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Background: Recent studies provide increasing evidence for a relevant role of lifestyle factors including diet in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis (MS). While the intake of saturated fatty acids and elevated salt worsen the disease outcome in the experimental model of MS by enhanced inflammatory but diminished regulatory immunological processes, sugars as additional prominent components in our daily diet have only scarcely been investigated so far. Apart from glucose and fructose, galactose is a common sugar in the so-called Western diet., Methods: We investigated the effect of a galactose-rich diet during neuroinflammation using myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE) as a model disease. We investigated peripheral immune reactions and inflammatory infiltration by ex vivo flow cytometry analysis and performed histological staining of the spinal cord to analyze effects of galactose in the central nervous system (CNS). We analyzed the formation of advanced glycation end products (AGEs) by fluorescence measurements and investigated galactose as well as galactose-induced AGEs in oligodendroglial cell cultures and induced pluripotent stem cell-derived primary neurons (iPNs)., Results: Young mice fed a galactose-rich diet displayed exacerbated disease symptoms in the acute phase of EAE as well as impaired recovery in the chronic phase. Galactose did not affect peripheral immune reactions or inflammatory infiltration into the CNS, but resulted in increased demyelination, oligodendrocyte loss and enhanced neuro-axonal damage . Ex vivo analysis revealed an increased apoptosis of oligodendrocytes isolated from mice adapted on a galactose-rich diet. In vitro , treatment of cells with galactose neither impaired the maturation nor survival of oligodendroglial cells or iPNs. However, incubation of proteins with galactose in vitro led to the formation AGEs, that were increased in the spinal cord of EAE-diseased mice fed a galactose-rich diet. In oligodendroglial and neuronal cultures, treatment with galactose-induced AGEs promoted enhanced cell death compared to control treatment., Conclusion: These results imply that galactose-induced oligodendrocyte and myelin damage during neuroinflammation may be mediated by AGEs, thereby identifying galactose and its reactive products as potential dietary risk factors for neuroinflammatory diseases such as MS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer ML declared a shared affiliation with the authors KK and FM to the handling editor at the time of the review., (Copyright © 2024 Haase, Kuhbandner, Mühleck, Gisevius, Freudenstein, Hirschberg, Lee, Kuerten, Gold, Haghikia and Linker.)

Dietary advanced glycation endproducts (AGEs), abundantly present in Westernized diets, are linked to negative health outcomes, but their impact on the gut microbiota has not yet been well investigated in humans. We investigated the effects of a 4-week isocaloric and macronutrient-matched diet low or high in AGEs on the gut microbial composition of 70 abdominally obese individuals in a double-blind parallel-design randomized controlled trial (NCT03866343). Additionally, we investigated the cross-sectional associations between the habitual intake of dietary dicarbonyls, reactive precursors to AGEs, and the gut microbial composition, as assessed by 16S rRNA amplicon-based sequencing. Despite a marked percentage difference in AGE intake, we observed no differences in microbial richness and the general community structure. Only the Anaerostipes spp. had a relative abundance >0.5% and showed differential abundance (0.5 versus 1.11%; p = 0.028, after low- or high-AGE diet, respectively). While the habitual intake of dicarbonyls was not associated with microbial richness or a general community structure, the intake of 3-deoxyglucosone was especially associated with an abundance of several genera. Thus, a 4-week diet low or high in AGEs has a limited impact on the gut microbial composition of abdominally obese humans, paralleling its previously observed limited biological consequences. The effects of dietary dicarbonyls on the gut microbiota composition deserve further investigation.

Background: Endogenously formed advanced glycation end products (AGEs) may be important drivers of microvascular dysfunction and the microvascular complications of diabetes. AGEs are also formed in food products, especially during preparation methods involving dry heat., Objectives: We aimed to assess cross-sectional associations between dietary AGE intake and generalized microvascular function in a population-based cohort., Methods: In 3144 participants of the Maastricht Study (mean ± SD age: 60 ± 8 y, 51% men) the dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of our ultra-performance LC-tandem MS dietary AGE database and an FFQ. Microvascular function was determined in the retina as flicker light-induced arteriolar and venular dilation and as central retinal arteriolar and venular equivalents, in plasma as a z score of endothelial dysfunction biomarkers (soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1, soluble E-selectin, and von Willebrand factor), in skin as the heat-induced skin hyperemic response, and in urine as 24-h albuminuria. Associations were evaluated using multiple linear regression adjusting for demographic, cardiovascular, lifestyle, and dietary factors., Results: Overall, intakes of CML, CEL, and MG-H1 were not associated with the microvascular outcomes. Although higher intake of CEL was associated with higher flicker light-induced venular dilation (β percentage change over baseline: 0.14; 95% CI: 0.02, 0.26) and lower plasma biomarker z score (β: -0.04 SD; 95% CI: -0.08, -0.00 SD), the effect sizes were small and their biological relevance can be questioned., Conclusions: We did not show any strong association between habitual intake of dietary AGEs and generalized microvascular function. The contribution of dietary AGEs to generalized microvascular function should be further assessed in randomized controlled trials using specifically designed dietary interventions., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: The incidence of inflammatory bowel disease (IBD) continues to increase worldwide. Multiple factors, including diet, loss of the intestinal barrier function, and imbalance of the immune system can cause IBD. A balanced diet is important for maintaining a healthy bowel and preventing IBD from occurring. The effects of probiotic Lactobacillus gasseri-fermented Maillard reaction products (MRPs) prepared by reacting whey protein with galactose on anti-inflammation and intestinal homeostasis were investigated in this study, which compared MPRs and probiotics separately., Results: In an animal colitis model induced by 2% dextran sulfate sodium (DSS), FWG administration alleviated colon length loss and maintained intestinal immune system homeostasis as reflected by down-regulated interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α output, and metallopeptidase-9, and epithelial barrier balance as reflected by up-regulated occludin, E-cadherin, and zonula occludens-1 production in the colon. Furthermore, the expression of splenic cytokines such as IL-6, TNF-α, and IL-10 was up-regulated in the FWG-treated mice in a comparable amount to the control group to ensure the balance of immune responses., Conclusion: This study showed that the use of FWG protects the intestines from colitis caused by DSS and maintains immune balance. FWG increased antioxidant enzyme activity, increased intestinal permeability, and regulated the balance of pro- and anti-inflammatory cytokines in the intestines and spleen. Continued intake of FWG can alleviate IBD symptoms through the preservation of mucosal immune responses, epithelial junction and homeostasis through the regulated splenic cytokines. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

Diabetic keratopathy (DK) is an important diabetic complication at the ocular surface. Chronic low-grade inflammation mediated by the NLRP3 inflammasome promotes pathogenesis of diabetes and its complications. However, the effect of the NLRP3 inflammasome on DK pathogenesis remains elusive. Wild-type (WT) and Nlrp3 knockout (KO) C57 mice were used to establish a type I diabetes model by intraperitoneal injection of streptozotocin. The effect of the NLRP3 inflammasome on diabetic corneal wound healing and never regeneration was examined by a corneal epithelial abrasion model. Western blot, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA) and pharmacological treatment were performed to investigate the regulatory mechanism of advanced glycation end products (AGEs) on NLRP3 inflammasome activation and corneal wound healing in vivo . The cultured mouse corneal epithelial cells (TKE2) were used to evaluate the effect and mechanism of AGEs on NLRP3 inflammasome activation in vitro . We revealed that NLRP3 inflammasome-mediated inflammation and pyroptosis contributed to DK pathogenesis. Under physiological conditions, the NLRP3 inflammasome was required for corneal wound healing and nerve regeneration. However, under a diabetic scenario, sustained activation of the NLRP3 inflammasome resulted in postponed corneal wound healing and impaired nerve regeneration. Mechanistically, the accumulated AGEs promoted hyperactivation of the NLRP3 inflammasome through ROS production. Moreover, genetically and pharmacologically blocking the AGEs/ROS/NLRP3 inflammasome axis significantly expedited diabetic corneal epithelial wound closure and nerve regeneration. Our results revealed that AGEs-induced hyperactivation of the NLRP3 inflammasome resulted in delayed diabetic corneal wound healing and impaired nerve regeneration, which further highlighted the NLRP3 inflammasome as a promising target for DK treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The increased incidence of obesity, diabetes mellitus, aging, and associated comorbidities indicates the interplay between genetic and environmental influences. Several dietary components have been identified to play a role in the pathogenesis of the so-called "modern diseases", and their complications including advanced glycation end products (AGEs), which are generated during the food preparation and processing. Diet-derived advanced glycation end products (dAGEs) can be absorbed in the gastrointestinal system and contribute to the total body AGEs' homeostasis, partially excreted in the urine, while a significant amount accumulates to various tissues. Various in vitro, in vivo, and clinical studies support that dAGEs play an important role in health and disease, in a similar way to those endogenously formed. Animal studies using wild type, as well as experimental, animal models have shown that dAGEs contribute significantly to the pathogenesis of various diseases and their complications, and are involved in the changes related to the aging process. In addition, they support that dAGEs' restriction reduces insulin resistance, oxidative stress, and inflammation; restores immune alterations; and prevents or delays the progression of aging, obesity, diabetes mellitus, and their complications. These data can be extrapolated in humans and strongly support that dAGEs' restriction should be considered as an alternative therapeutic intervention.

Cataracts are the major cause of blindness worldwide, largely resulting from aging and diabetes mellitus. Advanced glycation end products (AGEs) have been identified as major contributors in cataract formation because they alter lens protein structure and stability and induce covalent cross-linking, aggregation, and insolubilization of lens crystallins. We investigated the potential of the deglycating enzyme fructosamine-3-kinase (FN3K) in the disruption of AGEs in cataractous lenses. Macroscopic changes of equine lenses were evaluated after ex vivo intravitreal FN3K injection. The mechanical properties of an equine lens pair were evaluated after treatment with saline and FN3K. AGE-type autofluorescence (AF) was measured to assess the time-dependent effects of FN3K on glycolaldehyde-induced AGE-modified porcine lens fragments and to evaluate its actions on intact lenses after in vivo intravitreal FN3K injection of murine eyes. A potential immune response after injection was evaluated by analysis of IL-2, TNFα, and IFNγ using an ELISA kit. Dose- and time-dependent AF kinetics were analyzed on pooled human lens fragments. Furthermore, AF measurements and a time-lapse of macroscopic changes were performed on intact cataractous human eye lenses after incubation with an FN3K solution. At last, AF measurements were performed on cataractous human eyes after crossover topical treatment with either saline- or FN3K-containing drops. While the lenses of the equine FN3K-treated eyes appeared to be clear, the saline-treated lenses had a yellowish-brown color. Following FN3K treatment, color restoration could be observed within 30 min. The extension rate of the equine FN3K-treated lens was more than twice the extension rate of the saline-treated lens. FN3K treatment induced significant time-dependent decreases in AGE-related AF values in the AGE-modified porcine lens fragments. Furthermore, in vivo intravitreal FN3K injection of murine eyes significantly reduced AF values of the lenses. Treatment did not provoke a systemic immune response in mice. AF kinetics of FN3K-treated cataractous human lens suspensions revealed dose- and time-dependent decreases. Incubation of cataractous human eye lenses with FN3K resulted in a macroscopic lighter color of the cortex and a decrease in AF values. At last, crossover topical treatment of intact human eyes revealed a decrease in AF values during FN3K treatment, while showing no notable changes with saline. Our study suggests, for the first time, a potential additional role of FN3K as an alternative treatment for AGE-related cataracts.

Background: Diet is a modifier of metabolic syndrome which in turn is associated with World Trade Center obstructive airways disease (WTC-OAD). We have designed this study to (1) assess the dietary phenotype (food types, physical activity, and dietary habits) of the Fire Department of New York (FDNY) WTC-Health Program (WTC-HP) cohort and (2) quantify the association of dietary quality and its advanced glycation end product (AGE) content with the development of WTC-OAD., Methods: WTC-OAD, defined as developing WTC-Lung Injury (WTC-LI; FEV 1  < LLN) and/or airway hyperreactivity (AHR; positive methacholine and/or positive bronchodilator response). Rapid Eating and Activity Assessment for Participants-Short Version (REAP-S) deployed on 3/1/2018 in the WTC-HP annual monitoring assessment. Clinical and REAP-S data of consented subjects was extracted (7/17/2019). Diet quality [low-(15-19), moderate-(20-29), and high-(30-39)] and AGE content per REAP-S questionnaire were assessed for association with WTC-OAD. Regression models adjusted for smoking, hyperglycemia, hypertension, age on 9/11, WTC-exposure, BMI, and job description., Results: N = 9508 completed the annual questionnaire, while N = 4015 completed REAP-S and had spirometry. WTC-OAD developed in N = 921, while N = 3094 never developed WTC-OAD. Low- and moderate-dietary quality, eating more (processed meats, fried foods, sugary drinks), fewer (vegetables, whole-grains),and having a diet abundant in AGEs were significantly associated with WTC-OAD. Smoking was not a significant risk factor of WTC-OAD., Conclusions: REAP-S was successfully implemented in the FDNY WTC-HP monitoring questionnaire and produced valuable dietary phenotyping. Our observational study has identified low dietary quality and AGE abundant dietary habits as risk factors for pulmonary disease in the context of WTC-exposure. Dietary phenotyping, not only focuses our metabolomic/biomarker profiling but also further informs future dietary interventions that may positively impact particulate matter associated lung disease.

Several randomized clinical trials (RCTs) have investigated the effect of dietary advanced glycation end products (AGE) on obesity factors and related hormones in adults; results were conflicting. Therefore, a study was performed to assess the effect of low advanced glycation end products diet on obesity and related hormones. A comprehensive literature search without any limitation on language was conducted using the following bibliographical databases: Web of Science, Scopus, Ovid MEDLINE, Cochrane, and Embase up to October, 2019. From the eligible trials, 13 articles were selected for the systematic review and meta-analysis. Our systematic reviews and meta-analyses have shown a significant decrease in BMI (WMD: - 0.3 kg/m 2 ; 95% CI: - 0.52, - 0.09, p = 0.005; I 2  = 55.8%), weight (WMD: - 0.83 kg; 95% CI: - 1.55, - 0.10, p = 0.026; I 2  = 67.0%), and leptin (WMD: - 19.85 ng/ml; 95% CI: - 29.88, - 9.82, p < 0.001; I 2  = 81.8%) and an increase in adiponectin (WMD: 5.50 µg/ml; 95% CI: 1.33, 9.67, p = 0.010; I 2  = 90.6%) levels after consumption of the low AGE diets compared to the high AGE diets. Also, the effect of intake of low AGE compared to high AGE diets was more pronounced in subgroup with duration > 8 weeks for the BMI and weight. Overall, according to our results, although low AGE diets appeared to be statistically significant in reducing the prevalence of obesity and chronic diseases compared to high consumption of dietary AGEs. But, no clinical significance was observed. Therefore, to confirm these results clinically, further prospective studies should be conducted in this regard. The study protocol was registered in the in International prospective register of systematic reviews (PROSPERO) database as CRD42020203734.

Introduction: High serum concentrations of advanced glycation end-products (AGEs) in older adults and diabetics are associated with an increased risk of cognitive impairment. The aim of this pilot study was to assess the feasibility of long-term adherence to a dietary intervention designed to decrease intake and exposure to circulating AGEs among older adults with type 2 diabetes., Methods: Herein, 75 participants were randomized to either a standard of care (SOC) control arm or to an intervention arm receiving instruction on reducing dietary AGEs intake. The primary outcome was a change in serum AGEs at the end of the intervention. Secondary and exploratory outcomes included adherence to diet and its association with circulating AGEs. Cognitive function and brain imaging were also assessed but were out of the scope of this article (ClinicalTrials.gov Identifier: NCT02739971)., Results: The intervention resulted in a significant change over time in several serum AGEs compared to the SOC guidelines. Very high adherence (above 80%) to the AGE-lowering diet was associated with a greater reduction in serum AGEs levels. There were no significant differences between the two arms in any other metabolic markers., Conclusions: A long-term dietary intervention to reduce circulating AGEs is feasible in older adults with type 2 diabetes, especially in those who are highly adherent to the AGE-lowering diet.

Background: Advanced glycation end products (AGEs) are reactive metabolites produced as a by-product of sugar metabolism and are consumed through the diet in high-fat and highly processed foods. They are associated with chronic inflammatory diseases, and evidence suggests that they play a role in carcinogenesis. The authors evaluated the association of dietary AGE intake and the risk of postmenopausal invasive breast cancer., Methods: This was a prospective cohort study of 183,548 postmenopausal women in the National Institutes of Health-AARP Diet and Health Study. The main outcome was incident invasive breast cancer. AGE intake was estimated from food-frequency questionnaires. Incident breast cancer cases were identified through state cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals for developing breast cancer according to AGE intake quintiles. Multivariable regression models were adjusted for breast cancer risk factors., Results: The mean follow-up was 12.8 years, and 9851 breast cancers (1978 advanced stage) were identified. The median AGE daily intake was 5932 kilo units per 100 kilocalories (KU/1000 kcal). Women with higher intake tended to have lower education levels, higher body mass index, less physical activity, were current smokers, and had higher fat and meat intake. The highest quintile of AGE intake (compared with the lowest) was associated with an increased risk of breast cancer (HR, 1.09; 95% CI, 1.02-1.16; P = .03) after adjusting for breast cancer risk factors and particularly was associated with 37% of advanced-stage tumors (HR, 1.37; 95% CI, 1.09-1.74; P < .02) after adjusting for risk factors and fat and meat intake., Conclusions: Dietary AGEs may play a role in the development of postmenopausal breast cancer., (© 2020 American Cancer Society.)

Industrial heat treatment of milk results in protein glycation. A high protein glycation level has been suggested to compromise the post-prandial rise in plasma amino acid availability following protein ingestion. In the present study, we assessed the impact of glycation level of milk protein on post-prandial plasma amino acid responses in humans. Fifteen healthy, young men (age 26 (SEM 1) years, BMI 24 (SEM 1) kg/m2) participated in this randomised cross-over study and ingested milk protein powder with protein glycation levels of 3, 20 and 50 % blocked lysine. On each trial day, arterialised blood samples were collected at regular intervals during a 6-h post-prandial period to assess plasma amino acid concentrations using ultra-performance liquid chromatography. Plasma essential amino acid (EAA) concentrations increased following milk protein ingestion, with the 20 and 50 % glycated milk proteins showing lower overall EAA responses compared with the 3 % glycated milk protein (161 (SEM 7) and 142 (SEM 7) v. 178 (SEM 9) mmol/l × 6 h, respectively; P ≤ 0·011). The lower post-prandial plasma amino acid responses were fully attributed to an attenuated post-prandial rise in circulating plasma lysine concentrations. Plasma lysine responses (incremental AUC) following ingestion of the 20 and 50 % glycated milk proteins were 35 (SEM 4) and 92 (SEM 2) % lower compared with the 3 % glycated milk protein (21·3 (SEM 1·4) and 2·8 (SEM 0·7) v. 33·3 (SEM 1·7) mmol/l × 6 h, respectively; P < 0·001). Milk protein glycation lowers post-prandial plasma lysine availability in humans. The lower post-prandial availability of lysine following ingestion of proteins with a high glycation level may compromise the anabolic properties of a protein source.

Purpose: We used a human corneal epithelial cell (HCE) line to determine the involvement of the advanced glycation end products (AGEs) / receptor for AGEs (RAGE) couple in corneal epithelium wound healing., Methods: After wounding, HCE cells were exposed to two major RAGE ligands (HMGB1 and AGEs), and wound healing was evaluated using the in vitro scratch assay. Following wound healing, the HCE cells were used to study the influence of the RAGE ligands on HCE proliferation, invasion, and migration. Activation of the nuclear factor (NF)-κB signaling pathway by the AGEs/RAGE couple was tested using a luciferase reporter assay. Functional transcriptional regulation by this pathway was confirmed by quantification of expression of the connexin 43 target gene. For each experiment, specific RAGE involvement was confirmed by small interfering RNA treatments., Results: AGEs treatment at a dose of 100 µg/mL significantly improved the wound healing process in a RAGE-dependent manner by promoting cell migration, whereas HMGB1 had no effect. No significant influence of the AGEs/RAGE couple was observed on cell proliferation and invasion. However, this treatment induced an early activation of the NF-κB pathway and positively regulated the expression of the target gene, connexin 43, at both the mRNA and protein levels., Conclusions: Our results demonstrate that the RAGE pathway is activated by AGEs treatment and is involved in the promotion of corneal epithelial wound healing. This positive action is observed only during the early stages of wound healing, as illustrated by the quick activation of the NF-κB pathway and induction of connexin 43 expression.

Melanoidins are the final Maillard reaction products (protein-carbohydrate complexes) produced in food by prolonged and intense heating. We assessed the impact of the consumption of melanoidins from barley malts on gut microbiota. Seventy-five mice were assigned into five groups, where the control group consumed a non-melanoidin malt diet, and other groups received melanoidin-rich malts in increments of 25% up to 100% melanoidin malts. Feces were sampled at days 0, 1, 2, 3, 7, 14, and 21 and the microbiota was determined using V4 bacterial 16S rRNA amplicon sequencing and short-chain fatty acids (SCFA) by gas chromatography. Increased melanoidins was found to result in significantly divergent gut microbiota profiles and supported sustained SCFA production. The relative abundance of Dorea , Oscillibacter , and Alisitpes were decreased, while Lactobacillus , Parasutterella , Akkermansia , Bifidobacterium , and Barnesiella increased. Bifidobacterium spp. and Akkermansia spp. were significantly increased in mice consuming the highest melanoidin amounts, suggesting remarkable prebiotic potential.

Background: Advanced glycation end products (AGEs) are an important risk factor for the development of cognitive decline in aging and late-onset neurodegenerative diseases including Alzheimer's disease. However, whether and how dietary AGEs exacerbate cognitive impairment and brain mitochondrial dysfunction in the aging process remains largely unknown., Objective: We investigated the direct effects of dietary AGEs on AGE adducts accumulation, mitochondrial function, and cognitive performance in mice., Methods: Mice were fed the AGE+ diet or AGE- diet. We examined levels of AGE adducts in serum and cerebral cortexes by immunodetection and immunohistochemistry, determined levels of reactive oxygen species by biochemical analysis, detected enzyme activity associated with mitochondrial respiratory chain complexes I & IV and ATP levels, and assessed learning and memory ability by Morris Water Maze and nesting behavior., Results: Levels of AGE adducts (MG-H1 and CEL) were robustly increased in the serum and brain of AGE+ diet fed mice compared to the AGE- group. Furthermore, greatly elevated levels of reactive oxygen species, decreased activities of mitochondrial respiratory chain complexes I & IV, reduced ATP levels, and impaired learning and memory were evident in AGE+ diet fed mice compared to the AGE- group., Conclusion: These results indicate that dietary AGEs are important sources of AGE accumulation in vivo, resulting in mitochondrial dysfunction, impairment of energy metabolism, and subsequent cognitive impairment. Thus, reducing AGEs intake to lower accumulation of AGEs could hold therapeutic potential for the prevention and treatment of AGEs-induced mitochondrial dysfunction linked to cognitive decline.

Background: Autoclaving rodent diets is common in laboratory animals, but autoclaving increases the formation of dietary advanced glycation end-products (AGE). We studied the effect of autoclaved (AC) diet alone or in combination with a diet high in bioavailable phosphorus on biochemistries of chronic kidney disease-mineral and bone disorder (CKD-MBD), intestinal gene expression, and oxidative stress., Methods: Male CKD rats (Cy/+) and normal littermates were fed 1 of 3 diets: AC 0.7% phosphorus grain-based diet for 28 weeks (AC); AC diet for 17 weeks followed by non-autoclaved (Non-AC) 0.7% phosphorus casein diet until 28 weeks (AC + Casein); or Non-AC diet for 16 weeks followed by a Non-AC purified diet until 30 weeks (Non-AC + Casein)., Results: AC diets contained ~3× higher AGEs and levels varied depending on the location within the autoclave. Rats fed the AC and AC + Casein diets had higher total AGEs and oxidative stress, irrespective of kidney function. Kidney function was more severely compromised in CKD rats fed AC or AC + Casein compared to Non-AC + Casein. There was a disease-by-diet interaction for plasma phosphorus, parathyroid hormone, and c-terminal fibroblast growth factor-23, driven by high values in the CKD rats fed the AC + Casein diet. Compared to Non-AC + Casein, AC and AC + Casein-fed groups had increased expression of receptor of AGEs and intestinal NADPH oxidase dual oxidase-2, independent of kidney function., Conclusions: Autoclaving rodent diets impacts the progression of CKD and CKD-MBD, highlighting the critical importance of standardizing diets in experiments., (© 2020 S. Karger AG, Basel.)

Context: Consumption of dietary advanced glycation end products (AGEs) is associated with oxidative stress, inflammation, and other chronic conditions commonly associated with obesity., Objective: To analyze the effects of dietary AGEs on complications associated with obesity., Data Sources: This systematic review was conducted and reported according to PRISMA guidelines. The PubMed, Cochrane, and Scopus databases were searched, using the terms "advanced glycation end products," "overweight," and "obesity." The last search was performed in October 2018., Data Extraction: Six studies that evaluated the effects of low-AGE and high-AGE diets were included in the review. The duration of the studies ranged from 1 day to 12 weeks. A comparison of all the compiled data was conducted by the authors., Data Analysis: Circulating and urinary AGE markers, besides soluble receptor for AGEs, were considered as the primary outcomes. The secondary outcomes were cardiometabolic, inflammatory, glycemic, anthropometric, and renal markers., Conclusions: AGE-RAGE interactions can activate the NF-κB (nuclear factor kappa B) signaling pathway and inhibit the PI3K-AKT pathway in adipocytes, which may explain their association with chronic diseases. This interaction can be considered as a novel explanation for the pathogenesis of obesity. AGEs can also be used as a biomarker for monitoring responses to dietary interventions in overweight and obese people., Systematic Review Registration: PROSPERO registration no. CRD42018082745., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

New Findings: What is the central question of this study? Does acute exposure to high molecular weight advanced glycation end products (HMW-AGEs) alter cardiomyocyte contractile function? What is the main finding and its importance? Ventricular cardiomyocytes display reduced Ca 2+ influx, resulting in reduced contractile capacity, after acute exposure to HMW-AGEs, independent of activation of their receptor. Given that HMW-AGEs are abundantly present in our Western diet, a better understanding of underlying mechanisms, especially in patients already displaying altered cardiac function, should be gained for these compounds., Abstract: Sustained elevated levels of high molecular weight advanced glycation end products (HMW-AGEs) are known to promote cardiac dysfunction. Recent data suggest that acutely elevated levels of AGEs occur in situations of increased oxidative stress. Whether this increase might have detrimental effects on cardiac function remains unknown. In this study, we investigated whether acute exposure to HMW-AGEs affects cardiomyocyte function via activation of their receptor (RAGE) signalling pathway. Single cardiomyocytes from the left ventricle of adult male rats were obtained by enzymatic dissociation through retrograde perfusion of the aorta. Functional experiments were performed in cardiomyocytes pre-incubated with or without an anti-RAGE antibody. Unloaded cell shortening and L-type Ca 2+ current amplitude were evaluated in the presence or absence of HMW-AGEs (200 μg ml -1 ). Expression of RAGE, c-Jun N-terminal kinase (JNK) and phosphorylated JNK (pJNK) were assessed by western blot. Experiments were performed at room temperature. After 4 min application of HMW-AGEs, unloaded cell shortening was significantly reduced. This impaired contractile function was related to reduced Ca 2+ influx. These alterations were also observed in cardiomyocytes pre-incubated with anti-RAGE antibody. Our study demonstrates that acute exposure to elevated levels of HMW-AGEs leads to direct and irreversible cardiomyocyte dysfunction, independent of RAGE activation., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Thermally processed food contains advanced glycation end products (AGEs) including N(epsilon)-(carboxymethyl)lysine (CML). Higher AGEs or circulating CML were shown to be associated with pregnancy complications such as preeclampsia and gestational diabetes. It is unclear whether this association is causal. The aim of our study was to analyze the effects of dietary CML and CML-containing thermally processed food on metabolism in pregnant rats. Animals were fed with standard or with AGE-rich diet from gestation day 1. Third group received standard diet and CML via gavage. On gestation day 18, blood pressure was measured, urine and blood were collected and the oral glucose tolerance test was performed. Plasma AGEs were slightly higher in pregnant rats fed with the AGE-rich diet (p=0.09). A non-significant trend towards higher CML in plasma was found in the CML group (p=0.06). No significant differences between groups were revealed in glucose metabolism or markers of renal functions like proteinuria and creatinine clearance. In conclusion, this study does not support the hypothesis that dietary AGEs such as CML might induce harmful metabolic changes or contribute to the pathogenesis of pregnancy complications. The short duration of the rodent gestation warrants further studies analyzing long-term effects of AGEs/CML in preconception nutrition.

Objective: Advanced glycation end products (AGEs) are uremic toxins that result from hyperglycemia, oxidative stress, and systemic inflammation. AGEs are also formed in food during cooking. On the other hand, malnutrition may contribute to AGE formation through its association with oxidative stress and inflammation. AGE accumulation can be measured by skin autofluorescence (SAF) and elevated SAF is independently associated with higher mortality on hemodialysis (HD). We aimed to investigate associations between SAF, dietary AGE intake, and markers of malnutrition in persons receiving HD., Design and Methods: This was a single center cross-sectional study that included 120 participants on HD dialyzing at least 3 times per week for 3-4 hours. SAF was measured using an Autofluorescence Reader. Dietary AGE, energy, protein and fat intake, handgrip strength (HGS), anthropometric measurements and biochemistry were also assessed. The Subjective Global Assessment was performed to evaluate the nutritional status., Results: SAF was higher in malnourished participants and correlated negatively with serum albumin and cholesterol, HGS and energy, protein and fat intake and positively with C-reactive protein and chronological age; SAF did not correlate with dietary AGE intake. Multivariable linear regression analysis showed that diabetes, smoking, serum albumin, HGS, protein intake, and dialysis vintage were independent predictors of increased SAF., Conclusions: Markers of malnutrition were more important determinants of increased SAF than high dietary AGE intake in this HD population. Nutritional interventions aiming to reduce SAF by correcting malnutrition should therefore be investigated. The observed association between higher SAF and malnutrition may in part explain the previously reported association between higher SAF and mortality on HD., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Advanced glycation end products (AGEs) are formed in in vivo, and accumulate in tissues and body fluids during ageing. Endogenous AGE-modified proteins show altered structure and function, and may interact with receptor for AGEs (RAGE) resulting in production of reactive oxygen species, inflammatory, atherogenic and diabetogenic responses. AGEs are also formed in thermally processed foods. Studies in rodents document that dietary AGEs are partially absorbed into circulation, and accumulate in different tissues. Knowledge on the health effects of high dietary intake of AGEs is incomplete and contradictory. In this overview we discuss the data from experimental and clinical studies, either those supporting the assumption that restriction of dietary AGEs associated with health benefits, or data suggesting that dietary intake of AGEs associates with positive health outcomes. We polemicize whether the effects of exaggerated intake or restriction of highly thermally processed foods might be straightforward interpreted as the effects of AGEs-rich vs. AGEs-restricted diets. We also underline the lack of studies, and thus a poor knowledge, on the effects of different single chemically defined AGEs administration, concurrent intake of different dietary AGEs, of load with dietary AGEs corresponding to the habitual diet in humans, and on those of dietary AGEs in vulnerable populations, such as infants and particularly elderly., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We recently reported augmentation of lipid peroxidation products in the liver of intrauterine growth-restricted (IUGR) piglets fed a high load of Maillard reaction products (MRPs) during suckling period. The underlying mechanisms of MRPs effects remain unknown. Here, we studied the long-term impact of MRPs exposure on liver oxidative status of IUGR juvenile pigs. Livers of 54-day-old pigs suckled with formula containing either a high (HHF, n=8) or a low (LHF: n=8) load of MRPs were analyzed for protein carbonylation levels , activities and messenger RNA (mRNA) expression of glutathione (GSH) and main antioxidant regulators of redox homeostasis [Superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measured. In addition, mRNA levels of miRNA-21 and miRNA-155 were measured. The liver of HHF group exhibited a high level of lipid peroxidation with significantly increased expression and activity of SOD. Further in liver of HHF group, CAT activity was decreased as compared with LHF group, though with comparable total protein carbonyl contents, GSH contents, and expression of GPx and microRNAs (miRNA-21 and miRNA-155). Our findings suggest that the potential mechanism of MRPs-mediated oxidative stress programming in liver of IUGR piglets may occur via impairment of antioxidant defenses.

Background & Aims: Advanced glycation endproducts (AGEs) are formed by the reaction between reducing sugars and proteins. AGEs in the body have been associated with several age-related diseases. High-heat treated and most processed foods are rich in AGEs. The aim of our study was to investigate whether dietary AGEs, are associated with plasma and urinary AGE levels., Methods: In 450 participants of the Cohort on Diabetes and Atherosclerosis Maastricht study (CODAM study) we measured plasma and urine concentrations of the AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) using UPLC-MS/MS. We also estimated dietary intake of CML, CEL and MG-H1 with the use of a dietary AGE database and a food frequency questionnaire (FFQ). We used linear regression to investigate the association between standardized dietary AGE intake and standardized plasma or urinary AGE levels, after adjustment for age, sex, glucose metabolism status, waist circumference, kidney function, energy- and macro-nutrient intake, smoking status, physical activity, alcohol intake, LDL-cholesterol and markers of oxidative stress., Results: We found that higher intake of dietary CML, CEL and MG-H1 was associated with significantly higher levels of free plasma and urinary CML, CEL and MG-H1 (βCML = 0.253 (95% CI 0.086; 0.415), βCEL = 0.194 (95% CI 0.040; 0.339), βMG-H1 = 0.223 (95% CI 0.069; 0.373) for plasma and βCML = 0.223 (95% CI 0.049; 0.393), βCEL = 0.180 (95% CI 0.019; 0.332), βMG-H1 = 0.196 (95% CI 0.037; 0.349) for urine, respectively). In addition, we observed non-significant associations of dietary AGEs with their corresponding protein bound plasma AGEs., Conclusion: We demonstrate that higher intake of dietary AGEs is associated with higher levels of AGEs in plasma and urine. Our findings may have important implications for those who ingest a diet rich in AGEs., (Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Membrane damage via the Maillard reaction products of half-fin anchovy hydrolysates and glucose (designated as HAHp(9.0)-G MRPs) was evaluated using an in vitro Escherichia coli (E. coli) model. The incubation of HAHp(9.0)-G MRPs led to a significant increase in outer and inner membrane permeability. Furthermore, membrane integrity was seriously destroyed, as observed by scanning electron microscopy and indicated by the decreased fluorescence signal of 4',6-diamidino-2-phenylindole stain. Interestingly, HAHp(9.0)-G MRPs induced significant hydrogen peroxide (H 2 O 2 ) production in E. coli after 3 h of incubation, which contributed to the antibacterial activity of HAHp(9.0)-G MRPs. As one of the reactive oxygen species, excess H 2 O 2 in vivo might impair the antioxidant balance. Therefore, the oxidative status of healthy mice after short-term intake of HAHp(9.0)-G MRPs was investigated. After the administration of HAHp(9.0)-G MRPs at low dose (0.1 g per kg per day body weight) and high dose (1.0 g per kg per day body weight) for 14 days, the body weight of female mice decreased, and the body weight of male mice increased. However, the administration of HAHp(9.0)-G MRPs did not affect the hepatic antioxidant defense in either female or male mice. Some positive responses, like increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) as well as decreased lipid peroxidation (LPO) content, were detected, especially in liver. Though the decrease in catalase activity indicated that the glycation compounds from HAHp(9.0)-G MRPs might be absorbed in vivo, the lower SOD/GPx ratios of HAHp(9.0)-G MRPs-fed groups than those of the normal groups also suggested that the administration of HAHp(9.0)-G MRPs could reduce LPO stress in mice. Our results suggest that a higher antioxidant status could be generated in the healthy animals after fed with HAHp(9.0)-G MRPs for 14 days.

The contribution of environmental factors to pancreatic islet damage in type 1 diabetes remains poorly understood. In this study, we crossed mice susceptible to type 1 diabetes, where parental male (CD8 + T cells specific for IGRP 206-214 ; NOD8.3) and female (NOD/ShiLt) mice were randomized to a diet either low or high in AGE content and maintained on this diet throughout pregnancy and lactation. After weaning, NOD8.3 + female offspring were identified and maintained on the same parental feeding regimen for until day 28 of life. A low AGE diet, from conception to early postnatal life, decreased circulating AGE concentrations in the female offspring when compared to a high AGE diet. Insulin, proinsulin and glucagon secretion were greater in islets isolated from offspring in the low AGE diet group, which was akin to age matched non-diabetic C57BL/6 mice. Pancreatic islet expression of Ins2 gene was also higher in offspring from the low AGE diet group. Islet expression of glucagon, AGEs and the AGE receptor RAGE, were each reduced in low AGE fed offspring. Islet immune cell infiltration was also decreased in offspring exposed to a low AGE diet. Within pancreatic lymph nodes and spleen, the proportions of CD4 + and CD8 + T cells did not differ between groups. There were no significant changes in body weight, fasting glucose or glycemic hormones. This study demonstrates that reducing exposure to dietary AGEs throughout gestation, lactation and early postnatal life may benefit pancreatic islet secretion and immune infiltration in the type 1 diabetic susceptible mouse strain, NOD8.3.

We have previously shown that an isoenergetic low advanced glycation end products (AGEs) diet matched for macronutrient content improved insulin sensitivity compared to high AGE diet. Here, we evaluated the differences in micronutrient intake of these two dietary patterns and if they could explain differences in insulin sensitivity. Participants consumed the intervention diets each for 2 weeks with 4 weeks of habitual dietary intake (washout) in-between. Dietary analysis revealed that the high AGE diet contained greater levels of retinol equivalents (RE) (478.9 + 151.3 μg/day versus 329.0 + 170.0 μg/day; p < .006), vitamin A (806.3 + 223.5 (μg RE)/day versus 649.1 + 235.8 (μg RE)/day; p < .05) and thiamine (2.3 + 0.6 mg/day versus 1.6 + 0.4 mg/day; p = .014) compared to the low AGE diet. The changes in polyunsaturated fat, retinol, vitamin A and thiamine did not correlate with changes in insulin sensitivity (all p > .1) therefore are unlikely to explain observed changes in insulin sensitivity. (clinicaltrials.gov:NCT00422253).

Background and Aims: Modern diets are high in advanced glycation end-products (dAGEs), derived from processing methods, exerting a pivotal role in promoting atherosclerotic risk. In this cross-sectional study we investigate the relationship between dAGE intake, arterial stiffness, inflammatory profile and macronutrient composition, in subjects with type 2 diabetes without overt cardiovascular disease., Methods and Results: Arterial stiffness, carboxy-methyl-lysine, endogenous secretory receptor for AGEs (esRAGE), high sensitivity C reactive protein (hs-CRP), S100A12 and macronutrient intake were evaluated in 85 subjects with type 2 diabetes. The subjects were stratified into two groups according to dAGE consumption: high and low dAGE intake (≥ or <15.000 kU/day, respectively). Subjects with high dAGE intake (n = 45) showed a higher augmentation, augmentation index and pulse wave velocity (PWV) compared with those subjects with low dAGE intake (18 ± 5.4 vs 12.2 ± 6.3 mmHg, P < 0.05; 38.3 ± 5.4 vs 29.3 ± 10%; 9.2 ± 1.4 m/sec vs 7.9 ± 1.7, P < 0.05, respectively). hs-CRP were higher in subjects with high dAGE intake [0.42 (0.18-0.54) vs 0.21 (0.14-0.52) mg/dL, P < 0.05] whereas esRAGE plasma levels were lower [0.16 (0.23-0.81) vs 0.2 (0.14-0.54) ng/dL, P < 0.05]. Simple regression analysis showed a correlation between dAGEs and fat intake. Multivariate analysis showed an independent association between augmentation, systolic blood pressure (BP) and dAGE consumption; BMI and esRAGE were the major determinants of PWV., Conclusions: Our data suggests that a chronic high dAGE diet could lead to a vascular dysfunction and inflammatory activation, contributing to the development of vascular complications in subjects with type 2 diabetes. Testing this hypothesis may represent a direction of future research., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Hepatocyte cell death is a key feature of nonalcoholic steatohepatitis (NASH); however, the pathogenesis of NASH currently remains unclear. We aimed to investigate the effects of intracellular glyceraldehyde (GA)-derived advanced glycation end-products (GA-AGEs) on human hepatocyte cell death. The accumulation of intracellular GA-AGEs has been associated with the induction of DNA damage and hepatocyte necrotic cell death. Among intracellular GA-AGEs, caspase-3 has been identified as a GA-AGE-modified protein with abrogated protein function. Furthermore, the activation of caspase-3 and induction of hepatocyte apoptosis by camptothecin, a DNA-damaging agent, was suppressed by a treatment with GA. These results suggest the inhibitory effects of GA-AGE-modified caspase-3 on the induction of DNA-damage-induced apoptosis, which is associated with hepatocyte necrosis. Therefore, the suppression of necrosis, the inflammatory form of cell death, by the accumulation of GA-AGEs and GA-AGE-modified caspase-3 may represent a novel therapeutic target for the pathogenesis of NASH.

Bread crust (BC) is one of the major sources of Maillard reaction products (MRPs) in the Western diet. This work was designed to analyze the impact of diets containing important levels of MRPs from BC on intestinal bacterial growth and short chain fatty acids (SCFAs) production in adult rats. Additionally, the pools of compounds excreted in feces attending to their molecular weights were analyzed. Rats were fed for 88days a control diet or diets containing BC or its soluble high molecular weight (HMW), soluble low molecular weight (LMW) or insoluble fractions, respectively. Intestinal (cecum) microbiota composition was determined by qPCR analysis. Consumption of the BC diet lowered (P<0.05) Lactobacillus spp. and Bifidobacterium spp. log 10 counts (8 and 14%, respectively), an effect for which soluble LMW and HMW fractions of BC seemed to be responsible. In these same animals, Escherichia/Shigella counts increased by around 45% (P<0.05), a fact which correlated with a higher production of formic acid in feces (r=0.8197, P=0.0458), and likely caused by the combined consumption of all MRPs contained in the BC. A significant 5-fold increment (P<0.05) was detected in the fecal proportion of propionic acid in the BC group, one of the products that have largely been associated with anti-inflammatory actions. Regarding the distribution of MRPs in feces, only the LMW fed group exhibited a predominance of those ranging between 90,000-1000Da, whereas the rest of the groups presented higher amounts of products above 90,000Da. It is concluded that dietary Maillard reaction products are in vivo fermented by the gut microbiota, thereby changing both the pattern of SCFAs production and the microbiota composition., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Studies examining the effects of consumption of diets low in advanced glycation end products (AGEs) on cardiometabolic parameters are conflicting. Hence, we performed a meta-analysis to determine the effect of low AGE diets in reducing cardiometabolic risk factors. Seventeen randomised controlled trials comprising 560 participants were included. Meta-analyses using random effects models were used to analyse the data. Low AGE diets decreased insulin resistance (mean difference [MD] -1.3, 95% CI -2.3, -0.2), total cholesterol (MD -8.5 mg/dl, 95% CI -9.5, -7.4) and low-density lipoprotein (MD -2.4 mg/dl, 95% CI -3.4, -1.3). There were no changes in weight, fasting glucose, 2-h glucose and insulin, haemoglobin A1c, high-density lipoprotein or blood pressure. In a subgroup of patients with type 2 diabetes, a decrease in fasting insulin (MD -7 µU/ml, 95% CI -11.5, -2.5) was observed. Tumour necrosis factor α, vascular cell adhesion molecule-1, 8-isoprostane, leptin, circulating AGEs and receptor for AGEs were reduced after consumption of low AGE diets with increased adiponectin and sirtuin-1. Our findings suggest that diets low in AGEs may be an effective strategy for improving cardiometabolic profiles in individuals with and without type 2 diabetes.

Because of the paucity of information regarding metabolic effects of advanced glycation end products (AGEs) on liver, we evaluated effects of AGEs chronic administration in (1) insulin sensitivity; (2) hepatic expression of genes involved in AGEs, glucose and fat metabolism, oxidative stress and inflammation and; (3) hepatic morphology and glycogen content. Rats received intraperitoneally albumin modified (AlbAGE) or not by advanced glycation for 12 weeks. AlbAGE induced whole-body insulin resistance concomitantly with increased hepatic insulin sensitivity, evidenced by activation of AKT, inactivation of GSK3, increased hepatic glycogen content, and decreased expression of gluconeogenesis genes. Additionally there was reduction in hepatic fat content, in expression of lipogenic, pro-inflamatory and pro-oxidative genes and increase in reactive oxygen species and in nuclear expression of NRF2, a transcription factor essential to cytoprotective response. Although considered toxic, AGEs become protective when administered chronically, stimulating AKT signaling, which is involved in cellular defense and insulin sensitivity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Rivaroxaban is an oral direct factor Xa inhibitor approved for the treatment of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation. Despite its efficacy, rivaroxaban therapy results in adverse effects and complications, such as bleeding. Angiotensin II (AngII) is implicated in many cardiovascular conditions, such as hypertension and heart failure. In this study, we investigate whether AngII influences anticoagulant effects of rivaroxaban by using an experimental mouse model with type 2 diabetes mellitus and advanced glycation end product (AGE)-exposed human umbilical vein endothelial cells (HUVECs). We found that AngII promoted the anticoagulant effects of rivaroxaban in KKAy mice. The combination of rivaroxaban and AngII enhanced in vivo tissue factor pathway inhibitor (TFPI) activity and induced TFPI expression and activity in AGE-exposed HUVECs. Angiotensin type 2 receptor (AT2R) and Mas antagonists attenuated the AngII-enhanced anticoagulant action of rivaroxaban in vivo, and abolished the increased endothelial TFPI expression and activity. However, angiotensin type 1 receptor (AT1R) antagonist exerted no effects. Additionally, combination of rivaroxaban and AngII induced aortic AT2R and Mas expression. Our data suggest that the anticoagulant effects of rivaroxaban are promoted by AngII via AT2R and Mas signaling. These findings are significant for the clinical administration of rivaroxaban.

RAGE is important in the development of neurodegenerative diseases. The present study was designed to investigate the effect of hydrogen sulfide (H 2 S, an endogenous gaseous mediator) on the cytotoxicity caused by RAGE activation during the chronic oxidative stress. Aβ 1-42 decreased cell viability and induced cell senescence in SH-SY5Y cells. Treatment with advanced glycation end products (AGEs) induced cell injury in HEK293 cells stably expressing RAGE (HEK293-RAGE) and stimulated inflammatory responses in SH-SY5Y cells. Pretreatment of SH-SY5Y cells with an H 2 S donor, NaHS, significantly attenuated the above harmful effects caused by Aβ 1-42 or AGEs. Western blotting analysis shows that oxidative stress enhanced RAGE protein expression which was attenuated by either NaHS or over-expression of cystathionine β-synthase (CBS), a critical enzyme for producing H 2 S in brain cells. Both Western blots and split GFP complementation analysis demonstrate that NaHS reduced H 2 O 2 -enhanced RAGE dimerization. Immunofluorescence analysis shows that H 2 O 2 up-regulated the membrane expression of wild-type RAGE. However, H 2 O 2 -enhanced expression of the RAGE harboring C259S/C310S double mutation (DM-RAGE) was observed in the endoplasmic reticulum. Treatment with NaHS attenuated the effects of H 2 O 2 on the protein expression of WT-RAGE, but not that of DM-RAGE. Cycloheximide chase and ubiquitination assays show that NaHS reduced the half-life of WT-RAGE to a similar level of DM-RAGE. S-sulfhydration assay with the tag-switch technique demonstrate that H 2 S may directly S-sulfhydrate the C259/C301 residues. Our data suggest that H 2 S reduces RAGE dimer formation and impairs its membrane stability. The lowered plasma membrane abundance of RAGE therefore helps to protect cells against various RAGE mediated pathological effects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Diets enriched with advanced glycation end products (AGE) have recently been related to muscle dysfunction processes. However, it remains unclear whether long-term exposure to an AGE-enriched diet impacts physiological characteristics of skeletal muscles. Therefore, we explored the differences in skeletal muscle mass, contractile function and molecular responses between mice receiving a diet high in AGE (H-AGE) and low in AGE (L-AGE) for 16 weeks. There were no significant differences between L-AGE and H-AGE mice with regard to body weight, food intake or epididymal fat pad weight. However, extensor digitorum longus (EDL) and plantaris (PLA) muscle weights in H-AGE mice were lower compared with L-AGE mice. Higher levels of N ε -(carboxymethyl)-l-lysine, a marker for AGE, in EDL muscles of H-AGE mice were observed compared with L-AGE mice. H-AGE mice showed lower muscle strength and endurance in vivo and lower muscle force production of PLA muscle in vitro. mRNA expression levels of myogenic factors including myogenic factor 5 and myogenic differentiation in EDL muscle were lower in H-AGE mice compared with L-AGE mice. The phosphorylation status of 70-kDa ribosomal protein S6 kinase Thr389, an indicator of protein synthesis signalling, was lower in EDL muscle of H-AGE mice than that of L-AGE mice. These findings suggest that long-term exposure to an AGE-enriched diet impairs skeletal muscle growth and muscle contractile function, and that these muscle dysfunctions may be attributed to the inhibition of myogenic potential and protein synthesis.

Aim: To determine if manipulation of dietary advanced glycation end product (AGE), intake affects non-alcoholic fatty liver disease (NAFLD) progression and whether these effects are mediated via RAGE., Methods: Male C57Bl6 mice were fed a high fat, high fructose, high cholesterol (HFHC) diet for 33 wk and compared with animals on normal chow. A third group were given a HFHC diet that was high in AGEs. Another group was given a HFHC diet that was marinated in vinegar to prevent the formation of AGEs. In a second experiment, RAGE KO animals were fed a HFHC diet or a high AGE HFHC diet and compared with wildtype controls. Hepatic biochemistry, histology, picrosirius red morphometry and hepatic mRNA were determined., Results: Long-term consumption of the HFHC diet generated significant steatohepatitis and fibrosis after 33 wk. In this model, hepatic 4-hydroxynonenal content (a marker of chronic oxidative stress), hepatocyte ballooning, picrosirius red staining, α-smooth muscle actin and collagen type 1A gene expression were all significantly increased. Increasing the AGE content of the HFHC diet by baking further increased these markers of liver damage, but this was abrogated by pre-marination in acetic acid. In response to the HFHC diet, RAGE(-/-) animals developed NASH of similar severity to RAGE(+/+) animals but were protected from the additional harmful effects of the high AGE containing diet. Studies in isolated Kupffer cells showed that AGEs increase cell proliferation and oxidative stress, providing a likely mechanism through which these compounds contribute to liver injury., Conclusion: In the HFHC model of NAFLD, manipulation of dietary AGEs modulates liver injury, inflammation, and liver fibrosis via a RAGE dependent pathway. This suggests that pharmacological and dietary strategies targeting the AGE/RAGE pathway could slow the progression of NAFLD., Competing Interests: Conflict-of-interest statement: To the best of our knowledge, no conflict of interest exists.

Advanced glycation end products (AGEs) are associated with various diseases, especially during aging and the development of diabetes and uremia. To better understand these biological processes, investigation of the in vivo kinetics of AGEs, i.e., analysis of trafficking and clearance properties, was carried out by molecular imaging. Following the preparation of Cy7.5-labeled AGE-albumin and intravenous injection in BALB/cA-nu/nu mice, noninvasive fluorescence kinetics analysis was performed. In vivo imaging and fluorescence microscopy analysis revealed that non-enzymatic AGEs were smoothly captured by scavenger cells in the liver, i.e., Kupffer and other sinusoidal cells, but were unable to be properly cleared from the body. Overall, these results highlight an important link between AGEs and various disorders associated with them, which may serve as a platform for future research to better understand the processes and mechanisms of these disorders.

Background and Objectives: Diabetes is a major risk factor for periodontitis and there is a close relationship between the degree of hyperglycemia and the severity of periodontitis. Advanced glycation end-products (AGEs) accumulate in various tissues under diabetic conditions. AGEs in the periodontal tissues probably play a role in upregulating periodontal inflammation; however, the association of AGEs with the severity of periodontitis has not been fully clarified. Lipopolysaccharide from Porphyromonas gingivalis (P-LPS) is a potent pathogenic factor in periodontitis. Although the independent effect of AGE or P-LPS on osteoblastic cells has been reported in vitro, the effect of adding both has not been clearly elucidated. In this study, to explore factors aggravating diabetic periodontitis, we investigated the effects of AGE and P-LPS on the expression of osteoblastic markers and the expression of inflammation-related markers in vitro., Material and Methods: Rat bone marrow cells were cultured, and alkaline phosphatase activity and bone nodule formation were evaluated as osteoblastic markers. Reverse transcription-polymerase chain reaction was performed to determine the mRNA expression of molecules associated with bone and inflammation. Protein levels of osteocalcin and interleukin-1β (IL-1β) were measured using enzyme-linked immunosorbent assay., Results: AGEs and P-LPS independently reduced alkaline phosphatase activity and bone nodule formation. The addition of both AGE and P-LPS (AGE+P-LPS) further decreased these markers. Reverse transcription-polymerase chain reaction analysis revealed that AGE+P-LPS markedly decreased the mRNA expression of osteoblast-related molecules such as type 1 collagen, osteocalcin and Cbfa1, and markedly increased that of inflammation-related molecules such as IL1β and S100A8. AGE and P-LPS decreased the protein level of osteocalcin and increased that of IL-1β, and a further increase of IL-1β was detected for AGE+P-LPS., Conclusion: AGEs and P-LPS inhibited the expression of osteoblastic markers and increased the levels of inflammatory markers in rat bone marrow cells, suggesting that both AGE and P-LPS may be important factors associated with the aggravation of diabetic periodontitis., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The consumption of advanced glycation end products (AGEs) has increased because of modern food processing and has been linked to the development of type 2 diabetes in rodents., Objective: We determined whether changing dietary AGE intake could modulate insulin sensitivity and secretion in healthy, overweight individuals., Design: We performed a double-blind, randomized, crossover trial of diets in 20 participants [6 women and 14 men; mean ± SD body mass index (in kg/m(2)): 29.8 ± 3.7]. Isoenergetic- and macronutrient-matched diets that were high or low in AGE content were alternately consumed for 2 wk and separated by a 4-wk washout period. At the beginning and end of each dietary period, a hyperinsulinemic-euglycemic clamp and an intravenous glucose tolerance test were performed. Dietary, plasma and urinary AGEs N(€)-(carboxymethyl)lysine (CML), N(€)-(carboxyethyl)lysin (CEL), and methylglyoxal-derived hydroimadazolidine (MG-H1) were measured with the use of mass spectrometry., Results: Participants consumed less CML, CEL, and MG-H1 during the low-AGE dietary period than during the high-AGE period (all P < 0.05), which was confirmed by changes in urinary AGE excretion. There was an overall difference in insulin sensitivity of -2.1 mg · kg(-1) · min(-1) between diets (P = 0.001). Insulin sensitivity increased by 1.3 mg · kg(-1) · min(-1) after the low-AGE diet (P = 0.004), whereas it showed a tendency to decrease by 0.8 mg · kg(-1) · min(-1) after the high-AGE diet (P = 0.086). There was no difference in body weight or insulin secretion between diets (P = NS)., Conclusions: A diet that is low in AGEs may reduce the risk of type 2 diabetes by increasing insulin sensitivity. Hence, a restriction in dietary AGE content may be an effective strategy to decrease diabetes and cardiovascular disease risks in overweight individuals. This trial was registered at clinicaltrials.gov as NCT00422253., (© 2016 American Society for Nutrition.)

Aim: Apoptosis participated in the pathological process of myocardial ischemia/reperfusion (I/R) injury. Previous studies have reported that endogenous substance sRAGE protect against I/R injury through inhibiting myocardial apoptosis. But the mechanisms are currently unknown. Prior work has demonstrated that ubiquitin proteasome system (UPS) dysfunction is closely related to apoptosis. We explored the potential role of UPS in the effect of sRAGE inhibition on I/R-induced myocardial apoptosis., Methods and Results: Adult male C57BL mice treated with sRAGE (100μg/day, i.p.) or saline were performed to ligate left anterior descending coronary artery (LAD) as an in vivo model. As an in vitro model, primary murine cardiomyocytes pretreated with sRAGE or sRAGE-containing adenovirus were simulated I/R by "ischemia buffer". The TUNEL and caspase-3 activity were assessed. Also the activity and expression of proteasome were detected. sRAGE decreased the number of TUNEL-positive cardiomyocytes and caspase-3 activity, however, the inhibition of sRAGE on I/R-induced apoptosis was abolished by proteasome inhibitor Bortezimb (BTZ). sRAGE inhibited the decreased proteasome activity, also the reduction in protein and gene levels of β1i and β5i following I/R. Suppression of STAT3 blocked the inhibition of sRAGE on apoptosis induced by I/R. The chromatin immunoprecipitation (CHIP) results confirmed that sRAGE promoted activating STAT3 binding to β1i and β5i promoter., Conclusions: Our data suggest that the inhibition of sRAGE on I/R-induced apoptosis is associated with activation and expression of proteasome, including improved proteasome activity and elevated β1i and β5i expression mediated by STAT3 activation. We predict that sRAGE is a novel intervention to target UPS activation for preventing and treating myocardial apoptosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

There is growing evidence of the involvement of advanced glycation end products (AGEs) in the pathogenesis of neurodegenerative processes including Alzheimer's disease (AD) and their function as a seed for the aggregation of Aβ, a hallmark feature of AD. AGEs are formed endogenously and exogenously during heating and irradiation of foods. We here examined the effect of a diet high in AGEs in the context of an irradiated diet on memory, insoluble Aβ42 , AGEs levels in hippocampus, on expression of the receptor for AGEs (RAGE), and on oxidative stress in the vasculature. We found that AD-like model mice on high-AGE diet due to irradiation had significantly poorer memory, higher hippocampal levels of insoluble Aβ42 and AGEs as well as higher levels of oxidative stress on vascular walls, compared to littermates fed an isocaloric diet. These differences were not due to weight gain. The data were further supported by the overexpression of RAGE, which binds to Aβ42 and regulates its transport across the blood-brain barrier, suggesting a mediating pathway. Because exposure to AGEs can be diminished, these insights provide an important simple noninvasive potential therapeutic strategy for alleviating a major lifestyle-linked disease epidemic., (© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Objective: Accumulation of advanced glycation end products (AGEs) contributes to the development of diabetic ulcers. Recent evidence indicates that AGEs administration enhanced autophagy in many cell types. As a positive trigger of autophagy, the effect of AGEs on autophagy in skin tissues and fibroblasts remains unknown., Methods: Skin tissues were isolated from Spreqne-Dawley rats and immunohistochemical staining was performed to analyze the location of LC3 and FOXO1 in skin tissues. Then primary cultured foreskin fibroblast cells with treated with AGEs and the effect of AGEs on autophagy was investigated. Protein level expressions of LC3, Beclin-1 and FOXO1 in fibroblasts were analyzed by Western blotting. Autophagic flux is detected with autophagy inhibitor chloroquine and mRFP-GFP-LC3 tandem construct., Results: Compared with skin from normal rats, immunohistochemical staining shows a predominant LC3 localization in fibroblasts cytoplasm in diabetic rats. Elevated expression of FOXO1 also existed in diabetic rats dermis fibroblasts when compared with normal rats in immunohistochemical analysis. In human skin fibroblasts cells, AGEs administration stimulated the autophagy related LC3-II/LC3-I and Beclin-1 expressions and increased autophagy flux. In mRFP-GFP-LC3 puncta formation assays, both autolysosome and autophagosome were increased in human fibroblasts after treatment with AGEs. Fibroblasts exposed to AGEs also have increased FOXO1 expression compared with control group., Conclusion: AGEs could induce autophagy at least in part via regulating the FOXO1 activity in diabetic skin tissues and fibroblasts., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Advanced glycosylation end products (AGEs) are endogenous inflammatory mediators that induce apoptosis of mesenchymal stem cells. A potential mechanism includes increased generation of reactive oxygen species (ROS). MicroRNA-223 (miR-223) is implicated in the regulation of cell growth and apoptosis in several cell types. Here, we tested the hypothesis that antioxidants N-acetylcysteine (NAC) and ascorbic acid 2-phosphate (AAP) inhibit AGE-induced apoptosis via a microRNA-dependent mechanism in human adipose tissue-derived stem cells (ADSCs). Results showed that AGE-HSA enhanced apoptosis and caspase-3 activity in ADSCs. AGE-HSA also increased ROS generation and upregulated the expression of miR-223. Interestingly, reductions in ROS generation and apoptosis, and upregulation of miR-223 were found in ADSCs treated with antioxidants NAC and AAP. Furthermore, miR-223 mimics blocked antioxidant inhibition of AGE-induced apoptosis and ROS generation. Knockdown of miR-223 amplified the protective effects of antioxidants on apoptosis induced by AGE-HSA. miR-223 acted by targeting fibroblast growth factor receptor 2. These results indicate that NAC and AAP suppress AGE-HSA-induced apoptosis of ADSCs, possibly through downregulation of miR-223.

Dietary advanced glycation end products (AGE) formed during heating of food have gained interest as potential nutritional toxins with adverse effects on inflammation and glucose metabolism. In the present study, we investigated the short-term effects of high and low molecular weight (HMW and LMW) dietary AGE on insulin sensitivity, expression of the receptor for AGE (RAGE), the AGE receptor 1 (AGER1) and TNF-α, F2-isoprostaglandins, body composition and food intake. For 2 weeks, thirty-six Sprague-Dawley rats were fed a diet containing 20% milk powder with different proportions of this being given as heated milk powder (0, 40 or 100%), either native (HMW) or hydrolysed (LMW). Gene expression of RAGE and AGER1 in whole blood increased in the group receiving a high AGE LMW diet, which also had the highest urinary excretion of the AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1). Urinary excretion of N ε-carboxymethyl-lysine increased with increasing proportion of heat-treated milk powder in the HMW and LMW diets but was unrelated to gene expression. There was no difference in insulin sensitivity, F2-isoprostaglandins, food intake, water intake, body weight or body composition between the groups. In conclusion, RAGE and AGER1 expression can be influenced by a high AGE diet after only 2 weeks in proportion to MG-H1 excretion. No other short-term effects were observed.

Bisphosphonates such as alendronate are antiosteoporotic drugs that inhibit the activity of bone-resorbing osteoclasts and secondarily promote osteoblastic function. Diabetes increases bone-matrix-associated advanced glycation end products (AGEs) that impair bone marrow progenitor cell (BMPC) osteogenic potential and decrease bone quality. Here we investigated the in vitro effect of alendronate and/or AGEs on the osteoblastogenic, adipogenic, and chondrogenic potential of BMPC isolated from nondiabetic untreated rats. We also evaluated the in vivo effect of alendronate (administered orally to rats with insulin-deficient Diabetes) on long-bone microarchitecture and BMPC multilineage potential. In vitro , the osteogenesis (Runx2, alkaline phosphatase, type 1 collagen, and mineralization) and chondrogenesis (glycosaminoglycan production) of BMPC were both decreased by AGEs, while coincubation with alendronate prevented these effects. The adipogenesis of BMPC (PPAR γ , intracellular triglycerides, and lipase) was increased by AGEs, and this was prevented by coincubation with alendronate. In vivo , experimental Diabetes (a) decreased femoral trabecular bone area, osteocyte density, and osteoclastic TRAP activity; (b) increased bone marrow adiposity; and (c) deregulated BMPC phenotypic potential (increasing adipogenesis and decreasing osteogenesis and chondrogenesis). Orally administered alendronate prevented all these Diabetes-induced effects on bone. Thus, alendronate could improve bone alterations in diabetic rats by preventing the antiosteogenic, antichondrogenic, and proadipocytic effects of AGEs on BMPC.

It has been suggested that advanced glycation end (AGE) products, via cognate receptor activation, are implicated in several diseases, including Alzheimer's disease. The NMDA receptor-nitric oxide pathway appears to be influenced by AGE products and involved in the pathogenesis of this type of dementia. In this study, C57BL/6J (WT) and transgenic (Tg2576) mice expressing human mutant amyloid precursor protein were kept on prolonged (8 months) diets containing regular or high amounts of AGE products. After the decapitation of 11-months old mice, brain tissue analyses were performed [expressions of the NR1, NR2A and NR2B subunits of NMDA receptors, activities of neuronal, endothelial and inducible nitric oxide synthase (nNOS, eNOS and iNOS)]. Moreover, levels of malondialdehyde and of human amyloid β 1-42 were estimated. We found increased activity of nNOS in WT mice maintained on a high compared to regular AGE diet; however, no similar differences were found in Tg2576 mice. In addition, we observed an increase in NR1 expression in Tg2576 compared to WT mice, both kept on a diet high in AGE products. Correlation analyses performed on mice kept on the regular AGE diet supported close links between particular subunits (NR2A-NR2B, in WT as well as in Tg2576 mice), between subunits and synthase (NR2A/NR2B-nNOS, only in WT mice) or between particular synthases (nNOS-iNOS, only in WT). Correlation analysis also revealed differences between WT mice kept on both diets (changed correlations between NR2A/NR2B-nNOS, between nNOS-eNOS and between eNOS-iNOS). Malondialdehyde levels were increased in both Tg2576 groups when compared to the corresponding WT mice, but no effects of the diets were observed. Analogously, no significant effects of diets were found in the levels of soluble or insoluble amyloid β 1-42 in Tg2576 mice. Our results demonstrate that prolonged ingestion of AGE products can influence the NMDA receptor-nitric oxide pathway in the brain and that only WT mice, not Tg2576 mice, are able to maintain homeostasis among subunits and synthases or among particular synthases. The prolonged application of AGE products enhanced differences between 11-months old Tg2576 and WT mice regarding this pathway. Observed differences in the pathway between WT mice kept on regular or high AGE diets suggest that the prolonged application of a diet low in AGE products could have beneficial effects in older or diabetic people and perhaps also in people with Alzheimer's disease.

Scope: Formula-derived dietary advanced glycation end products (AGEs) may promote programming of inflammation and oxidative stress in the kidney of intrauterine growth retardation (IUGR) piglets., Methods and Results: IUGR piglets received either a low temperature heated formula (n = 8) or a high temperature heated formula (HHF: n = 8) or suckled naturally for 3 wk postnatally. Then they were fed with normal ad libitum regular diet. N(ε)-carboxymethyllysine (CML) was measured in plasma, feces, and formula by HPLC/MS-MS. CML was detected by immunofluorescence in kidney cells. Target renin-angiotensin-apoptotic, pro-inflammatory genes-p62 NF-κB, and soluble receptor of AGE (sRAGE) levels were quantified. Compared with that in controls, free CML and plasma urea increased significantly in the HHF-fed group at PND36 (p < 0.05). CML was detected in the nuclei of renal tubular cells of formula-fed piglets but not in suckled ones. This presence of CML was associated with the activation of the soluble receptor of AGE. AT1, AT2, caspase 3, caspase 8, NF-κB, p62 NF-κB, and total protein oxidation in kidney were higher in HHF-fed group as compared to LHF-fed group (p < 0.05)., Conclusion: Food processes aimed at reducing the concentration of AGEs in infant formula are urgently needed and may be therapeutically relevant for premature and/or IUGR babies., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: The aim of this study was to review the effect of a low advanced glycation end product (AGEs) diet, exercise, and a combination of both on circulating AGE levels as well as on plasma lipids and anthropometric parameters., Methods: Forty-three overweight or obese men (body mass index [BMI] >25 kg/m(2)), 30 to 55 y, participated in a 12-wk study and were randomly assigned to one of three groups: low AGE diet, exercise with habitual food intake, or exercise plus low AGE diet. Exercise was for 45 min at 65% to 75% of their maximum heart rate three times a week. We measured somatometric variables (BMI and waist circumference), blood glucose, lipids, and serum AGEs (N(ε)-[Carboxymethyl]Lysine [CML] and methylglyoxal [MG]) at baseline and at 12 wk., Results: Exercise alone was associated with decreased somatometric variables; the low AGE diet had the same effects and decreased serum CML and MG and when combined with exercise reproduced all these effects, but also decreased triacylglycerols and increased high-density lipoprotein. Correlation analysis showed that both changes of CML and MG correlated with changes in dietary AGEs (P < 0.020 and P < 0.038, respectively); change in maximum oxygen consumption correlated inversely with change in weight and triacylglycerols. Regression analyses, including change in dietary AGEs and in dietary calories, showed that change in dietary AGEs was the independent determinant of change in CML (P < 0.020) and MG (P < 0.038)., Conclusions: An AGE-restricted diet reduces serum AGE and indices of body fat. The addition of exercise to the restricted diet has the same effects but also improves lipid profile., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/objectives: The level of skin autofluorescence (AF) at a given moment is an independent predictor of mortality in hemodialysis (HD) patients. Skin AF is a measure of the accumulation of advanced glycation end products (AGEs). The aim of the study was to estimate the influence of nutrition on the 1-year increase of skin AF (ΔAF) in HD patients., Subjects/methods: A total of 156 HD patients were enrolled in this study. Skin AF, body mass index (BMI), superoxide dismutase, myeloperoxidase, C-reactive protein, inter-cellular adhesion molecule-1, von Willebrand factor and heart-type fatty acid-binding protein were measured four times at intervals of approximately half a year. Data from the monthly routine blood analysis were also used. Daily calorie, protein and AGE intakes were assessed from food recordings over a period of 1 week., Results: A J-shaped relation was found between baseline BMI and ΔAF (P=0.01). The lowest point of the J-shaped curve is found for BMI=24.3 kg/m(2). In the univariate analysis of the contributors to the 1-year ΔAF, we found that beside BMI=24.3 kg/m(2), AGE and calorie intakes, as well as myeloperoxidase and HD vintage, had a P <0.10. The sole independent predictor of the 1-year ΔAF was BMI=24.3 kg/m(2) (P=0.01)., Conclusions: It appears that calorie, protein and AGE intakes hardly influence the 1-year ΔAF in HD patients. BMI of HD patients of around 24 kg/m(2) resulted in a lower 1-year ΔAF.

Advanced glycation end products (AGE) have been implicated in the development of diabetic retinopathy. Characterization of the early stages of diabetic retinopathy is retinal pericytes loss, which is the result of pericytes migration. In this study, we investigated the pathological mechanisms of AGE on the migration of retinal pericytes and confirmed the inhibitory effect of myricetin on migration in vitro and in vivo. Migration assays of bovine retinal pericytes (BRP) were induced using AGE-BSA and phosphorylation of Src, ERK1/2, focal adhesion kinase (FAK-1) and paxillin were determined using immunoblot analysis. Sprague-Dawley rats (6 weeks old) were injected intravitreally with AGE-BSA and morphological and immunohistochemical analysis of p-FAK-1 and p-paxillin were performed in the rat retina. Immunoblot analysis and siRNA transfection were used to study the molecular mechanism of myricetin on BRP migration. AGE-BSA increased BRP migration in a dose-dependent manner via receptor for AGEs (RAGE)-dependent activation of the Src kinase-ERK1/2 pathway. AGE-BSA-induced migration was inhibited by an ERK1/2 specific inhibitor (PD98059), but not by p38 and Jun N-terminal kinase inhibitors. AGE-BSA increased FAK-1 and paxillin phosphorylation in a dose- and time-dependent manner. These increases were attenuated by PD98059 and ERK1/2 siRNA. Phosphorylation of FAK-1 and paxillin was increased in response to AGE-BSA-induced migration of rat retinal pericytes. Myricetin strongly inhibited ERK1/2 phosphorylation and significantly suppressed pericytes migration in AGE-BSA-injected rats. Our results demonstrate that AGE-BSA participated in the pathophysiology of retinal pericytes migration likely through the RAGE-Src-ERK1/2-FAK-1-paxillin signaling pathway. Furthermore, myricetin suppressed phosphorylation of ERK 1/2-FAK-1-paxillin and inhibited pericytes migration., (Copyright © 2014 Elsevier Inc. All rights reserved.)