Serum sRAGE Levels Research Articles

Estimation of Soluble Receptor Advanced Glycation End-Products in Diabetic Patients Type 2 Patients in Najaf City, Iraq

Diabetes is a complex metabolic disruption affecting the glucose level of the human body. Intracellular hyperglycemia promotes mitochondrial reactive oxygen species (ROS) production, ROS directly improve the expression of inflammatory, these inflammations are associated with the level of soluble receptors for advanced glycation end-products (sRAGE) in serum. in this work assessed the level of (sRAGE) and study its potential as a biomarker for diabetes mellitus. The research included 108 Iraqis between the ages of (35-65) years of both sexes. The individuals were divided into two groups, (63) with type 2 diabetes mellitus (T2DM) and (45) control group, most of the tests serum have been measurements by colourimetric methods, and sRAGE levels in serum were evaluated by ELISA Technique. The results of the investigation showed that the sRAGE mean was more elevated compared to the mean of the control group (p < 0.00001). Statistical study of Pearson's correlation illustrated that the sRAGE level is high positively with FBG, and HBA1C (r = 0.878, p < 0.00001), (r = 0.422, P=0.05) respectively. While, negatively correlation with insulin level (r = -0.204, p = 0.010). Furthermore, most the sRAGE level denoted a positive significant correlation with kidney function parameters inclusive urea, creatinine, and ACR, except eGFR was a negative significant (r = 0.422, p = 0.05), (r = 0.501, p = 0.01), (r = 0.435, p = 0.030), (r = -0.539, p = 0.011) respectively. These results support a strong relationship between serum sRAGE level and indicators of hyperglycemia, so we can conclude that it is a great biomarker for predicting of diabetes mellitus. Keywords: ELISA, HOMA, Insulin, sRAGE, Inflamations.

An investigation of the relationship between rheumatological diseases and soluble receptor for advanced glycation end products.

Soluble receptor for advanced glycation end products (sRAGE) is one of the forms of RAGE. It is a trap receptor that has a role in inhibiting pro-inflammatory processes that will occur with the combination of RAGE and its ligands. Our study aims to examine the level of sRAGE in rheumatological inflammatory diseases and its relationship with these diseases. A total of 60 patients with Behçet's disease (BD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and 22 healthy control individuals were included in the study. Comorbidity status, sRAGE levels, disease activity scores, demographic and laboratory data of the patients were recorded. Serum sRAGE levels in these diseases and healthy controls were determined by Enzyme-Linked Immunosorbent Assay (ELISA) kit spectrophotometrically. Serum sRAGE levels in the patient groups were significantly higher when compared to the healthy control group (p < 0.001 for all). On the other hand, when the patient groups were compared with each other in terms of sRAGE levels, there was no significant difference (p > 0.05 for all). The serum sRAGE levels were not correlated with C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and disease activity scores (p > 0.05 for all). Serum sRAGE levels increased in BD and in other inflammatory rheumatological diseases. However, this increase does not directly correlate with inflammatory markers and disease activity scores. These results suggest that serum sRAGE level may not be used as a biomarker for disease activity in BD and in other rheumatological diseases.

Low output syndrome after cardiac surgery is mediated through extra corporal circulation induced RAGE activation

ObjectiveCoronary artery bypass grafting (CABG) is a surgical procedure routinely performed using extracorporeal circulation (ECC). This on‐pump CABG is known to be associated with severe postoperative organ failure including cardiac dysfunction and low cardiac output syndrome. Mechanisms inducing cardiac dysfunction are complex but may include on‐pump CABG induced inflammation due to exposure of the blood to the bypass circuit, potentially increasing serum concentrations of inflammatory mediators. High‐mobility group box 1 (HMGB1) functions as an inflammatory mediator and has been shown to induce cardiovascular dysfunction in sepsis and impair cardiomyocyte contractility in experimental models. However, the impact of HMGB1 on on‐pump CABG induced myocardial dysfunction is not known. Therefore, we tested the hypothesis that on‐pump CABG associated increases in serum concentrations of inflammatory mediators induce cardiomyocyte dysfunction in vitro and investigated potential mechanism including the role of the HMGB1‐RAGE (receptor for advanced glycation end products) axis.ApproachAfter institutional revenue board approval, informed consent, and IACUC approval, serum samples (n = 18) were collected from CABG patients pre, 1, 6, and 24 h after aortic de‐clamping. TNFa, IL‐1b, IL‐6, HMGB1, and sRAGE serum concentrations were analyzed by ELISA. Primary murine cardiomyocytes were incubated with patient serum and single cell contractility was assessed at frequencies between 0.5 and 10Hz using an optical contractility system (IonOptics LLC, Westwood, MA).ResultsIL‐6, HMGB1, and sRAGE serum levels were increased after CABG (Figure 1). In preliminary studies we incubated murine cardiomyocytes with human serum collected from healthy volunteers and determined the highest serum concentrations that did not affect cardiomyocyte contractility. Cardiomyocytes were incubate with human serum and serum collected pre‐surgery had no effects on murine cardiomyocyte contractility. However, primary murine cardiomyocytes incubated with serum collected 1h and 6h after aortic de‐clamping showed a significant decrease in % peak shortening. Pre‐incubation with the RAGE antibody FPS‐ZM1 (Cayman, Hamburg, Germany) prevented the serum induced cardiomyocyte dysfunction (Figure 2).Conclusionon‐pump CABG increased protein serum concentrations of inflammatory cytokines including HMGB1. HMGB1 has been shown to cleave and activate RAGE. sRAGE serum levels have been increased after on‐pump CABG. Deactivating RAGE with the high‐affinity inhibitor FPS‐ZM1 prevented serum induced cardiomyocyte dysfunction, suggesting that the HMGB1‐RAGE axis is mediating on‐pump CABG associated low‐cardiac‐output syndrome.

Increased ACE2, sRAGE, and Immune Activation, but Lowered Calcium and Magnesium in COVID-19.

The characterization of new biomarkers that could help externally validate the diagnosis of COVID-19 and optimize treatments is extremely important. Many studies have established changes in immune-inflammatory and antibody levels, but few studies measured the soluble receptor for the advanced glycation end product (sRAGE), angiotensin-converting enzyme 2 (ACE2), calcium, and magnesium in COVID-19. To evaluate serum advanced glycation end-product receptor (sRAGE) and angiotensin converting enzyme (ACE)2 and peripheral oxygen saturation (SpO2) and chest CT scan abnormalities (CCTA) in COVID-19. sRAGE, ACE2, interleukin (IL)-6, IL-10, C-reactive protein (CRP), calcium, magnesium, and albumin were measured in 60 COVID-19 patients and 30 healthy controls. COVID-19 is characterized by significantly increased IL-6, CRP, IL-10, sRAGE, ACE2, and lowered SpO2, albumin, magnesium, and calcium. COVID-19 with CCTAs showed lower SpO2 and albumin. SpO2 was significantly inversely correlated with IL-6, IL-10, CRP, sRAGE, and ACE2, and positively with albumin, magnesium, and calcium. Neural networks showed that a combination of calcium, IL-6, CRP, and sRAGE yielded an accuracy of 100% in detecting COVID-19 patients, with calcium being the most important predictor followed by IL-6 and CRP. Patients with positive IgG results showed a significant elevation in the serum level of IL-6, sRAGE, and ACE2 compared to the negatively IgG patient subgroup. The results show that immune-inflammatory and RAGE pathways biomarkers may be used as an external validating criterion for the diagnosis of COVID-19. Those pathways coupled with lowered SpO2, calcium, and magnesium are drug targets that may help reduce the consequences of COVID-19.

The Value of Serum HMGB1 and sRAGE in the Diagnosis, Efficacy Monitoring and Prognosis of Newly Diagnosed Multiple Myeloma

To evaluate the value of high mobility group protein B1 (HMGB1) and soluble receptor for advanced glycation end products (sRAGE) in the diagnosis, efficacy monitoring and prognosis of newly diagnosed multiple myeloma (MM) patients. Fifty newly diagnosed MM patients before and after chemotherapy and 50 hematological outpatients from October 2018 to May 2020 were selected. Enzyme linked immunosorbent assay (ELISA) was used to detect the serum HMGB1 and sRAGE levels of the patients. ROC was used to further analyze the efficacy of serum HMGB1 and sRAGE levels on the diagnosis of MM. At the same time, the serum levels of HMGB1 and sRAGE before and after chemotherapy were compared, and their values in the evaluation of curative effect of MM patients were analyzed. According to the mean values of serum HMGB1 and sRAGE, all the patients were divided into different groups, the clinical characteristics and survival status of the patients were compared. Before treatment the serum HMGB1 level of the patients in MM group was higher than that in control group, while sRAGE level was lower (t=11.363,6.127, P<0.001). The AUC of serum HMGB1 and sRAGE in the MM patients was 0.955 and 0.811, respectively. After 3 courses of chemotherapy, HMGB1 level of the patients in CR group was lower than before chemotherapy, while in PD group was higher, as well as sRAGE level of the patients in PR group (P<0.05). There were significant differences in R-ISS stage, HGB, CRP, ESR, CD56, CD117, D13S319 deletion between HMGB1 high expression group and HMGB1 low expression group (χ2=3.920, 6.522, 6.65, 4.16, 3.945, 6.65, 4.16, P<0.05), while there were significant differences in ISS stage, CRP and CD56 between sRAGE low expression group (28 cases) and sRAGE high expression group (22 cases) (χ2=4.565, 4.711, 5.547, P<0.05). Kaplan-Meier survival analysis showed that the patients in HMGB1 low expression group had better survival condition, for PFS Tlow>Thigh (χ2=9.470, P<0.05), and for OS Tlow>Thigh (χ2=7.808, P<0.05); there was no difference in the survival of sRAGE high expression group and low expression group, for PFS Tlow<Thigh (χ2=1.661, P>0.05), and for OS Tlow<Thigh (χ2=2.048, P>0.05). Cox analysis showed that LDH and HMGB1 were the factors affecting the prognosis of the patients, and both of them affected PFS (HR=2.771, 95% CI: 1.002-7.662, P=0.049; HR=6.022, 95% CI: 1.689-21.470, P=0.006), while HMGB1 also affected OS (HR=4.275, 95% CI: 1.183-15.451, P=0.027). The serum HMGB1 and sRAGE have certain auxiliary value for the diagnosis and curative effect monitoring of newly diagnosed MM patients, and serum HMGB1 is expected to be an auxiliary detection index for the prognosis of MM.

Serum sRAGE and sE-selectin levels are useful biomarkers of lung injury and prediction of mortality in calves with perinatal asphyxia

The objective of the present study was to evaluate the biomarkers specific to lung endothelial and epithelial damage in the determination of lung injury and its severity in calves with perinatal asphyxia and to evaluate their prognostic importance among survivors and non-survivor calves. Ten healthy calves and 20 calves with perinatal asphyxia were enrolled in the study. Clinical examination and laboratory analysis were performed at admission. Serum concentrations of soluble advanced glycation end-product receptor (sRAGE), soluble E-selectin (sE-selectin), clara cell secretory protein (CC16), and soluble intercellular adhesion molecule-1 (sICAM-1) were measured to assess lung injury. Venous pH, sO2, HCO3, and BE of calves with perinatal asphyxia were significantly lower than the healthy calves. sRAGE, sE-selectin, pCO2, and lactate were significantly high in calves with asphyxia. ROC analysis showed that sRAGE, sE-selectin, pCO2, lactate, and respiratory rate were higher while HCO3 and BE were lower in the nonsurvivor calves than survivors. In conclusion, serum sRAGE and sE-selectin concentrations highlight the utility of these biomarkers in determining lung injury in calves with asphyxia. Also, pH, pCO2, lactate, HCO3, BE, and respiratory rate along with serum sRAGE and sE-selectin were useful indicators in the prediction of mortality.

Relationship between familial mediterranean fever and soluble receptor for advanced glycation end products

Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory disease worldwide and is characterized by recurrent fever and serositis. Serum soluble receptor for advanced glycation end products (sRAGE) is an isoform of RAGE and sRAGE acts as a trap receptor for ligands and blocks the RAGE–ligand axis. This study aimed to examine the change in sRAGE levels in FMF and to investigate its relationship with inflammation. This study included patients with FMF (n=20) and healthy controls (n=22). Morbidity status, sRAGE levels, demographic and laboratory data were recorded. Pregnant women, individuals aged &lt;18 years, and those with other chronic inflammatory diseases were excluded. Statistical Package for Social Sciences (SPSS) Version 22.0 was used to conduct all statistical analyses and all data are expressed as mean and standard deviation (SD). The serum sRAGE levels were 12.21±6.70 ng/mL and 4.44±2.89 ng/mL in the patient and control groups, respectively. Accordingly, the sRAGE levels of patients with FMF were significantly higher (p&lt;0.001). Comorbidities had no effect on the sRAGE levels of the patient group and no correlation was found between the sRAGE and inflammatory biomarkers. sRAGE levels are elevated in FMF but does not seem to be a promising candidate as a biomarker for FMF.

Circulating soluble receptor of advanced glycation end product is associated with bicuspid aortic aneurysm progression via NF-κB pathway.

OBJECTIVESPatients with bicuspid aortic valve (BAV) have a high risk of aortic dilation and adverse vascular events. Previous studies had reported soluble receptor for advanced glycation end products (sRAGE) to compete with receptor of advanced glycation end products (RAGE) for ligand binding and inhibit the activation of nuclear-factor kappa-B (NF-κB) pathway and matrix metalloproteinases (MMP) transcription. Thus, sRAGE serum levels may contribute to the clinical diagnosis and monitoring of ascending aorta aneurysm in patients with BAV.METHODSTo eliminate the confounding factors, 44 patients with BAV were divided into 3 subgroups according to the diameter of ascending aorta, and 20 patients with tricuspid aortic valve and normal-sized ascending aorta were selected as a control group. Protein levels and gene transcription of several variates were evaluated in the tissue and serum samples from these patients. Human aortic smooth muscle cells were treated with AGE-BSA in gradient concentrations, and changes in phenotype and protein and mRNA levels were detected.RESULTSSerum levels of sRAGE in the 3 BAV groups were obviously higher than those in the tricuspid aortic valve group, although there was negative correlation between the serum sRAGE levels and ascending aortic diameters among patients with BAV. Transcript expression levels of RAGE and NF-κBp65 mRNA were increased in the 3 BAV groups and RAGE/NF-κB pathway was activated with the progression of ascending aortic aneurysm. Abnormal activation of RAGE/NF-κB pathway was observed in AGE-BSA-treated human aortic smooth muscle cells.CONCLUSIONSOur study has shown a trend in serum levels of sRAGE among patients with BAV, and that the cellular and extracellular pathological processes are quite serious even in the normal-sized or slightly dilated aorta. Together, the findings indicated that sRAGE may be used as a biomarker to predict aneurysm expansion rates and the risk of adverse vascular events.

Serum Levels of Soluble Receptor for Advanced Glycation End Products Are Reduced in Euthyroid Children with Newly Diagnosed Hashimoto’s Thyroiditis: A Pilot Study

Objective: No data are available on advanced glycation end products (AGEs) and their soluble receptor (sRAGE) in pediatric patients with Hashimoto’s thyroiditis (HT). The present study was aimed to simultaneously evaluate serum levels of sRAGE, AGEs, and advanced oxidation protein products (AOPPs) and investigate the relationships between these oxidative stress markers and clinical and biochemical parameters of thyroid function in euthyroid children with HT. Design: This is a case-control study carried out in a single university hospital center. Methods: We enrolled 19 newly diagnosed euthyroid HT pediatric patients (3 M, 16 F; median age 12.44 years, range 6.54–15.81 years) and 16 age-, sex-, and BMI-matched healthy controls (5 M, 11 F; median age 12.83 years, range 5.68–15.07 years). None was on levothyroxine treatment. The exclusion criteria were autoimmune, inflammatory, and infection comorbidities. Patients did not differ significantly from controls with regard to lipid or for anthropometric parameters. Results: sRAGE levels were significantly lower in HT patients (median 414.30 pg/mL, range 307.30–850.30 pg/mL) than in controls (561.30, 273.20–1121.60 pg/mL; p = 0.034). No differences emerged between patients and controls with regard to serum AGEs (124.25 AU/g prot, 71.98–186.72 vs. 133.90, 94.06–200.78 AU/g prot, p = 0.707) and AOPPs (1.13 nmol/mL, 0.62–1.83 vs. 1.17, 0.76–1.42 nmol/mL, p = 0.545). Conclusions: sRAGE levels were decreased in euthyroid children/adolescents at the onset of HT, suggesting that autoimmunity per se seems to play an important role in such a reduction of sRAGE, irrespective of any functional alteration. Children and adolescents suffering from HT may exhibit increased susceptibility to oxidative damage, even when in euthyroid status.

Leptin and advanced glycation end products receptor (RAGE) in tuberculosis patients

IntroductionThe pathogenesis of consumptive syndrome of tuberculosis (TB) is largely unknown. Leptin concentrations may be high because of the host’s inflammatory response, contributing to weight loss in patients with TB. The receptor for advanced glycation end products (RAGE) is also associated with weight loss in patients with TB and is related to enhanced mortality. The objective of this study was to evaluate the association between leptin and AGE/RAGE.MethodsCase-control study. Leptin, AGE (carboxymethyl lysine, CML) and soluble RAGE (sRAGE) were measured from blood samples by ELISA.ResultsWe included in the study 34 patients with TB and 34 controls. We found an inverse correlation between serum leptin levels and sRAGE, only in cases (r = -0.609, p < 0.0001). sRAGE levels were lower in patients with TB who died as compared with patients who survive (21.90 ± 4.24 pg/mL vs 66.14 ± 29.49 pg/mL; p = 0.045). Leptin levels were higher in patients with TB who died as compared with patients who survive (14.11 [7.48–14.11] ng/mL vs 3.08 [0.54–6.34] ng/mL; p = 0.028).ConclusionsWe identified lower sRAGE levels and higher leptin levels in patients with TB who died as compared with patients who survive. In addition, an inverse and significant correlation between serum leptin and sRAGE levels was demonstrated. Future studies, with a larger sample size and in different settings, including not only hospitalized patients, are needed to confirm these findings.

Correlation between serum carnitine level and Soluble Receptors for Advance Glycation End Products(sRAGE) in Clomiphene Citrate Resistant- PCOS Women

The most frequently diagnosed condition in women at the age of reproduction is the polycystic ovarian syndrome (PCOS).it could be related to a complex endocrine condition, due to its heterogeneity and uncertainty about its etiology, as the clinical highlights of PCOS incorporate those related to reproductive signs such as decreased frequency of ovulation, irregular menstrual cycles, decreased fertility. Carnitine plays a substantial role in weight loss, glucose tolerance, insulin function and fatty acid metabolism. Thus carnitine plays a crucial role in controlling obesity, insulin resistance, oxidative stress that are associated with PCOS .While, AGEs are a diverse group of reactive molecules that are formed endogenously by non-enzymatic reactions of carbonyl group of carbohydrates with free amino groups of proteins, nucleic acids or lipids. The soluble form of receptors of AGE (sRAGE) could play an important role in management obesity, insulin resistance, hyperandrogenism, oxidative stress which could be related to PCOS. This study was aimed to investigate serum levels of carnitine &amp; soluble receptors for advanced glycation end products (sRAGE) in clomiphene resistant PCOS .Besides assessing the correlation between serum levels of carnitine ,as well as, soluble receptors of AGE with hormonal ( LH, FSH&amp; Testosterone) and metabolic ( serum glucose , serum insulin &amp; HOMA-IR) markers in these patients .&#x0D; The study included thirty women with clomiphene resistant PCOS and thirty apparently healthy women, as a control .In order to measure serum total carnitine and serum soluble receptor of advance glycation end product (sRAGE in PCOS and control groups.&#x0D; The results of our study have shown a decreased serum levels of total carnitine in PCOS group in comparison with control group (48.05 and 59.73 nmol/ml, respectively), but there was no significant elevation in serum levels of sRAGE in patients group as compared with control group .In addition to a significant correlation between serum total carnitine and serum sRAGE levels (r=0.45, P-value=0.03). &#x0D; In conclusion serum total carnitine level was low in Clomiphene resistant-PCOS patients in comparison with control group. Although, sRAGE levels in clomiphene resistant- PCOS patients were not significantly different from the age and BMI-matching controls, but a significant correlation between serum total carnitine and sRAGE was detected.&#x0D; Key words: Poly cystic ovarian syndrome, soluble receptor of advance glycation end products (sRAGE) , SerumTotal Carnitine

MO076REGULATION OF DIFFERENTIAL CELLULAR RESPONSE TO OXIDATIVE STIMULI IN SYSTEMIC LUPUS ERYTHEMATOSUS

Abstract Background and Aims Interaction of reactive oxygen species (ROS) with lipids, proteins, nucleic acids and hydro carbonates promotes acute and chronic tissue damage, mediates immunomodulation and triggers autoimmunity in systemic lupus erythematous (SLE) patients. The aim of the study was to determine the pathophysiological mechanisms of the oxidative stress-related damage and molecular mechanisms to counteract oxidative stimuli in lupus nephritis. Method Our study included 82 volunteers with SLE: 38 SLE volunteers with lupus nephritis (LN group) and 44 SLE volunteers without renal impairment (non-LN group) and a control group of 40 healthy volunteers. LN was diagnosed by histological exam (optic microscopy, electronic microscopy and immunofluorescence). Disease activity was measured by systemic SLE disease activity index (SLEDAI), urinary protein/creatinine ration, anti-dsDNA, C3, C4 and urinary β2-microglobulin. In the present paper, we evaluated in serum: Results We detected high lipid peroxidation, elevated oxidative DNA damage, excess accumulation of reactive carbonylic compounds, important oxidation of carbohydrates, disulphide bonds formation and high nitrotyrosination with statistically significant differences between groups, when compared LN and non-LN groups with control group. When compared LN and non-LN groups, our results showed: 3-Nitrotyrosine levels, the decrease of total and native serum thiols, pentosidine levels, sRAGE level and OGG1 activity correlated with disease activity markers in both LN and non-LN groups, while AGE correlated with disease activity only in non-LN group. Conclusion The cellular response to oxidative stimuli in SLE is concreted in the amplification of oxidative degradation of lipids, proteins, nucleic acid, hydro carbonates and in alteration of endogenous strategies for suppression /modulating oxidative stress. The defective DNA repair mechanism via OGG1 and the reduced regulatory effect of sRAGE in activation AGE-RAGE axis in LN group versus non-LN could explain alteration of renal architecture and development of renal injury.

The amelioration of T2DM rat femoral bone achieved by anti-osteoporosis of caprine CSN1S2 protein through bone morphogenetic protein signaling pathway.

We investigated the potential anti-glycation and anti-osteoporosis properties of Caprine milk CSN1S2 protein on the serum AGEs and sRAGE level, osteogenic factors expressions, femoral bone mesostructure, histomorphometry, and hydroxyapatite crystals changes in T2DM rats. Varying doses of Caprine milk CSN1S2 protein (0, 375, 750, and 1500 mg/kg BW) were used to treat the control and T2DM rats. We measured AGEs and sRAGE level; RUNX2, OSX, BMP2, and Caspase-3 expressions in rats using ELISA and immunohistochemistry, respectively. The mesostructure and histomorphometry of femoral bone was analyzed using SEM Microscope and BoneJ software, then hydroxyapatite crystal size was determined using SEM-XRD. T2DM rats showed a high level of AGEs and a low level of sRAGE, the RUNX2, OSX, and BMP2 expression was down regulated, BV, BV.TV, Tb.Th, Tb.Sp, increased and SMI levels declined, respectively. Vice versa, after administration of the CSN1S2 protein to T2DM rats, improvement in all levels of molecular and cellular markers was achieved. In the CSN1S2 highest dose, AGEs level declined and sRAGE level elevated in T2DM rats. The 375 and 750 mg/kgBW of CSN1S2 protein was able to upregulate the RUNX2, OSX, and BMP2 expression in T2DM rats, thus improving the normalization of osteoclasts and osteoblasts number. The whole dose of CSN1S2 triggered the thickening of trabecular bone wall, granule formation, and normalized the trabecular thickness (Tb.Th) parameter of T2DM rats. The hydroxyapatite crystal size was increased in the highest dose of CSN1S2-treated T2DM rats. This study indicated that CSN1S2 protein had a protective effect against osteoporosis in the T2DM rat bones by means of glycation pathway inhibition, bone histomorphometry and mesostructure improvement via bone morphometric protein signaling.

Biomarker Potential of the Soluble Receptor for Advanced Glycation End Products to Predict Bronchopulmonary Dysplasia in Premature Newborns.

Bronchopulmonary dysplasia (BPD) is a common cause of pulmonary disease in preterm infants. The soluble receptor for advanced glycation end products (sRAGE) is implicated in the development of various pulmonary diseases. The objectives of the current study were to investigate perinatal factors associated with serum sRAGE levels at birth and to establish whether serum sRAGE could be a biomarker for BPD. This retrospective single-center study was conducted at Fukushima Medical University Hospital's Department of Pediatrics Neonatal Intensive Care Unit from April 2014 to September 2020. Mechanically ventilated or oxygenated neonates born at <32 weeks gestational age and healthy control neonates were included in this study. Serum sRAGE levels in cord blood were measured using an enzyme-linked immunosorbent assay. Eighty-four preterm infants born at <32 weeks and 40 healthy infants were identified. The 84 born at <32 weeks were categorized as BPD (n = 34) or non-BPD (n = 50) neonates. The median gestational age (GA) and birthweight (BW) were significantly lower in BPD vs. non-BPD neonates (24.4 vs. 27.6 weeks, P < 0.001, 634 vs. 952 g, P < 0.001, respectively). Serum sRAGE at birth in all 124 preterm and term infants significantly correlated with BW (r = 0.417, P < 0.0001) and GA (r = 0.415, P < 0.0001). Among those born at <32 weeks, median serum sRAGE levels at birth were significantly lower in infants with BPD than without (1,726 vs. 2,797 pg/mL, P = 0.0005). Receiver operating characteristic analysis for sRAGE levels at birth in infants with and without BPD revealed that the area under the curve was 0.724 (95% confidence interval 0.714–0.834, P = 0.001). However, serum RAGE levels were not associated with severity of BPD. Serum sRAGE levels at birth were significantly correlated with BW and GA. Furthermore, serum sRAGE levels at birth could serve as a biomarker for predicting BPD, but not its severity.

Dysregulation of gastrointestinal RAGE (receptor for advanced glycation end products) expression in dogs with chronic inflammatory enteropathy

The pathogenesis of chronic inflammatory enteropathies (CIE) in dogs involves dysregulated innate immune responses. The receptor for advanced glycation end products (RAGE), a pattern recognition receptor, plays a role in chronic inflammation. Abrogation of proinflammatory RAGE signaling by ligand binding (e.g., S100/calgranulins) to soluble RAGE (sRAGE) might also be a novel therapeutic avenue. Serum sRAGE levels are decreased in canine CIE, but gastrointestinal tissue RAGE expression has not been investigated in dogs. Thus, the study aimed to evaluate the gastrointestinal mucosal RAGE expression in dogs with CIE. Further, the potential binding of RAGE to canine S100/calgranulin ligands was investigated.Epithelial RAGE expression was quantified in gastrointestinal (gastric, duodenal, ileal, and colonic) biopsies from 12 dogs with CIE and 9 healthy control dogs using confocal laser scanning microscopy. RAGE expression was compared between both groups of dogs and was tested for an association with patient characteristics, clinical variables, histologic lesion severity, and biomarkers of extra-gastrointestinal disease, systemic or gastrointestinal inflammation, function, or protein loss. Statistical significance was set at p < 0.05. RAGE:S100/calgranulin binding was assessed by immunoassay and electrophoretic techniques.RAGE expression was detected in all 59 biopsies from diseased and healthy control dogs evaluated. Epithelial RAGE expression in the duodenum and colon was significantly higher in dogs with CIE than in healthy controls (p < 0.04). Compared to healthy controls, RAGE expression in dogs with CIE also tended to be higher in the ileum but lower in the stomach. A slight (statistically not significant) shift towards more basal intestinal epithelial RAGE expression was detected in CIE dogs. Serum sRAGE was proportional to epithelial RAGE expression in the duodenum (p < 0.04), and RAGE expression in the colon inversely correlated with biomarkers of protein loss in serum (both p < 0.04). Several histologic morphologic and inflammatory lesion criteria and markers of inflammation (serum C-reactive protein and fecal calprotectin concentration) were related to epithelial RAGE expression in the duodenum, ileum, and/or colon. in vitro canine RAGE:S100A12 binding appeared more pronounced than RAGE:S100A8/A9 binding.This study showed a dysregulation of epithelial RAGE expression along the gastrointestinal tract in dogs with CIE. Compensatory regulations in the sRAGE/RAGE axis are an alternative explanation for these findings. The results suggest that RAGE signaling plays a role in dogs with CIE, but higher anti-inflammatory decoy receptor sRAGE levels paralleled RAGE overexpression. Canine S100/calgranulins were demonstrated to be ligands for RAGE.

DYSREGULATION OF GASTROINTESTINAL RAGE (RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS) EXPRESSION IN A SPONTANEOUS ANIMAL MODEL OF INFLAMMATORY BOWEL DISEASE

The receptor for advanced glycation end products (RAGE), a pattern recognition receptor, plays a role in chronic inflammation. Abrogation of proinflammatory RAGE signaling by ligand binding (e.g., S100/calgranulins) to soluble RAGE decoy (sRAGE) is a promising novel therapeutic avenue for chronic inflammatory diseases, such as inflammatory bowel disease (IBD). However, the opportunities for studying S100/calgranulin-RAGE pathways in conventional animal models are limited due to species differences in the expression and function of S100/calgranulins (e.g., lack of the S100A12 protein in rodents). The pathogenesis of IBD in dogs involves dysregulated innate immune responses, and serum sRAGE levels are decreased in canine IBD and normalize only with clinical remission. Thus, canine IBD may serve as a spontaneous model of IBD for such studies. This study evaluated gastrointestinal mucosal RAGE expression in dogs with IBD and the binding of RAGE to canine S100/calgranulin ligands.

AGE-RAGE Stress and Coronary Artery Disease.

Coronary artery atherosclerosis and atherosclerotic plaque rupture cause coronary artery disease (CAD). Advanced glycation end products (AGE) and its cell receptor RAGE, and soluble receptor (sRAGE) and endogenous secretory RAGE (esRAGE) may be involved in the development of atherosclerosis. AGE and its interaction with RAGE are atherogenic, while sRAGE and esRAGE have antiatherogenic effects. AGE-RAGE stress is a ratio of AGE/sRAGE. A high AGE-RAGE stress results in development and progression of CAD and vice-versa. AGE levels in serum and skin, AGE/sRAGE in patients with CAD, and expression of RAGE in animal model of atherosclerosis were higher, while serum levels of esRAGE were lower in patients with CAD compared with controls. Serum levels of sRAGE in CAD patients were contradictory, increased or decreased. This contradictory data may be due to type of patients used, because the sRAGE levels are elevated in diabetics and end-stage renal disease. AGE/sRAGE ratio is elevated in patients with reduced or elevated levels of serum sRAGE. It is to stress that AGE, RAGE, sRAGE, or esRAGE individually cannot serve as universal biomarker. AGE and sRAGE should be measured simultaneously to assess the AGE-RAGE stress. The treatment of CAD should be targeted at reduction in AGE levels, prevention of AGE formation, degradation of AGE in vivo, suppression of RAGE expression, blockade of RAGE, elevation of sRAGE, and use of antioxidants. In conclusion, AGE-RAGE stress would initiate the development and progression of atherosclerosis. Treatment modalities would prevent, regress, and slow the progression of CAD.

DYSREGULATION OF GASTROINTESTINAL RAGE (RECEPTOR FOR ADVANCED GLYCATION END PRODUCTS) EXPRESSION IN A SPONTANEOUS ANIMAL MODEL OF INFLAMMATORY BOWEL DISEASE

Abstract The receptor for advanced glycation end products (RAGE), a pattern recognition receptor, plays a role in chronic inflammation. Abrogation of proinflammatory RAGE signaling by ligand binding (e.g., S100/calgranulins) to soluble RAGE decoy (sRAGE) is a promising novel therapeutic avenue for chronic inflammatory diseases, such as inflammatory bowel disease (IBD). However, the opportunities for studying S100/calgranulin-RAGE pathways in conventional animal models are limited due to species differences in the expression and function of S100/calgranulins (e.g., lack of the S100A12 protein in rodents). The pathogenesis of IBD in dogs involves dysregulated innate immune responses, and serum sRAGE levels are decreased in canine IBD and normalize only with clinical remission. Thus, canine IBD may serve as a spontaneous model of IBD for such studies. This study evaluated gastrointestinal mucosal RAGE expression in dogs with IBD and the binding of RAGE to canine S100/calgranulin ligands. Epithelial RAGE expression was quantified in endoscopic gastrointestinal (i.e., gastric, duodenal, ileal, and colonic) biopsies from 12 dogs with IBD and 9 healthy control dogs by laser scanning microscopy. RAGE expression was compared between both groups of dogs and was tested for an association with patient characteristics, clinical variables, histologic lesion severity, and biomarkers of extra-gastrointestinal disease, systemic or gastrointestinal inflammation, function, or protein loss. Statistical significance (non-parametric tests) was set at p&amp;lt;0.05. RAGE:S100/calgranulin binding was investigated by immunoassay and electrophoretic techniques. RAGE expression was detected in all biopsies evaluated. Epithelial RAGE expression in the duodenum and colon was significantly higher in dogs with IBD than in healthy controls (p&amp;lt;0.04), with a trend for overexpression in the ileum, underexpression in the stomach, and a general shift towards more basal than apical epithelial RAGE expression. Serum sRAGE was correlated with duodenal RAGE expression. Several histologic (structural and inflammatory) lesion criteria and markers of gastrointestinal inflammation or protein loss were related to segmental RAGE expression (all p&amp;lt;0.04). In vitro, canine RAGE:S100A12 binding appeared more pronounced than RAGE:S100A8/A9 binding. Alterations in the epithelial expression of RAGE along the gastrointestinal tract provide evidence for a dysregulated sRAGE/RAGE axis as a characteristic of canine IBD. S100/calgranulin (S100A8/A9 and S100A12) proteins are ligands for RAGE in dogs. The role of RAGE signaling in IBD pathogenesis and its potential for developing novel targeted therapeutics warrants further exploration. Furthermore, canine IBD is a suitable spontaneous model for human IBD that may benefit further research into pathway-specific IBD treatment options that target the sRAGE/RAGE axis.

Significance of combined application of biomarkers in the diagnosis and prognosis assessment of patients with acute respiratory distress syndrome

To explore the clinical significance of the combined detection of Clara cell secretory protein 16 (CC16) and soluble receptor for advanced glycation end product (sRAGE) in the diagnosis and prognosis of acute respiratory distress syndrome (ARDS). 100 ARDS patients admitted to the intensive care unit (ICU) of Chu Hsien-I Memorial Hospital of Tianjin Medical University from July 2019 to September 2020 were enrolled as the ARDS group, and 100 non-ARDS patients admitted to the ICU during the same period were enrolled as the control group. The general information, vital signs, blood gas analysis, serum CC16 and sRAGE levels, duration of mechanical ventilation, length of ICU stay and prognosis during hospitalization were collected. The receiver operating characteristic (ROC) curve was drawn and the area under ROC curve (AUC) was calculated to evaluate the clinical value of CC16 and sRAGE lonely or combination in the diagnosis and prognosis of ARDS. The duration of mechanical ventilation in the ARDS group was significantly longer than that in the non-ARDS group (days: 15.44±3.04 vs. 12.61±3.73, P < 0.01), and the hospitalization mortality was higher (38.0% vs. 9.0%, P < 0.01), but there was no significant difference in gender, age, body mass index (BMI), acute physiology and chronic health evaluation II (APACHE II) score or the length of ICU stay between the two groups. There were 62 ARDS patients survived and 38 ARDS patients died during hospitalization. The APACHE II score of the death group was significantly higher than that of the survival group (23.55±2.83 vs. 19.40±4.10, P < 0.01), but there was no significant difference in age, BMI, oxygenation index, mean arterial pressure, duration of mechanical ventilation or the length of ICU stay between the two groups. The serum levels of CC16 and sRAGE in the ARDS group were significantly higher than those in the non-ARDS group [CC16 (mg/L): 38.78±14.70 vs. 21.87±2.45, sRAGE (pg/L): 2 470.95±288.70 vs. 2 013.22±131.15, both P < 0.01]; and the serum levels of CC16 and sRAGE of ARDS patients in the death group were significantly higher than those in the survival group [CC16 (mg/L): 42.02±10.81 vs. 30.52±9.47, sRAGE (pg/L): 2 638.34±324.07 vs. 2 279.91±163.70, both P < 0.01]. ROC curve showed that the AUC of CC16 and sRAGE in the diagnosis of ARDS alone were 0.859 [95% confidence interval (95%CI) was 0.808-0.911] and 0.821 (95%CI was 0.762-0.879), and the best cut-off values were 25.76 mg/L and 2 203.00 pg/L, respectively; the AUC of combined detection of CC16 and sRAGE was 0.932 (95%CI was 0.900-0.965) with the sensitivity of 89.0% and the specificity of 87.6%. The AUC of CC16 and sRAGE in predicting the death of patients with ARDS during hospitalization were 0.747 (95%CI was 0.651-0.843) and 0.819 (95%CI was 0.737-0.902), and the best cut-off values were 32.95 mg/L and 2 554.50 pg/L, respectively; the AUC of combined detection of CC16 and sRAGE was 0.900 (95%CI was 0.828-0.972) with the sensitivity of 88.7% and the specificity of 84.5%. Serum CC16 and sRAGE have clinical value for the diagnosis and prognosis of ARDS. The combined detection of them is superior to individual detection for early prediction of ARDS and prognosis.

Association analysis of 374T/A (rs1800624) receptor for advanced glycation end-products (RAGE) gene polymorphism with diabetic retinopathy in Pakistani patients.

Objectives:to determine the relationship of 374T/A (rs1800624) polymorphism in the gene encoding RAGE with Type-2 diabetes mellitus (T2DM), diabetic retinopathy (DR) and serum soluble RAGE (sRAGE) level in Pakistani patients.Methods:A case-control study, conducted from January 2017 to December 2018, involving 150 healthy controls (HC), 150 T2DM patients with no retinopathy (DNR) and 150 DR patients diagnosed by coloured fundus photography. Tetra-primer amplification refractory mutation system – polymerase chain reaction (T-ARMS-PCR) was used for genotyping. Serum sRAGE levels were measured by enzyme-linked immunosorbent assays (ELIZA).Results:The frequency of TT, TA and AA genotypes of rs1800624 polymorphism were: 92.7%, 6%, 1.3% in HC, 80%, 17.3%, 2.7% in DNR and 76.7%, 19.3%, 4.3% in DR groups. Heterozygous TA genotype and mutant A allele showed significant association with diabetes and DR vs HC. In dominant model, mutant allele showed significant association with DNR and DR vs HC. No significant association of rs1800624 was detected with DR and its sub-groups, non-proliferative DR (NPDR) and proliferative DR (PDR) vs DNR. Dividing NPDR into mild, moderate and severe, heterozygous TA genotype showed significant association with moderate and severe NPDR vs DNR. In DNR and DR groups, TA genotype was significantly associated with raised sRAGE.Conclusion:rs1800624 RAGE gene polymorphism might be a risk factor for T2DM and NPDR in Pakistani patients. Raised sRAGE levels have a positive correlation with PDR and are associated with heterozygosity of rs1800624 polymorphism in DNR and DR groups