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IntroductionsCystic fibrosis-related diabetes (CFRD) is associated with pulmonary decline, compromised nutritional status, and earlier mortality. Onset is often insidious, so screening for early detection of glycemic abnormalities is important. Continuous glucose monitoring (CGM) has been validated in people with CF and has been shown to detect early glycemic variability otherwise missed on 2-hour oral glucose tolerance testing (OGTT). We previously reported that CGM measures of hyperglycemia and glycemic variability are superior to hemoglobin A1c (HbA1c) in distinguishing those with and without CFRD. However, little is known about the long-term predictive value of CGM measures of glycemia for both the development of CFRD and their effect on key clinical outcomes such as weight maintenance and pulmonary function. In addition, there have been no studies investigating advanced glycation endproducts (AGE) assessed by skin autofluorescence in people with CF.MethodsIn this prospective observational study, CGM and HbA1c were measured at 2 to 3 time points 3 months apart in 77 adults with CF. Participants who did not have CFRD at the time of enrollment underwent OGTT at the baseline visit, and all participants had AGE readings at baseline. Follow up data including anthropometric measures, pulmonary function and CFRD status were collected by review of medical records 1- and 2-years after the baseline visits. We applied multivariable linear regression models correlating glycemic measures to change in key clinical outcomes (weight, BMI, FEV1) accounting for age, gender and elexacaftor/tezacaftor/ivacaftor (ETI) use. We also conducted logistic regression analyses comparing baseline glycemic data to development of CFRD during the 2-year follow up period.ResultsOf the 77 participants, 25 had pre-existing CFRD at the time of enrollment, and six participants were diagnosed with CFRD by the OGTT performed at the baseline visit. When adjusting for age, gender, and ETI use, multiple CGM measures correlated with weight and BMI decline after one year but not after two years. CGM and HbA1c at baseline did not predict decline in FEV1 (p>0.05 for all). In the 46 participants without a diagnosis of CFRD at baseline, two participants were diagnosed with CFRD over the following two years, but CGM measures at baseline did not predict progression to CFRD. Baseline AGE values were higher in individuals with CFRD and correlated with multiple measures of dysglycemia (HbA1c, AG, SD, CV, TIR, % time >140, >180, >250) as well as weight. AGE values also correlated with FEV1 decline at year 1 and weight decline at year 1 and year 2ConclusionsSeveral key CGM measures of hyperglycemia and glycemic variability were predictive of future decline in weight and BMI over one year in this population of adults with CF with and without CFRD. None of the baseline glycemic variables predicted progression to CFRD over 2 years. To our knowledge, this is the first report correlating AGE levels with key clinical and glycemic measures in CF. Limitations of these analyses include the small number of participants who developed CFRD (n=2) during the follow up period and the initiation of ETI by many participants, affecting their trajectory in weight and pulmonary function. These results provide additional data supporting the potential role for CGM in identifying clinically significant dysglycemia in CF. Future studies are needed to investigate CGM as a diagnostic and screening tool for CFRD and to understand the implications of AGE measures in this patient population.

ABSTRACT: Objective: The aim of this study was to compare peri-implant clinical and radiographic status and levels of advanced glycation endproducts (AGEs) in peri-implant sulcular fluid (PISF) in waterpipe users and cigarette smokers. Methods: Waterpipe users, cigarette smokers, and never smokers were included. Demographic details were collected using a questionnaire. Characteristics of implants (dimensions, jaw location, depth of placement, insertion torque, and duration in function) were recorded. Peri-implant modified plaque and gingival indices (mPI and mGI), probing depth (PD), and crestal bone loss (CBL) were recorded in all groups. Volume of PISF and levels of AGEs were determined using standard techniques. Sample-size estimation was done on data from a pilot investigation, and correlation between clinicoradiographic and immunoinflammatory parameters was assessed using logistic regression models. Probability values

The underlying molecular mechanisms for the development of non-alcoholic fatty liver (NAFL) and its progression to advanced liver diseases remain elusive. Glyoxalase 1 (Glo1) loss, leading to elevated methylglyoxal (MG) and dicarbonyl stress, has been implicated in various diseases, including obesity-related conditions. This study aimed to investigate changes in the glyoxalase system in individuals with non-pathological liver fat. Liver biopsies were obtained from 30 individuals with a narrow range of BMI (24.6–29.8 kg/m2). Whole-body insulin sensitivity was assessed using HOMA-IR. Liver biopsies were analyzed for total triglyceride content, Glo1 and Glo2 mRNA, protein expression, and activity. Liquid chromatography–tandem mass spectrometry determined liver dicarbonyl content and oxidation and glycation biomarkers. Liver Glo1 activity showed an inverse correlation with HOMA-IR and liver triglyceride content, but not BMI. Despite reduced Glo1 activity, no associations were found with elevated liver dicarbonyls or glycation markers. A sex dimorphism was observed in Glo1, with females exhibiting significantly lower liver Glo1 protein expression and activity, and higher liver MG-H1 content compared to males. This study demonstrates that increasing liver fat, even within a non-pathological range, is associated with reduced Glo1 activity.

Abstract Background There are no studies that have assessed advanced glycation end products (AGEs) and interleukin 17A (IL-17A) levels in whole saliva (WS) of patients with dental implants. The aim was to compare levels of AGEs and IL-17A in WS and peri-implant clinical and radiographic status of patients with and without osteoporosis at 6-years’ follow-up. Methods Osteoporotic (Group-1) and systemically healthy controls (Group-2) having undergone dental implant therapy at least 5 years ago were included. A questionnaire was used to collect information about age, gender, duration and treatment of osteoporosis, number and duration of implants in function, and frequencies of toothbrushing, flossing and hygiene visits. Modified bleeding and plaque indies (mBI and mPI), peri-implant probing depth (PD) and crestal bone loss (CBL) were recorded. WS was collected and levels of AGEs and IL-17A were determined using enzyme linked immunosorbent assay. Sample-size estimation was done and statistical analyses were doing using the independent t- and Wilcoxon rank-sum tests. Statistical significance was marked for P-values that were below 0.01. Results In patients with (n = 24) and without (n = 27) osteoporosis, implants were in function for 6.3 ± 0.27 and 6.6 ± 0.5 years, respectively. There was no significant difference in peri-implant mBI, PD, mPI and CBL in both groups. Levels of AGE in patients with (119.6 ± 26.5 μg/ml) and without (91.5 ± 14.6 μg/ml) osteoporosis were comparable. Levels of whole salivary IL-17A in patients without and with osteoporosis were 4.6 ± 0.3 and 5.1 ± 0.8 pg/ml, respectively. Flossing of full mouth interproximal spaces once and twice daily toothbrushing daily was reported by 100% patients with osteoporosis. Among patients with osteoporosis 75% and 25% individuals were receiving professional dental prophylaxis every 4 and 6 months, respectively. Conclusion Within the limitations of the present study osteoporotic patients are not at an increased risk of peri-implant diseases and can demonstrate salivary AGE and IL-17A levels comparable to non-osteoporotic individuals as long as oral hygiene is stringently maintained.

Abstract Background Back and neck pain are leading causes of global disability that are associated with intervertebral disc (IVD) degeneration. Causes of IVD degeneration are multifactorial, and diet, age, and diabetes have all been linked to IVD degeneration. Advanced glycation endproducts (AGEs) accumulate in the IVD as a result of aging, diet, and diabetes, and AGE accumulation in the IVD has been shown to induce oxidative stress and catabolic activity that result in collagen damage. An association between AGE accumulation and IVD degeneration is emerging, yet mechanism behind this association remains unclear. The Receptor for AGEs (RAGE) is thought to induce catabolic responses in the IVD, and the AGE receptor Galectin 3 (Gal3) had a protective effect in other tissue systems but has not been evaluated in the IVD. Methods This study used an IVD organ culture model with genetically modified mice to analyze the roles of RAGE and Gal3 in an AGE challenge. Results Gal3 was protective against an AGE challenge in the murine IVD ex vivo, limiting collagen damage and biomechanical property changes. Gal3 receptor levels in the AF significantly decreased upon an AGE challenge. RAGE was necessary for AGE‐induced collagen damage in the IVD, and RAGE receptor levels in the AF significantly increased upon AGE challenge. Discussion These findings suggest both RAGE and Gal3 are important in the IVD response to AGEs and highlight Gal3 as an important receptor with protective effects on collagen damage. This research improves understanding the mechanisms of AGE‐induced IVD degeneration and suggests Gal3 receptor modulation as a potential target for preventative and therapeutic treatment for IVD degeneration.

Abstract Background The aim was to assess the association between levels of advanced glycation endproducts (AGEs) in the gingival crevicular fluid (GCF) and periodontal parameters among cigarette-smokers and waterpipe-users. Methods Self-reported cigarette-smokers; waterpipe-users and never-smokers were included. Demographic data was recorded using a questionnaire. Periodontal parameters (plaque index [PI], gingival index [GI], clinical attachment loss [AL], probing depth [PD], and marginal bone loss [MBL]) were assessed in all groups. The GCF samples were collected using standard techniques and assessed for AGEs levels using enzyme-linked immunosorbent assay. Sample-size estimation was done and group-comparisons were done. Correlation between levels of GCF AGEs levels and periodontal parameters was assessed using a logistic regression model. Level of significance was set at P

Abstract Background Diabetes-associated osteoporosis are partly caused by accumulation of advanced glycation endproducts (AGEs). Glucagon-like peptide-1 (GLP-1) has been shown to regulate bone turnover. Here we explore whether GLP-1 receptor agonist (GLP1RA) can have a beneficial effect on bone in diabetes by ameliorating AGEs. Methods In the present study, we evaluated the effects of the GLP-1 receptor agonist liraglutide, insulin and dipeptidyl peptidase-4 inhibitor saxagliptin on Zucker diabetic fatty rats. Meanwhile, we observed the effect of GLP-1 on AGEs-mediated osteoblast proliferation and differentiation and the signal pathway. Results Liraglutide prevented the deterioration of trabecular microarchitecture and enhanced bone strength. Moreover, it increased serum Alpl, Ocn and P1NP levels and decreased serum CTX. In vitro we confirmed that GLP-1 could attenuate AGEs-mediated damage in osteogenic proliferation and differentiation. Besides, GLP-1 down-regulated the ROS that caused by AGEs and the mRNA and protein expression of Rage . Conclusions Altogether, our findings suggest that GLP-1 receptor agonist promotes osteoblastogenesis and suppresses bone resorption on obese type 2 diabetic rats to a certain degree. The mechanism of these effects may be partly mediated by AGEs-RAGE-ROS pathway via the interaction with GLP-1 receptor.

Background: Physical activity (PA) has substantial health benefits and is important in combatting chronic diseases, which have been associated with elevated levels of advanced glycation endproducts (AGEs). AGEs play a role in the aging process, and an association between PA and AGEs has been reported. We aimed to investigate the relationship between PA and AGE accumulation in a general population and in a population with chronic diseases. Methods: This large cross-sectional population study used data from adult participants in the LifeLines project, with participant information drawn from the LifeLines database as well data from patients with diabetes mellitus or renal and/or cardiovascular diseases. Tissue AGE accumulation was assessed non-invasively by skin-autofluorescence (SAF) using an AGE reader (DiagnOptics Technologies BV, Groningen, the Netherlands). PA was assessed using the short questionnaire to assess health-enhancing physical activity (SQUASH). Multivariate linear regression analyses were adjusted for age, body mass index, sex, and smoking status. Results: Data from 63,452 participants (general population n = 59,177, chronic disease n = 4275) were analyzed. The general population was significantly younger (43.58 ± 11.77 years, mean ± SD) and had significantly lower SAF (1.90 ± 0.42 arbitrary units (AU)) compared to the population with chronic disease (age: 55.51 ± 12.07 years; SAF: 2.27 ± 0.51 AU). In the group with chronic disease, more hours of moderate to vigorous physical activities per week were associated with lower SAF (β = –0.002, 95% confidence interval (95%CI): –0.002 to –0.001). For the general population, there was no association between hours of moderate to vigorous activity and SAF (β = 3.2 × 10–5, 95%CI: 0.000–0.001, p = 0.742). However, there was an association in the general population between total hours of PA per week and SAF (β = 4.2 × 10–4, 95%CI: 0.000–0.001, p < 0.001), but this association was not found in the chronic disease population (β = –3.2 × 10–4, 95%CI: –0.001 to 0.000, p = 0.347). Conclusion: Our study demonstrates that an inverse relationship exists between PA and AGE accumulation in the population with chronic disease. More hours of moderate to vigorous activity is associated with a significantly decreased SAF. More PA is associated with a lower SAF, even after adjusting for the established predictors (age, body mass index, smoking status, and sex). Our findings could help to promote health and prolong longevity.

Advanced glycation endproducts (AGEs) have been confirmed to play a causative role in the development of diabetic nephropathy (DN). In this study, we revealed that AGE-induced kidney injury with characteristic patterns in different stages and moesin phosphorylation plays a role in these processes. In WT mice treated with AGE-modified bovine serum albumin (AGE-BSA), distinct abnormal angiogenesis in Bowman’s capsule of the kidney emerged early after 1 m under AGE-BSA stimulation, while these neovessels became rare after 6 m. AGE-BSA also induced glomerular hypertrophy and mesangial expansion at 1 m but glomerular atrophy and fibrosis at 6 m. Electron microscopy imaging demonstrated the damage of foot process integrity in podocytes and the uneven thickening of the glomerular basement membrane in the AGE-BSA-treated group, which was more significant after 6 m of AGE-BSA treatment than 1 m. The kidney dysfunction appeared along with these AGE-induced morphological changes. However, these AGE-BSA-induced pathological changes were significantly attenuated in RAGE-knockout mice. Moreover, moesin phosphorylation was accompanied by AGE-BSA-induced alterations and moesin deficiency in mice attenuated by AGE-BSA-induced fibrosis. The investigation on glomerular endothelial cells (GECs) also confirmed that the phosphorylation of moesin T558 is critical in AGE-induced tube formation. Overall, this study suggests that AGEs mediate kidney injury with characteristic patterns by binding with RAGE and inducing moesin phosphorylation.

Background Advanced glycation endproducts (AGEs) have been linked to cardiovascular disease (CVD) in cohorts with and without diabetes. Data are lacking on prospective associations of various α‐dicarbonyl‐derived AGEs and incident CVD in the general population. We tested the hypothesis that major plasma AGEs are associated with new‐onset CVD in 2 population‐based cohorts of differing age and comorbidities. Methods and Results Analyses involved a random subcohort (n=466) from the Cardiovascular Health Study and a case‐cohort sample (n=1631) from the Multi‐Ethnic Study of Atherosclerosis. Five AGEs and 2 oxidative products were measured by liquid chromatography tandem mass spectrometry. Associations with CVD (myocardial infarction and stroke) were evaluated with Cox regression. Participants in the Cardiovascular Health Study were older than the Multi‐Ethnic Study of Atherosclerosis, and had more comorbidities, along with higher levels of all AGEs. During median follow‐up of 11 years, 439 participants in the Multi‐Ethnic Study of Atherosclerosis and 200 in the Cardiovascular Health Study developed CVD. After multivariable adjustment, carboxymethyl‐lysine, 3‐deoxyglucosone hydroimidazolones and a summary variable of all measured AGEs (principal component 1) were significantly associated with incident CVD in the Cardiovascular Health Study (HRs [95% CI]: 1.20 [1.01, 1.42], 1.45 [1.23, 1.72], and 1.29 [1.06, 1.56], respectively), but not the Multi‐Ethnic Study of Atherosclerosis. Oxidative products were not associated with CVD in either cohort. Conclusions We found α‐dicarbonyl‐derived AGEs to be associated with CVD in an older cohort, but not in a healthier middle‐aged/older cohort. Our results suggest that AGEs may exert detrimental cardiovascular effects only under conditions of marked dicarbonyl and oxidative stress. Further investigation of α‐dicarbonyl derivatives could lead to potential new strategies for CVD prevention in high‐risk older populations.

Advanced glycation end products (AGEs) excessive accumulation in the body either by exogenous intake or endogenous formation makes individuals prone to oxidative stress and inflammation damage. In this study, DCFH-DA fluorescence test and qPCR experiment were carried out to study the effect of some dietary flavonoids on AGEs induced toxicity. Among four tested flavonoids, it was found that hesperetin could significantly inhibit both AGEs-induced ROS production and gene expressions of TNF-α, IL-1β, IL-6, MCP-1, COX-2 and iNOS. High-throughput transcriptome analysis showed that the protective effect of hesperetin against AGEs-induced toxicity might be attributed to inhibit the activation of MAPK, JAK, NF-κB-related pathways. Furthermore, gene set enrichment analysis was performed using the MSigDB database and twenty-three key genes related were screened. This study might provide new ideas for the prevention of AGEs-related diseases and lay a theoretical foundation for the application of dietary flavonoids.

Posttranslational protein modification by lysine acylation is an emerging mechanism of cellular regulation and fine-tunes metabolic processes to environmental changes. In this review we focus on recently discovered pathways of non-enzymatic lysine acylation by reactive acyl-CoA species, acyl phosphates, and α-dicarbonyls. We summarize the metabolic sources of these highly reactive intermediates, demonstrate their reaction mechanisms, give an overview of the resulting acyl lysine modifications, and evaluate the consequences for cellular regulatory processes. Finally, we discuss interferences between lysine acylation and lysine ubiquitylation as a potential molecular mechanism of dysregulated protein homeostasis in aging and related diseases.

Aims: Non-invasively assessed skin autofluorescence (SAF) measures advanced glycation endproducts (AGEs) in the dermis. SAF correlates with dermal AGEs in Caucasians and Asians, but studies in dark-skinned subjects are lacking. In this pilot we aimed to assess whether SAF signal is representative of intrinsic fluorescence (IF) and AGE accumulation in dark skin. Methods: Skin biopsies were obtained in 12 dark-skinned subjects (6 healthy subjects, median age 22 years; 6 diabetes mellitus (DM) subjects, 65 years). SAF was measured with the AGE Reader, IF using confocal microscopy, and AGE distribution with specific antibodies. CML and MG-H1 were quantified with UPLC-MS/MS and pentosidine with HPLC and fluorescent detection. Results: SAF correlated with IF from the dermis (405nm, r = 0.58, p < 0.05), but not with CML (r = 0.54, p = 0.07). CML correlated with IF from the dermis (405nm, r = 0.90, p < 0.01). UV reflectance and the coefficient of variation of SAF were negatively correlated (r = -0.80, p < 0.01). CML and MG-H1 were predominantly present around blood vessels, in collagen and fibroblasts in the dermis. Conclusion: This proof of concept study is the first to compare non-invasive SAF with AGE levels measured in skin biopsies in dark-skinned subjects. SAF did not correlate with individual AGEs from biopsies, but was associated with IF. However, the intra-individual variance was high, limiting its application in dark-skinned subjects on an individual basis.

Proliferative diabetic retinopathy (PDR) involves persistent, uncontrolled formation of premature blood vessels with reduced number of pericytes. Our previous work showed that advanced glycation endproducts (AGEs) induced angiogenesis in human umbilical vein endothelial cells, mouse retina, and aortic ring, which was associated with moesin phosphorylation. Here we investigated whether moesin phosphorylation may contribute to pericyte detachment and the development of PDR. Primary retinal microvascular pericytes (RMPs) were isolated, purified from weanling rats, and identified by cellular markers α-SMA, PDGFR-β, NG2, and desmin using immunofluorescence microscopy. Effects of AGE-BSA on proliferation and migration of RMPs were examined using CCK-8, wound healing, and transwell assays. Effects on moesin phosphorylation were examined using western blotting. The RMP response to AGE-BSA was also examined when cells expressed the non-phosphorylatable Thr558Ala mutant or phospho-mimicking Thr558Asp mutant of moesin or were treated with ROCK inhibitor Y27632. Colocalization and interaction between CD44, phospho-moesin, and F-actin were observed. Experiments with cultured primary RMPs showed that AGE-BSA inhibited the proliferation, enhanced the migration, and increased moesin phosphorylation in a dose- and time-dependent manner. AGE-BSA also triggered the rearrangement of F-actin and promoted the interaction of CD44 with phospho-moesin in RMPs. These effects were abrogated in cells expressing the non-phosphorylatable moesin mutant and the application of ROCK inhibitor Y27632 attenuated AGE-induced alteration in cultured RMPs by abolishing the phosphorylation of moesin. However, those AGE-induced pathological process occurred in RMPs expressed the phospho-mimicking moesin without AGE-BSA treatment. It is concluded that AGEs could activate ROCK to mediate moesin phosphorylation at Thr558, and resulting phospho-moesin interacts with CD44 to form CD44 cluster, which might stimulate the migration of RMPs and subsequent RMP detachment in microvessel. This pathway may provide new drug targets against immature neovessel formation in PDR.

There is increasing evidence for the role of intestinal permeability as a contributing factor in the pathogenesis of diabetes; however, the molecular mechanisms are poorly understood. Advanced glycation endproducts, of both exogenous and endogenous origin, have been shown to play a role in diabetes pathophysiology, in part by their ligation to the receptor for advanced glycation endproducts (RAGE), leading to a proinflammatory signalling cascade. RAGE signalling has been demonstrated to play a role in the development of intestinal inflammation and permeability in Crohn’s disease and ulcerative colitis. In this review, we explore the role of AGE-RAGE signalling and intestinal permeability and explore whether activation of RAGE on the intestinal epithelium may be a downstream event contributing to the pathogenesis of diabetes complications.

Background: The association between coronary artery disease (CAD) and diabetes mellitus (DM) is strong but the physiologic mechanisms responsible for this association remain unclear. Patients with DM exhibit high circulating levels of glycated proteins and lipoproteins called advanced glycation end products (AGEs) which have been implicated in the development of oxidative damage to vascular endothelium. We examined the relationships between the presence and extent of CAD and AGEs in patients undergoing elective coronary artery catheterization in an urban teaching hospital. Methods: Patients with possible CAD (n = 364) were recruited prior to elective cardiac catheterization (52% male, 48% diabetic). Regression and correlation analyses were used to examine the relationship between serum AGE concentrations, soluble AGE receptor (sRAGE) concentration, HbA1c, LDL and the presence of obstructive CAD along with the burden of CAD measured by SYNTAX and SYNTAX II scores. Results: AGE and sRAGE levels did not significantly correlate with any of the studied coronary artery disease parameters. HbA1c showed positive correlation with both SYNTAX and SYNTAX II scores in patients with and without diabetes. Conclusion: In this cross-sectional study of patients with possible CAD, serum AGEs and sRAGE concentrations did not correlate with SYNTAX or SYNTAX II scores regardless of diabetic status. HbA1C correlated positively with the SYNTAX and SYNTAX II scores in both diabetic and non-diabetic populations.

In this study, cookies were incorporated with three polyphenols (rosmarinic acid, resveratrol, and epicatechin) at two concentrations (0.02% and 0.2%), and baked under three temperatures (150, 170, and 190 °C) to observe their interaction. They didn’t significantly change the cookie texture, but influence the color and pH. Temperature was a significant determinant to affect polyphenols’ stability and accordingly influenced cookies’ antioxidant capacity. 73.4%, 26.7% and 9.9% of rosmarinic acid, resveratrol, and epicatechin remained after baking at 190 °C for 10 min. Two addition levels of polyphenols decreased fluorescent advanced glycation endproducts (AGEs) by 18.58% to 40.29% and 28.60% to 62.05% respectively, while only resveratrol and epiatechin could reduce the level of glyoxal and methylglyoxal in cookies. In addition, we discovered that thermal processing could enhance the cytotoxicity of rosmarinic acid against cancer cells. Thus polyphenols were suggested as beneficial additives for enhancing antioxidant intake and lowering total fluorescent AGEs.

Hyperglycemia, when sustained over a long time in diabetes mellitus (DM), leads to biochemical and cellular abnormalities, primarily through the formation of advanced glycation end-products (AGEs). In the treatment of diabetes, beside blood-sugar-lowering medications, a consumption of herbal products that can inhibit the AGEs’ formation is recommended. This study investigated the in vitro antiglycoxidative potential of extracts and fractions from the rhizomes of Japanese, Giant, and Bohemian knotweeds (Reynoutria japonica (Houtt.), R. sachalinensis (F. Schmidt) Nakai, and R.× bohemica Chrtek et Chrtkova). Their effects on glycooxidation of bovine and human serum albumin were evaluated by incubation of the proteins with a mixture of glucose and fructose (0.5 M) and 150 µg/mL of extract for 28 days at 37 °C, followed by measuring early and late glycation products, albumin oxidation (carbonyl and free thiol groups), and amyloid-β aggregation (thioflavin T and Congo red assays). The highest antiglycoxidative activity, comparable or stronger than the reference drug (aminoguanidine), was observed for ethyl acetate and diethyl ether fractions, enriched in polyphenols (stilbenes, phenylpropanoid disaccharide esters, and free and oligomeric flavan-3-ols). In conclusion, the antiglycoxidative compounds from these three species should be further studied for potential use in the prevention and complementary treatment of DM.

Multiple sclerosis (MS) is a demyelinating autoimmune disease in which innate and adaptive immune cells infiltrate the central nervous system (CNS) and damage the myelin sheaths surrounding the axons. Upon activation, infiltrated macrophages, CNS-resident microglia, and astrocytes switch their metabolism toward glycolysis, resulting in the formation of α-dicarbonyls, such as methylglyoxal (MGO) and glyoxal (GO). These potent glycating agents lead to the formation of advanced glycation endproducts (AGEs) after reaction with amino acids. We hypothesize that AGE levels are increased in MS lesions due to the inflammatory activation of macrophages and astrocytes. First, we measured tissue levels of AGEs in brain samples of MS patients and controls. Analysis of MS patient and non-demented control (NDC) specimens showed a significant increase in protein-bound Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), the major AGE, compared to white matter of NDCs (107 ± 11 vs. 154 ± 21, p < 0.05). In addition, immunohistochemistry revealed that MGO-derived AGEs were specifically present in astrocytes, whereas the receptor for AGEs, RAGE, was detected on microglia/macrophages. Moreover, in cerebrospinal fluid from MS patients, α-dicarbonyls and free AGEs correlated with their respective levels in the plasma, whereas this was not observed for protein-bound AGEs. Taken together, our data show that MG-H1 is produced by astrocytes. This suggests that AGEs secreted by astrocytes have paracrine effects on RAGE-positive macrophages/microglia and thereby contribute to the pathology of MS.

Glyoxalase 1 (Glo1) is the rate-limiting enzyme in the detoxification of methylglyoxal (MGO) into D-lactate. MGO is a major precursor of advanced glycation endproducts (AGEs), and both are associated with development of age-related diseases. Since genetic variation in GLO1 may alter the expression and/or the activity of Glo1, we examined the association of nine SNPs in GLO1 with Glo1 expression and markers of MGO stress (MGO in fasting plasma and after an oral glucose tolerance test, D-lactate in fasting plasma and urine, and MGO-derived AGEs CEL and MG-H1 in fasting plasma and urine). We used data of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM, n = 546, 60 ± 7 y, 25% type 2 diabetes). Outcomes were compared across genotypes using linear regression, adjusted for age, sex, and glucose metabolism status. We found that SNP4 (rs13199033) was associated with Glo1 expression (AA as reference, standardized beta AT = −0.29, p = 0.02 and TT = −0.39, p = 0.3). Similarly, SNP13 (rs3799703) was associated with Glo1 expression (GG as reference, standardized beta AG = 0.17, p = 0.14 and AA = 0.36, p = 0.005). After correction for multiple testing these associations were not significant. For the other SNPs, we observed no consistent associations over the different genotypes. Thus, polymorphisms of GLO1 were not associated with Glo1 expression or markers of MGO stress, suggesting that these SNPs are not functional, although activity/expression might be altered in other tissues.

Purpose: Diabetes is accompanied by fundamental rearrangements in redox homeostasis. Hyperglycemia triggers the production of reactive oxygen and nitrogen species which contributes to tissue damage in various target organs. Proliferative diabetic retinopathy (PDR) is a common manifestation of diabetic complications but information on the possible role of reactive intermediates in this condition with special regard to the involvement of the vitreous in PDR-associated redox alterations is scarce. The aim of the study was to determine key parameters of redox homeostasis [advanced glycation endproducts (AGE); protein carbonyl and glutathione (GSH)] content in the vitreous in PDR patients. Methods: The study population involved 10 diabetic patients undergoing surgery for complications of proliferative diabetic retinopathy and 8 control (non-diabetic) patients who were undergoing surgery for epiretinal membranes. Vitreal fluids were assayed for the above biochemical parameters. Results: We found elevated levels of AGE in the vitreous of PDR patients (812.10 vs 491.69 ng AGE/mg protein). Extent of protein carbonylation was also higher in the samples of diabetic patients (2.08 vs 0.67 A/100 μg protein). The GSH content also increased in the vitreous of PDR patients as compared to the control group (4.54 vs 2.35 μmol/μg protein), respectively. Conclusion: The study demonstrates that diabetes-associated redox alterations also reach the vitreous with the most prominent changes being increased protein carbonylation and increased antioxidant levels.

The effects of capsaicin (CAPS) on protein glycation and the subsequent formation of advanced glycation endproducts (AGEs) were assessed. In vitro glycation assays showed that CAPS retards the late stages of glycation and crosslinking reaction. The dual mechanisms of action involving antioxidant and dicarbonyl trapping activities may contribute to the antiglycation effects. In a rat model of streptozotocin-induced permanent hyperglycaemia, 12 weeks of CAPS administration led to a reduction in the levels of circulating and tissue AGEs, as well as activation of the receptor for AGEs (RAGE). The levels of oxidative biomarkers, evaluated by assessing 8-isoprostane and lymphocyte DNA damage, were also decreased in the CAPS-treated groups compared with the diabetic group. Intriguingly, the reduction of serum and renal soluble RAGE (sRAGE) observed in diabetic rats was restored by CAPS administration. This study is the first to demonstrate that CAPS can reduce the burden of AGEs, thus relieving glycative stress in diabetics.

This study evaluated the potential antioxidant and antidiabetic properties in vitro of four millet grain varieties cultivated in South Korea. The free fractions were tested for their total antioxidant capacity using 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS+) and 2,2′-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assays, followed by α-glucosidase, α-amylase, and advanced glycation endproducts (AGEs) formation inhibition assays. The total phenolics, flavonoids, and condensed tannins in the free fractions ranged from 107.8 to 136.4 mg ferulic acid equivalent (FAE)/100 g, 101.3 to 115.8 mg catechin equivalent (CE)/100 g, and 17.65 to 59.54 mg catechin equivalent (CE)/100 g, respectively. Finger Italian millet had the highest total phenolic content (136.4 mg FAE/100 g) and flavonoid content (115.8 mg CE/100 g). Barnyard and finger Italian millet showed the highest DPPH (IC50 = 359.6 µg/mL and 436.25 µg/mL, respectively) and ABTS radical scavenging activity (IC50 = 362.40 µg/mL and 381.65 µg/mL, respectively). Similarly, finger Italian millet also exhibited significantly lower IC50 values for the percentage inhibition of α-glucosidase (18.07 µg/mL) and α-amylase (10.56 µg/mL) as compared with acarbose (IC50 = 59.34 µg/mL and 27.73 µg/mL, respectively) and AGEs formation (33.68 µg/mL) as compared with aminoguanidine (AG) (52.30 µg/mL). All eight phenolic compounds identified in finger Italian millet were flavonoids, with flavanols being the predominant subclass. Taken together, millet flavonoids play important roles in the prevention and management of type 2 diabetes, and hence finger Italian millet has the potential to be developed as a functional food.

Glyoxalase-1 (GLO1) is a ubiquitously expressed cytosolic protein which plays a role in the natural maintenance of cellular health and is abundantly expressed in human skeletal muscle. A consequence of reduced GLO1 protein expression is cellular dicarbonyl stress, which is elevated in obesity, insulin resistance and type 2 diabetes (T2DM). Both in vitro and pre-clinical models suggest dicarbonyl stress per se induces insulin resistance and is prevented by GLO1 overexpression, implicating a potential role for GLO1 therapy in insulin resistance and type 2 diabetes (T2DM). Recent work has identified the therapeutic potential of novel natural agents as a GLO1 inducer, which resulted in improved whole-body metabolism in obese adults. Given skeletal muscle is a major contributor to whole-body glucose, lipid, and protein metabolism, such GLO1 inducers may act, in part, through mechanisms in skeletal muscle. Currently, investigations examining the specificity of dicarbonyl stress and GLO1 biology in human skeletal muscle are lacking. Recent work from our lab indicates that dysregulation of GLO1 in skeletal muscle may underlie human insulin resistance and that exercise training may impart therapeutic benefits. This minireview will summarize the existing human literature examining skeletal muscle GLO1 and highlight the emerging therapeutic concepts for GLO1 gain-of-function in conditions such as insulin resistance and cardiometabolic disease.

Advanced glycation endproducts (AGEs) can be found in protein- and sugar-rich food products processed at high temperatures, which make up a vast amount of the Western diet. The effect of AGE-rich food products on human health is not yet clear and controversy still exists due to possible contamination of samples with endotoxin and the use of endogenous formed AGEs. AGEs occur in food products, both as protein-bound and individual molecules. Which form exactly induces a pro-inflammatory effect is also unknown. In this study, we exposed human macrophage-like cells to dietary AGEs, both in a protein matrix and individual AGEs. It was ensured that all samples did not contain endotoxin concentrations > 0.06 EU/mL. The dietary AGEs induced TNF-alpha secretion of human macrophage-like cells. This effect was decreased by the addition of N(ε)-carboxymethyllysine (CML)-antibodies or a receptor for advanced glycation endproducts (RAGE) antagonist. None of the individual AGEs induce any TNF-alpha, indicating that AGEs should be bound to proteins to exert an inflammatory reaction. These findings show that dietary AGEs directly stimulate the inflammatory response of human innate immune cells and help us define the risk of regular consumption of AGE-rich food products on human health.

Non-enzymatic modification of aminophospholipids by lipid peroxidation-derived aldehydes and reducing sugars through carbonyl-amine reactions are thought to contribute to the age-related deterioration of cellular membranes and to the pathogenesis of diabetic complications. Much evidence demonstrates the modification of aminophospholipids by glycation, glycoxidation and lipoxidation reactions. Therefore, a number of early and advanced Maillard reaction-lipid products have been detected and quantified in different biological membranes. These modifications may be accumulated during aging and diabetes, introducing changes in cell membrane physico-chemical and biological properties.

Phenolic acids have been identified in a variety of legumes including lima bean, broad bean, common bean, pea, jack bean, goa bean, adzuki bean, hyacinth bean, chicking vetch, garbanzo bean, dral, cow bean, rice bean, mung bean and soybean. The present study was carried out with the following aims: (1) to identify and quantify the individual phenolic acid and determine the total phenolic content (TPC); (2) to assess their antioxidant activity, inhibition activities of α-glucosidase, tyrosinase, and formation of advanced glycation endproducts; and (3) to investigate correlations among the phytochemicals and biological activity. Common bean possesses the highest antioxidant activity and advanced glycation endproducts formation inhibition activity. Adzuki bean has the highest α-glucosidase inhibition activity, and mung bean has the highest tyrosinase inhibition activity. There are significant differences in phytochemical content and functional activities among the bean species investigated. Selecting beans can help treat diseases such as dermatological hyperpigmentation illness, type 2 diabetes and associated cardiovascular diseases.

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS). The immune response in MS patients leads to the infiltration of immune cells in the CNS and their subsequent activation. Immune cell activation induces a switch towards glycolysis. During glycolysis, the dicarbonyl product methylglyoxal (MGO) is produced. MGO is a glycating agent that can rapidly form advanced glycation endproducts (AGEs). In turn, AGEs are able to induce inflammatory responses. The glyoxalase system is the endogenous defense system of the body to reduce the burden of MGO thereby reducing AGE formation. This system consists of glyoxalase-1 and glyoxalase-2 which are able to detoxify MGO to D-lactate. We investigated whether AGE levels are induced in experimental autoimmune encephalitis (EAE), an inflammatory animal model of MS. Twenty seven days post EAE induction, MGO and AGE (Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL), 5-hydro-5-methylimidazolone (MG-H1)) levels were significantly increased in the spinal cord of mice subjected to EAE. Yet, pyridoxamine treatment and glyoxalase-1 overexpression were unable to counteract AGE production during EAE and did not influence the clinical course of EAE. In conclusion, AGEs levels increase during EAE in the spinal cord, but AGE-modifying treatments do not inhibit EAE-induced AGE production and do not affect disease progression.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). The activation of inflammatory cells is crucial for the development of MS and is shown to induce intracellular glycolytic metabolism in pro-inflammatory microglia and macrophages, as well as CNS-resident astrocytes. Advanced glycation endproducts (AGEs) are stable endproducts formed by a reaction of the dicarbonyl compounds methylglyoxal (MGO) and glyoxal (GO) with amino acids in proteins, during glycolysis. This suggests that, in MS, MGO-derived AGEs are formed in glycolysis-driven cells. MGO and MGO-derived AGEs can further activate inflammatory cells by binding to the receptor for advanced glycation endproducts (RAGE). Recent studies have revealed that AGEs are increased in the plasma and brain of MS patients. Therefore, AGEs might contribute to the inflammatory status in MS. Moreover, the main detoxification system of dicarbonyl compounds, the glyoxalase system, seems to be affected in MS patients, which may contribute to high MGO-derived AGE levels. Altogether, evidence is emerging for a contributing role of AGEs in the pathology of MS. In this review, we provide an overview of the current knowledge on the involvement of AGEs in MS.

NMR is ideal for characterizing non-enzymatic protein glycation, including AGEs (advanced glycation endproducts) underlying tissue pathologies in diabetes and ageing. Ribose, R5P (ribose-5-phosphate) and ADPR (ADP-ribose), could be significant and underinvestigated biological glycating agents especially in chronic inflammation. Using [U-13C]ribose we have identified a novel glycoxidation adduct, 5-deoxy-5-desmethylpronyl-lysine, ‘norpronyl-lysine’, as well as numerous free ketones, acids and amino group reaction products. Glycation by R5P and ADPR proceeds rapidly with R5P generating a brown precipitate with PLL (poly-L-lysine) within hours. ssNMR (solid-state NMR) 13C–13C COSY identifies several crosslinking adducts such as the newly identified norpronyl-lysine, in situ, from the glycating reaction of 13C5-ribose with collagen. The same adducts are also identifiable after reaction of collagen with R5P. We also demonstrate for the first time bio-amine (spermidine, N-acetyl lysine, PLL) catalysed ribose 2-epimerization to arabinose at physiological pH. This work raises the prospect of advancing understanding of the mechanisms and consequences of glycation in actual tissues, in vitro or even ex vivo, using NMR isotope-labelled glycating agents, without analyses requiring chemical or enzymatic degradations, or prior assumptions about glycation products.

Accumulation of Advanced Glycation Endproducts (AGEs) in body tissues plays a major role in the development of diabetic complications. Here, the inhibitory effect of bioactive metabolites isolated from fruit hulls of Garcinia mangostana on AGE formation was investigated through bio-guided approach using aminoguanidine (AG) as a positive control. Including G. mangostana total methanol extract (GMT) in the reaction mixture of bovine serum albumin (BSA) and glucose or ribose inhibited the fluorescent and non-fluorescent AGEs formation in a dose dependent manner. The bioassay guided fractionation of GMT revealed isolation of four bioactive constituents from the bioactive fraction; which were identified as: garcimangosone D (1), aromadendrin-8-C-glucopyranoside (2), epicatechin (3), and 2,3′,4,5′,6-pentahydroxybenzophenone (4). All the tested compounds significantly inhibited fluorescent and non-fluorescent AGEs formation in a dose dependent manner whereas compound 3 (epicatechin) was found to be the most potent. In search for the level of action, addition of GMT, and compounds 2–4 inhibited fructosamine (Amadori product) and protein aggregation formation in both glucose and ribose. To explore the mechanism of action, it was found that addition of GMT and only compound (3) to reaction mixture increased protein thiol in both glucose and ribose while compounds 1, 2 and 4 only increased thiol in case of ribose. In conclusion, phenolic compounds 1–4 inhibited AGEs formation at the levels of Amadori product and protein aggregation formation through saving protein thiol.