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The current in-vivo study was premeditated to uncover the protective role of ezetimibe (EZ) against advanced glycation endproducts (AGEs)-related pathologies in experimental diabetes. Our results showed that EZ markedly improved the altered biochemical markers of diabetes mellitus (DM) (FBG, HbA1c, insulin, microalbumin, and creatinine) and cardiovascular disease (in-vivo lipid/lipoprotein level and hepatic HMG-CoA reductase activity) along with diminished plasma carboxymethyl-lysine (CML) and renal fluorescent AGEs level. Gene expression study revealed that EZ significantly down-regulated the renal AGEs-receptor (RAGE), nuclear factor-κB (NFκB-2), transforming growth factor-β (TGF-β1), and matrix metalloproteinase-2 (MMP-2) mRNA expression, however, the neuropilin-1 (NRP-1) mRNA expression was up-regulated. In addition, EZ also maintained the redox status via decreasing the lipid peroxidation and protein-bound carbonyl content (CC) and increasing the activity of high-density lipoprotein (HDL)-associated-paraoxonase-1 (PON-1) and renal antioxidant enzymes as well as also protected renal histopathological features. We conclude that EZ exhibits antidiabetic and reno-protective properties in diabetic rats. [ABSTRACT FROM AUTHOR]

Glycation reactions play a key role in post-translational modifications of amino acids in food proteins. Questions have arisen about a possible pathophysiological role of dietary glycation compounds. Several studies assessed the metabolic fate of dietary glycation compounds into blood and urine, but studies about saliva are rare. We investigated here the dietary impact on salivary concentrations of the individual Maillard reaction products (MRPs) N-ε-fructosyllysine, N-ε-carboxymethyllysine (CML), N-ε-carboxyethyllysine (CEL), pyrraline (Pyr), and methylglyoxal-derived hydroimidazolone 1 (MG-H1). Quantitation was performed using stable isotope dilution analysis (LC-MS/MS). We describe here, that a low MRP diet causes a significant lowering of salivary levels of Pyr from 1.9 ± 0.4 ng/mL to below the LOD and MG-H1 from 2.5 ± 1.5 ng/mL to 0.7 ± 1.8 ng/mL. An impact on the salivary protein fraction was not observed. Furthermore, salivary Pyr and MG-H1 levels are modified in a time-dependent manner after a dietary intervention containing 1.2 mg Pyr and 4.7 mg MG-H1. An increase in mean salivary concentrations to 1.4 ng/mL Pyr and 4.2 ng/mL MG-H1 was observed within 30–210 min. In conclusion, saliva may be a useful tool for monitoring glycation compound levels by using Pyr and MG-H1 as biomarkers for intake of heated food. [ABSTRACT FROM AUTHOR]

Glycation reactions play a key role in post-translational modifications of amino acids in food proteins. Questions have arisen about a possible pathophysiological role of dietary glycation compounds. Several studies assessed the metabolic fate of dietary glycation compounds into blood and urine, but studies about saliva are rare. We investigated here the dietary impact on salivary concentrations of the individual Maillard reaction products (MRPs) N-ε-fructosyllysine, N-ε-carboxymethyllysine (CML), N-ε-carboxyethyllysine (CEL), pyrraline (Pyr), and methylglyoxal-derived hydroimidazolone 1 (MG-H1). Quantitation was performed using stable isotope dilution analysis (LC-MS/MS). We describe here, that a low MRP diet causes a significant lowering of salivary levels of Pyr from 1.9 ± 0.4 ng/mL to below the LOD and MG-H1 from 2.5 ± 1.5 ng/mL to 0.7 ± 1.8 ng/mL. An impact on the salivary protein fraction was not observed. Furthermore, salivary Pyr and MG-H1 levels are modified in a time-dependent manner after a dietary intervention containing 1.2 mg Pyr and 4.7 mg MG-H1. An increase in mean salivary concentrations to 1.4 ng/mL Pyr and 4.2 ng/mL MG-H1 was observed within 30–210 min. In conclusion, saliva may be a useful tool for monitoring glycation compound levels by using Pyr and MG-H1 as biomarkers for intake of heated food.

Dicarbonyl compounds contribute to the formation of advanced glycation endproducts (AGEs) and the development of insulin resistance and vascular complications. Dicarbonyl stress may already be detrimental in obesity. We evaluated whether diet-induced weight loss can effectively reverse dicarbonyl stress in abdominally obese men. Plasma samples were collected from lean (n = 25) and abdominally obese men (n = 52) in the fasting state, and during a mixed meal test (MMT). Abdominally obese men were randomized to 8 weeks of dietary weight loss or habitual diet, followed by a second MMT. The α-dicarbonyls methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG) and AGEs were measured by UPLC-MS/MS. Skin autofluorescence (SAF) was measured using the AGE reader. T-tests were used for the cross-sectional analysis and ANCOVA to assess the treatment effect. Postprandial glucose, MGO and 3-DG concentrations were higher in obese men as compared to lean men (p < 0.05 for all). Fasting dicarbonyls, AGEs, and SAF were not different between lean and obese men. After the weight loss intervention, fasting MGO levels tended to decrease by 25 nmol/L (95%-CI: -51-0.5; p = 0.054). Postprandial dicarbonyls were decreased after weight loss as compared to the control group: iAUC of MGO decreased by 57% (5280 nmol/L∙min; 95%-CI: 33–10526; p = 0.049), of GO by 66% (11,329 nmol/L∙min; 95%-CI: 495–22162; p = 0.041), and of 3-DG by 45% (20,175 nmol/L∙min; 95%-CI: 5351–35000; p = 0.009). AGEs and SAF did not change significantly after weight loss. Abdominal obesity is characterized by increased postprandial dicarbonyl stress, which can be reduced by a weight loss intervention. Registered under ClinicalTrials.gov Identifier no. NCT01675401. [ABSTRACT FROM AUTHOR]

Abstract Background Clinical chemistry tests for autism spectrum disorder (ASD) are currently unavailable. The aim of this study was to explore the diagnostic utility of proteotoxic biomarkers in plasma and urine, plasma protein glycation, oxidation, and nitration adducts, and related glycated, oxidized, and nitrated amino acids (free adducts), for the clinical diagnosis of ASD. Methods Thirty-eight children with ASD (29 male, 9 female; age 7.6 ± 2.0 years) and 31 age-matched healthy controls (23 males, 8 females; 8.6 ± 2.0 years) were recruited for this study. Plasma protein glycation, oxidation, and nitration adducts and amino acid metabolome in plasma and urine were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Machine learning methods were then employed to explore and optimize combinations of analyte data for ASD diagnosis. Results We found that children with ASD had increased advanced glycation endproducts (AGEs), N ε-carboxymethyl-lysine (CML) and N ω-carboxymethylarginine (CMA), and increased oxidation damage marker, dityrosine (DT), in plasma protein, with respect to healthy controls. We also found that children with ASD had increased CMA free adduct in plasma ultrafiltrate and increased urinary excretion of oxidation free adducts, alpha-aminoadipic semialdehyde and glutamic semialdehyde. From study of renal handling of amino acids, we found that children with ASD had decreased renal clearance of arginine and CMA with respect to healthy controls. Algorithms to discriminate between ASD and healthy controls gave strong diagnostic performance with features: plasma protein AGEs—CML, CMA—and 3-deoxyglucosone-derived hydroimidazolone, and oxidative damage marker, DT. The sensitivity, specificity, and receiver operating characteristic area-under-the-curve were 92%, 84%, and 0.94, respectively. Conclusions Changes in plasma AGEs were likely indicative of dysfunctional metabolism of dicarbonyl metabolite precursors of AGEs, glyoxal and 3-deoxyglucosone. DT is formed enzymatically by dual oxidase (DUOX); selective increase of DT as an oxidative damage marker implicates increased DUOX activity in ASD possibly linked to impaired gut mucosal immunity. Decreased renal clearance of arginine and CMA in ASD is indicative of increased arginine transporter activity which may be a surrogate marker of disturbance of neuronal availability of amino acids. Data driven combination of these biomarkers perturbed by proteotoxic stress, plasma protein AGEs and DT, gave diagnostic algorithms of high sensitivity and specificity for ASD.

Objective: The paper reports an attempt to develop and validate a HILIC UPLC/ QTof MS method for quantifying N-ε-carboxymethyl-L-lysine (CML) in vitro , testing N-ε- carboxy[D 2 ]methyl-L-lysine (d 2 -CML), and N-ε-carboxy[4,4,5,5-D 4 ]methyl-L-lysine (d 4 -CML) as internal standards., Methods: During the method development, several challenging questions occurred that hindered the successful completion of the method. The study emphasizes the impact of issues, generally overlooked in the development of similar analytical protocols. For instance, the use of glassware and plasticware was critical for the accurate quantification of CML. Moreover, the origin of atypical variation in the response of the deuterated internal standards, though widely used in other experimental procedures, was investigated., Result: A narrative description of the systematic approach used to address the various drawbacks during the analytical method development and validation is presented., Conclusion: Reporting those findings can be considered beneficial while bringing an insightful notion about critical factors and potential interferences. Therefore, some conclusion and ideas can be drawn from these trouble-shooting questions, which might help other researchers to develop more reliable bioanalytical methods, or to raise their awareness of stumbling blocks along the way., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Here we describe a general method for the synthesis of 2,5‐diaminoimidazoles, which involves a thermal reaction between α‐aminoketones and substituted guanylhydrazines without the need for additives. As one of the few known ways to access the 2,5‐diaminoimidazole motif, our method greatly expands the number of reported diaminoimidazoles and further supports our previous observations that these compounds spontaneously adopt the non‐aromatic 4(H) tautomer. The reaction works successfully on both cyclic and acyclic amino ketone starting materials, as well as a range of substituted guanylhydrazines. Following optimization, the method was applied to the efficient synthesis of the advanced glycation end product (AGE) methylglyoxal‐derived imidazolium crosslink (MODIC). We expect that this method will enable rapid access to a variety of biologically important 2,5‐diaminoimidazole‐containing products. [ABSTRACT FROM AUTHOR]

This Special Issue on "Advances in Glycation: from food to human health and disease" was planned after the XXV International Symposium on Glycoconjugates (Glyco25) in Milan in order to ask special attention of importance of glycation to glycoscience community. In addition, we also celebrate the 30th anniversary of JMARS (Japan Maillard Reaction Society), and dedicated to one of the pioneers of this field, Professor Vincent Monnier, MD. He contributed enormously to studies on glycation related to aging and diseases to date and also he contributed to establish IMARS (International Maillard Reaction Society) as well as JMARS. [ABSTRACT FROM AUTHOR]

Recently, several types of foods and drinks, including coffee, cream, and cake, have been found to result in high methylglyoxal (MG) levels in the plasma, thus causing both nutritional and health concerns. MG can be metabolized by phase-II enzymes in liver through the positive regulation of nuclear factor-erythroid 2-related factor 2 (Nrf2). In this study, we investigated the ability of scopoletin (SP) to protect against MG-induced hyperglycemia and insulin resistance. Recently, SP was shown to be a peroxisome proliferator-activated receptor-γ activator to elevate insulin sensitivity. We investigated the effects of oral administration of SP on the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats to understand the potential mechanism of scopoletin for diabetes protection. Our results suggested that SP activated Nrf2 by Ser40 phosphorylation, resulting in the metabolism of MG into d-lactic acid and the inhibition of AGEs generation, which reduced the accumulation of AGEs in the livers of MG-induced rats. In this manner, SP improved the results of the oral glucose tolerance test and dyslipidemia. Moreover, SP also increased the plasma translocation of glucose transporter-2 and promoted Akt phosphorylation caused by insulin treatment in MG-treated FL83B hepatocytes. In contrast, SP effectively suppressed protein tyrosine phosphatase 1B (PTP1B) expression, thereby alleviating insulin resistance. These findings suggest that SP acts as an anti-glycation and anti-diabetic agent, and thus has therapeutic potential for the prevention of diabetes.

Purpose: Advanced glycation endproducts (AGEs) are produced endogenously and also enter the body during the consumption of AGEs present in heat-processed food. It is unknown whether AGEs of dietary origin accumulate within the body of healthy individuals. AGEs can deposit within skin tissue long-term by crosslinking extracellular matrix proteins. The fluorescent nature of many AGEs enables their detection within the skin by non-invasively measuring skin autofluorescence (SAF). This study aimed to identify habitual dietary and lifestyle behaviours cross-sectionally associated with SAF in an adult population sample.Methods: 251 Healthy adult volunteers completed validated food frequency and physical activity questionnaires. Waist circumference, BMI, blood pressure and blood glucose was also measured. SAF was measured using an AGE Reader.Results: Significant positive correlations were found between SAF and chronological age (r = 0.63, P < 0.001), waist circumference (r = 0.28, P < 0.01), body weight (r = 0.24, P < 0.05), BMI (r = 0.23, P < 0.05) and consumption of meat and meat products (r = 0.22, P < 0.05). A negative correlation was found between SAF and cereal consumption (r = −0.21, P < 0.05). Cigarette smokers also had a significantly higher SAF than non-smokers (2.4 vs 2.0 U, P < 0.05). Regression analysis identified age, cigarette smoking, waist circumference and intake of meat products as significant predictors of SAF. The regression model explained 48% of the variation in SAF.Conclusions: Age, cigarette smoking, waist circumference and dietary consumption of meat/meat products were positively associated with SAF in this sample. Further research is required to determine whether frequent consumption of foods containing large quantities of dietary AGEs contribute to pathological disease processes in healthy individuals. [ABSTRACT FROM AUTHOR]

The aim of this study was to validate an ultra-performance liquid chromatography tandem mass-spectrometry (UPLC–MS/MS) method for the determination of advanced glycation endproducts (AGEs) in food items and to analyze AGEs in a selection of food items commonly consumed in a Western diet. N ε -(carboxymethyl)lysine (CML), N ε -(1-carboxyethyl)lysine (CEL) and N δ -(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were quantified in the protein fractions of 190 food items using UPLC–MS/MS. Intra- and inter-day accuracy and precision were 2–29%. The calibration curves showed perfect linearity in water and food matrices. We found the highest AGE levels in high-heat processed nut or grain products, and canned meats. Fruits, vegetables, butter and coffee had the lowest AGE content. The described method proved to be suitable for the quantification of three major AGEs in food items. The presented dietary AGE database opens the possibility to further quantify actual dietary exposure to AGEs and to explore its physiological impact on human health. [ABSTRACT FROM AUTHOR]

[Display omitted] • In diabetes, the excess glucose molecules present in plasma bind to the available proteins and generates AGEs. • AGEs contribute to various pathogenesis including diabetes related complications in heart, kidney and eye. • Our current work detects AGEs, just by adding metal salts (gold or silver) in solution that forms nanoparticles. • Concentration of AGEs and metal salts control formation and stabilization of the nanoparticles. • Development of this strategy hence can be used for low-cost detection of AGEs present in plasma. The elevated blood sugar in Type II diabetes results in protein glycation that leads to the formation of Advanced Glycation Endproducts (AGEs) and cause severe pathogenic complications such as cardiovascular diseases, nephropathies, retinopathies, neurodegenerative diseases, etc. In our earlier work we have shown that gold nanoparticles (AuNPs) can be synthesized both in presence and absence of external reducing agent by in vitro generated AGEs from Hemoglobin A0 (HbA0). In the current work we have found that these highly reactive Hb derived AGEs (Hb-AGEs) are also capable of reducing silver ions and synthesize silver nanoparticles (AgNPs) with a different plasmonic response than the control solutions. It was observed that the concentration of AGE and metal salts play a vital role in the formation of nanoparticles and time-dependent stabilization of the particles. The lowest detection limit (LOD) showed that the reactions are highly sensitive because as low as 1 ng/μl of AGEs can be detected. When reduction of the two metal ions (Au 3 + and Ag +) were compared it was found that the AuNPs could be a better choice for the colorimetric sensing due to the appearance of plasmon in the visible range, while AgNPs could serve as a cost-effective determinant of AGEs. Therefore, in conclusion we confirm that AGEs can be detected just by deploying metal salts in solution. [ABSTRACT FROM AUTHOR]

Fagopyrum tataricum is used for the treatment of type 2 diabetes mellitus in Taiwan. The aim of this study was to evaluate the inhibitory effects of 75 % ethanol extract of buckwheat (EEB) and rutin on carbohydrate-metabolized enzymes, including α-amylase and α-glucosidase, which are related to hyperglycemia. The rutin dosage (40 μg/mL) was equivalent to that of EEB (200 μg/mL). In addition, the antioxidant and antiglycation activities of EEB and rutin were investigated. Results showed that both EEB and rutin exerted free radical (DPPH and ABTS) scavenging activity. They also attenuated protein glycation to lower the generation of advanced glycation end-products (AGEs) through the suppression of fructosamine and α-dicarbonyl compounds. Moreover, EEB and rutin also inhibited α-amylase and α-glucosidase activity. Taken together, these findings suggest that EEB and rutin may reduce oxidative stress, AGEs formation, and carbohydrate-metabolized enzymes hence EEB may use as protection agent in diabetic patients. [ABSTRACT FROM AUTHOR]

Glyoxal-derived advanced glycation end-products (AGEs) are formed in physiological systems affecting protein/peptide function and structure. These AGEs are generated during aging and chronic diseases such as diabetes and are considered arginine glycating agents. Thus, the study of glyoxal-derived AGEs in lysine residues and amino acid competition is addressed here using acetylated and non-acetylated undecapeptides, with one arginine and one lysine residue available for glycation. Tandem mass spectrometry results from a Fourier transform ion cyclotron resonance mass spectrometer showed glycated species at both the arginine and lysine residues. One species with the mass addition of 116.01096 Da is formed at the arginine residue. A possible structure is proposed to explain this finding (Nδ-[2-(dihydroxymethyl)-2H,3aH,4H,6aH-[1, 3]dioxolo[5,6-d]imidazolin-5-yl]-L-ornithine-derived AGE). The second species corresponded to intramolecular crosslink involving the lysine residue and its presence is checked with ion-mobility mass spectrometry. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Highlights: [•] Total phenolics, proanthocyanidins and flavonols of white grape skins were studied. [•] Anti-glycation ability was studied by 2D-IEF/SDS–PAGE and fluorescence measurement. [•] White grape skins prevented pI shift (decrease in free –NH2 groups) of target protein. [•] Anti-glycation efficacy was higher for white grape skin phenolics than aminoguanidine. [•] White grape skins are potential food ingredients for diabetic and elderly people. [ABSTRACT FROM AUTHOR]

Carbonyl stress and accumulation of advanced glycation end-products (AGEs) in human tissues are involved in diabetic complications, atherosclerosis, Alzheimer's disease and aging. The objective of this study was to evaluate the in vitro protective effect of aqueous extracts of coffee silverskin (CS) in the formation of AGEs and trapping of carbonyl reactive species such as methylglyoxal (MGO). Aqueous extracts of CS from Arabica and Robusta coffee varieties were obtained under environment friendly extraction conditions. CS extracts were characterized by the analysis of dietary fiber, caffeine, chlorogenic acids (CGAs), total phenolic compounds, browning, melanoidins, and antioxidant capacity. CS extracts and CGA exhibited a dose-dependent anti-AGE capacity in the protein-glucose model system (37°C/21days) with an IC50 of 0.6mg/mL and 0.4mg/mL, respectively. Caffeine did not prevent AGE formation under the studied conditions. Regardless to protein-MGO assay (37°C/14days), the anti-AGE capacity of CS extracts and CGA was also dose-dependent with an IC50 of 1.3mg/mL and 0.1mg/mL, respectively. Caffeine weakly inhibited the reaction of protein and MGO. The MGO trapping capacity was established as a model for protection against carbonyl stress. Robusta CS was very effective for the direct trapping of MGO with an IC50 of 0.055mg/mL as compared with Arabica CS (IC50 of 0.6mg/mL). CGA and caffeine showed an IC50 for MGO trapping capacity of 0.14mg/mL and >10mg/mL, respectively. The highest CGA content in the Robusta CS extract could explain its higher MGO trapping activity as compared with the Arabica CS extract. The anti-AGE and MGO trapping capacities of CS may be associated to other chemical components besides CGA. In conclusion, aqueous CS extract may be considered as a natural source of inhibitors of in vitro formation of AGEs and carbonyl stress. The inhibitory effect of the coffee extracts may be associated to their carbonyl trapping capacity. [ABSTRACT FROM AUTHOR]

Abstract: We investigated the effects of cilostazol, a selective inhibitor of phosphodiesterase 3, on blood–brain barrier (BBB) integrity against ischemia–reperfusion injury enhanced by advanced glycation endproducts (AGEs). We used in vitro BBB models with primarily cultured BBB-related cells from rats (brain capillary endothelial cells, astrocytes and pericytes), and subjected cells to either normoxia or 3-h oxygen glucose deprivation (OGD)/24-h reoxygenation with or without AGEs. Treatment of AGEs did not affect the transendothelial electrical resistance (TEER) in the BBB model under normoxia, but there was a significant decrease in TEER under 3-h OGD/24-h reoxygenation conditions with AGEs. Cilostazol inhibited decreases in TEER induced by 3-h OGD/24-h reoxygenation with AGEs. Immunocytochemical and Western blot analyses showed that AGEs reduced the expression of claudin-5, the main functional protein of tight junctions (TJs). In contrast, cilostazol increased the expression of claudin-5 under 3-h OGD/24-h reoxygenation with AGEs. Furthermore, while AGEs increased the production of extracellular transforming growth factor (TGF)-β1, cilostazol inhibited the production of extracellular TGF-β1 and restored the integrity of TJs. Thus, we found that AGEs enhanced ischemia–reperfusion injury, which mainly included decreases in the expression of proteins comprising TJs through the production of TGF-β1. Cilostazol appeared to limit ischemia–reperfusion injury with AGEs by improving the TJ proteins and inhibiting TGF-β1 signaling. [Copyright &y& Elsevier]

Abstract: The renin–angiotensin system (RAS) is most well-known for its role in regulation and dysregulation of blood pressure as well as fluid and electrolyte homeostasis. Due to its ability to cause cardiovascular disease, the RAS is the target of a multitude of drugs that antagonize its pathophysiological effects. While the “classical” RAS is a systemic hormonal system, there is an increasing awareness of the existence and functional significance of local RASs in a number of organs, e.g., liver, kidney, heart, lungs, reproductive organs, adipose tissue and adrenal. The eye is one of these organs where a compelling body of evidence has demonstrated the presence of a local RAS. Individual components of the RAS have been shown to be present in many structures of the eye and their potential functional significance in ocular disease states is described. Because the eye is one of the most important and complex organs in the body, this review also discusses the implications of dysregulation of the systemic RAS on the pathogenesis of ocular diseases and how pharmacological manipulation of the RAS might lead to novel or adjunctive therapies for ocular disease states. [Copyright &y& Elsevier]

Glycation is a post-translational modification (PTM) that affects the physiological properties of peptides and proteins. In particular, during hyperglycaemia, glycation by α-dicarbonyl compounds generate α-dicarbonyl-derived glycation products also called α-dicarbonyl-derived advanced glycation end products. Glycation by the α-dicarbonyl compound known as glyoxal was studied in model peptides by MS/MS using a Fourier transform ion cyclotron resonance mass spectrometer. An unusual type of glyoxal-derived AGE with a mass addition of 21.98436 Da is reported in peptides containing combinations of two arginine-two lysine, and one arginine-three lysine amino acid residues. Electron capture dissociation and collisionally activated dissociation results supported that the unusual glyoxal-derived AGE is formed at the guanidino group of arginine, and a possible structure is proposed to illustrate the 21.9843 Da mass addition. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Abstract: Background: Advanced glycation endproducts (AGEs) and its receptors (RAGEs) are heterogeneous signaling proteins associated to diabetes and responsible of endothelial alterations leading to atherosclerosis progression and graft failure. The aim of this study was to investigate the role of statin in reducing AGEs related endothelial damage. Methods: Endothelial cell(EC) obtained from leftovers of saphenous vein grafts of non-diabetic patients were incubated with AGEs (2 and 20μM) and subsequently treated with Simvastatin. Neutrophils (PNM) adherence, ROS production and RAGE and peroxisome proliferator-activated receptors-gamma (PPAR-γ) expression were analyzed. As clinical validation of the in vitro findings, ECs of diabetic patients in optimized glycaemic control administered with a 3weeks Simvastatin regimen were similarly processed. Results: Simvastatin blunted the rise in PMN adhesion and ROS generation following stimulation of saphenous vein EC culture with AGEs in vitro. This effect was time dependent and was associated to an increase in PPAR-γ induction paralleled by a decrease in RAGEs expression. Parallely, data from diabetic patients administered with Simvastatin showed a similar significant reduction in PNM adhesion and ROS generation. Simvastatin treatment significantly decreased RAGEs expression in ECs from diabetic patients and determined a slight increase in PPAR-γ expression but the latter failed to reach statistical significance. Interference in the function of these two crucial pathways might be at the root of the statin antinflammatory and antithrombotic effect in the context of AGEs-associated damage. Conclusions: Despite the recently raised warning on the use of statins in the diabetic population, this study elucidates their cornerstone position in endothelial homeostasis of saphenous grafts in patients with controlled diabetes. [Copyright &y& Elsevier]

Highlights: [•] Vitexin and isovitexin are C-glycosylated derivatives of apigenin. [•] Isovitexin was found as the most potent inhibitor against AR, AGE, and ChEs. [•] Vitexin showed the most potent PTP1B inhibitory activity. [•] Apigenin rather than vitexin and isovitexin showed anti-inflammatory activity. [•] C-glycosylation of apigenin might relate to intensity of respective bioactivities. [Copyright &y& Elsevier]

When foods are heat processed, the sugars and lipids react with the proteins they contain via the Maillard and related reactions to form a wide range of products. As a result, the sensory, safety, nutritional and health-promoting attributes of the foods are affected. Reaction products include advanced glycation/lipoxidation endproducts (AGE/ALEs), acrylamide and heterocyclic amines (HAA), all of which may impact on human health and disease. Furthermore, some Maillard reaction products affect the growth of colonic bacteria and thermally-induced modification of dietary protein can affect allergenicity. This paper briefly reviews aspects of the Maillard reaction in food related to human health.

Abstract: The increasing prevalence of diabetes especially type 2 diabetes worldwide is indisputable. Diabetics suffer increased morbidity and mortality, compared to their non-diabetic counterparts, not only because of vascular complications, but also because of an increased fracture incidence. Both types 1 and 2 diabetes and some medications used to treat it are associated with osteoporotic fractures. The responsible mechanisms remain incompletely elucidated. In this review, we evaluate the role of glycemic control in bone health, and the effect of anti-diabetic medications such as thiazolidinediones, sulfonylureas, DPP-4 inhibitors, and GLP-1 agonists. In addition, we examine the possible role of insulin and metformin as anabolic agents for bone. Lastly, we identify the current and future screening tools that help evaluate bone health in diabetics and their limitations. In this way we can offer individualized treatment, to the at-risk diabetic population. [Copyright &y& Elsevier]

Purpose: We determined the association between novel and acid-labile skin collagen-linked advanced glycation endproducts (AGEs) and the progression of microvascular and neuropathic complications from baseline to near study closeout in the Diabetes Control and Complications Trial (DCCT). Methods: From a skin biopsy obtained near the close of the DCCT, proteolytic collagen digests were analyzed by liquid chromatography/mass spectrometry (LC/MS/MS) for glucosepane (GSPNE), glyoxal and methylglyoxal hydroimidazolones (G-H1 and MG-H1) and the glycation product fructose-lysine (FL) using isotope dilution method. Results: GSPNE and MG-H1 correlated with age and diabetes duration (P<0.02), while GSPNE and FL correlated with the history of glycemia expressed as mean A1c (P⩽0.003). Age and duration-adjusted GSPNE and FL levels were lower in intensive (INT) vs. conventional (CONV) treatment subjects in the primary prevention DCCT cohort (P<0.0001), and FL was lower in INT in the secondary intervention cohort (P<0.0001). GSPNE was associated with increased incidence of retinopathy progression (odds ratio (OR) / unit increase in GSPNE: 2.5 for 3 step progression on the ETDRS scale, P=0.003) and sustained≥3 microaneurysms (MA) (OR=4.8, P<0.0001) from DCCT baseline up to the time of the biopsy, and prevalence of microalbuminuria or AER>40 mg/24 h (OR=5.3, P<0.0001), and confirmed clinical neuropathy (OR= 3.4, P=0.015) at the time of the biopsy. GSPNE adjusted for mean A1c remained significant for ≥3 MA (P= 0.0252) and AER (P=0.0006). The strong association of complications with A1c was reduced or eliminated when adjusted for GSPNE. Conclusions: Glucosepane is a novel AGE marker of diabetic complications that is robustly associated with nephropathic, retinopathic and neuropathic outcomes despite adjustment for A1c, suggesting that it could be one mediator of these complications with possible diagnostic implications. [ABSTRACT FROM AUTHOR]

Advanced glycation endproducts (AGEs) form when proteins are heated with reducing sugars. Nε-(Carboxymethyl) lysine (CML), as one of the common AGEs studied in consumed foods, was determined by HPLC-MS/MS in this experiment. The aim of this work was to evaluate the performance of forming CML incubated by different heat treatments in saccharide - lysine model systems. Different heating treatment such as water heating (W- heating), drying oven heating (D- heating) and microwave heating (M- heating) in saccharide-lysine model systems can affect the production of CML. M-heating method showed higher formation of CML capacity than W-heating method and D-heating method. The higher temperature and higher molar ratio of saccharide to lysine can increase the CML content. The order of reactivity for the formation of CML was lactose > glucose > sucrose. [ABSTRACT FROM AUTHOR]

Incubation of proteins with glucose leads to their non-enzymatic glycation and formation of Amadori products known as an early glycation product. Oxidative cleavage of Amadori products is considered as a major route to advanced glycation endproducts (AGEs) formation in vivo. Non-enzymatic glycation of proteins or Maillard reaction is increased in diabetes mellitus due to hyperglycemia and leads to several complications such as blindness, heart disease, nerve damage, and kidney failure. The early and advanced glycation products are accumulated in plasma and tissues of diabetic patients and cause production of autoantibodies against corresponding products. The advanced glycation products are also associated with other diseases like cancer. This review summarizes current knowledge of these stage specific glycated products as common and early diagnostic biomarkers for the associated diseases and the complications with the aim of a novel therapeutic target for the diseases. [ABSTRACT FROM AUTHOR]

Abstract: Aspirin showed an inhibitory effect on the formation of pentosidine, a cross-linking advanced glycation endproduct, in collagen incubated with glucose in vitro. IC50 was evaluated at 10mmol/l. Aspirin might act by metallic ion chelating (as did EDTA and DTPA) and by oxygen radical scavenging. Since aspirin was reported to inhibit retinopathy in diabetic dogs, it could act partly by inhibiting advanced glycation endproduct accumulation in long-lived proteins like collagens. [Copyright &y& Elsevier]

Glycoxidation of collagens contributes to development of vascular complications in diabetes. Since flavonoids are potent antioxidants present in vegetal foods, it was interesting to examine their effect on the formation of a cross-linking advanced glycation endproduct, pentosidine, in collagens. Collagen was incubated with glucose (250 mM), in the presence of different flavonoids. Pentosidine was measured by HPLC, hydroxyproline colorimetrically. Monomeric flavonoids (25 and 250 µM) markedly reduced pentosidine/hydroxyproline values in a concentration- and structure-dependent manner. In decreasing order of their specific inhibitory activity, they rank as follows: myricetin ≥ quercetin > rutin > (+)catechin > kaempferol. Thus 3′-OH or 4-oxo + Delta2–3 increase the inhibitory activity; conjugation by Rha-Glc on 3-OH decreases it. Procyanidin oligomers from grape seed were more active than pine bark procyanidin oligomers: this may be related to the galloyl residues present in grape seed oligomers only. Procyanidin oligomers are known to be cleaved into monomers in the gastric milieu and monomeric flavonoids to be absorbed and recovered at micromolar concentrations (with a long plasmatic half-life) in extracellular fluids, in contact with collagens. Flavonoids are very potent inhibitors of pentosidine formation in collagens. They are active at micromolar concentrations; these might be achieved in plasma of diabetic patients after oral intake of natural flavonoids. [ABSTRACT FROM AUTHOR]

Abstract: Glucosamine and glyceraldehyde can nonenzymatically interact with proteins to form advanced glycation endproducts (AGEs). The objective of this investigation was to determine the effects of nonenzymatic glycation by glucosamine and glyceraldehyde on the secondary structure of human serum albumin (HSA) and human IgG and to also demonstrate the in vitro formation of AGEs by these two sugars under different conditions. The formation of AGEs was monitored by capillary electrophoresis, UV and fluorescence spectroscopy. The changes in the secondary structure of HSA and IgG were determined by circular dichroism (CD) and thermal melting (Tm) profiles of the native and glycated proteins. CD and Tm studies revealed that at 40mM sugar concentration, glucosamine had a stabilizing effect on HSA and destabilized IgG whereas glyceraldehyde destabilized both the α-helical and β-pleated conformations of HSA and IgG, respectively. HSA and IgG structures were also negatively impacted with 40mM glucose. [Copyright &y& Elsevier]

The adhesion of osteoblasts to bone extracellular matrix, of which type-I collagen constitutes >85%, can modulate diverse aspects of their physiology such as growth, differentiation and mineralisation. In this study we examined the adhesion of UMR106 rat osteoblast-like cells either to a control (Col) or advanced-glycation-endproduct-modified (AGEs-Col) type I collagen matrix. We investigated the possible role of different integrin receptors in osteoblastic adhesion, by co-incubating these cells either with β-peptide (conserved sequence 113–125 of the β subunit of integrins) or with two other peptides, RGD (Arg-Gly-Asp) and DGEA (Asp-Gly-Glu-Ala), which are recognition sequences for the α-subunits of α1,5β1 and α2β1 integrins. Collagen glycation inhibited the adhesion of UMR106 osteoblasts to the matrix (40% reduction versus Col, P<0.001). β-Peptide showed a dose- and glycation-dependent inhibitory effect on adhesion, and at a concentration of 100 μM decreased the attachment of UMR106 cells to both matrices (42% to Col, P<0.001; and 25% to AGEs-Col, P<0.01). The synthetic peptides RGD (1 mM) and DGEA (5 mM) inhibited the attachment of UMR106 cells to Col (30 and 20%, P<0.01 and P<0.001, respectively), but not to AGEs-Col. β-Peptide induced an increase in UMR106 cell clumping and a decrease in cellular spreading, while DGEA increased spreading with cellular extensions in multiple directions. These results indicate that both α and β integrin subunits participate in osteoblastic attachment to type-I collagen, probably through the α1,5β1 and α2β1 integrins. AGEs-modification of type-I collagen impairs the integrin-mediated adhesion of osteoblastic cells to the matrix, and could thus contribute to the pathogenesis of diabetic osteopenia. [Copyright &y& Elsevier]

Background. Glucose, an osmotic agent generally used in continuous ambulatory peritoneal dialysis (CAPD) dialysate, has a critical characteristic of forming advanced glycation endproducts (AGEs). We undertook this study to investigate whether a possible osmotic agent, trehalose, formed fewer AGEs than glucose. Methods. Hemoglobin (Hb), a counter-protein of AGE, was incubated in four kinds of medium; glucose-phosphate buffered saline (PBS), autoclaved glucose-PBS, trehalose-PBS, and autoclaved trehalose-PBS, for 3, 7, 14, and 30 days, respectively. Polymerization of the Hb molecule was detected by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and carboxymethylated Hb was detected by Western blotting, using specific mono-clonal antibody for carboxymethylated N-terminal valine-Hb (CMV-Hb). Results. PBS containing glucose showed bands of polymerized Hb molecule, a phenomenon which was markedly exaggerated by autoclaving. Likely, PBS containing glucose showed the formation of CMV-Hb in the long incubation of 30 days, and PBS containing autoclaved glucose showed accelerated formation of CMV-Hb in an incubation as short as 3 days. By contrast, PBS containing trehalose showed much less increase in a band of 30 k Dalton and in CMV-Hb formation even in autoclaved medium. Conclusions. Our present in vitro study clearly showed the superior characteristic of trehalose to produce fewer AGEs. Based upon the results of this study, we propose that the application of trehalose should be considered for CAPD solution. [ABSTRACT FROM AUTHOR]

Proteins are subject of posttranslational modification by sugars and their degradation products in vivo. The process is often referred as glycation. l-Dehydroascorbic acid (DHA), an oxidation product of l-ascorbic acid (vitamin C), is known as a potent glycation agent. A new product of modification of lysine &epsiv;-amino group by DHA was discovered as a result of the interaction between Boc-Lys and dehydroascorbic acid. The chromatographic and spectral analyses revealed that the structure of the product was 1-(5-ammonio-5-carboxypentyl)-3-oxido-4-(hydroxymethyl)pyridinium. The same compound was isolated from DHA modified calf lens protein after hydrolysis and chromatographic separation. The study confirmed that l-erythrulose is an important intermediate of modification of proteins by DHA. The structure of the reported product and in vitro experiments suggested that l-erythrulose could further transform to l-threose, l-erythrose and glycolaldehyde under conditions similar to physiological. The present study revealed that the modification of &epsiv;-amino groups of lysine residues by DHA is a complex process and could involve a number of reactive carbonyl species. [Copyright &y& Elsevier]

Protein denaturation occurs at sites of inflammation. We hypothesized that denatured protein may provide a more susceptible target for glycation, which is a known mediator of inflammation. We examined the effects of thermal denaturation on the susceptibility of protein glycation using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and aspartate aminotransferase (AAT) as our target proteins. GAPDH and AAT are ubiquitous proteins that exhibited very different thermal stabilities. Glycating agents, methylglyoxal (MG) and glyceraldehyde (Glyc), caused an increase in the formation of advanced glycation endproducts (AGEs) in native and denatured GAPDH and AAT. The effects of the glycating agents were more pronounced with the denatured proteins. In addition to nitroblue tetrazolium (NBT)- reactivity, our measured endpoints were absorbance (λ = 365 nm) and fluorescence (λex = 370 nm; λem = 470 nm) properties that are typically associated with protein glycation. We also looked at carnosine''s ability to prevent glycation of native and denatured protein. Carnosine, an endogenous histidine dipeptide, exhibits anti-inflammatory activity presumably due to its anti-oxidant and anti-glycation properties. Carnosine prevented Glyc-induced AGE formation in both native and denatured AAT suggesting that carnosine''s anti-inflammatory activity may be due in part to carnosine''s ability to prevent glycation of denatured protein. [Copyright &y& Elsevier]

Purpose: We aimed to investigate associations between serum levels of the advanced glycation endproduct methylglyoxal-derived hydroimidazolone (MG-H1) and retinopathy in a sample of patients with type 1 diabetes. Methods: We conducted a cross-sectional study in a Scandinavian ophthalmology outpatient clinic on 61 randomly selected patients with type 1 diabetes. Blood samples and retinal photographs were taken at the same visit. Serum levels of hydroimidazolone immunoreactivity were determined using an immunoassay, and levels of retinopathy were determined from seven standard field stereo photographs of each eye according to the ETDRS method. Results were compared between patients with and without retinopathy. Results: Hydroimidazolone quartiles were significantly associated with retinopathy (p = 0.013). The most profound increase in occurrence of retinopathy was observed from the lowest to the second-lowest hydroimidazolone quartile. Adjusted for duration of diabetes using logistic regression, a significant difference in the presence of retinopathy was found when comparing the lowest quartile with the rest (p = 0.022). Conclusions: In our patients with type 1 diabetes, serum levels of hydroimidazolone were found to be associated with retinopathy. This is in keeping with findings in a larger sample of patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]