Exogenous Advanced Glycation End-products Research Articles

Effects of exogenous advanced glycation end products on oxidative stress and renal injury in healthy mice

AbstractThis study evaluated the biological effects of exogenous advanced glycation end products (AGEs) on the induction of chronic kidney disease and the dose‐effect relationship. Male C57BL/6 mice were placed on four diets, including saline and three other diets differing only in AGEs content (low‐AGEs [LA], medium‐AGEs [MA], and high‐AGEs [HA] ratio, 1:3:5) for 4 weeks. With the increasing intake of AGEs, mice developed a significant increase in blood glucose and lipid levels, the fluorescence intensity of AGEs, Nε‐(carboxymethyl)‐lysine, Nε‐(carboxyethyl)‐lysine, and malondialdehyde levels, whereas their superoxide dismutase activity and glutathione levels were decreased significantly. HA had the highest urinary protein levels and the lowest creatinine clearance compared to the other groups. These suggested that AGEs are an essential contributor to increasing oxidative stress levels and intake of high‐level AGEs induces more severe kidney function impairment. Meanwhile, the AGEs intake damaged the kidney structure in a dose‐dependent manner, as evidenced by granular degeneration of kidney tubular epithelial cells and inflammatory cell infiltration. These findings shed light on the detrimental impacts of AGEs on human kidneys, which also will help reveal a dose‐effect relationship of AGEs.

PERINATAL EXPOSURE TO HIGH DIETARY AGES DELAYS PUBERTY ONSET AND DISRUPTS FOLLICULOGENESIS IN FEMALE OFFSPRING

Nutrition is an important source of exogenous advanced glycation end-products (AGEs) where thermally processed foods present in western-style diets contain large amounts of these pro-inflammatory molecules. Maternal nutrition and the intrauterine environment are important in determining susceptibility to reproductive and metabolic disturbances. The objective of this study was to determine whether perinatal exposure to high amounts of dietary AGEs affect metabolic and the reproductive parameters in female mice offspring. Animal experiments in a university setting. 7 week old female CD1 mice were placed on either a diet low (L-AGE) or high (H-AGE) in AGEs for 2 weeks before mating and then for additional 6 weeks throughout pregnancy and lactation. Offspring from L-AGE dams (n=10) and H-AGE dams (n=13) were all weaned onto the L-AGE diet and studied through 16 weeks of age. Offspring were counted and weighed at birth then weekly. Body weight, growth curve, pubertal onset (age at vaginal opening), estrus cyclicity (vaginal smear), serum levels of anti-Mullerian hormone (AMH), leptin and adiponectin as well as insulin tolerance test (ITT) and glucose tolerance test (GTT) were performed. Ovaries were harvested for follicular count and gene expression by RT-PCR. Data were reported as mean ± SEM. For GTT and ITT, the total area under the curve (AUC) for 120 minutes for glucose concentrations in mg/dL was calculated. Mann-Whitney U test and repeated measures ANOVA were performed as appropriate. Pups exposed to perinatal H-AGE diet had significantly lower body weight at birth compared to pups exposed to perinatal L-AGE diet (1.38 ± 0.1 vs. 1.58 ± 0.16 grams, p<0.05; respectively). Adult offspring exposed to perinatal H-AGE diet exhibited delayed growth and lower serum levels of leptin and AMH (p<0.05 for all). There was no significant difference in AUC for GTT (p=0.7) or ITT (p=0.2) between both groups. Perinatal exposure to H-AGE diet affected the reproductive potential in the adult female offspring by exhibiting delayed vaginal opening and irregular estrus cycles by spending less time in the proestrus phase and more time in the metestrus phase (p=0.04). Adult offspring exposed to perinatal H-AGE diet had significantly fewer corpora lutea (CL) in their ovarian sections, exhibited arrested folliculogenesis with most follicles in the secondary follicle stage, and had significantly lower ovarian mRNA expression levels of Amh (p=0.005), Amhr2 (p=0.02), and Cyp19a1 (p=0.03) compared to adult offspring exposed to perinatal L-AGE diet. These results indicate that perinatal exposure to a diet elevated in AGEs causes deficits in perinatal growth, pubertal onset, and reproductive organ development in female mice. Whether these findings translate to humans remains to be determined in future studies.

Non-nutritive sweeteners are in concomitant with the formation of endogenous and exogenous advanced glycation end-products

This study investigated the role of non-nutritive sweeteners in the formation of advanced glycation end-products (AGEs) and their reactive intermediates using endogenous and exogenous models. In the endogenous model, xylitol and sorbitol formed similar levels of reactive intermediates compared to sucralose. Protein-bound fluorescent AGEs, Nε-carboxymethyllysine (CML), and Nε-carboxyethyllysine (CEL) levels in the xylitol and sorbitol treatment were significantly higher compared to the sucralose treatment. In the exogenous model, sucralose treatment showed significantly higher glyoxal and fructosamine levels compared to xylitol and sorbitol, respectively. However, protein-bound fluorescent AGEs, CML, and CEL were lower in the sucralose treatment compared to other sugar treatments. The data suggest that the structure of sugar alcohols which are similar to reducing sugars may contribute to the formation of AGEs and their reactive intermediates in the endogenous model. The long-term effects of non-nutritive sweeteners consumption on AGEs formation and health implications should be verified with population studies.

Maize bran feruloylated oligosaccharides inhibited AGEs formation in glucose/amino acids and glucose/BSA models.

Various Maillard reaction systems were established to investigate the effect of maize bran feruloylated oligosaccharides (FOs) on the formation of both endogenous and exogenous advanced glycation end-products (AGEs) under different pH values. The formation of AGEs and four kinds of dicarbonyl compounds (glyoxal, methylglyoxal, 3-deoxyglucosulose, 2,3-butanedione) were determined by fluorescence spectrophotometry and HPLC, respectively. Results showed that maize bran FOs effectively inhibited the production of fluorescent AGEs. Moreover, increase in pH, temperature and concentration of FOs in reaction systems elevated the inhibition effects of feruloylated oligosaccharides, fluorescent AGEs and dicarbonyl compounds. Mainly because of the ester bond of FOs at high pH and/or temperature systems are readily to be hydrolyzed, resulting in the release of ferulic acid.

An Overview of Dietary Approaches to Prevent the Development of Diabetic Retinopathy

Various researchers suggest that in up to 50% of patients with type 1 diabetes and 30% of those with type II diabetes, potentially vision-threatening retinal changes develop over time. Diabetic retinopathy is a common micro-vascular complication of diabetes mellitus. The present review outlines the dietary strategies to manage these complications of diabetes mellitus and studies the relationship between diet and retinopathy-associated risk factors in the development and progression of diabetic retinopathy. Though retinopathy therapy is currently limited to invasive procedures like laser photocoagulation and vitrectomy but there is a paradigm shift in favor of a preventive and protective, natural and safe dietary approach which can be used in treatment or prevention of diabetic retinopathy. Dietary carbohydrates, fats, proteins, dietary fibers, vitamins, antioxidants, minerals, phyto-estrogens, exogenous advanced glycation end-products, herbs, spices and protective dietary approaches play a role in development of diabetic retinopathy. This rationale can be applied to food interventions e.g. changing the composition of diet which favors metabolic improvements in type II diabetes and diabetic retinopathy. The ophthalmologists should encourage an interdisciplinary approach with endocrinologists and dietitian for optimal care of diabetic patient so as to prevent the development of diabetic retinopathy.

Potential of glycative stress targeting for cancer prevention

Glycative stress from endogenous and exogenous advanced glycation end-products (AGEs) has been implicated to cancer development and progression. Dicarbonyl compounds, the main AGE precursors and crosslinked AGE forms may directly react with proteins, lipids and nucleic acids, modify their structure and affect tissue microenvironment. They may also induce elevation of reactive oxygen species (ROS) and enhance cellular oxidative stress, an important regulator of cancer hallmarks. Moreover, the activation of AGE-receptor for AGE (RAGE) signalling pathways mediates inflammation, oxidative stress, autophagy and apoptosis leading to genomic instability and cancer initiation.Here, we provide evidence on the impact of glycative stress in promoting human tumorigenesis and we discuss the potential application of anti-glycating agents, RAGE and glyoxalase-1 inhibitors in cancer prevention.

Effects of Long-Term Exposure of Exogenous Advanced Glycation Endproducts on Vertebral Bone Microarchitecture; Sex-Differences on Structure Derived Mechanical Properties

IntroductionAccumulation of advanced glycation end products (AGE) are commonly associated with diabetic complications, including increased painful intervertebral disc pathologies, osteoporosis, and bone fracture risk. Exogenous AGEs develop by processing food at high temperatures and can accumulate in bone where they crosslink collagen. A clinical study reported association of increased serum AGE levels with vertebral fracture risk in women but not in men, highlighting gender effects. The purpose of this study was to investigate the sex-dependent effects of exogenous AGEs on vertebral bone quantity, quality, and mechanical behavior. Material and MethodsC57BL/6 mice (female, n = 8/group; male, n = 4/group) were pair-fed isocaloric diets containing low AGE amounts (LAGE, 7.6 μg/mg chow) or high AGE amounts (HAGE, 40.9 μg/mg chow) for 6 months; after euthanasia, blood glucose and serum AGEs were analyzed. Lumbar spines were μCT-scanned (resolution=4.9μm; SkyScan 1172, Bruker Corp., Belgium). Hydroxyapatite phantoms were similarly scanned for density calibration. Cortical bone analysis included tissue mineral density (TMD), BMD, cross sectional thickness (Ct.Th), bone surface are (BSA) and porosity. Trabecular bone analysis included trabecular thickness, separation (Tb.Sp), number (Tb.Nm), TMD, BMD, BVF, bone surface to volume ratio (BS/BV), Structure Model Index (SMI) and fabric anisotropy. A validated analytical model was used to calculate trabecular bone anisotropic compressive and shear moduli. Male/female and HAGE/LAGE differences were analyzed via Student's t-tests (p < 0.05). All experiments were approved by the Institutional Animal Care and Use Committee. ResultsSerum AGE levels were significantly increased in female HAGE mice compared with LAGE mice (p < 0.01). No differences were observed between blood glucose levels among groups. Dietary comparisons indicated that female trabecular BS/BV and porosity were significantly increased by HAGE-diet whereas trabecular BMD, compressive and shear moduli, and cortical BMD were decreased. In males dietary comparisons revealed only a significant increase in trabecular porosity. Male cortical bone remained unchanged. Sex comparisons within LAGE-diet group revealed that female trabecular bone had significantly reduced Tb.Nm, BMD, degree of anisotropy, compressive and shear moduli, and significantly increased Tb.Sp, porosity, and SMI compared with LAGE males. LAGE females also had significantly decreased cortical BSA and significantly increased Ct.Th compared with LAGE males. Sex comparisons of female versus male HAGE-diet groups revealed no significant differences. ConclusionResults indicated more pronounced detrimental effects on cortical and trabecular bone in females on HAGE-diet than in males. These sex-dependent effects suggest that AGEs effects on vertebral bone may be hormonally mediated. This work showed for the first time significant alterations to the elastic compressive and shear properties of vertebra following variations in dietary AGE levels. Changes in trabecular architecture and density manifested as functional changes, especially in females, warranting further post-yield and fracture analysis. Importantly, this study investigated the sex dependent effects of AGEs on vertebral bone quality and quantity independent from serum glucose (diabetes). Further research of AGE effects on cell turnover and cellular modifications to bone microarchitecture and mineralization is necessary to validate the link between changes in bone quality, quantity and function.

Role of PPARα in down-regulating AGE-induced TGF-β and MMP-9 expressions in chondrocytes

Peroxisome proliferator-activated receptor is closely associated with the pathogenesis of osteoarthritis. The level of exogenous advanced glycation end-products (AGEs) in articular cartilage is highly associated with the severity of osteoarthritic lesions. However, their interactions and role in promoting osteoarthritisprogression remain unclear. Here, we investigated the effect of AGEs on transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9 expression, and discussed the correlation between AGEs and osteoarthritis, possible signaling pathways and mechanism in rabbit chondrocytes. TGF-β and MMP-9 mRNA and protein expression, catalase (CAT) and superoxide dismutase (SOD) activity, and malondialdehyde (MDA) and reactive oxygen species (ROS) levels were analyzed in chondrocytes treated with different concentrations of AGEs using RT-PCR and/or western blot; we detected NF-κB nuclear translocation by immunofluorescence. AGE treatment significantly increased TGF-β and MMP-9 mRNA and protein expression compared to controls (P < 0.01) in a dose-dependent manner (highest at 100 μg/mL). AGE-induced TGF-β and MMP-9 expressions in chondrocytes were significantly inhibited by anti-RAGE and PDTC (0.1 mM) treatment (P < 0.01). Furthermore, AGE-treatment significantly decreased CAT and SOD activity and increased MDA levels in a concentration-dependent manner compared to controls (P < 0.05), significantly promoting NF-κB nuclear translocation. AGE significantly inhibited the increased expression of TGF-β and MMP- 9, and induced chondrocyte damage. Its mechanism is associated with RAGE activation, increased ROS expression, and activation of the NF- κB signaling pathways.

The relationship between dietary advanced glycation end products and indicators of diabetes severity in Mexicans and non-Hispanic whites: a pilot study

Diet is an important source of exogenous advanced glycation end products (AGEs). Dietary AGEs content depends on nutrient composition and on the way food is processed/cooked. The objective of our study was to compare AGEs intake of two different ethnic groups (Mexicans and non-Hispanic whites) with type 2 diabetes mellitus (DM) and to study the relationship between dietary AGEs and diabetes-related complications. Complications were self-reported by subjects (n = 65) and categorized according to a published DM disease severity index as low risk or moderate-high risk. Dietary records for 10 days were used to estimate dietary AGEs from a published food table. Non-Hispanic whites had higher intake of dietary AGEs (natural logarithm was used, LogAGEs) when compared with Mexicans, which was consistent with their higher intake of saturated fat. In addition, for each unit increase in the LogAGEs, a participant was 3.7 times more likely to have moderate-high risk for cardiovascular disease.

Exogenous advanced glycation end products induce tau hyperphosphorylation and spatial memory deficit through RAGE-mediated Akt/GSK-β pathway

Exogenous advanced glycation end products induce tau hyperphosphorylation and spatial memory deficit through RAGE-mediated Akt/GSK-β pathway

Protective actions of microalgae against endogenous and exogenous advanced glycation endproducts (AGEs) in human retinal pigment epithelial cells

The formation and accumulation of advanced glycation endproducts (AGEs) is a key pathophysiological process involved in various diabetic complications such as diabetic retinopathy. In the present study, for the first time, protective effects of three microalgal strains, including their extracts and active compounds, against both endogenous and exogenous AGEs in cell-based models were investigated. Results showed that in cultured human-derived retinal pigment epithelial ARPE-19 cells, the extract of Chlorella zofingiensis and its nutritional ingredient astaxanthin exhibited significant inhibitory effects on the formation of endogenous N(ε)-carboxymethyllysine (CML), a key AGE representative, through the suppression of intracellular oxidative stress. On the other hand, extracts of Chlorella zofingiensis, Chlorella protothecoides and Nitzschia laevis as well as their nutritional ingredients, namely astaxanthin, lutein and eicosapentaenoic acid (EPA), attenuated the deleterious effects induced by exogenous AGEs, such as cell proliferation and mRNA upregulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP)-2, which are critical steps involved in the pathogenesis of diabetic retinopathy. These results suggested the positive roles of astaxanthin, lutein and EPA in controlling the development of diabetes. These microalgae, therefore, might be regarded as beneficial foods and preventive agent choices for patients with diabetic retinopathy.

Cardiovascular Complications in Diabetes

Cardiovascular complications are mainly responsible for the high morbidity and mortality in people with diabetes. The awareness of physicians for the importance of primary prevention increased lately and numerous strategies have been developed. The spectrum ranges from pharmacologic treatment to vitamins and dietetic interventions. Some interesting concepts such as focusing on exogenous advanced glycation end products have emerged, but definitive results on their clinical relevance are still lacking. A major problem of the primary prevention is the choice of the method applied for screening, the criteria used to classify risk patients, as well as the choice of therapy. Guidelines provide goals to be achieved and offer alternatives for treatment, but the medical decision has to be made on an individualized basis. In this overview, we will comprehensively focus on the most important pathomechanisms and clinically relevant approaches, aiming at the early diagnosis and treatment of diabetes along with coronary heart disease. When primary prevention fails, we advocate a more aggressive treatment of critically ill patients, followed by optimal secondary prevention meeting on-target goals precisely.

Short-term effect of orlistat on dietary glycotoxins in healthy women and women with polycystic ovary syndrome

Exogenous advanced glycation endproducts (AGEs, known atherogenic molecules) abundant in everyday precooked, rich in fat, overheated meals can possibly contribute to the increased risk for diabetes and cardiovascular disease in women with polycystic ovary syndrome (PCOS). The aim of the present study was to investigate the effect of a lipase inhibitor on absorbed food glycotoxins in healthy women and those with PCOS. A 2-day protocol was followed. In the first day, a meal rich in AGE was provided, which on the second day was followed by two 120-mg capsules of lipase inhibitor, orlistat. Serum AGE levels were evaluated at baseline (0 hours), and at 3 and 5 hours postmeal during the study. Thirty-six women were studied, 15 controls (mean age, 28.80 ± 5.47 years; body mass index, 25.85 ± 6.73 kg/m 2) and 21 with PCOS (mean age, 25.29 ± 5.06 years; body mass index, 30.40 ± 7.51 kg/m 2) (University Hospital, Athens, Greece, institutional practice). Serum AGE levels, on day 1, were significantly increased both in the control group and in the PCOS group as compared with basal values (control group, 14.1%; PCOS group, 6.0%; P < .001). The corresponding rise was significantly lower on day 2 when the same meal was combined with orlistat (control group, 4.1%; PCOS group, 2.0%; P < .01). A limitation of the study is that it is a nonplacebo, nonrandomized therapeutic trial where each subject is considered as its own control. In conclusion, this study demonstrated the beneficial effect of orlistat on the absorption of food glycotoxins.