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.     

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.     

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.     

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.     

The mechanism by which dietary AGEs are a risk to human health is via their interaction with RAGE: arguing against the motion

We are interested in the regulation of intracellular calcium and the various diseases associated with an altered regulation of this second messenger. More recently, we also became interested in pathologies involving the Ca2+-binding S100 proteins and AGEs and their association with the multifunctional Receptor for Advanced Glycation Endproducts (RAGE).     

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".     

肉制品加工过程中晚期糖基化终产物形成、检测及抑制研究进展

晚期糖基化终产物(advanced glycation end products, AGEs)是还原糖的羰基与蛋白质、脂质或核酸的游离氨基通过美拉德反应等途径产生的一系列结构复杂的化合物总称。目前已有不少研究证明AGEs在体内的积累会导致衰老、糖尿病、阿尔兹海默症等相关慢性疾病的发生, 也会引起肿瘤的发展与恶化。近年来, 随着国民生活水平的不断提高, 肉制品消费的不断增加, 其加工过程中AGEs的生成逐渐引起广泛关注。本文阐述了肉类加工过程中AGEs的结构、分类、形成途径与机制、检测方法, 总结了在不同加工方式下, 采用不同检测方法测量肉类中羧甲基赖氨酸和羧乙基赖氨酸的含量, 并重点介绍了AGEs形成的影响因素及其抑制, 旨在为肉制品加工过程中AGEs的生成控制等深入研究提供理论基础。     

Genetic variability in the RAGE gene: possible implications for nutrigenetics, nutrigenomics, and understanding the susceptibility to diabetic complications

Complex chemical processes called nonenzymatic glycation and glycoxidation are one of the interesting examples of potentially harmful interaction between nutrition and disease. This review summarizes factors influencing the extent of glycoxidation in health and disease and especially focuses on the role of genetic variability in "glycoxidation-related genes" in a disease and diet-related pathogenesis. Possible interaction between genetic variability in relevant loci and dietary advanced glycation end products (AGEs) is considered. As AGEs possess a wide range of chemical and biological effects, the interindividual functional variability in systems dealing with glycoxidation could have a significant nutrigenomic and nutrigenetic consequences.     

山奈、白芷和香叶对猪肉加热过程中晚期糖化终末产物含量的影响

采用超高效液相色谱—串联质谱联用仪结合羧甲基赖氨酸(Nε-carboxymethyllysine,CML)和羧乙基赖氨酸(Nε-carboxyethyllysine,CEL)的同位素内标物作为AGEs的分析方法,研究了山奈、白芷和香叶3种食用香料的添加以及加热(100℃,5～120 min)对猪肉中结合态CML和CEL含量的影响。研究表明:加热对猪肉中AGEs的产生有促进作用,且AGEs的含量随着加热时间的延长而增加,经120min加热后的猪肉中CML和CEL的含量约为生肉的5～8倍,分别达到(35.60±2.20)～(40.68±5.66)mg/kg(CML)和(13.32±1.49)～(16.85±2.44)mg/kg(CEL)。在0～40min的加热时间过程中,加入或未加入香料的猪肉中CML[R~2=0.971～0.996;k=0.355～0.590mg/(kg·min)]和CEL[R~2=0.942～0.997;k=0.150～0.368mg/(kg·min)]的形成均符合零级反应动力学方程。香料的添加对于猪肉在加热过程中AGEs形成的影响因香料的种类、加热时间、肉的批次的不同而不同,总体来说,香料对猪肉加热过程中CML的形成影响较小,但是对CEL的形成有一定的促进作用,尤其是加热5 min处理的肉样,其CEL含量增加13%～61%。