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Background/Aim: Accumulation of advanced glycation end products (AGEs) is a major cause of diabetes mellitus (DM) skin complications. Methylglyoxal (MGO), a reactive dicarbonyl compound, is a crucial intermediate of AGEs generation. N-acetyl-L-cysteine (NAC), an active ingredient of some medicines, can induce endogenous GSH and hydrogen sulfide generation, and set off a condensation reaction with MGO. However, there is rare evidence to show NAC can alleviate DM-induced skin injury through inhibition of AGEs generation or toxicity. The present study aimed to observe the effects of NAC on MGO-induced inflammatory injury and investigate the roles of AGEs and its receptor (RAGE) in NAC’s dermal protection in human HaCaT keratinocytes. Methods: The cells were exposed to MGO to simulate a high MGO status in diabetic blood or tissues. The content of AGEs in serum or cell medium was measured with ELISA. The protective effects of NAC against MGO-induce injury were evaluated by administration before MGO one hour, in virtue of cell viability, mitochondrial membrane potential, inflammation reaction, nuclear factor (NF)-κB activation, matrix metalloproteinase (MMP)-9 expression, as well as cellular behavioral function. Results: We found the AGEs levels of patients with DM were elevated comparing with healthy volunteers. The in vitro AGEs generation was also able to be enhanced by the exposure of HaCaT cells to MGO, which reduced dose-dependently cellular viability, damaged mitochondrial function, triggered secretion of interleukin (IL)-6 and IL-8, activated NF-κB and upregulated MMP-9 expression. Furthermore, the exposure caused cellular adhesion and migration dysfunction, as well as collagen type I inhibition. Importantly, before the exposure to MGO, the preconditioning with NAC significantly attenuated MGO-induced AGEs generation, improved cellular viability and mitochondrial function, partially reversed the overexpression of proinflammatory factors and MMP-9, as well as the activation of NF-κB. Lastly, NAC blocked MGO-induced RAGE upregulation, and inhibition of RAGE with its neutralizing antibody significantly alleviated MGO-induced NF-κB activation, MMP-9 upregulation and inflammatory injury in HaCaT cells. Conclusion: The present work indicates the administration of NAC can prevent MGO-induced dermal inflammatory injury through inhibition of AGEs/RAGE signal, which may provide a basal support for the treatment of diabetic skin complications with NAC-containing medicines in the future.

The modern Western diet is rich in advanced glycation end products (AGEs). We have previously shown an association between dietary AGEs and markers of inflammation and oxidative stress in a population of end stage renal disease (ESRD) patients undergoing peritoneal dialysis (PD). In the current pilot study we explored the effects of dietary AGEs on the gut bacterial microbiota composition in similar patients. AGEs play an important role in the development and progression of cardiovascular (CVD) disease. Plasma concentrations of different bacterial products have been shown to predict the risk of incident major adverse CVD events independently of traditional CVD risk factors, and experimental animal models indicates a possible role AGEs might have on the gut microbiota population. In this pilot randomized open label controlled trial, twenty PD patients habitually consuming a high AGE diet were recruited and randomized into either continuing the same diet (HAGE, n = 10) or a one-month dietary AGE restriction (LAGE, n = 10). Blood and stool samples were collected at baseline and after intervention. Variable regions V3-V4 of 16s rDNA were sequenced and taxa was identified on the phyla, genus, and species levels. Dietary AGE restriction resulted in a significant decrease in serum Nε-(carboxymethyl) lysine (CML) and methylglyoxal-derivatives (MG). At baseline, our total cohort exhibited a lower relative abundance of Bacteroides and Alistipes genus and a higher abundance of Prevotella genus when compared to the published data of healthy population. Dietary AGE restriction altered the bacterial gut microbiota with a significant reduction in Prevotella copri and Bifidobacterium animalis relative abundance and increased Alistipes indistinctus, Clostridium citroniae, Clostridium hathewayi, and Ruminococcus gauvreauii relative abundance. We show in this pilot study significant microbiota differences in peritoneal dialysis patients' population, as well as the effects of dietary AGEs on gut microbiota, which might play a role in the increased cardiovascular events in this population and warrants further studies.

Abstract Context Reduced bone material strength index (BMSi) and increased cortical porosity (CtPo) have emerged as potentially contributing to fracture risk in type 2 diabetes mellitus (T2DM) patients. Objective To determine whether BMSi or CtPo are related to other diabetic complications. Design Cross-sectional observational study. Setting Subjects recruited from a random sample of southeast Minnesota residents. Participants A total of 171 T2DM patients (mean age, 68.8 years) and 108 age-matched nondiabetic controls (mean age, 67.3 years). Main Measures Bone material strength index was measured using microindentation, skin advanced glycation end-products (AGEs) measured using autofluorescence, high-resolution peripheral quantitative computed tomography at the distal radius and tibia, assessment of diabetic microvascular complications including urine microalbuminuria, retinopathy, neuropathy, and vascular disease (ankle brachial index and transcutaneous oxygen tension [TcPO2]). All analyses were adjusted for age, sex, and body mass index. Results Skin AGEs were negatively correlated with the BMSi in both T2DM (r = -0.30, P < 0.001) and control (r = -0.23, P = 0.020) subjects. In relating diabetic complications to CtPo, we found that T2DM patients with clinically significant peripheral vascular disease (TcPO2 ≤ 40 mm Hg) had higher (+21.0%, P = 0.031) CtPo at the distal tibia as compared to controls; in these subjects, CtPo was negatively correlated with TcPO2 at both the distal tibia (r = -0.39, P = 0.041) and radius (r = -0.41, P = 0.029). Conclusions Our findings demonstrate that bone material properties are related to AGE accumulation regardless of diabetes status, while CtPo in T2DM patients is linked to TcPO2, a measure of microvascular blood flow.

Glycation process refers to reactions between reduction sugars and amino acids that can lead to formation of advanced glycation end products (AGEs) which are related to changes in chemical and functional properties of biological structures that accumulate during aging and diseases. The aim of this study was to perform and analyze in vitro glycation by fructose and methylglyoxal (MGO) using salivary fluid, albumin, lysozyme, and salivary α-amylase (sAA). Glycation effect was analyzed by biochemical and spectroscopic methods. The results were obtained by fluorescence analysis, infrared spectroscopy (total attenuated reflection—Fourier transform, ATR-FTIR) followed by multivariate analysis of principal components (PCA), protein profile, immunodetection, enzymatic activity and oxidative damage to proteins. Fluorescence increased in all glycated samples, except in saliva with fructose. The ATR-FTIR spectra and PCA analysis showed structural changes related to the vibrational mode of glycation of albumin, lysozyme, and salivary proteins. Glycation increased the relative molecular mass (Mr) in protein profile of albumin and lysozyme. Saliva showed a decrease in band intensity when glycated. The analysis of sAA immunoblotting indicated a relative reduction in intensity of its correspondent Mr after sAA glycation; and a decrease in its enzymatic activity was observed. Carbonylation levels increased in all glycated samples, except for saliva with fructose. Thiol content decreased only for glycated lysozyme and saliva with MGO. Therefore, glycation of salivary fluid and sAA may have the potential to identify products derived by glycation process. This opens perspectives for further studies on the use of saliva, an easy and non-invasive collection fluid, to monitor glycated proteins in the aging process and evolution of diseases.

Advanced glycation end products (AGEs) derived from food are compounds readily formed during heating and processing through non-enzymatic glycation reactions such as the Maillard reaction. Since a variety and quantity of AGEs are formed within shorter times in food than in the body, their long-term excessive intake is a growing concern as a contributing factor to the onset of various diseases, including diabetes and age-related diseases. Therefore, investigating the formation and presence of AGEs in food and understanding their contribution to health risks has become critically important. Since AGEs with different characteristics exist in various forms in foods, it is essential to develop efficient sample preparation and sensitive and accurate analytical methods. Generally, analysis of free AGEs requires deproteinization, and bound AGEs are hydrolyzed using hydrochloric acid or enzymes to form free AGEs, which are then purified by defatting, reduction, and solid-phase extraction. While immunological techniques and instrumental analytical methods such as chromatography have been developed for the detection and analysis of AGEs, liquid chromatography-tandem mass spectrometry is widely used due to its high sensitivity, specificity, and operability. This review summarizes trends and challenges in sample preparation and analytical techniques for analyzing AGE formation and presence in food, based on papers reported over the past 20 years.

Continuous metabolic monitoring is essential for assessing lifestyle-related disease risks. Hair, an easily accessible tissue, allows for long-term metabolic evaluation, with glycated proteins linked to diabetic complications found in hair. We established a mass spectrometry system to detect advanced glycation end products (AGEs) in hair samples from humans and rats, assessing their variations with aging and disease. Hair samples were hydrolyzed and processed using a cation-exchange column for mass spectrometric analysis. Regardless of temperature variations, the levels of AGEs [ N ε -(carboxymethyl)lysine (CML), and methylglyoxal-derived hydroimidazolone-1 (MG-H1)] in human hair remained stable for one week. Age and CML levels, or AGEs z-scores combined with CML and CEL levels in human hair samples, were positively correlated. In streptozotocin-induced insulin-deficient diabetic model (DM) rats, hair CEL and MG-H1 levels were higher than in non-diabetic rats. Receiver operating characteristic curve analysis showed an area under the curve of 1 for hair CEL and MG-H1 levels. Serum and hair CML levels were positively correlated. Hair AGE levels vary more between DM and non-DM rats than serum AGE levels. They remain stable under heat treatment and correlate with age, indicating that hair analysis is an effective non-invasive method for assessing metabolic fluctuations.

Background Bone mineral density (BMD) measurements are widely used to assess fracture risk. However, the finding that some fracture patients had high BMD together with the low contribution of drugs to osteoporosis suggests that bone strength factors other than BMD contribute to bone quality. We evaluated the amount of advanced glycation end products (AGEs) by non-invasive assays of serum and urine as well as by skin autofluorescence to measure the levels of a representative AGE, pentosidine, to investigate whether pentosidine can serve as an indirect indicator of AGEs formation in bone collagen. Methods A total of 100 spinal surgery patients without fragility fracture (54 males and 46 females) treated at our hospital were enrolled. The amount of pentosidine in blood, urine, skin and bone (lumbar lamina) samples from these patients was measured. AGE accumulation was assessed by measuring skin autofluorescence. We examined the correlation between pentosidine content in tissues and body fluid, as well as skin AGEs with age, height, body weight, BMI, and estimated glomerular filtration rate (eGFR). Results A significant age-related increase in pentosidine levels in tissues was observed, while there was a significant negative correlation between tissue pentosidine and eGFR. The amount of skin pentosidine was significantly and positively correlated with pentosidine content of the bone in those under 50 years of age. Urine pentosidine also correlated positively with bone pentosidine and skin pentosidine, but only in females. The total amount of AGEs in skin did not correlate with bone pentosidine. Conclusion In this study, the strong correlation between the pentosidine content in each sample and eGFR may indicate that renal dysfunction with advancing age increases oxidative stress and induces AGEs formation in collagen-containing tissues. The correlation of skin pentosidine concentration and eGFR, with AGEs formation in bone collagen suggests that pentosidine would be a useful indirect index of decreased bone quality. Skin AGEs estimated by autofluorescence in clinical situations may not be suitable as an indirect assessment of bone quality. Because urine pentosidine correlated positively with bone pentosidine and skin pentosidine in females, urine pentosidine may be a candidate for an indirect assessment of bone quality.

Background/objectivesThe incidence of obesity continues to increase worldwide and while the underlying pathogenesis remains largely unknown, nutrient excess, manifested by “Westernization” of the diet and reduced physical activity have been proposed as key contributing factors. Western-style diets, in addition to higher caloric load, are characterized by excess of advanced glycation end products (AGEs), which have been linked to the pathophysiology of obesity and related cardiometabolic disorders. AGEs can be “trapped” in adipose tissue, even in the absence of diabetes, in part due to higher expression of the receptor for AGEs (RAGE) and/or decreased detoxification by the endogenous glyoxalase (GLO) system, where they may promote insulin resistance. It is unknown whether the expression levels of genes linked to the RAGE axis, including AGER (the gene encoding RAGE), Diaphanous 1 (DIAPH1), the cytoplasmic domain binding partner of RAGE that contributes to RAGE signaling, and GLO1 are differentially regulated by the degree of obesity and/or how these relate to inflammatory and adipocyte markers and their metabolic consequences.Subjects/methodsWe sought to answer this question by analyzing gene expression patterns of markers of the AGE/RAGE/DIAPH1 signaling axis in abdominal subcutaneous (SAT) and omental (OAT) adipose tissue from obese and morbidly obese subjects.ResultsIn SAT, but not OAT, expression of AGER was significantly correlated with that of DIAPH1 (n = 16; β̂=0.719, [0.260, 1.177]; q = 0.008) and GLO1 (n = 16; β̂=0.773, [0.364, 1.182]; q = 0.004). Furthermore, in SAT, but not OAT, regression analyses revealed that the expression pattern of genes in the AGE/RAGE/DIAPH1 axis is strongly and positively associated with that of inflammatory and adipogenic markers. Remarkably, particularly in SAT, not OAT, the expression of AGER positively and significantly correlated with HOMA-IR (n = 14; β̂=0.794, [0.338, 1.249]; q = 0.018).ConclusionsThese observations suggest associations of the AGE/RAGE/DIAPH1 axis in the immunometabolic pathophysiology of obesity and insulin resistance, driven, at least in part, through expression and activity of this axis in SAT.

Dietary advanced glycation end-products (dAGEs) have been hypothesized to be associated with a higher risk of colorectal cancer (CRC) by promoting inflammation, metabolic dysfunction, and oxidative stress in the colonic epithelium. However, evidence from prospective cohort studies is scarce and inconclusive. We evaluated CRC risk associated with the intake of dAGEs in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Dietary intakes of three major dAGEs: Nε-carboxy-methyllysine (CML), Nε-carboxyethyllysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated in 450,111 participants (median follow-up = 13 years, with 6162 CRC cases) by matching to a detailed published European food composition database. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of dAGEs with CRC were computed using multivariable-adjusted Cox regression models. Inverse CRC risk associations were observed for CML (HR comparing extreme quintiles: HRQ5vs.Q1 = 0.92, 95% CI = 0.85–1.00) and MG-H1 (HRQ5vs.Q1 = 0.92, 95% CI = 0.85–1.00), but not for CEL (HRQ5vs.Q1 = 0.97, 95% CI = 0.89–1.05). The associations did not differ by sex or anatomical location of the tumor. Contrary to the initial hypothesis, our findings suggest an inverse association between dAGEs and CRC risk. More research is required to verify these findings and better differentiate the role of dAGEs from that of endogenously produced AGEs and their precursor compounds in CRC development.

Several epidemiological studies have identified diabetes as a risk factor for colorectal cancer (CRC). The potential pathophysiological mechanisms of this association include hyperinsulinemia, insulin-like growth factor (IGF) axis, hyperglycemia, inflammation induced by adipose tissue dysfunction, gastrointestinal motility disorder, and impaired immunological surveillance. Several studies have shown that underlying diabetes adversely affects the prognosis of patients with CRC. This review explores the novel anticancer agents targeting IGF-1R and receptor for advanced glycation end products (RAGE), both of which play a vital role in diabetes-induced colorectal tumorigenesis. Inhibitors of IGF-1R and RAGE are expected to become promising therapeutic choices, particularly for CRC patients with diabetes. Furthermore, hypoglycemic therapy is associated with the incidence of CRC. Selection of appropriate hypoglycemic agents, which can reduce the risk of CRC in diabetic patients, is an unmet issue. Therefore, this review mainly summarizes the current studies concerning the connections among diabetes, hypoglycemic therapy, and CRC as well as provides a synthesis of the underlying pathophysiological mechanisms. Our synthesis provides a theoretical basis for rational use of hypoglycemic therapies and early diagnosis and treatment of diabetes-related CRC.