (sRAGE), [a decoy of the advanced glycation end-products (AGE)-RAGE axis] and D-lactate, (a metabolite of methylglyoxal) in the inflammatory response to diabetic ketoacidosis (DKA). Methods: Sixteen children and adolescents with type 1 diabetes (T1D) had blood samples obtained, 6-12 hours into treatment, at three weeks and three months post start of treatment. sRAGE and D-lactate concentrations at three months were considered baseline. Expression of RAGE was investigated in the myocardium of a newly diagnosed and untreated young person with fatal T1D/DKA. Results: sRAGE 6-12 hours after the start of treatment was 39% lower than the values at two weeks (p=0.0036) and at three months (p=0.0023) post treatment. D-lactate was higher during treatment than at three weeks (p=0.04) and at three months (p=0.035). Conclusion: sRAGE concentration was decreased during treatment, compared to concentrations at two weeks and three months after treatment. The increased D-lactate during treatment was in keeping with the known increase in dicarbonyls at this time. The finding of RAGE expression in a young myocardium prior to DKA treatment suggested cardiovascular inflammation pre-treatment and at a young age.

Serum soluble receptor for advanced glycation end-products during acute bronchiolitis in infant: Prospective study in 93 cases.

INTRODUCTION: Acute bronchiolitis is a major cause of acute respiratory distress in infants. The soluble receptor for advanced glycation end-products (sRAGE) is a biomarker of pulmonary damage processes, with a diagnostic and a prognostic value in acute respiratory distress syndrome (ARDS). The RAGE pathway is also implicated in the pathogenesis of other respiratory diseases like asthma, but the value of sRAGE levels in acute bronchiolitis remains under-investigated. MATERIAL AND METHODS: A prospective, observational, and analytical study was conducted at Clermont-Ferrand University Hospital. The main objective was to evaluate the correlation between serum sRAGE and clinical severity of bronchiolitis in hospitalized infants aged <1 year. We analyzed correlations between serum sRAGE and Wainwright score, short-term morbidity attributable to bronchiolitis, causal viruses and risk for recurrent wheezing at 1 year. RESULTS: The study included 93 infants. sRAGE levels were significantly lower in acute bronchiolitis patients (mean 1101 pg/mL) than in controls (2203 pg/mL, P < 0.001) but did not correlate with clinical severity. No correlation was found between serum sRAGE and severity score, respiratory viruses, and recurrent wheezing at 1 year. Serum sRAGE levels were negatively correlated with age (r = -0.45, P < 0.001). CONCLUSION: Serum sRAGE levels are decreased in acute bronchiolitis but not correlated with disease severity. sRAGE levels should be age-adjusted in infants. Serum sRAGE levels measured in the setting of acute bronchiolitis were not predictive of recurrent wheezing.

Controlled immobilization of His-tagged proteins for protein-ligand interaction experiments using Ni²âº-NTA layer on glass surfaces.

Gold surfaces functionalized with nickel-nitrilotriacetic acid (Ni²âº-NTA) as self-assembled monolayers (SAM) to immobilize histidine (His)-tagged biomolecules are broadly reported in the literature. However, the increasing demand of using microfluidic systems and biosensors takes more and more advantage on silicon technology which provides dedicated glass surfaces and substantially allows cost and resource savings. Here we present a novel method for the controlled oriented immobilization of His-tagged proteins on glass surfaces functionalized with a Ni²âº-NTA layer. Exemplarily, the protein pattern morphology after immobilization on the Ni²âº-NTA layer of His6-tagged soluble receptor for advanced glycation endproducts (sRAGE) was investigated and compared to non-oriented immobilization of sRAGE on amino SAM by using scanning electron microscopy (SEM). Moreover, we demonstrated interaction of immobilized sRAGE with three structurally different ligands, S100A12, S100A4, and glycated low density lipoproteins (glycLDL), by means of peak-force tapping atomic force microscopy (PF-AFM). We showed a clear discrimination of different protein-ligand orientations by differential height measurements.

Total soluble and endogenous secretory receptor for advanced glycation endproducts (RAGE) in IBD.

BACKGROUND AND AIMS: Recruitment and activation of neutrophils, with release of specific proteins such as S100 proteins, is a feature of inflammatory bowel disease (IBD). Soluble forms of the receptor for advanced glycation endproducts (sRAGE), and variants such as endogenous secretory (esRAGE), can act as decoy receptors by binding ligands, including S100A12. The aims of this study were to determine total sRAGE and esRAGE concentrations in patients with IBD and correlate these with C-reactive protein (CRP), endoscopic scores and clinical disease activity scores. METHODS: EDTA-plasma was collected from patients undergoing colonoscopy including those with Crohn's disease (CD: n=125), ulcerative colitis (UC: n=79) and control patients without endoscopic signs of inflammation (non-IBD: n=156). Concentrations of sRAGE and esRAGE were determined by enzyme-linked immunosorbent assay and plasma CRP concentrations measured. Standard clinical disease activity and endoscopic severity scores were defined for all subjects. RESULTS: Plasma sRAGE concentrations were lower in UC (but not CD) than non-IBD subjects (p<0.01). Whilst sRAGE concentrations correlated negatively with endoscopic activity in UC (p<0.05), this was not seen in CD. In contrast, esRAGE correlated negatively with disease activity in both UC (p=0.002) and CD (p=0.0001). Furthermore, sRAGE and esRAGE concentrations correlated inversely with CRP values (p<0.0001). CONCLUSIONS: Although total sRAGE varied with activity in UC, esRAGE concentrations correlated inversely with endoscopic disease activity and CRP levels in both UC and CD. Additional studies are required to further define the significance of sRAGE and esRAGE in IBD.

Serum S100A12 may be a useful biomarker of disease activity in adult-onset Still's disease.

OBJECTIVE: S100A12 and soluble receptor for advanced glycation endproducts (sRAGE) have been suggested as biomarkers of disease activity in patients with systemic juvenile idiopathic arthritis. We investigated the clinical significance of these markers in adult-onset Still's disease (AOSD). METHODS: Blood samples were collected from 37 patients with active AOSD and 38 healthy controls (HC). Of the patients with AOSD, followup samples were collected from 19 patients after resolution of disease activity. RESULTS: Serum S100A12 (547.9 ± 148.4 ng/ml) in patients with AOSD was higher than those of HC (272.3 ± 133 ng/ml, p < 0.001). The sRAGE levels of AOSD (514.1 ± 273.6 pg/ml) were lower than those of HC (850.3 ± 405.8 pg/ml, p < 0.001). Serum S100A12 correlated with serum sRAGE (r = -0.228, p = 0.049). Serum S100A12 correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin, and systemic score, whereas sRAGE did not correlate with any disease activity markers. In addition, the level of S100A12 was decreased after disease activity was resolved in followed-up patients with AOSD (505.7 ± 161.3 ng/ml vs 361.3 ± 162.5 ng/ml, p = 0.01). Further, the change of S100A12 was well correlated with that of ESR, CRP, and systemic score. CONCLUSION: S100A12 levels showed strong correlations with known disease activity markers such as ESR, CRP, ferritin, and systemic score. In the followup patients with AOSD, most patients showed decreased S100A12 levels after resolution of disease activity. These results suggest that serum S100A12 can be a reliable clinical marker for monitoring disease activity and treatment response.

Advanced glycation endproducts in food and their effects on health.

Advanced glycation endproducts (AGEs) form by Maillard-reactions after initial binding of aldehydes with amines or amides in heated foods or in living organisms. The mechanisms of formation may include ionic as well as oxidative and radical pathways. The reactions may proceed within proteins to form high-molecular weight (HMW) AGEs or among small molecules to form low-molecular weight (LMW) AGEs. All free amino acids form AGEs, but lysine or arginine side chains dominate AGE formation within proteins. The analysis of AGEs in foods and body fluids is most often performed by ELISA or LC-MS; however, none of the methodologies cover all HMW and LMW AGEs. Most research is, therefore, carried out using 'representative' AGE compounds, most often N(ε)-carboxymethyl-lysine (CML). Only LMW AGEs, including peptide-bound forms, and carbonyls may be absorbed from the gut and contribute to the body burden of AGEs. Some AGEs interact with specific pro- or anti-inflammatory receptors. Most studies on the biological effects of AGEs have been carried out by administering heated foods. The pro-inflammatory and deteriorating biological effects of AGEs in these studies, therefore, need further confirmation. The current review points out several research needs in order to address important questions on AGEs in foods and health.