Glycolaldehyde‐modified β‐lactoglobulin AGEs are unable to stimulate inflammatory signaling pathways in RAGE‐expressing human cell lines

Scope: Advanced glycation endproducts (AGEs) are suspected to stimulate inflammatory signaling pathways in target tissues via activation of the receptor for AGEs. Endotoxins are generally recognized as potential contamination of AGE preparations and stimulate biological actions that are very similar as or identical to those induced by AGEs. Methods and results: In our study, we used glycolaldehyde‐modified β‐lactoglobulin preparations as model AGEs and employed two methods to remove endotoxin using either affinity columns or extraction with Triton X‐114 (TX‐114). Affinity column‐purified AGEs retained their ability to stimulate inflammatory signaling as measured by mRNA expression of inflammatory cytokines in the human lung epithelial cell line Beas2b. However, glycolaldehyde‐modified AGEs purified by extraction with TX‐114 did not show any stimulation of mRNA expression of inflammatory cytokines. The presence of a cell stimulating endotoxin‐like activity was demonstrated in the detergent phase after extraction with TX‐114, thus indicating that not AGEs but a lipophilic contamination was responsible for the stimulation of inflammatory signaling. Conclusion: Our results demonstrate that glycolaldehyde‐modified AGEs are unable to induce inflammatory signaling in receptor for AGE‐expressing cells. The observed cell‐activating activity can be ascribed to an endotoxin‐like lipophilic contamination present in AGE preparations and affinity column purification was insufficient to remove this contamination.     

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.     

Toxicity of the AGEs generated from the Maillard reaction: on the relationship of food-AGEs and biological-AGEs

Advanced glycation end products (AGEs) are generated in the late stages of Maillard reaction in foods and biological systems. These products are mostly formed by the reactions of reducing sugar or degradation products of carbohydrates, lipids, and ascorbic acid. AGEs exist in high concentration in foods, but in relatively low concentrations in most of the biological systems. Recently, some AGEs have been reported to be toxic, and were proposed to be causative factors for various kinds of diseases, especially diabetes and kidney disorder, through the association with receptor of AGE (RAGE). It has also been reported that food-derived AGEs (food-AGEs) may not be a causative factor for pro-oxidation. However, the relationship of food-AGEs and biological-derived AGEs (biological-AGEs) is not clear. In this review, the following issues are discussed: the formation of AGEs in foods and biological systems; identification of the main AGEs in foods and biological systems; absorption of food-AGEs; the effects of AGEs in vivo; relationship between food-AGEs and biological-AGEs; possible defense mechanism against AGEs in vivo and finally, the problems to be solved concerning the toxicity of AGEs.     

Advanced glycosylation end products and nutrition--a possible relation with diabetic atherosclerosis and how to prevent it

ABSTRACT:  Advanced glycosylation end product (AGE) levels are elevated in diabetic patients and may contribute to the excessive cardiovascular disease in this population, promoting oxidant stress and chronic vascular inflammation. AGEs in people with diabetes mellitus are formed mainly by protein and lipid glucosylation in an environment of chronic hyperglycemia and also by prolonged thermal food processing (diet derived AGEs). This brief review summarizes current literature about food derived AGEs and their relationship with diabetic vascular disease and supports the importance of low AGE diet as an essential preventive or therapeutic intervention against atheromatosis progress.     

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.     

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.     

The Inhibition of Advanced Glycation End Products by Carnosine and Other Natural Dipeptides to Reduce Diabetic and Age‐Related Complications

As people age they are at a greater risk for many disorders including cardiovascular, renal, and neurodegenerative diseases, and these conditions are exacerbated by diabetes. An important cause of the maladies associated with both age and diabetes is the formation of advanced glycation end products (AGEs). AGE formation is initiated by glycation reactions between reducing sugars and free amine groups. A cascade of other reactions follows, leading to alterations in membrane function and damage to the proteome, such as protein crosslinking. Compounds that prevent these reactions are currently being researched, but peptides hold great potential as they tend to lack toxicity, are absorbed intact, are easily produced, and are cheaper than other options. Of the peptides researched, carnosine is the most promising. Research suggests that carnosine is absorbed into the plasma unaltered and intact. Carnosine has been shown to prevent AGE formations through reduction of blood glucose, prevention of early glycation, and even reversing previously formed AGEs. Other promising peptides and amino acids include β‐alanine, L‐histidine, homocarnosine, anserine, and glutathione. If bioactive peptides and amino acids can minimize the formation of AGEs, foods containing these peptides could be used to improve health.     

Accumulation and effects of dietary advanced glycation end products on the gastrointestinal tract in rats

The gastrointestinal (GI) tract represents the first barrier against the penetration of organisms by dietary advanced glycation end products (AGEs), but the tissue accumulation of AGEs and AGE‐induced effects on the GI tract have yet to be completely elucidated. This study aimed to investigate the tissue accumulation of AGEs and AGE‐induced oxidative stress and inflammation in the GI tract of rats after long‐term consumption of AGEs from bread crust (BC). The GI tract was then removed to analyse carboxymethyllysine (CML) and malondialdehyde (MDA) contents, the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH‐Px) and the levels of tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6). This study demonstrates that the oral intake of AGEs promotes their accumulation in the GI tract, and AGEs attenuate the first‐line antioxidant defence and stimulate the inflammatory response of the GI tract by downregulating enzymatic antioxidative pathways and increasing inflammatory cytokine levels.     

末端糖基化产物抑制剂的研究进展

目前研究表明人体的衰老和糖尿病的一些并发症,都与体内的糖基化反应(美拉德反应)所产生的末端糖基化产物有关。为了延迟体内的糖基化反应,末端糖基化产物抑制剂成为了相关研究领域的热点。为此,从末端糖基化产物的形成原理、病理学危害、抑制机理及天然产物中的抑制剂方面做阐述,并对未来研究领域进行展望。     

Effects of flavonoids on the expression of the pro-inflammatory response in human monocytes induced by ligation of the receptor for AGEs

Increasing evidence has shown advanced glycation end products (AGEs) receptor ligation (RAGE) to be an important part of complex interactions of the oxidative stress and pro-inflammatory responses. In this study, flavonoids were used to monitor the protective effects against the oxidative damage and inflammation mediated by AGEs in human monocytes. S100B (RAGE ligand) treatment in human THP-1 monocytic cells (THP-1) significantly increased gene expression of the pro-inflammatory cytokines TNF-alpha and IL-1beta; chemokines MCP-1 and IP-10; adhesion factors platelet endothelial cell adhesion molecule (PECAM-1) and beta2-integrin; and pro-inflammatory cyclooxygenase-2 (COX-2). S100B treatment with quercetin and catechin in THP-1 cells had inhibitory effects on the expression of pro-inflammatory genes and protein levels. Quercetin and catechin could regulate S100B-activated oxidant stress-sensitive pathways through blocking p47phox protein expression. Treatment with quercetin and catechin could eliminate reactive oxygen species (ROS) to reduce oxidative stress stimulated by S100B in THP-1 cells. Quercetin and catechin also showed different regulatory abilities on mitogen-activated protein kinase (MAPK) signaling pathways by inhibiting protein expression in S100B-stimulated inflammatory responses in THP-1 cells. This study suggests that quercetin and catechin may be of benefit for diabetic vascular complications due to its antioxidant abilities against AGE-mediated oxidative stress through oxidative stress-sensitive and oxidative stress-responsive signaling pathways, which lead to inflammation in human monocytes.     

Effect of plant polyphenols on the formation of advanced glycation end products from β-lactoglobulin

Dietary exposure to advanced glycation end products (AGEs) formed from proteins and reducing sugars is of increasing concern to human health. AGEs may form in protein-based powders containing sugars for instant beverages during drying and storage of the product. Chlorogenic acid, a plant phenol characteristic of coffee, was found to protect against the formation of AGEs at a concentration of 50mM during heating of β-lactoglobulin in the presence of glucose as a reducing sugar in 30% aqueous ethanol at 70°C. Epicatechin, a plant phenol characteristic of green tea, had no similar effect for the equivalent concentration of phenol on the formation of AGEs. Immunochemical detection (ELISA) using polyclonal antibodies raised against AGEs showed a dose-dependent effect of protection by chlorogenic acid on AGE formation and is recommended for routine quality control of sugar containing milk-based powders for instant beverages.     

Anti-AGE activity of poplar-type propolis: mechanism of action of main phenolic compounds

This study aimed to compare the protective effect of two geographically distinct propolis against the formation of advanced glycation end products (AGEs). The polyphenol content of propolis extracts (EEPs) was analysed using HPLC-DAD-MS profiling and evaluated for their protective effects against pentosidine-like AGEs. Dicarbonyl trapping capacities of major EEP compounds were determined using a methylglyoxal scavenging in vitro assay. Both propolis samples were characterised with high levels of pinobanksin derivatives exhibiting strong anti-AGE properties. EEPs reduced AGE formation more effectively than well-known natural AGE inhibitors such as quercetin or chlorogenic acid. Individual evaluations of the five major compounds in EEPs showed that flavonoids strongly inhibit the formation of AGEs by trapping dicarbonyl intermediates, whereas compounds such as caffeic acid derivatives only act as antioxidant agents. Propolis is thus a promising candidate for the prevention and control of AGE-related chronic diseases.     

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.     

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.     

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.     

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.     

桑椹花色苷对晚期糖基化末端产物抑制作用及其机制分析

晚期糖基化末端产物(Advanced Glycation End Products,AGEs)是蛋白质游离氨基与还原糖羰基反应形成的一类复杂物质的总称,是诱发糖尿病等多种慢性病的重要因素之一,而多酚类化合物能够抑制AGEs的形成。为了探讨桑椹花色苷对AGEs的抑制机制,建立牛血清蛋白(BSA)/葡萄糖(Glucose)生成AGEs模拟反应体系,以0.5%酸性乙醇提取、AB-8型大孔树脂纯化的桑椹花色苷为抑制剂,测定反应体系中蛋白质羰基、巯基含量变化、羟基自由基(·OH)对AGEs形成的影响,利用SDS-PAGE凝胶电泳技术分析BSA的分子量变化。研究结果表明,随着桑椹花色苷浓度的增加,反应体系中的AGEs含量显著降低(P0.05)。桑椹花色苷可显著抑制·OH诱导的AGEs的形成(P0.05)。桑椹花色苷通过保护巯基和抑制蛋白质形成羰基而抑制AGEs生成;SDS-PAGE图谱显示,桑椹花色苷可阻断糖基化反应导致的蛋白质交联物的形成。     

添加糖与酱油对油炸鲟鱼晚期糖化终末产物形成的影响研究

本论文首次分析糖和酱油添加对油炸鲟鱼晚期糖化终末产物（AGEs）形成的影响。以鲟鱼肉为原料，添加绵白糖（0%、1%、2%、3%）、酱油（0%、1%、2%）并制备油炸鲟鱼饼（170 ℃/9 min），分析鲟鱼饼AGEs以及其前体物质糠氨酸、二羰基化合物的变化规律。结果表明，仅添加绵白糖时，油炸鲟鱼饼AGEs以及其前体物质糠氨酸、二羰基化合物含量随绵白糖添加水平增加而逐渐增加；仅添加酱油时，油炸鲟鱼饼糠氨酸、荧光AGEs、羧乙基赖氨酸（CEL）含量随着酱油添加水平增加而逐渐增加，而羧甲基赖氨酸（CML）、甲基乙二醛氢咪唑酮（MG-H1）含量随着酱油添加水平的增加而显著减少（P<0.05），添加酱油对AGEs抑制作用与酱油成分对二羰基化合物消耗有关。当绵白糖和酱油同时添加时，进一步促进糠氨酸、荧光AGEs和MG-H1的形成，两者对油炸鲟鱼饼AGEs形成具有显著交互作用（P<0.05）。因此，添加绵白糖会促进AGEs的形成，而酱油由于其复杂成分导致其添加对不同AGEs标志物形成影响各异。这些工作将为油炸水产品AGEs形成与控制提供理论依据与指导。