Advanced Glycation End Products,Inflammation, and Chronic Metabolic Diseases: Links in a Chain?

Advanced glycation end products (AGEs) are a diverse group of compounds produced when reducing sugars react with proteins or other compounds to form glycosylated molecules. AGEs may form endogenously, and glycation of molecules may negatively affect their function. AGEs may also be consumed in food form with dietary AGEs reported to be particularly high in foods treated with high heat: baked, broiled, grilled, and fried foods. Whether dietary AGEs are absorbed in significant quantities and whether they are harmful if absorbed is a question under current debate. The American Diabetes Association makes no recommendation regarding avoidance of these foods, but many researchers are concerned that they may be pro-inflammatory and way worsen cardiac function, kidney function, diabetes and its complications and may even contribute to obesity.     

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.     

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.     

Effect of elementary and advanced glycation products of nisin on its preservative efficacy and digestibility

Nisin used as a natural preservative in variety of food systems was subjected to glycation at 95 °C in high molar concentration. The elementary glycation end products (EGEs) and the advanced glycated end products (AGEs) formed were tested as compared to non-glycation nisin (NN) for their antibacterial activity against some food spoilage organisms such as Staphylococcus aureus, Bacillus cereus, Micrococcus luteus, Clostridium botulinum and Lactobacillus sake. The extent of hydrolysis of EGEs and AGEs by trypsin was also compared with the (NN) as control. The results have illustrated that antibacterial activity of nisin was substantially affected by the process of glycation in case of all the five organisms selected for the study, suggesting that the glycation of nisin, whether invivo or invitro will adversely affect the preservation of foods. Moreover glycation also reduced the tryptic digestibility of EGEs by 5.2% and AGEs by 50.325% as compared to NN. The data indicated that amount of nisin, if added to carbohydrate consisting foods should be increased accordingly to claim the reported shelf life of the products and food labelling in such products needs cardinal modification. Although hydrolysis of glycated nisin by trypsin is slightly decreased, however; it will not produce any adverse effect on human digestion in view of the minute amount of nisin present in the food system.     

食源性晚期糖基化终末产物检测技术研究进展

晚期糖基化终末产物（advanced glycation end products,AGEs）是还原糖与蛋白质自由氨基间发生美拉德反应形成的一类异质性共价化合物的总称。研究发现食源性AGEs摄入后会在体内蓄积并对机体健康产生有害影响,因此有必要开展食物中各类AGEs的检测分析研究。食品中的AGEs种类繁多、结构复杂,目前缺少通用的检测分析方法。因此,本文针对食源性AGEs的结构和类型、与人体健康的关系以及相关检测技术进行综述,重点介绍食源性AGEs的免疫分析和仪器分析方法,深入探讨各类技术的特点和优劣势,并对后续研究方向进行展望,以期为食源性AGEs检测技术的发展以及相关研究体系的形成提供参考和借鉴。     

Naturally occurring inhibitors against the formation of advanced glycation end-products

Advanced glycation end-products (AGEs) are the final products of the non-enzymatic reaction between reducing sugars and amino groups in proteins, lipids and nucleic acids. Recently, the accumulation of AGEs in vivo has been implicated as a major pathogenic process in diabetic complications, atherosclerosis, Alzheimer's disease and normal aging. The early recognition of AGEs can ascend to the late 1960s when a non-enzymatic glycation process was found in human body which is similar to the Maillard reaction. To some extent, AGEs can be regarded as products of the Maillard reaction. This review firstly introduces the Maillard reaction, the formation process of AGEs and harmful effects of AGEs to human health. As AGEs can cause undesirable diseases or disorders, it is necessary to investigate AGE inhibitors to offer a potential therapeutic approach for the prevention of diabetic or other pathogenic complications induced by AGEs. Typical effective AGE inhibitors with different inhibition mechanisms are also reviewed in this paper. Both synthetic compounds and natural products have been evaluated as inhibitors against the formation of AGEs. However, considering toxic or side effects of synthetic molecules present in clinical trials, natural products are more promising to be developed as potent AGE inhibitors.     

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.     

Influence of dietary advanced glycation end products on wound healing in nondiabetic mice

The present study was to determine advanced glycation end products (AGEs) in foods from different processes, and the influence of dietary AGEs on wound healing in nondiabetic mice. AGEs mixtures were extracted from local fast foods and foods prepared in lab. A BSA-AGEs mixture made by incubating glucose with bovine serum albumin (BSA) was used as a positive control. Burns were made on the skin of mice. The results showed that foods processed by high temperatures generated higher dietary AGEs. Nonwounded mice showed no observable adverse response to high dietary AGEs. However, high dietary AGEs caused severe inflammatory responses in wounded mice. The plasma level of high mobility group box 1 (HMGB1) and its mRNA in white blood cells were found to be significantly higher in the wounded mice fed with high dietary AGEs than others. We conclude that dietary AGEs worsen inflammation and delay wound healing in nondiabetic burned mice, which might be mediated by HMGB1.     

食品中晚期糖基化终产物的研究进展

晚期糖基化终产物(advanced glycation end products,AGEs)被认为和氧化应激、多种慢性疾病以及人体衰老等具有密切关系,近年来成为医药和健康领域的研究热点,但在食品领域研究相对较少。事实上,食物由于不同的加工处理方法和存放条件,可能会产生AGEs;若长期摄入AGEs可能增加体内的AGEs水平从而对人体造成危害,对食品中AGEs的研究已引起食品领域科学家的关注。文中主要对食品中AGEs的生成机理、主要种类、检测方法、对人体的影响,以及控制方法等几方面进行综述。     

Dietary advanced glycation end products--a risk to human health? A call for an interdisciplinary debate

Physiological consequences resulting from protein-bound Maillard compounds in foods must be discussed carefully. This was the idea behind the debate, which is put for discussion by the papers by Sebekova and Somoza, who argued for the motion that dietary advanced glycation end products (AGEs) are a health risk, and by Ames, who provided evidence against the motion. In this two excellent reviews, numerous arguments based on papers published in high-impact journals are given for each of the opinions. The fact that no final conclusion can be drawn, may reflect the need for a more comprehensive examination of this issue in the future. For a deeper understanding of biological consequences resulting from heated foods, the relationships between well-defined biological effects and well-characterized chemical structures must be studied. Prerequisite for this is profound chemistry--pure compounds, exact concentrations, and unambiguous analytical techniques. A real "risk assessment" is much too complex than to leave it up to one discipline alone. It must be a comprehensive and interdisciplinary approach, joining the resources of biology, medicine, and chemistry.     

多酚对食源性晚期糖基化终末产物及其诱导的相关疾病的抑制作用研究进展

晚期糖基化终末产物通过引起活性氧产生、激活氧化应激反应从而诱发各种慢性代谢性疾病，如糖尿病性肾病、阿尔茨海默病、动脉粥样硬化和骨关节炎等。因此，晚期糖基化终末产物被认为是一种促进宿主细胞死亡和器官损伤的强毒性分子。多酚是自然界中常见的一种次生代谢产物，其结构多样，具有抗氧化、抗炎、抗菌等多种生物活性。天然产物多酚可通过捕获自由基、阻断炎症信号通路和与微生物相互作用等多种机制减少晚期糖基化终末产物的产生并抑制相关疾病的发生。本文综述了多酚对晚期糖基化产物及相关疾病的抑制作用，以期为多酚抑制晚期糖基化产物的进一步研究提供科学参考。     

The Role of Dietary Advanced Glycation End Products in Metabolic Dysfunction

Advanced glycation end products (AGEs) are a heterogeneous group of molecules produced, non‐enzymatically, from the interaction between reducing sugars and the free amino groups of proteins, nucleic acids, and lipids. AGEs are formed as a normal consequence of metabolism but can also be absorbed from the diet. They have been widely implicated in the complications of diabetes affecting cardiovascular health, the nervous system, eyes, and kidneys. Increased levels of AGEs are also detrimental to metabolic health and may contribute to the metabolic abnormalities induced by the Western diet, which is high in processed foods and represents a significant source of AGEs. While increased AGE levels are a consequence of diabetic hyperglycaemia, AGEs themselves activate signaling pathways, which compromise insulin signaling and pancreatic β‐cell function, thus, contributing to the development of type 2 diabetes mellitus (T2DM). Furthermore, AGEs may also contribute to the obesogenic effects of the Western diet by promoting hypothalamic inflammation and disrupting the central control of energy balance. Here, the role of dietary AGEs in metabolic dysfunction is reviewed with a focus on the mechanisms underpinning their detrimental role in insulin resistance, pancreatic β‐cell dysfunction, hypothalamic control of energy balance, and the pathogenesis of T2DM and obesity.     

Lactic acid fermentation as a tool for increasing the folate content of foods

Folate is an essential micronutrient involved in numerous vital biological reactions. The dietary consumption of naturally occurring vitamin B9 is often inadequate in many countries, and supplementation or fortification programs (using synthetic folic acid) are implemented to alleviate folate deficiency. Other food-based alternatives are possible, such as the use of lactic acid bacteria (LAB) to synthesize folate during fermentation. Many studies have been conducted on this topic, and promising results were reported for some fermented dairy products. However, in other studies, folate consumption by LAB or rather low folate production were observed, resulting in fermented foods that may not significantly contribute to the recommended B9 intake. In addition, the optimum conditions for folate biosynthesis by LAB are still not clear. The aim of this review was thus to (i) clarify the ability of LAB to produce folate in food products, (ii) check if the production of folate by LAB in various fermented foods is sufficient to meet human vitamin B9 requirements and (iii) suggest ways to optimize folate production by LAB in fermented food products.     

Impact of Maillard reaction products on nutrition and health: Current knowledge and need to understand their fate in the human digestive system

The Maillard Reaction (MR) is a non-enzymatic chemical reaction which results in the linkage between the amino group of amino acids and the carbonyl group of reduced sugars. MR products (MRPs) are common components of processed foods, mainly as a result of heating, especially in the Western diet. MRPs are classified as into three stages: initial, intermediate, and final stages, indicative of increased complexity and size, incurring different flavor, aroma, and texture. MRPs presence is known to reduce the nutritional quality of foods, particularly by reducing protein digestibility. Early reports have linked MRPs, especially advanced glycation end-products (AGEs) present in high concentration in the typical Western diet, to health conditions and diseases. However conflicting data has since been reported, and only a few (acrylamide, heterocyclic amines and 5-Hydroxymethylfurfural) MRPs have documented potential toxic or carcinogenic effects. High molecular weight MRPs are not available for direct absorption in the higher gastrointestinal tract, and are thus mostly metabolized by resident colonic microbes. MRPs have been the subject of sparse research interest in comparison with other non-digestible dietary elements. In this review, we outline the state of knowledge on MRPs in nutrition and health, and highlight the need to develop the limited knowledge on their impact on the gut microbiota and which metabolites derive from MRPs fermentation.     

Bioactive peptides: Production and functionality

Milk proteins exert a wide range of nutritional, functional and biological activities. Many milk proteins possess specific biological properties that make these components potential ingredients of health-promoting foods. Increasing attention is being focused on physiologically active peptides derived from milk proteins. These peptides are inactive within the sequence of the parent protein molecule and can be liberated by (1) gastrointestinal digestion of milk, (2) fermentation of milk with proteolytic starter cultures or (3) hydrolysis by proteolytic enzymes. Milk protein derived peptides have been shown in vivo to exert various activities affecting, e.g., the digestive, cardiovascular, immune and nervous systems. Studies have identified a great number of peptide sequences with specific bioactivities in the major milk proteins and also the conditions for their release have been determined. Industrial-scale technologies suitable for the commercial production of bioactive milk peptides have been developed and launched recently. These technologies are based on novel membrane separation and ion exchange chromatographic methods being employed by the emerging dairy ingredient industry. A variety of naturally formed bioactive peptides have been found in fermented dairy products, such as yoghurt, sour milk and cheese. The health benefits attributed to peptides in these traditional products have, so far, not been established, however. On the other hand, there are already a few commercial dairy products supplemented with milk protein-derived bioactive peptides whose health benefits have been documented in clinical human studies. It is envisaged that this trend will expand as more knowledge is gained about the multifunctional properties and physiological functions of milk peptides.     

A critical evaluation of fluorescence as a potential marker for the Maillard reaction

During storage of foods and biological systems, fluorescent products are developed through the Maillard reaction, along with the brown pigments. Fluorescent products have been proposed as early indicators of this reaction. The aim of present work was to compare the kinetics of fluorescence and pigment development in order to define adequate early markers. Model glucose–aminoacid systems were prepared in several salts and buffers and stored at 55 °C. Pigment and florescence development was evaluated as a function of time. The results showed that, under unfavourable conditions for the reaction (low pH, presence of retardant salts), fluorescence was detected after important colour changes had occurred. However, under favourable conditions for the reaction (neutral pH, accelerating salts) fluorescent products could be considered as adequate markers because they sensitively reflected early steps of the reaction. Compositional factors and/or environmental conditions are the key factors for defining the performance of fluorescence as an adequate early marker.     

Microbiology of food taints

Fresh and processed foods are often spoilt by the presence of undesirable flavours and odours caused by microbial action. The aim of this paper is to review the current knowledge of microbiologically induced taints that occur in a wide range of foodstuffs, including meats, poultry, fish, crustaceans, milk, dairy products, fruits, vegetables, cereals and cereal products. Examples have been chosen where the compounds responsible for the taint have been identified and sufficient data obtained to demonstrate the involvement of microorganisms. However, in some cases the full identity of the causative organism may not have been elucidated. The types of microorganisms covered by this review include bacteria, fungi, yeasts, actinomycetes and cyanobacteria. Although cyanobacteria do not in general infect foods, their presence in aqueous systems and water supplies can lead to off-flavours in aquatic organisms and processed foodstuffs. Several examples of each of these processes are discussed. Wherever possible, the likely biosynthetic pathway used by the microorganism to produce the offending compound in a foodstuff is indicated.     

大豆7S蛋白-糖体系晚期糖基化终产物形成因素

目的:在大豆蛋白糖基化改性过程中会引发非酶糖基化反应,形成有害的晚期糖基化终产物(advanced glycation end products,AGEs),为提高食品安全性,模拟糖基化加工条件,构建大豆7S蛋白-糖体系模型,考察影响该体系AGEs形成的因素并进行有效调控。方法:采用荧光光谱法(λ_(ex)/λ_(em)=340 nm/465 nm)检测糖种类、还原糖质量浓度、pH值、反应温度、抑制剂种类及其浓度对AGEs形成的影响,采用十二烷基硫酸钠-聚丙烯酰胺凝胶电泳表征有害产物的形成及抑制效果。结果:糖种类为果糖、蛋白质与葡萄糖质量浓度配比1∶4、pH 9.2、反应温度121℃条件下产生荧光性AGEs的作用效果最强,4种黄酮类化合物槲皮素、染料木素、芦丁和木犀草素对荧光性AGEs的形成均可达到较好的抑制效果,且呈现良好的剂量-效应关系。结论:糖的种类与抑制剂种类对AGEs的形成有一定影响;降低还原糖质量浓度、降低pH值和降低反应温度,添加0.1 mmol/L大豆源染料木素可有效抑制大豆加工过程中有害产物AGEs的形成。     

Inhibition of advanced glycation endproduct formation by foodstuffs

The Maillard reaction, which is generally termed nonenzymatic browning or glycation, has been implicated in accelerated aging and diabetic complications in vivo. Although the molecular basis of glycation-induced pathogenesis is not well understood, the following have been noted: (1) protein glycation leads to the formation and accumulation of toxic advanced glycation endproducts (AGEs); (2) AGEs can permanently alter the structure and function of body proteins; and (3) the interaction between AGE-modified proteins and AGE-specific receptors (RAGEs) on the cell surface induces the overproduction of reactive oxygen species (ROSs) and inflammatory mediators, which leads to cellular disorders in biological systems. To date, studies that have examined the contribution of protein glycation to disease-states have primarily focused on the deleterious effects and related mechanisms of these glycotoxins. However, it remains unknown whether phytochemicals exert protective effects against glycotoxin-induced damage. Thus, the development and investigation of AGE inhibitors, especially the natural anti-AGE agents without adverse effects, may provide a therapeutic approach for delaying and preventing premature aging and diabetic complications. In this review, we provide an outline of anti-glycation properties of foodstuffs and/or their active components, and discuss their mechanisms of action.     

Dietary advanced glycation endproducts (AGEs) and their health effects--PRO

Thermal processing of food results in the formation of various novel compounds, among others advanced glycation endproducts (AGEs). AGEs result from nonenzymatic glycation reactions between reducing sugars and free amino groups of proteins, peptides, or amino acids. Due to their potential noxious effects, alimentary AGEs are also called glycotoxins. This review provides a summary of the available evidence on the health effects of exaggerated intake of thermally treated food. Data from experimental studies in rodents and from clinical studies in healthy volunteers and in patients suffering from selected diseases in which AGEs are of pathogenetic importance (diabetes, chronic renal failure) are summarized. It is concluded that, an exaggerated intake of thermally processed foods may exert in vivo diabetogenic and nephrotoxic effects, induce low-grade inflammation, enhance oxidative stress, and promote atherosclerosis.