Dietary AGEs and ALEs and risk to human health by their interaction with the receptor for advanced glycation endproducts (RAGE)--an introduction

The receptor for advanced glycation endproducts (RAGE) has a well-substantiated role in cell dysfunction and mechanisms of inflammatory disease. The physiological agonists of RAGE are less certain: S100/calgranulin proteins, high mobility group-1 protein HMGB1 and other proteins are candidate agonists. It increasingly appears unlikely proteins modified by advanced glycation endproducts are effective agonists in vivo. In the following debate, Professors Ann Marie Schmidt and Claus Heizmann gave arguments and evidences for and against the motion. Recent evidence suggesting the activation of RAGE impairs the enzymatic defence against glycation provided by glyoxalase 1 (Glo 1) suggests that studies of RAGE will continue to be of importance to our understanding of the physiological significance of protein glycation.     

Advanced glycation endproducts (AGEs) as uremic toxins

Products of non‐enzymatic glycation accumulate both in diabetic and non‐diabetic patients with renal failure. The increase in concentration is presumably due to increased generation, secondary to oxydative stress and due to decreased (renal) elimination; whether accumulation of AGEs of dietary origin plays a role is currently under investigation. AGE's have been related to progression of diabetic (and possibly also non‐diabetic) renal disease and to a number of complications of the uremic syndrome. These comprise beta‐2‐microglobulin‐derived dialysis‐related amyloidosis, dyslipidemia, vascular dysfunction and accelerated atherogenesis. A specific case is AGE related damage to the peritoneal membrane in CAPD patients. Removal of AGE by dialysis is negligible and even high flux dialysis eliminates only a quantitatively limited amount of AGE. In contrast, a rapid decrease of AGE concentrations in plasma is noted after renal transplantation. Dietary AGEs may contribute significantly to the total AGE load of the body, particularly in uremia.     

Advanced glycation endproducts (AGEs) as uremic toxins.

Products of non-enzymatic glycation accumulate both in diabetic and non-diabetic patients with renal failure. The increase in concentration is presumably due to increased generation, secondary to oxidative stress and due to decreased (renal) elimination; whether accumulation of AGEs of dietary origin plays a role is currently under investigation. AGE's have been related to progression of diabetic (and possibly also non-diabetic) renal disease and to a number of complications of the uremic syndrome. These comprise beta-2-microglobulin-derived dialysis-related amyloidosis, dyslipidemia, vascular dysfunction and accelerated atherogenesis. A specific case is AGE related damage to the peritoneal membrane in CAPD patients. Removal of AGE by dialysis is negligible and even high flux dialysis eliminates only a quantitatively limited amount of AGE. In contrast, a rapid decrease of AGE concentrations in plasma is noted after renal transplantation. Dietary AGEs may contribute significantly to the total AGE load of the body, particularly in uremia.     

Inhibitory effects of microalgal extracts on the formation of advanced glycation endproducts (AGEs)

The antiglycative activities of 20 microalgae at different growth phases were evaluated for the first time. In a bovine serum albumin (BSA)-glucose system, ethyl acetate fractions of green microalgae Chlorella and diatom Nitzschia laevis exhibited the highest inhibitory effects against the formation of total advanced glycation endproducts (AGEs) (inhibition rates: 81.76–88.02% and 91.68%) at the concentration of 500 ppm. Such abilities were higher than the effect of 1 mM aminoguanidine (AG) solution (inhibition rate: 80.51%), a commonly used inhibitor of glycation process. In addition to total AGEs, these fractions were also found to be effective in the blockage of the formation of two specific AGEs, pentosidine and N^ε-Carboxymethyllysine (CML). Different from many other plant species, AGE inhibitory abilities of selected microalgae were not due to the presence of phenolic compounds. HPLC and gas chromatography (GC) analysis revealed that carotenoids in Chlorella and unsaturated fatty acids, mainly of linoleic acid, arachidonic acid and eicosapentaenoic acid in Nitzschia laevis contributed to their strong antiglycative capacities.     

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.     

Curcumin against advanced glycation end products (AGEs) and AGEs-induced detrimental agents

Objectives: This study was aimed to review and collate effects of curcumin on generation of advanced glycation end products (AGEs) and AGEs induced detrimental agents.Methods: Pubmed, Googlescholar, ScienceDirect, and Scopus databases were searched. Searching was not limited to specific publication period. Only English language original articles (in vitro, experimental and human) which had examined the effect of curcumin on AGEs formation and AGEs induced apoptosis, oxidative stress or inflammatory responses were included. To review effect of curcumin on AGEs formation, search terms were as following: ‘‘curcumin” (title) and AGEs or pentosidine or methylglyoxal or carboxymethyllysine or glucosylation (title/abstract). Totally 104 articles were searched which 19 were selected for review. To review effect of curcumin on AGEs induced harmful agents, key words were as following: “curcumin” (title) and AGEs (title/abstract) and apoptosis or oxidative stress or DNA damage or cell injury or inflammatory or cell death or cell proliferation (title/abstract). Totally 126 articles were searched which 18 were found appropriate for review.Results: Regarding curcumin and AGEs formation, ten eligible articles (1 human trial, 5 animal models and 4 in vitro) and with regarding curcumin and AGEs-induced complications, 17 articles (5 on apoptosis, 9 on oxidative stress, and 3 on inflammatory responses) were selected. Except one, all studies indicated that curcumin is able to prevent AGEs formation and AGEs-induced disturbances with different potential mechanisms.Conclusion: Curcumin can inhibit AGEs formation and AGEs-induced disturbances. More RCT researches are suggested to evaluate beneficial effect of curcumin regarding AGEs in different age-related chronic diseases, with specific attention to AGEs memberships.     

Evidence against dietary advanced glycation endproducts being a risk to human health

In vivo, advanced glycation endproducts (AGEs) are linked to various diseases, particularly those associated with diabetes. AGEs are also formed when many foods are thermally processed. The extent to which dietary AGEs are absorbed by the gastrointestinal (GI) tract and their possible role in the onset and promotion of disease are currently of considerable interest. This paper reviews information that supports the argument that dietary AGEs are not a risk to human health.     

Dietary advanced lipid oxidation endproducts are risk factors to human health

Lipid oxidation in foods is one of the major degradative processes responsible for losses in food quality. The oxidation of unsaturated fatty acids results in significant generation of dietary advanced lipid oxidation endproducts (ALEs) which are in part cytotoxic and genotoxic compounds. The gastrointestinal tract is constantly exposed to dietary oxidized food compounds, after digestion a part of them are absorbed into the lymph or directly into the blood stream. After ingestion of oxidized fats animals and human have been shown to excrete in urine increase amounts of malondialdehyde but also lipophilic carbonyl compounds. Oxidized cholesterol in the diet was found to be a source of oxidized lipoproteins in human serum. Some of the dietary ALEs, which are absorbed from the gut to the circulatory system, seems to act as injurious chemicals that activate an inflammatory response which affects not only circulatory system but also organs such as liver, kidney, lung, and the gut itself. We believe that repeated consumption of oxidized fat in the diet poses a chronic threat to human health. High concentration of dietary antioxidants could prevent lipid oxidation and ALEs generation not only in foods but also in stomach condition and thereby potentially decrease absorption of ALEs from the gut. This could explains the health benefit of diets containing large amounts of dietary antioxidants such those present in fruits and vegetables, or products such as red-wine or tea consuming during the meal.     

大黄素对食品模型中晚期糖基化终产物的抑制作用

通过建立L-赖氨酸-葡萄糖(Lys-Glc)反应体系,以大黄素作为抑制剂,利用NBT还原法、紫外分光光度法、高效液相色谱法及荧光分光光度法分别研究大黄素对果糖胺、乙二醛(GO)、5-羟甲基糠醛(5-HMF)、类黑精、羧甲基赖氨酸(CML)及荧光性AGEs和戊糖素的抑制作用。结果表明:大黄素对氧化产物及由氧化产物进一步生成的中、末期产物GO、CML、类黑素有较好的抑制作用,对果糖胺、5-HMF有一定的抑制作用。大黄素对戊糖素、荧光性AGEs无明显抑制作用,延迟其产生。可见大黄素作为一种蒽醌类物质,对糖基化反应中氧化产物的抑制作用与其抗氧化性有关。     

Advanced glycation end-products (AGEs) in foods and their detecting techniques and methods: A review

BackgroundAdvanced glycation end-products (AGEs) are a sort of complex products formed by the Maillard reaction between the carbonyls of reducing sugars and the free amino groups of amino acids. Some of AGEs ingested through foods accumulate in human body, causing a series of chronic diseases. However, due to the complex and varied structures, there is lack of systematic reviews on dietary AGEs.Scope and approachThis paper summarizes the aspects of AGE formation, influencing factors and hazards, as well as their distribution in foods. The detecting methods available for dietary AGEs are also highlighted. Finally, the main challenges and future efforts for studying AGEs in foods and their effects on health are discussed.Key findings and conclusionsThe study of AGEs has great significance in foods and human health. Although great advances in understanding the effects of AGEs in human body are made, more unequivocal guidance for dietary AGEs to people should be provided in future.     

杏仁种皮黑色素抑制晚期糖基化末端产物(AGEs)的研究

建立牛血清蛋白-葡萄糖(BSA-Glucose)、牛血清蛋白-果糖(BSA-Fructose)和牛血清蛋白-丙酮醛(BSA-Methylglyoxal)的美拉德模拟反应体系,在体系中添加不同浓度的杏仁种皮黑色素,氨基胍(AG)作为阳性对照,37℃下反应,以荧光强度(Ex=370 nm,Em=440 nm)表示晚期糖基化末端产物(AGEs)含量,分析BSA-Glucose体系中蛋白质巯基、羰基含量变化,通过反相高效液相色谱/二极管阵列法(RP-HPLC-DAD)分析杏仁种皮黑色素对丙酮醛(Methylglyoxal,MGO)的清除效果。结果表明,杏仁种皮黑色素对BSAGlucose、BSA-Fructose、BSA-Methylglyoxal体系中AGEs的形成均有显著的抑制作用(P<0.05),抑制率最高分别达到73.81%、42.22%、38.57%。杏仁种皮黑色素能显著升高BSA-Glucose中蛋白质巯基含量(P<0.05),对MGO也具有清除作用,清除率随着时间的延长而升高,当反应24 h时,清除率达到最高,为63.54%。     

Dietary advanced glycation end‐products: Perspectives linking food processing with health implications

Dietary advanced glycation end products (dAGEs) are complex and heterogeneous compounds derived from nonenzymatic glycation reactions during industrial processing and home cooking. There is mounting evidence showing that dAGEs are closely associated with various chronic diseases, where the absorbed dAGEs fuel the biological AGEs pool to exhibit noxious effects on human health. Currently, due to the uncertain bioavailability and rapid renal clearance of dAGEs, the relationship between dAGEs and biological AGEs remains debatable. In this review, we provide the most updated information on dAGEs including their generation in processed foods, analytical and characterization techniques, metabolic fates, interaction with AGE receptors, implications on human health and reducing strategies. Available evidence demonstrating a relevance between dAGEs and food allergy is also included. AGEs are ubiquitous in foods and their contents largely depend on the reactivity of carbonyl and amino groups, along with surrounding condition mainly pH and heating procedures. Once being digested and absorbed into the circulation, two separate pathways can be involved in the deleterious effects of dAGEs: an AGE receptor‐dependent way to stimulate cell signals, and an AGE receptor‐independent way to dysregulate proteins via forming complexes. Inhibition of AGEs formation during food processing and reduction in the diet are two potent approaches to restrict health‐hazardous dAGEs. To elucidate the biological role of dAGEs toward human health, the following significant perspectives are raised: molecular size and complexity of dAGEs; interactions between unabsorbed dAGEs and gut microbiota; and roles played by concomitant compounds in the heat‐processed foods.     

Arguing for the motion: yes, RAGE is a receptor for advanced glycation endproducts

Advanced glycation endproducts (AGEs) are an heterogenous class of compounds formed by diverse stimuli, including hyperglycemia, oxidative stress, inflammation, renal failure, and innate aging. Recent evidence suggests that dietary sources of AGE may contribute to pathology. AGEs impart diverse effects in cells; evidence strongly suggests that crosslinking of proteins by AGEs may irrevocably alter basement membrane integrity and function. In addition, the ability of AGEs to bind to cells and activate signal transduction, thereby affecting broad properties in the cellular milieu, indicates that AGEs are not innocent bystanders in the diseases of AGEing. Here, we present evidence that receptor for AGE (RAGE) is a receptor for AGEs.     

Assay of advanced glycation endproducts in selected beverages and food by liquid chromatography with tandem mass spectrometric detection

Food and beverages contain protein glycation adducts--both early-stage adducts and advanced glycation endproducts. We determined the concentrations of glycation adducts in selected food and beverages by liquid chromatography with triple quadrupole mass spectrometric detection. Cola drink contained low concentrations of glycation free adducts, whereas pasteurised and sterilised milk were rich sources of heat-stable glycation adduct residues--Nepsilon-carboxymethyl-lysine and Nepsilon-carboxyethyl-lysine. Laboratory rodent food was a rich source of advanced glycation endproducts. Measurement of glycation adducts in 24 h urine samples of normal and diabetic rats indicated that < 10% of glycation adduct residue consumption was excreted. Induction of diabetes by streptozotocin led to a 2-fold increase in urinary excretion of Nepsilon-carboxymethyl-lysine and a 27-fold increase in urinary excretion of methylglyoxal-derived hydroimidazolone Ndelta-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine - the latter was decreased by high-dose thiamine therapy that also prevented the development of nephropathy. We conclude that cola drinks are a poor source of glycation adduct whereas thermally processed milk is rich in glycation adducts. Dietary glycation adducts residues probably have low bioavailability. Experimental diabetes is associated with a marked increase in exposure to endogenous formation of methylglyoxal-derived hydroimidazolone which is linked to the development of diabetic nephropathy.     

Inhibitory effect of mung bean extract and its constituents vitexin and isovitexin on the formation of advanced glycation endproducts

The anti-glycation activity of four kinds of beans including mung bean, black bean, soybean and cowpea were evaluated. Aqueous alcohol extract of mung bean exhibited the strongest inhibitory activity against the formation of fluorescent advanced glycation endproducts (AGEs) in a bovine serum albumin (BSA)-glucose model, and the inhibitory activities of extracts of the four beans were found to be highly correlated with their total phenolic contents (R² = 0.95). Subsequent HPLC analysis of mung bean extract revealed two major phenolics which were purified and identified as vitexin and isovitexin by spectral methods. In the anti-glycation assays, both vitexin and isovitexin showed significant inhibitory activities against the formation of AGEs induced by glucose or methylglyoxal with efficacies of over 85% at 100 μM. In another assay, vitexin and isovitexin failed to directly trap reactive carbonyl species, such as methylglyoxal, suggesting that their anti-glycation activities may mainly be due to their free radical scavenging capacity.     

Evaluation of the in vitro inhibitory effects of buckwheat enhanced wheat bread extracts on the formation of advanced glycation end-products (AGEs)

In this study, the inhibitory effects of extracts from buckwheat enhanced wheat breads, on the formation of fluorescent advanced glycation end-products (AGEs) were studied in bovine serum albumin (BSA)/glucose and BSA/methylglyoxal (MGO) systems. Correlations with total phenolic compounds (TPC), total flavonoids (TF) as well as rutin (Ru) and quercetin (Q) contents were also identified.     

Radio fluorination and positron emission tomography (PET) as a new approach to study the in vivo distribution and elimination of the advanced glycation endproducts N epsilon-carboxymethyllysine (CML) and N epsilon-carboxyethyllysine (CEL).

After synthesis of fluorine-18 labelled analogues by [18F]fluorobenzoylation at the alpha-amino group, biodistribution and elimination of individual advanced glycation endproducts, namely N epsilon-carboxymethyllysine and N epsilon-carboxyethyllysine, were studied in comparison to lysine in rats after intravenous injection using positron emission tomography (PET). The [18F]radiofluorinated amino acids were fast distributed via the blood, followed by a rapid excretion through the kidneys. Elimination kinetics were similar for both AGEs and lysine. For CML and CEL, but not for lysine, a temporary liver accumulation could be observed, which was not connected with any metabolisation or enterohepatic circulation. No further accumulation in any tissues was observable, indicating that increased tissue levels of CML or CEL, which have been described for certain disorders, are exclusively derived from endogenous origin and should not depend on a dietary intake. However, under uremic conditions, an impaired kidney function might result in a significant increase of the AGE-load of blood and tissues. PET based on 18F-labelled AGEs proved to be a promising tool to elucidate the physiological fate of post-translationally modified amino acids and to clarify the role of AGEs as possible "glycotoxins".