Significance of nitrosative stress and glycoxidation products in the diagnosis of COVID-19.

Nitrosative stress promotes protein glycoxidation, and both processes can occur during an infection with the SARS-CoV-2 virus. Therefore, the aim of this study was to assess selected nitrosative stress parameters and protein glycoxidation products in COVID-19 patients and convalescents relative to healthy subjects, including in reference to the severity of COVID-19 symptoms. The diagnostic utility of nitrosative stress and protein glycoxidation biomarkers was also evaluated in COVID-19 patients. The study involved 218 patients with COVID-19, 69 convalescents, and 48 healthy subjects. Nitrosative stress parameters (NO, S-nitrosothiols, nitrotyrosine) and protein glycoxidation products (tryptophan, kynurenine, N-formylkynurenine, dityrosine, AGEs) were measured in the blood plasma or serum with the use of colorimetric/fluorometric methods. The levels of NO (p = 0.0480), S-nitrosothiols (p = 0.0004), nitrotyrosine (p = 0.0175), kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan fluorescence was significantly (p < 0.0001) lower in COVID-19 patients than in the control group. Significant differences in the analyzed parameters were observed in different stages of COVID-19. In turn, the concentrations of kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan levels were significantly (p < 0.0001) lower in convalescents than in healthy controls. The ROC analysis revealed that protein glycoxidation products can be useful for diagnosing infections with the SARS-CoV-2 virus because they differentiate COVID-19 patients (KN: sensitivity-91.20%, specificity-92.00%; NFK: sensitivity-92.37%, specificity-92.00%; AGEs: sensitivity-99,02%, specificity-100%) and convalescents (KN: sensitivity-82.22%, specificity-84.00%; NFK: sensitivity-82,86%, specificity-86,00%; DT: sensitivity-100%, specificity-100%; AGE: sensitivity-100%, specificity-100%) from healthy subjects with high sensitivity and specificity. Nitrosative stress and protein glycoxidation are intensified both during and after an infection with the SARS-CoV-2 virus. The levels of redox biomarkers fluctuate in different stages of the disease. Circulating biomarkers of nitrosative stress/protein glycoxidation have potential diagnostic utility in both COVID-19 patients and convalescents.

Association of four differently processed diets with plasma and urine advanced glycation end products and serum soluble receptor for advanced glycation end products concentration in healthy dogs.

Advanced glycation end products (AGEs), formed via the Maillard reaction (MR) during processing of foods, have been implicated in inflammatory and degenerative diseases in human beings. Cellular damage is primarily caused by AGE binding with the receptor for AGEs (RAGE) on cell membranes. An isoform of RAGE, soluble RAGE (sRAGE), acts as a decoy receptor binding circulating AGEs preventing cellular activation. Pet food manufacturing involves processing methods similar to human food processing that may increase dietary AGEs (dAGEs). We hypothesized that diet, plasma and urine AGEs, and serum sRAGE concentrations would differ between thermally processed diets. This study examined the association of four differently processed diets: ultra-processed canned wet food (WF); ultra-processed dry food (DF); moderately processed air-dried food (ADF) and minimally processed mildly cooked food (MF) on total plasma levels of the AGEs, carboxymethyllysine (CML), carboxyethyllysine (CEL), methylglyoxal hydroimidazolone-1, glyoxal hydroimidazolone-1, argpyrimidine, urine CML, CEL and lysinoalanine, and serum sRAGE concentration. Ultra-high-performance liquid chromatography-tandem mass spectrometry was used to measure AGEs. sRAGE concentration was measured using a commercial canine-specific enzyme-linked immunosorbent assay kit. Total dAGEs (mg/100 kcal as fed) were higher in WF than in other diets. Plasma total AGEs (nM/50 µL) were significantly higher with WF, with no difference found between DF, ADF, and MF; however, ADF was significantly higher than MF. Urine CML (nmol AGEs/mmol creatinine) was significantly higher with DF than with WF and MF. There were no significant differences in total urine AGEs or serum sRAGE concentration between diets. In conclusion, different methods of processing pet foods are associated with varied quantities of AGEs influencing total plasma AGE concentration in healthy dogs. Serum sRAGE concentration did not vary across diets but differences in total AGE/sRAGE ratio were observed between MF and WF and, ADF and DF.

Association between plasma sRAGE and emphysema according to the genotypes of AGER gene.

BACKGROUND: Higher soluble receptor for advanced glycation end product (sRAGE) levels are considered to be associated with severe emphysema. However, the relationship remains uncertain when the advanced glycation end-product specific receptor (AGER) gene is involved. We aimed to analyse the association between sRAGE levels and emphysema according to the genotypes of rs2070600 in the AGER gene. METHODS: We genotyped rs2070600 and measured the plasma concentration of sRAGE in each participant. Emphysema was quantified based on the chest computed tomography findings. We compared sRAGE levels based on the presence or absence and severity of emphysema in each genotype. Multiple logistic and linear regression models were used for the analyses. RESULTS: A total of 436 participants were included in the study. Among them, 64.2% had chronic obstructive pulmonary disease and 34.2% had emphysema. Among the CC-genotyped participants, the sRAGE level was significantly higher in participants without emphysema than in those with emphysema (P < 0.001). In addition, sRAGE levels were negatively correlated with emphysema severity in CC-genotyped patients (r = - 0.268 P < 0.001). Multiple regression analysis revealed that sRAGE was an independent protective factor for the presence of emphysema (adjusted odds ratio, 0.24; 95% confidence interval (CI) 0.11-0.51) and severity of emphysema (ß = - 3.28, 95% CI - 4.86 to - 1.70) in CC-genotyped participants. CONCLUSION: Plasma sRAGE might be a biomarker with a protective effect on emphysema among CC-genotyped patients of rs2070600 on the AGER gene. This is important in determining the target group for the future prediction and treatment of emphysema.

High glycemic albumin representing prestroke glycemic variability is associated with hemorrhagic transformation in patients receiving intravenous thrombolysis.

We evaluated the impact of prestroke glycemic variability estimated by glycated albumin (GA) on symptomatic hemorrhagic transformation (SHT) in patients with intravenous thrombolysis (IVT). Using a multicenter database, we consecutively enrolled acute ischemic stroke patients receiving IVT. A total of 378 patients were included in this study. Higher GA was defined as GA ≥ 16.0%. The primary outcome measure was SHT. Multivariate regression analysis and a receiver operating characteristic curve were used to assess risks and predictive ability for SHT. Among the 378 patients who were enrolled in this study, 27 patients (7.1%) had SHT as defined by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SHTSITS). The rate of SHTSITS was higher in the higher GA group than in the lower GA group (18.0% vs. 1.6%, p < 0.001). A higher GA level (GA ≥ 16.0%) significantly increased the risk of SHTSITS (adjusted odds ratio [OR], [95% confidence interval, CI], 12.57 [3.08-41.54]) in the logistic regression analysis. The predictive ability of the GA level for SHTSITS was good (AUC [95% CI]: 0.83 [0.77-0.90], p < 0.001), and the cutoff value of GA in SHT was 16.3%. GA was a reliable predictor of SHT after IVT in acute ischemic stroke in this study.

Higher habitual intake of dietary dicarbonyls is associated with higher corresponding plasma dicarbonyl concentrations and skin autofluorescence: the Maastricht Study.

BACKGROUND: Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown. OBJECTIVES: To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs. METHODS: In 2566 individuals of the population-based Maastricht Study (age: 60 ± 8 y, 50% males, 26% with type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by combining FFQs with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in > 200 commonly consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Skin AGEs were measured as skin autofluorescence (SAF), using the AGE Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle. RESULTS: Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17 mg/d, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (ß: 0.08; 95% CI: 0.02, 0.13) and SAF (ß: 0.12; 95% CI: 0.07, 0.17). Dietary GO was associated with plasma GO (ß: 0.10; 95% CI: 0.04, 0.16) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF. CONCLUSIONS: Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined. The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).

Colorimetric and Fluorometric Profiling of Advanced Glycation End Products.

Profiling of advanced glycation end products (AGEs) is an emerging area of clinical significance for disease diagnosis and prognosis. Typically, concentrations of AGEs are estimated in laboratories by trained personnel using sophisticated equipment. Herein, a facile approach for colorimetric and fluorometric profiling of AGEs is reported for rapid and on-site analysis. The concentrations of AGE levels in plasma are estimated via changes in optical properties of polythiophenes (PTs) upon interaction with aptamers (Apts) in the presence and in the absence of AGEs. To validate the proposed approach, glyceraldehyde-derived AGEs (AGE class 1 [AGE1]), the biomarker associated with cardiovascular diseases and diabetes, are used as a model system. Colorimetric analysis yielded linear responses for AGE1 for clinically relevant concentration ranges between 1.5 and 300 µg/mL with a limit of detection (LOD) of ∼1.3 µg/mL. Subsequently, an approach utilizing PTs with four different pendant groups in conjunction with four different Apts is demonstrated for qualitative colorimetric profiling and for quantitative fluorometric profiling of up to four AGEs in clinical matrices. Principal component analysis (PCA) of fluorometric responses of AGE-spiked samples yielded distinct responses for the different AGEs tested. Thus, the proposed approach ascertains rapid profiling of spiked AGEs in plasma samples without the requirement of preanalytical processing and advanced instrumentation, thereby facilitating on-site diagnosis.

The performance of glycated albumin as a biomarker of hyperglycemia and cardiometabolic risk in children and adolescents in the United States.

OBJECTIVE: Diabetes and prediabetes are growing concerns among US youth. Fasting glucose (FG) and HbA1c are standard diabetes screening tests, but HbA1c may be unreliable in some settings and fasting is burdensome in children. Glycated albumin (GA) is a non-fasting test that was recently cleared for clinical use in the United States, but studies in youth without diabetes are limited. RESEARCH DESIGN AND METHODS: We conducted a cross-sectional analysis in 6826 youth without diabetes aged 8-19 years in the 1999-2004 National Health and Nutrition Examination Survey. We evaluated the associations of GA with HbA1c, FG, and cardiometabolic risk factors. RESULTS: GA was poorly correlated with HbA1c (ρ = 0.074) and FG (ρ = -0.047) and was negatively associated with body mass index (BMI) and cardiometabolic risk factors. Compared to youth in the highest tertile of GA (≥13.5%), those in the lowest GA tertile (<12.4%) had a higher prevalence of obesity (29.9% vs. 7.6%), low high-density lipoprotein cholesterol (29.7% vs. 16.5%), and hypertensive blood pressure (4.0% vs. 2.7%). These inverse associations persisted after adjustment for age, sex, race/ethnicity, serum albumin, and C-reactive protein. CONCLUSIONS: GA was poorly correlated with traditional markers of hyperglycemia in youth without diabetes. Counterintuitively, there was a negative association between GA and BMI. Among youth without diabetes, GA does not identify youth at high cardiometabolic risk, and it does not appear to be an appropriate biomarker for screening of hyperglycemia.

Skin Advanced Glycation End Products among Subjects with Type 2 Diabetes Mellitus with or without Distal Sensorimotor Polyneuropathy.

MATERIALS AND METHODS: We included 132 subjects (88 men) with a mean age of 64.57 years and median T2DM duration of 14.5 years. Skin AGEs were measured with AGE reader mu connect (Diagnoptics) on the dominant arm. The device enables single and automated triplicate measurements: both of these were performed. DSPN was diagnosed through the neuropathy disability score (NDS). Small nerve fibre function was assessed by temperature and pinprick sensation on the foot. Bilateral measurement of the vibration perception threshold (VPT) on the hallux was carried out by using a neurothesiometer (Horwell Scientific Laboratory Supplies). RESULTS: Single and triplicate AGE measurements were positively correlated with each other (Pearson's correlation coefficient r = 0.991, 95%CI = 0.987-0.994, p < 0.001). AGEs were higher among subjects with vs. those without DSPN (p < 0.001). Furthermore, they were higher among subjects with reduced vs. normal temperature sensation (p < 0.001), among subjects with reduced vs. normal pinprick sensation (p = 0.002), among those with abnormal vs. normal monofilament examination (p < 0.001), and among those with abnormal vs. normal VPT (p < 0.001). AGEs were correlated with NDS, VPT, and monofilament score. CONCLUSIONS: In T2DM, skin AGEs are increased in the presence of DSPN. This holds true both for large and for small nerve function impairment. Moreover, AGEs are correlated with DSPN severity.

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.

Serum Expression of ESM-1, HMWA, and AGEs and Its Relationship with Disease Severity in Patients with Gestational Hypertension.

OBJECTIVE: The research is to investigate the expression and the relationship between serum endothelial cell-specific molecular molecule-1 (ESM-1), high molecular weight adiponectin (HMWA), and late glycosylation terminal product (AGEs) in patients with gestational hypertension. METHODS: 75 patients with pregnant hypertension who were treated in our hospital from June 2019 to June 2020 were selected as the case group, and 70 healthy pregnant women with pregnancy examination at the same period in our hospital were selected as the control group to analyze the changes in serum ESM-1, HMWA, and AGEs levels and the correlation with the degree of illness and their predictive value. RESULTS: Serum ESM-1 and AGEs were significantly higher in the case group than in the control group. Serum HMWA was significantly lower than that in the control group (P < 0.05). The gestational hypertensive serum ESM-1 and AGEs was significantly lower than in patients with mild preeclampsia and severe preeclampsia. Serum HMWA was significantly higher than in patients with mild preeclampsia and severe preeclampsia. Serum ESM-1 and AGEs of mild preeclampsia were significantly lower than in patients with severe preeclampsia. Serum HMWA was significantly higher than in patients with severe preeclampsia (P < 0.05). The result of correlation analysis shows a positive correlation between serum ESM-1 and AGEs (P < 0.05). A negative correlation was observed between HMWA and the degree of illness (P < 0.05). CONCLUSION: Serum ESM-1, HMWA, and AGEs are abnormally expressed in gestational hypertension, are closely related to the degree of condition, and have important clinical significance for condition control.

Advanced Glycation End Products Increase Salivary Gland Hypofunction in d-Galactose-Induced Aging Rats and Its Prevention by Physical Exercise.

A declined salivary gland function is commonly observed in elderly people. Advanced glycation end products (AGEs) are believed to contribute to the pathogenesis of aging. Although physical exercise is shown to increase various organ functions in human and experimental models, it is not known whether it has a similar effect in the salivary glands. In the present study, we evaluated the AGEs burden in the salivary gland in the aging process and the protective effect of physical exercise on age-related salivary hypofunction. To accelerate the aging process, rats were peritoneally injected with D-galactose for 6 weeks. Young control rats and d-galactose-induced aging rats in the old group were not exercised. The rats in the physical exercise group ran on a treadmill (12 m/min, 60 min/day, 3 days/week for 6 weeks). The results showed that the salivary flow rate and total protein levels in the saliva of the d-galactose-induced aging rats were reduced compared to those of the young control rats. Circulating AGEs in serum and secreted AGEs in saliva increased with d-galactose-induced aging. AGEs also accumulated in the salivary glands of these aging rats. The salivary gland of aging rats showed increased reactive oxygen species (ROS) generation, loss of acinar cells, and apoptosis compared to young control mice. However, physical exercise suppressed all of these age-related salivary changes. Overall, physical exercise could provide a beneficial option for age-related salivary hypofunction.

Correlation between hyperglycemia and glycated albumin with retinopathy of prematurity.

To determine the association between hyperglycemia, glycated albumin (GlyA) and retinopathy of prematurity (ROP). Prospective study of all infants under ROP screening from March 2017 to July 2019. All demographic, clinical and laboratory data were collected. Glucose was measured at birth and every 8 h for the first week and serum GlyA was evaluated at birth, 1st, 2nd and 4th weeks after birth. Reference range for GlyA was obtained. Univariate logistic regression was used to examine risk factors for ROP followed by multivariate regression. A total of 152 infants were included in the study. Median gestational age was 30 weeks and median birth weight 1240 g. Thirty-three infants (21.7%) had ROP. Hyperglycemia was present in 24 (72.7%) infants diagnosed with any ROP versus 6 (0.05%) in those without ROP. Median GlyA at birth, 1st, 2nd and 4th and respective reference ranges were 8.50% (6.00-12.65), 8.20% (5.32-11.67), 8.00% (5.32-10.00) and 7.90% (5.30-9.00) respectively. After multivariate logistic regression, hyperglycemia but not GlyA, remained a significant risk factor for ROP overpowering the other recognized risk factors (Exp (B) 28.062, 95% CI for Exp(B) 7.881-99.924 p < 0.001). In our cohort, hyperglycemia but not GlyA, remained a significant risk factor for ROP overpowering the other recognized risk factors.

Urinary excretion of amino acids and their advanced glycation end-products (AGEs) in adult kidney transplant recipients with emphasis on lysine: furosine excretion is associated with cardiovascular and all-cause mortality.

Arginine (Arg) and lysine (Lys) moieties of proteins undergo various post-translational modifications (PTM) including enzymatic NG- and Nε-methylation and non-enzymatic NG- and Nε-glycation. In a large cohort of stable kidney transplant recipients (KTR, n = 686), high plasma and low urinary concentrations of asymmetric dimethylarginine (ADMA), an abundant PTM metabolite of Arg, were associated with cardiovascular and all-cause mortality. Thus, the prediction of the same biomarker regarding mortality may depend on the biological sample. In another large cohort of stable KTR (n = 555), higher plasma concentrations of Nε-carboxymethyl-lysine (CML) and Nε-carboxyethyl-lysine (CEL), two advanced glycation end-products (AGEs) of Lys, were associated with higher cardiovascular mortality. Yet, the associations of urinary AGEs with mortality are unknown. In the present study, we measured 24 h urinary excretion of Lys, CML, and furosine in 630 KTR and 41 healthy kidney donors before and after donation. Our result indicate that lower urinary CML and lower furosine excretion rates are associated with higher mortality in KTR, thus resembling the associations of ADMA. Lower furosine excretion rates were also associated with higher cardiovascular mortality. The 24 h urinary excretion rate of amino acids and their metabolites decreased post-donation (varying as little as - 24% for CEL, and as much as - 62% for ADMA). For most amino acids, the excretion rate was lower in KTR than in donors pre-donation [except for S-(1-carboxyethyl)-L-cysteine (CEC) and NG-carboxyethylarginine (CEA)]. Simultaneous GC-MS measurement of free amino acids, their PTM metabolites and AGEs in urine is a non-invasive approach in kidney transplantation.

Advanced Glycation End-Products in Common Non-Infectious Liver Diseases: Systematic Review and Meta-Analysis.

BACKGROUND: Excessive intake of fructose, glucose and alcohol is associated with the development of non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). At the same time, these dietetic factors create an environment favorable for the generation of advanced glycation end-products. For this reason, advanced glycation end-products (AGEs) are hypothesized to play role in the development of NAFLD and ALD. In this systematic review and meta-analysis, we explore the relationship between NAFLD and ALD with AGE levels, including their diagnostic accuracy. METHODS: The systematic review and meta-analysis has been pre-registered with PROSPERO (CRD42021240954) and was performed in accordance with the PRISMA guidelines. Meta-analyses were performed using the meta R package. RESULTS: We have obtained 11 studies meeting our inclusion criteria, reporting data on 1844 participants (909 with NAFLD, 169 with ALD and 766 healthy controls). NAFLD was associated with significantly higher AGE fluorescence and serum N-(carboxyethyl)lysine (CEL) levels. Patients with alcoholic cirrhosis had significantly higher levels of N-(carboxymethyl)lysine (CML). Only individual studies examined AGEs in the context of their diagnostic accuracy. AGE fluorescence distinguished low and moderate steatosis with an AUC of 0.76. The ratio of CML, CEL and pentosidine to a soluble variant of the AGE receptor differentiated patients with NAFLD from healthy controls with high AUC (0.83-0.85). Glyceraldehyde-derived AGE separated non-alcoholic fatty liver (NAFL) from non-alcoholic steatohepatitis (NASH) with acceptable performance (AUC 0.78). CONCLUSIONS: In conclusion, NAFLD and ALD are associated with significantly higher levels of several AGEs. More research is needed to examine the diagnostic accuracy of AGEs, however individual studies show that AGEs perform well in distinguishing NAFL from NASH.

The role of serum and dietary advanced glycation endproducts in relation to cardiac function and structure: The Hoorn Study.

BACKGROUND AND AIMS: This study aims to investigate the relationship of serum and dietary advanced glycation endproducts (AGEs) with cardiac function and structure after eight years of follow-up. METHODS AND RESULTS: We included 370 Hoorn Study participants (aged 66.4 ± 6.1, 47% women). Serum protein-bound AGEs [Nε-(carboxymethyl)lysine, Nε-(carboxyethyl)lysine, and pentosidine], as well as echocardiography to assess left atrium volume index (LAVI), left ventricle ejection fraction (LVEF), and left ventricle mass index (LVMI), were measured at baseline and after 8 years of follow-up. Dietary AGEs [Nε-(carboxymethyl)lysine and Nε-(carboxyethyl)lysine] were estimated at baseline with a validated food-frequency questionnaire and an AGEs database. Increased pentosidine [-1.4% (-2.6;-0.2)] and overall serum AGEs Z-scores over time [-2.1% (-3.8;-0.5)] were associated with decreased LVEF at follow-up, adjusted for confounders. Glucose metabolism status was an effect modifier (P-for-interaction = 0.04). In participants with impaired glucose metabolism, but not type 2 diabetes, increased pentosidine was associated with decreased LVEF [-4.2 (-8.0;-0.3)%]. Higher dietary Nε-(carboxyethyl)lysine [1.9 (0.1; 3.7)%] and overall dietary AGEs Z-scores [2.1 (0.1; 4.2)%] were associated with higher LVEF at follow-up. However, prior cardiovascular disease (CVD) was an effect modifier (P = 0.02). We found a stronger, non-significant, association of higher dietary (carboxyethyl)lysine with higher LVEF at follow-up in participants without CVD [2.3 (-0.1; 4.7)%] compared to participants with CVD [0.6 (-2.1; 3.4)%]. CONCLUSION: Overall serum AGEs were longitudinally associated with impaired systolic function. Future research should focus on including changes in dietary AGEs intake over time and the relation of dietary AGEs with cardiac measures needs to be established in intervention studies using low AGEs diets.

Association between glucose intolerance and chemotherapy-induced lung injury in patients with lung cancer and interstitial lung disease.

PURPOSE: Cytotoxic chemotherapy-induced lung injury is a fatal complication in patients with lung cancer and interstitial lung disease (ILD). We aimed to evaluate the association between hyperglycemia and this form of lung injury in patients with lung cancer concomitant with ILD. METHODS: From 1147 patients with advanced lung cancer, we retrospectively enrolled 98 patients with ILD whose hemoglobin A1c (HbA1c) levels were measured, and investigated the association between HbA1c levels and cytotoxic chemotherapy-induced lung injury. In 73 patients whose serum samples were retained, we measured serum levels of advanced glycation end products (AGE) and assessed the association of AGE levels with HbA1c levels and cytotoxic chemotherapy-induced lung injury. RESULTS: The incidence of cytotoxic chemotherapy-induced lung injury was significantly higher in patients with HbA1c levels ≥ 5.8% than in those with HbA1c levels < 5.8%, but not in those with HbA1c levels ≥ 6.5% than in those with HbA1c levels < 6.5%. The multivariate logistic regression model revealed that HbA1c level ≥ 5.8% was a significant risk factor for this complication [odds ratio 3.178 (95% confidence interval 1.057-9.556), P = 0.040]. In addition, serum AGE levels were significantly higher in patients with HbA1c levels ≥ 5.8% than in those with HbA1c levels < 5.8% [median (interquartile range); 0.129 (0.023-0.290) and 0.474 (0.213-1.109) µg/mL, P = 0.001]. CONCLUSION: Glucose intolerance (e.g., HbA1c level ≥ 5.8%) may be a risk factor of cytotoxic chemotherapy-induced lung injury, which might be associated with elevated AGE production due to hyperglycemia.

Improvement in Redox Homeostasis after Cytoreductive Surgery in Colorectal Adenocarcinoma.

Colorectal cancer (CRC) as one the most common cancer type is associated with oxidative stress. Surgery is the only curative modality for early-stage CRC. The aim of this study was to evaluate the oxidative damage biomarkers as well as enzymatic and nonenzymatic antioxidants in patients with CRC before and after tumor resection and in healthy controls. 60 patients with stage I/II colorectal adenocarcinoma and 43 healthy controls were recruited in this study. We measured plasma levels of oxidative damage biomarkers, including advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), malondialdehyde (MDA), and oxidized low-density lipoprotein (ox-LDL) at baseline and after tumor removal. We also evaluated the plasma activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) as enzymatic antioxidants and the ferric reducing antioxidant power (FRAP) assay for nonenzymatic antioxidant capacity. Patients with CRC had significantly higher AGE, AOPP, MDA, and ox-LDL and also FRAP levels and higher SOD and GPx and lower CAT activity levels compared to healthy controls (p < 0.05). We did not observe any statistically significant correlation between redox biomarkers and the size and stage of the tumor. AGEs (72.49 ± 4.7 vs. 67.93 ± 8.8, p < 0.001), AOPP (137.64 ± 21.9 vs. 119.08 ± 33.1, p < 0.001), MDA (3.56 ± 0.30 vs. 3.05 ± 0.33, p < 0.001), and ox-LDL (19.78 ± 0.97 vs. 16.94 ± 1.02, p < 0.001) concentrations reduced significantly after tumor removal. The largest effect sizes were found in ox-LDL (d = -2.853, 95% CI 2.50-3.19) and MDA (d = -1.617, 95% CI 0.43-0.57). Serum FRAP levels (1097.5 ± 156.7 vs. 1239.3 ± 290, p < 0.001) and CAT (2.34 ± 0.34 vs. 2.63 ± 0.38, p < 0.001), GPx (102.37 ± 6.58 vs. 108.03 ± 6.95, p < 0.001), and SOD (5.13 ± 0.39 vs. 5.53 ± 0.31, p < 0.001) activity levels increased significantly after surgery. The largest effect sizes among antioxidants were seen in SOD (d = 1.135, 95% CI 0.46-0.34) and GPx (d = 0.836, 95% CI 0.35-0.23). This study indicated that patients with colorectal cancer had higher levels of oxidative stress and antioxidant activity compared to healthy controls. After surgical resection of tumor, we observed a substantial improvement in redox homeostasis.

Effect of Advanced Glycation End Products on Cognition in Older Adults with Type 2 Diabetes: Results from a Pilot Clinical Trial.

BACKGROUND: Dietary advanced glycation end-products (AGEs) are linked to cognitive decline. However, clinical trials have not tested the effect of AGEs on cognition in older adults. OBJECTIVE: The aim of the current pilot trial was to examine the feasibility of an intervention to reduce dietary AGEs on cognition and on cerebral blood flow (CBF). METHODS: The design is a pilot randomized controlled trial of dietary AGEs reduction in older adults with type 2 diabetes. Seventy-five participants were randomized to two arms. The control arm received standard of care (SOC) guidelines for good glycemic control; the intervention arm, in addition to SOC guidelines, were instructed to reduce their dietary AGEs intake. Global cognition and CBF were assessed at baseline and after 6 months of intervention. RESULTS: At baseline, we found a reverse association between AGEs and cognitive functioning, possibly reflecting the long-term toxicity of AGEs on the brain. There was a significant improvement in global cognition at 6 months in both the intervention and SOC groups which was more prominent in participants with mild cognitive impairment. We also found that at baseline, higher AGEs were associated with increased CBF in the left inferior parietal cortex; however, 6 months of the AGEs lowering intervention did not affect CBF levels, despite lowering AGEs exposure in blood. CONCLUSION: The current pilot trial focused on the feasibility and methodology of intervening through diet to reduce AGEs in older adults with type 2 diabetes. Our results suggest that participants with mild cognitive impairment may benefit from an intensive dietary intervention.

Association of serum advanced glycation (AGEs) end products, apolipoprotein-B and zinc in severity of T2DM retinopathy.

Advanced glycation end products (AGEs), lipids and lipoproteins and antioxidant enzymes are involved in the development of diabetic retinopathy (DR). AGEs and modified Apolipoprotein-B (Apo-B) lead to the formation of reactive oxygen species causing damage to the retina leading to DR. Zinc has antioxidant properties and protects the retina against reactive oxygen species. The current study aimed to compare the levels of serum AGEs, Apo-B and zinc in non-diabetics and type II diabetics without and with DR. Serum AGEs and Apo-B were measured by ELISA while zinc was measured by atomic absorption spectrophotometry. The impact of all three markers on the severity of DR was calculated, individually as well as together as a model, to determine the relationship of these markers with severity of diabetic retinopathy. Regression analysis showed that AGEs, Apo-B and zinc were all contributing significantly to the severity of DR, together having an 82.8% impact on it (R2=0.828). The model of the three parameters was best fit to indicate the severity of DR (p-value = 0.553). This study provides a basis for further validation of the suggested model with prospective studies which can then be used in clinical setups to predict the individuals at risk.

Advanced glycation end products and their receptors in serum of patients with type 2 diabetes.

Glycation is a non-enzymatic process involving the reaction of reducing sugars or reactive oxoaldehyde with proteins, lipids or nucleic acids, which results in the formation of advanced glycation end products (AGEs). The presented work discusses the glycation process in people with advanced stage of type 1 or type 2 diabetes. The concentration of different AGEs and their receptors for 58 serum samples was determined by ELISA and by spectrofluorimetric methods. In addition to fluorescent low molecular weight and protein-bound AGEs, we have also marked a new class of AGEs: melibiose-derived glycation product (MAGE). Our attention was also focused on the two groups of AGEs receptors: scavenger receptors (SR-A and SR-B) and RAGE. The correlation between the SR-AI scavenging receptors concentration and the fluorescence of AGEs as well as diabetes biological markers: GFR, creatinine contentration and HbA1c was demonstrated. A relationship between the concentration of AGEs and their receptors was also found in serum sample of patients treated with the metformin and aspirin. Furthermore, the concentration of SR-AI scavenger and the fluorescence of total AGEs was significantly lower in treated patients than in non treated patients. AGEs have also been found to contribute to the development of cardiovascular disease, atherosclerosis and diabetic complications, what could be deduced from the correlation of AGEs level and HDL cholesterol or uric acid level. Thus, it was confirmed that AGEs are involved in the pathomechanism of diabetes and other degenerative diseases. Nowadays, it is believed that AGEs due to the long time remaining in the body may be an important diagnostic marker. Their determination may allow monitoring the progression of the disease and the effectiveness of the therapy.