Serum Advanced Glycation End Products Research Articles

Serum Advanced Glycation End Products and Their Soluble Receptor as New Biomarkers in Systemic Lupus Erythematosus.

It has been postulated that advanced glycation end products (AGEs) and their soluble receptor (sRAGE) may play a relevant role as inducers in the chronic inflammatory pathway in various conditions, among them, in immune-mediated diseases such as systemic lupus erythematosus (SLE). However, previous studies show conflicting results about their association with SLE characteristics and their usefulness as disease biomarkers. We aimed to study the association of specific serum AGEs (pentosidine, Nξ-(carboxymethyl)lysine (CML), Nξ-(carboxyethyl)lysine (CEL)), sRAGE levels and AGEs (specific serum AGEs and skin AGEs) to sRAGE ratios with various disease parameters, in order to clarify their potential as new biomarkers in SLE and to study their relationship with cardiovascular disease (CVD). To this aim, serum pentosidine, CML, CEL and sRAGE were measured via ELISA, and skin AGEs levels were measured by skin autofluorescence. Correlations of pentosidine levels with demographic and clinical data, indexes of activity, accrual damage and patient-reported outcomes were analyzed through multiple linear regression models, while correlations of the rest of the AGEs, sRAGE and AGE to sRAGE ratios (non-normal) were analyzed using both an OLS regression model and a GML. All of the analyses were adjusted for confounders. A total of 119 SLE patients were recruited. Serum AGEs and sRAGEs were significantly associated with SLE activity indexes and/or demographic or disease characteristics: pentosidine with pulmonary manifestations; CML with anti-dsDNA antibodies, IL-6, disease duration and non-Caucasian ethnicities; CEL with anti-dsDNA antibodies, IL-6 and accumulated number of manifestations; and sRAGE with male gender, photosensitivity and being on specific immunosuppressants. These results suggest that the AGE-sRAGE axis may serve as a novel biomarker for managing and prognosticating this disease. Its correlation with certain antibodies, demographics and disease presentations may indicate a distinct clinical phenotype associated with varying levels of AGEs and/or sRAGE. The significance of specific AGE/sRAGE ratios, introduced in this study for the first time, warrants additional investigation in forthcoming research. Our study did not confirm the link between serum AGEs and CVD, which merits further exploration through studies designed for this specific purpose.

Evaluation of Serum Advanced Glycation End Product Levels and Microvascular Complications in Children and Adolescents with Type 1 Diabetes Mellitus.

Advanced glycation end products (AGEs) are irreversible macromolecules formed by nonenzymatic reactions due to chronic hyperglycemia. The aim of this study was to assess the relationship between AGEs and the microvascular complications of children and adolescents with type 1 diabetes mellitus (T1DM). Twenty-six T1DM patients with microvascular complications and 58 complication-naive patients who were similar regarding age, sex, and pubertal status enrolled in the study. Anthropometric, biochemical, ophthalmologic, and neurologic variables were compared with serum AGEs levels by the fluorescence method. There was no significant difference observed between the patients with complications and those without complications in terms of serum levels of AGEs and other biochemical parameters. However, the duration of T1DM and urine microalbumin-creatinine ratio (uACR) were significantly higher in the complication-positive group (P < .001). Serum levels of AGEs were found to be similar when retinopathy, peripheral, and optic neuropathy were separately compared with the complication-naive group (P > .05). However, patients with nephropathy had significantly higher serum levels of AGEs than patients without complications (P = .023). In addition, there was a significant positive correlation between serum AGEs levels and uACR (P = .042) but not other parameters (P > .05). This study is the first to evaluate the association between serum AGEs levels and microvascular complications in children and adolescents with T1DM. Our study highlights that serum AGEs levels are significantly correlated with nephropathy but not with retinopathy and neuropathy. Further long-term studies with a larger sample size are required to establish a better relationship between diabetic complications and AGEs. Cite this article as: Kırkgöz T, Acar S, Küme T, et al. Evaluation of serum advanced glycation end product levels and microvascular complications in children and adolescents with type 1 diabetes mellitus. Turk Arch Pediatr. 2024;59(1):31-37.

Relationship between serum AGE precursor levels, oxidative stress, and quality of life in patients receiving hemodialysis

Introduction/Objective. The aim of this study was to determine the relationship between serum advanced glycation end product (AGE) precursors, oxidative stress levels, and quality of life in hemodialysis patients. Methods. A descriptive form and the Kidney Disease Quality of Life Form (KDQOL-36) were used in the study. Serum levels of AGE precursors [methylglyoxal (MGO) and glyoxal (GO)] and oxidative stress [malondialdehyde (MDA)] were determined in blood samples taken from the patients. Results. The KDQOL-36 subscale scores were 71.65 ? 17.76 for the symptoms/problems list, 66.35 ? 19.06 for the effect of kidney disease, 40.6 ? 24.01 for the kidney disease burden, 41.6 ? 9.83 SF-12 for physical health, and 37.83 ? 9.69 for SF-12 mental health. The serum levels were 3.96 ? 1.01 ?mol/L for MDA, 1029.87 ? 314.43 ng/mL for GO, and 115.2 ? 75.54 ng/mL for MGO. A positive and significant correlation was detected between serum MGO and GO (r = .285, p &lt; 0.01) and MDA (r = 0.284, p &lt; 0.01). A positive correlation was noted between serum MDA and GO (r = 1,000, p &lt; 0.05) and a negative correlation with kidney disease burden (r = -0.205, p &lt; 0.05). A negative and significant correlation was detected between GO and kidney disease burden (r = -0.204, p &lt; 0.05). Conclusion. Serum MGO, GO, and MDA levels were high in patients undergoing hemodialysis. High serum MDA levels are associated with high serum GO and MGO levels. High serum levels of MDA and GO had a negative impact on the quality of life of hemodialysis patients.

An Oversampling Technique for Handling Imbalanced Data in Patients with Metabolic Syndrome and Periodontitis

Objectives: Periodontitis has been suggested to be associated with several systemic diseases and conditions including obesity, metabolic syndrome, diabetes, chronic renal disease, respiratory disorders, and cardiovascular diseases. Metabolic syndrome (MetS) is a collection of impairment and is a risk factor for type 2 diabetes and cardiovascular disease. Our study is aimed to handle MetS unbalanced data using the synthetic minority over-sampling technique (SMOTE) to increase accuracy and reliability.&#x0D; Materials and Methods: Six metabolic syndrome patients and 26 systemically healthy subjects with periodontitis were recruited in this study. Clinical parameters (Plaque index (PI), gingival index (GI), probing pocket depth (PPD), clinical attachment loss (CAL), and bleeding on probing (BOP)) were obtained, smoking status and body-mass index (BMI), systemic diseases, fasting glucose levels, hemoglobin A1c (HbA1c) levels and serum advanced glycation end-products (AGE) levels were recorded by one examiner. First, the data was pre-processed by removing missing values, outliers and normalizing the data. Then, SMOTE technique was used to oversample the minority class. SMOTE works by creating synthetic data points that are similar to the existing minority class instances. The experimental dataset included numerous machine learning algorithms and assessed accuracy using both pre- and post-oversampling methods.&#x0D; Results: Our findings suggest that by increasing the sample size of a study, researchers can gain more accurate and reliable results. This is especially important when studying a population with a lower sample size, as the results may be skewed.&#x0D; Conclusion: SMOTE may result in over fitting on numerous copies of minority class samples.

Assessment of Visual Evoked Potential to Detect Visual Pathway Dysfunction in Gestational Diabetes Mellitus: A Longitudinal Case-Control Study With Postpartum Follow-up.

The increasing prevalence of gestational diabetes mellitus (GDM) during pregnancy has opened the opportunity to study its short- and long-term effects on maternal ophthalmic health. Visual evoked potential (VEP) is a non-invasive electrophysiological test that detects functional disturbances along the visual pathway before the physical signs of diabetic retinopathy (DR) can set in.This longitudinal study is aimed at the assessment of changes in VEP in GDM during different stages of pregnancy and 6-12 weeks after parturition by comparing it with normoglycemic controls. Diagnosed cases of GDM were recruited along with normoglycemic controls at 24-28 weeks of gestation.Each participant was required to attend two follow-up appointments at 32-38 weeks of gestation and 6-12 weeks after parturition. A blood sample was taken in a fasting state to record biochemical parameters. VEP was recorded using Neuropack S1 MEB-9400 electrodiagnostic equipment (Nihon Kohden, Tokyo, Japan) in a dark room by providing pattern reversal stimuli to each eye. A total of 29 participants (15 in the control group and 14 in the GDM group) completed the entire study procedure.The observed mean P100 latency of both eyes in the GDM group was recorded longer as compared to that in the control group at baseline and during late pregnancy. Although the mean P100 latency saw a significant decline in postpartum visits as compared to that in late pregnancy, the values were higher than in the control group. P100 latency at baseline correlated significantly to serum advanced glycated end products' (AGE'S) levels in the GDM group. Our study findings reflect that the diagnosis of GDM is associated with significant changes in VEP during and after pregnancy as compared to that of healthy pregnant women.

Unveiling the molecular basis of inflamm-aging induced by advanced glycation end products (AGEs)-modified human serum albumin (AGE-HSA) in patients with different immune-mediated diseases

Increased serum advanced glycation end products (AGEs) are commonly found in the patients with Diabetes mellitus (DM), aging-related diseases, and immune-mediated diseases. These diseases are notorious for vasculopathy, immune dysfunctions, and low-grade inflammation mimicking inflamm-aging. However, the molecular basis of inflamm-aging related to AGEs remains elucidation. In this study, we incubated human serum albumin (HSA) and glucose at 37 °C in 5% CO2 incubator for 0–180 days to generate AGE-HSA. We found the mixture gradually changing the color from transparancy to brown color and increased molecular weight during incubation. The pH value also gradually decreased from 7.2 to 5.4 irrelevant to ionic charge or [Ca2+] concentration, but dependent on gradual glycation of the alkaline amino acids, lysine and arginine. Functionally, 40 μg/mL of AGE-HSA decreased IL-2 production from human Jurkat T cell line via suppressing p-STAT3, p-STAT4, and p-STAT6 with an increased tendency of senescence-associated β-galactosidase (SA-βgal) expression but irrelevant to change of Th1/Th2/Treg subpopulations. In contrast, AGE-HSA enhanced CC motif chemokine ligand 5 (CCL-5), IL-8, macrophage migration inhibitor factor (MIF), and interleukin 1 receptor antagonist (IL-1Ra) but suppressed SA-βgal expression by human macrophage-like THP-1 cells. Interestingly, AGE-HSA abrogated the HSA-induced soluble intercellular adhesion molecules 1 (sICAM-1), sE-selectin and endothelin release from human coronary artery endothelial cells (HCAEC) and enhanced SA-βgal expression. The accelerated and increased HSA glycations by individual inflammation-related cytokine such as IL-2, IL-6, IL-17, TGF-β, or TNF-α in the in vitro study reflect increased serum AGE levels in patients with immune-mediated diseases. In conclusion, AGE-HSA can exert immunosuppresive, inflammatory and vasculopathic effects mimicking inflamm-aging in these patients.

Correlation between serum advanced glycation end products and dietary intake of advanced glycation end products estimated from home cooking and food frequency questionnaires

Background & aimsTo our knowledge the association between dietary advanced glycation end-products (dAGEs) and cardiometabolic disease is limited. Our aim was to examine the association between dAGEs and serum concentration of carboxymethyl-lysine (CML) or soluble receptor advanced glycation end-products (sRAGEs), and to assess the difference on dAGEs and circulating AGEs according to lifestyle and biochemical measures. Methods and results52 overweight or obese adults diagnosed with type 2 diabetes were included in this cross-sectional analysis. dAGEs were estimated from a Food Frequency Questionnaire (FFQ) or from a FFQ + Home Cooking Frequency Questionnaire (HCFQ). Serum concentrations of CML and sRAGEs were measured by ELISA. Correlation tests were used to analyze the association between dAGEs derived from the FFQ or FFQ + HCFQ and concentrations of CML or sRAGEs. Demographic characteristics, lifestyle factors and biochemical measures were analyzed according to sRAGEs and dAGEs using student t-test and ANCOVA.A significant inverse association was found between serum sRAGEs and dAGEs estimated using the FFQ + HCFQ (r = −0.36, p = 0.010), whereas no association was found for dAGEs derived from the FFQ alone. No association was observed between CML and dAGEs. dAGEs intake estimated from the FFQ + HCFQ was significantly higher among younger and male participants, and in those with higher BMI, higher Hb1Ac levels, longer time with type 2 diabetes, lower adherence to Mediterranean diet, and higher use of culinary techniques that generate more AGEs (all p values p < 0.05). ConclusionsThese results show knowledge on culinary techniques is relevant to derive the association between dAGEs intake and cardiometabolic risk factors.

Are dietary and serum advanced glycation end-products related to inflammation and oxidation biomarkers in breast cancer patients: a follow-up study.

This study is aimed at evaluating the relationship between dietary and serum advanced glycation end-products (AGEs) with serum inflammatory and oxidative stress biomarkers in breast cancer (BC). A sample of BC patients was followed for 12 months (March 2020-January 2022). Three-day food consumption record and serum samples were taken before surgery (T1), before chemotherapy (T2), at the 6th month of chemotherapy (T3), and at the 12th month of chemotherapy (T4). Dietary AGE intake was represented by carboxymethyl lysine (dCML). Serum levels of CML, inflammation, and oxidation biomarkers were determined with biochemical blood tests. The results were compared according to human epidermal growth factor receptor-2 (HER2) status. Thirty-two women with BC and 32 age and body mass index-matched healthy women participated. No significant correlation was found between dCML and serum CML, inflammatory or oxidative stress biomarkers at T1, T2, and T4. A weak positive correlation was demonstrated between dCML and serum malondialdehyde levels (rho=0.355, p=0.046) at T3. The serum CML, inflammation, and oxidation biomarker levels of the HER2- group were significantly higher than those of the HER2+ group at T1. This study suggests that there is limited correlation between dCML and serum inflammation and oxidative stress biomarkers in BC patients. Inflammation and oxidative biomarker levels appear to decline with treatment although dietary and serum AGE levels show not a corresponding significant decline. The HER2- subtype appears to be associated with higher dietary and serum AGEs and higher inflammatory and oxidative stress biomarkers.

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

BackgroundTo 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).MethodsThis 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.ResultsA 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.ConclusionsSerum 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.

Berberine Suppresses Gestational Diabetes in Streptozotocin-induced Diabetes Mellitus Rats by Suppression of Inflammatory Mediators

Abstract: Background: Gestational diabetes mellitus (GDM) is a serious health condition witnessed among females who experience insulin resistance and glucose intolerance with the onset of pregnancy. Multiple risk factors prevail both to the gestating mother and the growing fetus at the time of pregnancy which may prolong even postpartum. Aim: Berberine, a natural plant extract known for its anti-inflammatory and potent antidiabetic activity was used to clinically suppress the risk factors involved in Gestational diabetes mellitus. Materials and Methods: Female Wistar rats were used as the models for this study. Streptozotocin was administered to induce diabetes in the female rat model. Berberine was administered to the test animals and monitored with regular analysis of body weight, fetal-placental weight and index, Foetal Blood Glucose (FBG), Serum advanced glycation end products (AGEs), and antioxidant enzyme concentrations. Biochemical parameters, lipids, and pro-inflammatory cytokine levels were assayed to study the influence of Berberine. Results: Upon investigating, it was observed that Berberine produced remarkable activity in suppressing glucose intolerance and insulin resistance by targeting multiple criteria, including inflammatory mediators enlisted above. Conclusion: From this study, it is evident that Berberine can be used as a therapeutic agent to treat gestational diabetes. Keywords: Gestational diabetes mellitus, Inflammation, Berberine, Antioxidant, Antidiabetic.

Abstract PD12-09: PD12-09 Serum Advanced Glycation End-Products are Associated with Breast Cancer Prognosis

Abstract Background: Tumor characteristics such as grade, stage and receptor status are associated with breast cancer (BC) prognosis. Less is known about modifiable factors and BC prognosis. Advanced glycation end-products (AGEs) are reactive metabolites produced as a by-product of sugar metabolism, generated in conditions of increased oxidative stress. AGEs irreversibly accumulate in our tissues over time with pathogenic effects on genetic fidelity, protein function, cell signaling pathways, and chronic inflammatory diseases. The total body AGE pool is composed of endogenous AGEs and exogenous AGEs (consumed mainly through processed foods and those cooked at high temperatures). Serum AGE (sAGE) levels, a reflection of total body AGE, are higher in people with poor diet quality, lower levels of physical activity, and in women with BC compared to healthy controls. AGEs promote growth, migration and invasion in BC cell lines and activate prognostic inflammatory mediators such as interleukin-6 and C-reactive protein. Dietary AGEs have been associated with increased BC risk and increased mortality after BC diagnosis whereas lifestyle interventions can lower dietary and sAGE levels. The impact of sAGE levels, a better estimate of total body AGE than dietary AGE, on BC prognosis has not been previously evaluated. Methods: The Women’s Healthy Eating and Living (WHEL) study randomized 3088 BC patients stage I-III who completed their primary therapy to a high-vegetable, low-fat diet or control and followed for a median of 7.3 years. Main outcomes were invasive BC events (recurrence or new primary N=518), death due to BC (N=262) and deaths from any cause (N=315). sAGE was measured as the AGE metabolite carboxymethyllysine (ug/ml) from WHEL fasting blood specimens at study entry. sAGE was logged and corrected for plate batch effect via linear regression and analyzed in continuous scale and in quintiles. The Kaplan-Meier method and Cox regression model were performed for risk impact of sAGE on overall survival (OS), recurrence free survival (RFS), breast cancer specific survival (BCSS) and distant metastasis free survival (DMFS). We additionally adjusted in Cox models for potential confounding variables (age, race, BMI, smoking, alcohol use, physical activity, tumor characteristics). Results: 2564 participants had sAGE available. After excluding samples for excessive variabilities, 2315 samples were analyzed. Raw corrected sAGE ranged from 0.0-48.15 ug/ml (median 7.39); logged and corrected range -5.04-1.67. sAGE was positively associated with BMI (p&amp;lt;.0001, rs 0.10) and negatively associated with physical activity (p&amp;lt; .001, rs.-0.06). sAGE was not significantly associated with tumor stage, grade, receptor status, or race or menopausal status. Comparing the highest quintile (logged and corrected range=0.33~1.67) to the lowest quintile (range=-5.04~-0.30), sAGE was significantly associated with all survival outcomes (Table 1). As a continuous variable, AGE was associated with worse OS (HR 1.38, P=.031, β .32) and RFS (HR 1.29, P=.028, β .25) with a trend towards worse DMFS (HR 1.28, P=.067, β .25) and BCSS (HR 1.36, P=.06, β .31). Conclusions: Higher sAGEs are associated with worse survival outcomes in BC and may represent a novel, lifestyle-linked, modifiable prognostic biomarker in BC. Interventions aimed at lowering sAGE levels should be tested for their impact on known prognostic biomarkers as well as clinical outcomes. Individualized cancer-specific lifestyle recommendations are a crucial but currently lacking component of personalized cancer medicine. Citation Format: Lindsay L. Peterson, Yu Tao, Jingqin Luo, Graham A. Colditz, Yikyung Park, Jennifer A. Ligibel, David Turner. PD12-09 Serum Advanced Glycation End-Products are Associated with Breast Cancer Prognosis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD12-09.

Analysis of Serum Advanced Glycation Endproducts Reveals Methylglyoxal-Derived Advanced Glycation MG-H1 Free Adduct Is a Risk Marker in Non-Diabetic and Diabetic Chronic Kidney Disease

Accumulation of advanced glycation endproducts (AGEs) is linked to decline in renal function, particularly in patients with diabetes. Major forms of AGEs in serum are protein-bound AGEs and AGE free adducts. In this study, we assessed levels of AGEs in subjects with and without diabetes, with normal renal function and stages 2 to 4 chronic kidney disease (CKD), to identify which AGE has the greatest progressive change with decline in renal function and change in diabetes. We performed a cross-sectional study of patients with stages 2-4 CKD, with and without diabetes, and healthy controls (n = 135). Nine protein-bound and free adduct AGEs were quantified in serum. Most protein-bound AGEs increased moderately through stages 2-4 CKD whereas AGE free adducts increased markedly. Methylglyoxal-derived hydroimidazolone MG-H1 free adduct was the AGE most responsive to CKD status, increasing 8-fold and 30-fold in stage 4 CKD in patients without and with diabetes, respectively. MG-H1 Glomerular filtration flux was increased 5-fold in diabetes, likely reflecting increased methylglyoxal glycation status. We conclude that serum MG-H1 free adduct concentration was strongly related to stage of CKD and increased in diabetes status. Serum MG-H1 free adduct is a candidate AGE risk marker of non-diabetic and diabetic CKD.

Ultra-lung-protective ventilation and biotrauma in severe ARDS patients on veno-venous extracorporeal membrane oxygenation: a randomized controlled study

BackgroundUltra-lung-protective ventilation may be useful during veno-venous extracorporeal membrane oxygenation (vv-ECMO) for severe acute respiratory distress syndrome (ARDS) to minimize ventilator-induced lung injury and to facilitate lung recovery. The objective was to compare pulmonary and systemic biotrauma evaluated by numerous biomarkers of inflammation, epithelial, endothelial injuries, and lung repair according to two ventilator strategies on vv-ECMO.MethodsThis is a prospective randomized controlled study. Patients were randomized to receive during 48 h either ultra-lung-protective ventilation combining very low tidal volume (1–2 mL/kg of predicted body weight), low respiratory rate (5–10 cycles per minute), positive expiratory transpulmonary pressure, and 16 h of prone position or lung-protective-ventilation which followed the ECMO arm of the EOLIA trial (control group).ResultsThe primary outcome was the alveolar concentrations of interleukin-1-beta, interleukin-6, interleukin-8, surfactant protein D, and blood concentrations of serum advanced glycation end products and angiopoietin-2 48 h after randomization. Enrollment was stopped for futility after the inclusion of 39 patients. Tidal volume, respiratory rate, minute ventilation, plateau pressure, and mechanical power were significantly lower in the ultra-lung-protective group. None of the concentrations of the pre-specified biomarkers differed between the two groups 48 h after randomization. However, a trend to higher 60-day mortality was observed in the ultra-lung-protective group compared to the control group (45 vs 17%, p = 0.06).ConclusionsDespite a significant reduction in the mechanical power, ultra-lung-protective ventilation during 48 h did not reduce biotrauma in patients with vv-ECMO-supported ARDS. The impact of this ventilation strategy on clinical outcomes warrants further investigation.Trial registration Clinical trial registered with www.clinicaltrials.gov (NCT03918603). Registered 17 April 2019.

Skin and Serum Advanced Glycation End Products in Adults With Type 1 Diabetes

Skin advanced glycation end products (AGEs) may better correlate with diabetes control, duration and complications than serum AGEs, as they reflect long-term tissue accumulation. We evaluated whether, in individuals with type 1 diabetes (T1D): 1). skin AGEs correlate with serum AGEs; 2). AGEs correlate with HbA1c and diabetes duration; 3). AGEs differ in those with microvascular complications from those without.

Impact of elevated serum advanced glycation end products and exercise on intact and injured murine tendons

ABSTRACT Overview: Delayed tendon healing is a significant clinical challenge for those with diabetes. We explored the role of advanced glycation end-products (AGEs), a protein modification present at elevated levels in serum of individuals with diabetes, on injured and intact tendons using a mouse model. Cell proliferation following tissue injury is a vital component of healing. Based on our previous work demonstrating that AGEs limit cell proliferation, we proposed that AGEs are responsible for the delayed healing process commonly observed in diabetic patients. Further, in pursuit of interventional strategies, we suggested that moderate treadmill exercise may support a healing environment in the presence of AGEs as exercise has been shown to stimulate cell proliferation in tendon tissue. Materials and Methods: Mice began receiving daily intraperitoneal injections of bovine serum albumin (BSA)-Control or AGE-BSA injections (200μg/ml) at 16-weeks of age. A tendon injury was created in the central third of both patellar tendons. Animals assigned to an exercise group began a moderate treadmill protocol one week following injury. The intact Achilles tendon and soleus muscle were also evaluated to assess the effect of BSA and AGE-BSA on un-injured muscle and tendon. Results: We demonstrate that our injection dosing and schedule lead to an increase in serum AGEs. Our findings imply that AGEs indeed modulate gene expression following a patellar tendon injury and have modest effects on gene expression in intact muscle and tendon. Conclusions: While additional biomechanical analysis is warranted, these data suggest that elevated serum AGEs in persons with diabetes may impact tendon health.

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

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

Evaluation of paraoxonase activity and association with serum advanced glycation end products as reliable markers of oxidative stress in Hashimoto's thyroiditis.

Oxidative stress has been implicated in the pathogenesis of autoimmune thyroiditis, also referred to as Hashimoto's thyroiditis (HT), and several biomarkers have been measured to evaluate the impact and clinical relevance of oxidative stress in this setting. Recently, advanced glycation end products (AGEs) have been proposed as reliable markers of oxidative stress in HT. In the present study, we investigated the relationship of AGEs with antioxidant paraoxonase (PON-1) activity as potential combined markers of oxidative stress. We measured the levels of AGEs, and advanced oxidation protein products (AOPPs) and PON-1 activity by spectrophotometric methods, in the serum of 40 HT patients (36 F; mean age 35.4 ± 11.5 yr) and 38 age-, sex- and BMI-matched healthy controls. All subjects were euthyroid at recruitment and none was on LT-4 therapy. Serum levels of AGEs were significantly higher (median 378 vs 290 AU/g protein; P<0.001), while PON1 activity was significantly lower (median 165 vs 201 U/L; P<0.05) in HT patients compared to controls: the two parameters were inversely correlated (P<0.01), clearly indicating a pro-oxidant imbalance in HT patients. At stepwise regression analysis, TPOAb positivity was an independent predictor of both PON-1 activity (P = 0.002) and AGEs levels (P = 0.000). Increased formation and accumulation of AGEs contribute to enhanced oxidative stress, along with a decrease in PON-1 activity in HT. As a consequence, AGEs levels and alteration in PON 1 may serve as useful markers for monitoring the levels of oxidative stress in this disorder.

126 Antioxidant-Containing Kibble Supplemented to Adult Cats Elicited Improvements in Antioxidant Outcomes and C-Reactive Protein

Abstract The objective of this study was to evaluate oxidative health biomarkers in healthy male and female adult cats (n=30; 10 male and 20 female, avg age and BW + SD 3.34 ± 3.19 years; 3.85 ± 1.07 kg) fed an adult maintenance diet (Blue Buffalo Healthy Living Adult Chicken and Brown Rice) without (control diet) and supplemented with an antioxidant-containing kibble (test diet; proprietary blend containing blueberries, cranberries, and other antioxidant-containing ingredients). Both diets analyzed as 35.9% crude protein, 19.8% fat, 2.1% crude fiber, 6.4% moisture, 28.6% carbohydrate as-is. We hypothesized that test feeding would reduce serum pro-oxidative biomarkers, compared with control feeding. The study protocol was first approved by the Institutional Animal Care and Use Committee. All cats were fed a base kennel maintenance diet (no added antioxidants beyond maintenance requirements) for 14d before treatment phase. Animals were then randomized to control or test for a 28d treatment period in a randomized cross-over design. Base kennel maintenance diet was provided for a 14d washout, followed by another treatment period. Serum was collected on days 0, 14, and 28 of for biomarkers analysis. Data were analyzed as a mixed models 2-way ANCOVA (SAS v9.4). Significant differences between treatments were set at P&amp;lt;0.05. Average daily food intake and body weight were similar between treatments for the duration of the study. Serum advanced glycation end-products and malondialdehyde were significantly (P&amp;lt;0.05) less when animals consumed test diet compared with control diet. Interestingly, serum C-reactive protein (CRP) was decreased and Fms-related tyrosine kinase 3 ligand was greater (P&amp;lt;0.05) when cats were fed test diet compared with control diet. These data suggest that inclusion of an antioxidant-containing kibble extruded to preserve antioxidant activity to a base kibble exhibits some favorable modulation to serum antioxidant markers and CRP in cats. These observations warrant additional research to elucidate the effects.

125 Evaluation of Antioxidant-Containing Kibble on Serum Antioxidant Biomarkers in Adult Beagles

Abstract The objective of this study was to evaluate oxidative health biomarkers in healthy male and female adult Beagles (n=30, 13 male and 17 female; avg age and BW + SD 4.46 ± 1.41 years; 9.83 ± 2.37 kg) fed a commercial adult maintenance diet (Blue Buffalo Life Protection Formula Adult Chicken and Brown Rice) without (control diet) and supplemented with an antioxidant-containing kibble (test diet; a proprietary blend containing blueberries, cranberries, and other antioxidant-containing ingredients). Both diet offerings analyzed as 25.6% crude protein, 14.4% crude fat, 2.6% crude fiber, 8.6% moisture, 42.6% carbohydrate as-is. We hypothesized that test diet feeding would reduce serum pro-oxidative biomarkers, compared with control diet feeding. The study protocol was first approved by the Institutional Animal Care and Use Committee. All dogs were fed a base kennel maintenance diet (no added antioxidants beyond maintenance requirements) for 14d before treatment phase. Animals were then randomized to control or test for a 28-d treatment period in a randomized cross-over design. Base kennel maintenance diet was provided for a 14d washout, followed by another treatment period. Serum was collected on days 0, 14, and 28 of each treatment period for biomarker analysis. Data were analyzed as a mixed models 2-way ANCOVA (SAS v9.4). Significant differences between treatments were set at P&amp;lt;0.05 and a trend at P&amp;lt;0.10. Average daily food intake and body weight were similar between treatments for the entire study. Serum advanced glycation end-products and malondialdehyde tended (P&amp;lt;0.10) to be reduced when animals were fed test diet compared with control diet. No differences were observed in other antioxidant biomarkers. These data suggest that addition of an antioxidant-containing kibble extruded to preserve antioxidant activity to a maintenance diet results in some favorable modulation of serum antioxidant markers in dogs. The observed trends suggest additional research to elucidate the effects.

First trimester screening of serum advanced glycation end products levels of pregnant women who have risk factors for gestational diabetes and their obstetric outcomes: a preliminary case-control study

Advanced glycation end-products (AGE) are complex compounds formed by nonenzymatic glycosylation of proteins, nucleic acids, and lipids with glucose in the blood. We aimed to investigate whether there was a difference in first-trimester serum AGE levels of pregnant women with and without risk factors for gestational diabetes mellitus (GDM) and their obstetric outcomes. There were 44 women in study group who have risk factors for GDM and 44 as controls. Demographic features, serum AGE levels, adverse perinatal and neonatal outcomes were compared between groups. Five patients (11.4%) in the study group and one patient (2.3%) in the control group were diagnosed as GDM (p = .2). The serum AGE values were not statistically different between the study and control groups. There were no statistical differences between groups in terms of adverse perinatal and neonatal outcomes. However, in the group with adverse perinatal outcome (n = 25), AGE values were higher than the control group. The results of our preliminary study suggested that high-risk women for GDM did not have increased serum levels of AGE in the first trimester. Nevertheless, a high first-trimester serum AGE level was found to be associated with adverse perinatal outcomes. IMPACT STATEMENT What is already known on this subject? Advanced glycation end products (AGE) are markers that are associated with diabetes and its complications. For pregnant women, a high third trimester serum AGEs levels were found in women who had gestational diabetes. What do the results of this study add? The results of our study revealed that first trimester screening of serum AGE levels of women who had risk factors for gestational diabetes was not discriminate. Nevertheless, a high first trimester serum AGE levels was associated with adverse perinatal outcome. What are the implications of these findings for clinical practice and/or further research? Whether reducing exogenous sources of AGE (western-style diet, smoking) before pregnancy will be associated with better pregnancy outcomes should be investigated in future studies.