Group Of Advanced Glycation End-products Research Articles

Gut Metabolism of Sugars: Formation of Glycotoxins and Their Intestinal Absorption

Glycotoxins include the group of advanced glycation end-products (AGEs) and their precursors, most of them highly reactive intermediary compounds of sugar metabolism. Glycotoxins and products of the Maillard reaction are present in high concentrations in foods rich in sugars and processed at high temperatures and are often associated with the flavour of the food. Proteins undergoing this type of molecular modification are targets for gut peptidases and may be absorbed into circulation. AGEs are associated with the toxic effects of glucose in diabetic patients, and some studies have shown that they also contribute to metabolically unhealthy obesity and prediabetes development. Restriction of dietary glycotoxins was shown to improve insulin resistance in humans. However, the real contribution of dietary AGEs to such mechanisms is still not understood. This review summarizes the current knowledge about glycotoxin formation from dietary sugars, their digestion throughout the gastrointestinal system, and the mechanisms of their intestinal absorption.

Another Player in the Field: Involvement of Glycotoxins and Glycosative Stress in Insulin Secretion and Resistance

The term glycotoxins includes the group of advanced glycation end-products (AGEs) and their precursors, most of them highly reactive intermediary compounds, such as methylglyoxal (MG). Glycotoxins were initially thought to participate in the development of diabetic complications because of their increased formation from glucose. However, they also form and accumulate in tissues since the early stages of disease, such as metabolically unhealthy obesity and prediabetes. Such accumulation has been suggested to result from dysregulated activity of detoxification systems, such as the glyoxalase system, as well as increased dietary consumption, namely from high-glucose and high-fructose foods processed at high temperatures. Although some studies may have used supraphysiological doses, in vitro systems and animal models have shown glycotoxin-induced insulin resistance. Moreover, dietary glycotoxin restriction was shown to improve insulin resistance in humans and glyoxalase (GLO)-1 upregulation improved insulin sensitivity and metabolic function. This review summarizes the current knowledge about glycotoxin involvement in the development of insulin resistance, the mechanisms involved and the usefulness of GLO-1 modulation, and a possible therapeutic strategy to improve insulin sensitivity.

Products of Early and Advanced Glycation in the Soy Milk Proteome.

Thermal processing of soy milk kills pathogens and denatures anti-nutrition factors warranting microbiological safety, better digestibility, and longer storage. Additionally, Maillard reactions are triggered, yielding glycated proteins (Amadori/Heyns products) and a heterogeneous group of advanced glycation end-products (AGEs). These modifications alter the nutritional value, antigenicity, and digestibility of proteins. They also raise concerns about potentially toxic effects. This study aims at characterizing these modifications in proteins from different soy milk products. Here, glycation and AGE-modification sites in the proteome of ultrahigh-temperature-treated natural soy milk, soy milk sweetened with hexose (fructose)-containing sweeteners (SSM), and sucrose as well as soy-based infant formulas (SIFs) from different manufacturers are reported for the first time. A bottom-up proteomic approach based on nano reversed-phase high-perfomance liquid chromatography-electrospray ionization-tandem mass spectrometry (nanoRP-HPLC-ESI-MS/MS) (collision-induced dissociation (CID) and electron transfer dissociation modes) identified 229 glycated peptides and 128 AGE-modified peptides resembling 53 proteins. The glycation sites are mainly derived from hexoses, whereas Nδ -carboxyethylarginine and methylglyoxal-derived hydroimidazolone are the main AGEs in soy milk. The qualitative and quantitative data obtained here indicate that early glycation increases with harsher processing conditions (SIFs) and the addition of hexose-containing sweeteners (SSMs), whereas the latter sweeteners (but not the harsher processing) triggered more AGE modifications.

Association of advanced glycation end products in Dupuytren disease

BackgroundAdvanced glycation end products are associated with aging, hyperglycemia, and oxidative stress. Accumulation of advanced glycation end products can cause various pathological conditions; however, the association of Dupuytren’s disease with advanced glycation end products has not been demonstrated yet. The aim of this study is to investigate the association of Dupuytren’s disease with advanced glycation end products.MethodsNormal palmar fascia from five patients with carpal tunnel syndrome (control group) and Dupuytren’s cords from five patients (Dupuytren’s disease group) were harvested. The tissues were stained using an anti-advanced glycation end products antibody, anti-receptor for advanced glycation end products antibody, and an anti-reactive oxygen species modulator 1 antibody. The expression of nicotinamide adenine dinucleotide phosphate oxidase-1 and nicotinamide adenine dinucleotide phosphate oxidase-4 genes was also assessed using real-time PCR. For in vitro analysis, the cells harvested from the control and Dupuytren’s disease groups were used. After 3 days of exposure to four types of media (control group, control + advanced glycation end products group, Dupuytren’s disease group, Dupuytren’s disease + advanced glycation end products group), superoxide detection reagent was detected using a total reactive oxygen species/superoxide detection kit.ResultsImmunostaining of the palmar fasciae of the Dupuytren’s disease group showed higher expressions of advanced glycation end products and receptor for advanced glycation end products than that in the control group. The expression of nicotinamide adenine dinucleotide phosphate oxidase oxidase-1 and nicotinamide adenine dinucleotide phosphate oxidase-4 as well as reactive oxygen species modulator 1, an oxidatively damaged protein, was also higher in the Dupuytren’s disease group than in the control group. In an in vitro cell culture, the addition of advanced glycation end products to the Dupuytren’s disease-derived cells produced more superoxide free radicals.ConclusionsThese data suggest that the advanced glycation end products receptor for advanced glycation end products interaction produced free radicals via nicotinamide adenine dinucleotide phosphate oxidase activation in Dupuytren’s disease patients. Further studies are required to confirm these results.

Advanced glycation end-products accelerate the cardiac aging process through the receptor for advanced glycation end-products/transforming growth factor-β-Smad signaling pathway in cardiac fibroblasts.

The current study was carried out to evaluate the effect of advanced glycation end-products (AGE) on cardiac aging and to explore its underlying mechanisms. Neonatal rat cardiac fibroblasts were cultured and divided into four groups: control; AGE; AGE + receptor for AGE antibody and AGE + SB431542 (transforming growth factor-β [TGF-β]/Smad signaling pathway inhibitor, 10 μmol/L) group. After being cultured for 48 h, the cells were harvested and the senescence-associated beta-galactosidase expression was analyzed. Then the level of p16, TGF-β, Smad/p-smad and matrix metalloproteinases-2 was evaluated by western blot. Significantly increased senescence-associated beta-galactosidase activity as well as p16 level was observed in the AGE group. Furthermore, AGE also significantly increased the TGF-β1, p-smad2/3 and metalloproteinases-2 expression in cardiac fibroblasts (all P < 0.01). Meanwhile, either pretreatment with receptor for AGE-Ab or SB431542 significantly inhibited the upregulated cardiac senescence (beta-galactosidase activity and P16) and fibrosis-associated (TGF-β1, p-smad2/3 and metalloproteinases-2) markers induced by AGE. Taken together, all these results suggested that AGE are an important factor for cardiac aging and fibrosis, whereas the receptor for AGE and TGF-β/Smad signaling pathway might be involved in the AGE-induced cardiac aging process.

Oxidative degradation of N(ε)-fructosylamine-substituted peptides in heated aqueous systems.

Glycation, or non-enzymatic glycosylation, is a common protein modification formed by reactions between reducing sugars (i.e. aldoses and ketoses) with protein amino groups. Resulting Amadori and Heyns compounds, respectively, can be oxidatively degraded yielding a structurally heterogeneous group of advanced glycation end-products. We have studied this process in aqueous conditions at 95 °C in terms of appearing products and their formation kinetics in the presence or absence of reactive oxygen species (ROS)-generating systems (iron(II) sulfate). RP-HPLC-ESI-MS revealed 20 products, 12 of which were confirmed after synthesis by identical retention times and fragmentation patterns. These products accumulated during the incubation period of 4 h (N(ε)-carboxymethyl-, N(ε)-formyl- and N(ε)-methyl lysine) or appeared intermediately (2-aminoadipic semialdehyde, N(ε)-ethanalyl lysine). Acidic and basic amino acid residues near the glycation site and elevated ROS levels in the reaction mixture had significant effects on both product formation and degradation kinetics.

Abstract 11598: Increased Advanced Glycation End-Products Accelerate the Progress of Left Ventricular Hypertrophy Under Condition of Elevated Oxidative Stress or Insulin Resistance in Patients With Hypertension

Background: Elevated oxidative stress or insulin resistance has been shown to promote the production of advanced glycation end-products (AGEs) in patients with hypertension (HT). Because AGEs enhance left ventricular hypertrophy (LVH) via the activation of nuclear factor-kappa B, it is considered that increased AGEs contribute to LVH in HT patients. The aim of this study was to investigate the effect of increased AGEs on LVH in them. Methods: Eighty five HT patients aged 65 ± 9 years were prospectively followed up for a year, whose blood pressure was controlled under 140/90mmHg. We assessed patients’ glucose and lipid metabolism and neurohumoral factors including plasma noradrenaline and renin activity as clinical characteristics. We measured serum malondialdehyde-modified LDL-cholesterol (MDA-LDL) and plasma pentosidine as parameters of oxidative stress and AGEs, respectively. Homeostasis model assessment ratio (HOMA-R), estimate glomerular filtration rate (eGFR) and left ventricular mass index (LVMI) were assessed as parameters of insulin resistance, renal function and LVH, respectively. All parameters were assessed before and after one-year observation period. We examined the change in each parameter from baseline to the value measured after the observation period ([[Unable to Display Character: &amp;#8895;]]MDA-LDL, [[Unable to Display Character: &amp;#8895;]]pentosidine, [[Unable to Display Character: &amp;#8895;]]HOMA-R and [[Unable to Display Character: &amp;#8895;]]LVMI). We divided patients into two groups based on the median of baseline pentosidine: high AGEs and low AGEs groups. We compared baseline values between the two groups. We analyzed the relationships among [[Unable to Display Character: &amp;#8895;]]MDA-LDL, [[Unable to Display Character: &amp;#8895;]]HOMA-R, [[Unable to Display Character: &amp;#8895;]]Pentosidine and [[Unable to Display Character: &amp;#8895;]]LVMI, and performed stepwise multiple regression analysis using parameters of clinical characteristics and AGEs to detect the predictors for the LVH progress after one year. Results: Baseline LVMI was significantly higher in the high AGEs group than in the low AGEs group (P&lt;0.05). [[Unable to Display Character: &amp;#8895;]]Pentosidine was positively correlated with [[Unable to Display Character: &amp;#8895;]]MDA-LDL (r=0.34, P&lt;0.01),[[Unable to Display Character: &amp;#8895;]]HOMA-R (r=0.37, P&lt;0.01) and [[Unable to Display Character: &amp;#8895;]]LVMI (r=0.39, P&lt;0.05). Multiple regression analysis detected pentosidine as a significant independent predictor for the LVH progress (β=0.407, P=0.005) (R2=0.315). Conclusion: Increased AGEs accelerated the LVH progress under condition of elevated oxidative stress or insulin resistance in HT patients.

Role of heme oxygenase-1 in high glucose and advanced glycation end-products-induced oxidative stress in THP-1 cells

Objective To investigate the effects of heme oxygenase-1(HO-1)on oxidative stress in THP-1 cells incubated with high glucose and advanced glycation end-products(AGE).Methods THP-1 cells were incubated with normal glucose(5 mmoL/L),hish glucose(15 mmol/L)+AGE(100 μg/ml),high glucose+AGE+zinc protoporphyrin(ZnPP,inhibitor of HO-1),and ZnPP(normal glucose),respectively.The levels of reactive oxygen species(ROS).maiondialdehyde(MDA),and tumor necrosis factor-α(TNF-α)were determined in the four groups while expressions of HO-1 mRNA and protein were detected by RT-PCR and Western blotting respectively.Results The levels of ROS,MDA,and TNF-αin high glucose+AGE and ZnPP groups were hisher than those in normal glucose group(all P<0.05).The levels of ROS and TNF-α in high glucose+AGE+ZnPP group were even higher compared with high glucose+AGE group(all P<0.05),along with decreased expressions of HO-1 mRNA and protein(0.39±0.02 vs 0.89±0.09,0.38±0.00 vs 0.81±0.02,both P<0.05).Conclusions The oxidative injury and inflammation in THP-1 cells induced by high glacose and AGE age exaggerated by HO-1 inhibitor.HO-1 may play an important role in diabetic oxidative stress. Key words: Heme oxygenase-1; Zinc protoporphyrin; Advanced glycation end-products; Oxidative stress; THP-1 cells

Yeast protein glycation in vivo by methylglyoxal

Protein glycation by methylglyoxal is a nonenzymatic post-translational modification whereby arginine and lysine side chains form a chemically heterogeneous group of advanced glycation end-products. Methylglyoxal-derived advanced glycation end-products are involved in pathologies such as diabetes and neurodegenerative diseases of the amyloid type. As methylglyoxal is produced nonenzymatically from dihydroxyacetone phosphate and d-glyceraldehyde 3-phosphate during glycolysis, its formation occurs in all living cells. Understanding methylglyoxal glycation in model systems will provide important clues regarding glycation prevention in higher organisms in the context of widespread human diseases. Using Saccharomyces cerevisiae cells with different glycation phenotypes and MALDI-TOF peptide mass fingerprints, we identified enolase 2 as the primary methylglyoxal glycation target in yeast. Two other glycolytic enzymes are also glycated, aldolase and phosphoglycerate mutase. Despite enolase's activity loss, in a glycation-dependent way, glycolytic flux and glycerol production remained unchanged. None of these enzymes has any effect on glycolytic flux, as evaluated by sensitivity analysis, showing that yeast glycolysis is a very robust metabolic pathway. Three heat shock proteins are also glycated, Hsp71/72 and Hsp26. For all glycated proteins, the nature and molecular location of some advanced glycation end-products were determined by MALDI-TOF. Yeast cells experienced selective pressure towards efficient use of d-glucose, with high methylglyoxal formation as a side effect. Glycation is a fact of life for these cells, and some glycolytic enzymes could be deployed to contain methylglyoxal that evades its enzymatic catabolism. Heat shock proteins may be involved in proteolytic processing (Hsp71/72) or protein salvaging (Hsp26).

Glycation in food and metabolic transit of dietary AGEs (advanced glycation end-products): studies on the urinary excretion of pyrraline.

Pyrraline [epsilon-(2'-formyl-5'-hydroxymethyl-pyrrolyl)-L-norleucin] belongs to the group of AGEs (advanced glycation end-products) formed in the final stage of the Maillard reaction in foods and in vivo. As it is generally accepted that AGEs are pathophysiologically relevant in aging and in diseases such as diabetes and uraemia, physiological consequences resulting from the ingestion of dietary AGEs are discussed, but balance studies for well defined AGEs are still lacking. The aim of our study was to investigate the influence of nutrition on the urinary excretion of pyrraline. After the first day without dietary restrictions, seven healthy volunteers were asked, starting on the morning of day 2, to ingest a diet virtually free of Maillard compounds (i.e. no cooked or roasted foods, no bakery products, no coffee, etc.). Dietary control was stopped on the morning of day 5. We collected 24 h urine samples for these 5 days, which were analysed for free pyrraline by reverse-phase HPLC with UV detection at 297 nm. We found that urinary excretion of free pyrraline was directly affected by the composition of the diet, decreasing from 4.8+/-1.1 mg/day on day 1 to levels of 1.6, 0.4 and 0.3 mg/day on days 2, 3 and 4 respectively, followed by a significant increase to 3.2+/-1.4 mg/day on the 5th day. The results of this work prove, for the first time, that urinary excretion of pyrraline is strongly dependent on its dietary intake. Thus the influence of nutrition should be taken into consideration in studies directed to the physiological role of glycation compounds.