Perspective Cite This: J. Agric. Food Chem. 2018, 66, 2065−2070
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Perspective of Advanced Glycation End Products on Human Health Jer-An Lin,†,‡ Chi-Hao Wu,†,§ and Gow-Chin Yen*,‡,∥ ‡
Graduate Institute of Food Safety and ∥Department of Food Science and Biotechnology, National Chung Hsing University, 145 Xingda Road, Taichung 40227, Taiwan § Department of Human Development and Family Studies, National Taiwan Normal University, 162, Section 1, Heping East Road, Taipei 106, Taiwan ABSTRACT: In the last 20 years, the effects of advanced glycation end products (AGEs) on health have received increasing attention. High AGE levels in the body correlate with the progression of many diseases, such as diabetes, cardiovascular disease, and some cancers. However, whether AGEs are a cause of these diseases or represent accompanying symptoms of these diseases still needs to be elucidated by more comprehensive research. Recently, many researchers have begun to investigate the effects of AGE intake-induced variations of gut microbiota on disease progression, which will further explain the impact of AGEs on health and open a new chapter in AGE research. KEYWORDS: AGEs, cancer, diabetes, cardiovascular disease, microbiota
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INTRODUCTION In 1912, French chemist Louis-Camille Maillard found in his study of food that reducing sugar molecules reacted chemically with the lysine side chains and N-terminal amine groups on proteins and amino acids, leading to browning;1 this chemical reaction is the origin of the reaction known as the “Maillard reaction”. In today’s dietary patterns, the characteristics of most foods (especially heat-processed foods), such as aroma and color, are closely related to Maillard reaction products because Maillard reaction substrates exist widely in foods. Common dietary components, such as biscuits, bread, tea, coffee, fried and barbecued food, and fast food products, are quite typical Maillard-reaction-related foods. Early studies of the Maillard reaction focused primarily on the reduced nutritional value of proteins and amino acids as a result of sugar modification and the chemistry of Maillard flavor generation. As glycated hemoglobin is found in the blood of diabetic patients,2 the effects of the Maillard reaction on the organism began to receive attention. The end products of the Maillard reaction in organisms are the so-called advanced glycation end products (AGEs). However, disagreements exist regarding the types of compounds covered by AGEs. Generally, AGEs do not cover all Maillard reaction products.3 Compounds discussed in most of the AGE studies are mainly substances produced from Amadori products via rearrangement and a series of chemical reactions and products from interaction reactions between the degradation and fragmentation products of reducing sugars (such as glucose and fructose) and free lysine/arginine or protein lysine/arginine residues.4 Of these compounds, Nε-carboxymethyllysine (CML) was the first AGE discovered5 and is also a well-studied AGE marker. Therefore, many studies use CML as the AGE marker. However, different AGEs not only have different chemical characteristics but also have different physiological effects (such as the ability to induce macrophage endocytosis).6 Given that AGEs and their protein adducts accumulate in various lesions, investigations of the relationship between AGEs and diseases have recently gained attention, and this research © 2018 American Chemical Society
boom culminated in the discovery of the receptor for AGEs (RAGE). Numerous studies suggest that RAGE acts as a bridge between AGEs and diseases. AGE protein adducts can generate large amounts of reactive oxygen species (ROS) by activating RAGE on cells. This AGE−RAGE−ROS loop leads to the activation of inflammatory cells and the release of RAGE ligands with different physiological effects, such as S100 proteins or HMGB1, to change immune homeostasis, resulting in tissue damage and lesion formation.7 This AGE−RAGE axis is even related to the development of cancer.8 In addition, AGE protein adducts also stimulate the activation of different cellular signaling pathways through RAGE, affecting cell physiology.9,10 AGEs also cause cross-linking, leading to stiffness in tissues, such as tendons, intervertebral discs, skin, arteries, and vaginal tissues.11 As the pathological role of AGEs is clarified, scholars have begun to explore whether prolonged ingestion of large amounts of dietary AGEs promotes the onset of diseases or disease deterioration. A recent book edited by Uribarri details the role of dietary AGEs in disease and health over the past 2 decades.12 Although there is no standardized analytical method for AGEs, the consumption of foods rich in AGEs can indeed increase the content of AGEs in vivo13,14 and change in vivo redox and immune homeostasis to affect disease development.12 Dietary exposure to AGEs in humans has been reported to be approximately 100−300 μmol/day or 16 000 AGE kU/day.4 However, increases in AGEs in vivo are not necessarily directly derived from AGEs in the diet but may result from the intestinal digestion of food.15,16 Given that AGE-induced oxidative stress and chronic inflammation are involved in many disease processes, the physiological mechanisms that reduce AGE production, inhibit AGE function, or clear AGEs as well as dietary factors17,18 and pharmacological drugs19 with Received: Revised: Accepted: Published: 2065
December 19, 2017 February 5, 2018 February 8, 2018 February 8, 2018 DOI: 10.1021/acs.jafc.7b05943 J. Agric. Food Chem. 2018, 66, 2065−2070
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early and mid-Maillard reaction products undergo autoxidation and/or lysis and degradation to produce the highly reactive precursors of AGEs. Among them, the most widely investigated are dicarbonyls, including glyoxal (GO), methylglyoxal (MG), and 3-deoxyglucosone (3-DG). These precursors react with amino-group-bearing substances (mainly lysine and arginine groups) to produce AGEs (Figure 1A).4,17 However, AGE precursors, such as dicarbonyls, are not only produced by the Maillard reaction. Other biochemical reactions, such as lipid oxidation, protein degradation, and glycolysis, also represent sources of AGE precursors in foods or organisms.8 Therefore, AGEs are not derived exclusively from the Maillard reaction. The main synthesis pathways of AGEs in vivo and in food as well as AGE precursors and common AGE types are summarized in Figure 1. AGE Analysis. AGE analysis mainly consists of two categories. One is analyte preparation, i.e., the isolation of AGEs from samples through steps of extraction, hydrolysis, and purification. According to the different extraction methods, free AGEs and protein/peptide-bound AGEs can be obtained.20 The second category is measurement of the AGE samples by immunochemical or instrumental methods. Analyte preparation for these two methods is totally different. In general, analyte preparation is less complicated for immunochemical methods than for instrumental analysis. The most common method for AGE immunochemical analysis is enzyme-linked immunosorbent assay (ELISA). Previously, various types of polyclonal/monoclonal antibodies to a protein-bound AGE epitope(s) were published for application in ELISA, of which the protein-bound AGEs commonly used for antibody generation include AGE−bovine serum albumin (BSA), AGE−keyhole limpet hemocyanin (KLH), AGE−collagen, and AGE−ribonuclease (RNase).21 In the AGE ELISA, commonly used antibodies include the 6D1222 and 4G9 (6C7) monoclonal antibodies12,15 that specifically react with CML protein adducts and the 3D11 mAb monoclonal antibody12 that specifically reacts with MGmodified protein. To date, approximately 300 types of AGE ELISA commercial kits are available that are suitable for the detection of protein/peptide-bound AGE accumulation in humans, mice, rats, rabbits, guinea pigs, and other species. Despite the simplicity and speed of ELISA analysis, the actual concentration of AGEs in the test samples cannot be measured by ELISA (ELISA results are typically represented in arbitrary units), and numerous doubts exist about the accuracy of using ELISA to detect AGEs in food. Given that the matrix of food is complex, the validity of the antibodies used in ELISA must be confirmed in different food matrices before AGE measurements. However, most of the AGE ELISA kits do not perform the test to confirm the validity of antibodies. Therefore, the values of some food AGE content databases established using ELISA are still being questioned by many scholars in the AGE field. 4,18 However, recent studies have confirmed the consistency of the results of immunochemical and instrumental analyses of dietary AGEs.23 The objective of the instrumental analysis is to separate the target by chromatography and further determine the target using a visible light/ultraviolet/fluorescence detector or mass analyzer.20 Key factors influencing the instrumental analysis of AGE results include sample pretreatment steps (including the type of extraction solution used, inorganic salts/organic salts, pH, etc.), hydrolysis methods (acid/base or enzyme), reaction temperature, reaction time, environmental gas (aerobic/
these biochemical features have been investigated intensively in the past decade. Most of these substances have multiple biochemical properties, such as antiglycation and antioxidation, which increase the difficulty in clarifying the major mechanisms by which these substances affect AGEs and impact their applicability. In the following sections, AGE chemistry, analysis, and experimental models will be introduced. Furthermore, current knowledge on the homeostasis of AGEs in the body and the effects of AGEs on human health will be elaborated.
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FUNDAMENTAL KNOWLEDGE OF AGES AGE Chemistry. The entire process wherein glycosamine condensates and forms melanoidins after a series of complex chemical reactions is known as the Maillard reaction.3 Amadori products generated during the initial reaction are rearranged and chemically modified via oxidization or non-oxidization reactions to produce AGEs (Figure 1A).4,18 In addition, reducing sugars participating in the Maillard reaction and the
Figure 1. (A) AGE chemistry and (B) AGE precursors and common AGEs with different characteristics: GO, glyoxal; MG, methylglyoxal; 3-DG, 3-deoxyglucosone; GOLD, glyoxal-lysine dimer; MOLD, methylglyoxal-lysine dimer; CML, Nε-carboxymethyllysine; CEL, Nεcarboxyethyllysine; and MG-H1, Nδ-(5-hydro-5-methyl-4-imidazolon2-yl)ornithine. 2066
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Figure 2. Scheme of circulating AGE homeostasis. (∗) Glycation compounds mainly include monosaccharides and dicarbonyl and carbonyl compounds. (#) Biological/chemical reactions in vivo include metabolic reactions, glucose autoxidation, lipid peroxidation, and possibly other freeradical-induced fragmentation/degradation of organic compounds.
the association of AGEs with disease progression4,10,12 and methods to reduce the physiological impacts of AGEs.17,19 Among the above types of studies on AGEs, the largest number of studies focus on the physiological effects of AGEs in vivo and related inhibition methods,8,10,12 of which the most common research model involves investigating the biochemical characteristics of AGE−BSA and the inhibition of the physiological effects of AGE−BSA. Albumin is the most abundant protein in the blood, with a half-life of approximately 21 days, and is therefore the most prominent target for glycation in the circulatory system.25 Glycated albumin can be phagocytosed by macrophages and neutralized by free RAGE, thus reducing cell and tissue stimulation. However, if the glycated albumin content is too high in the body, it may affect the immune balance and burst oxidative stress, resulting in tissue inflammatory damage. This phenomenon is common in people with diabetes. Therefore, glycated albumin is an important pathogenic factor in many diabetic complications, because it can affect most of the cells and tissues in the body through the circulatory system. As a result of the above reasons, many studies have been designed with the main axis of AGE−BSA biochemical characteristics, and these types of studies have also become the most common experimental model in AGE studies. Related studies have included an analysis of the biochemical characteristics of BSA modified by different glycation agents (RAGE-binding ability, amount of different AGE residues, fluorescence intensity, and browning degree), effects of AGE−BSA on the physiological properties of different cells and tissues, blockade of AGE−BSAinduced responses, and means for elimination of AGE−BSA (including inactivation of AGE precursors). However, as a
anaerobic), and shaking intensity during the reaction. All of these factors affect the result of subsequent analysis and detection. AGEs with different chemical structures have different sensitivities to acid, alkali, temperature, and enzyme reactions. Therefore, when AGEs with different characteristics are analyzed, each type of AGE must have an internal standard to calibrate the effect of sample pretreatment on the analysis results to obtain objective and accurate results. However, at present, no standard procedure is available for sample pretreatment for the analysis of AGEs in vivo and in food. As a result, it is difficult to discuss and compare the AGE values listed in many studies, despite the use of similar AGE analysis methods. In recent years, the rapid determination of in vivo AGEs using AGE fluorescence has attracted considerable attention as a result of the correlation between the accumulation of AGEs in vivo and the degree of aging as well as many chronic metabolic diseases.24 Related technologies have been used in the development of medical testing equipment, such as AGE Reader (Diagnoptics Technologies BV), which can be used for risk assessment of aging and cardiovascular disease and diabetes-related diseases. Common Experimental Models in AGE Studies. Common AGE research can be divided into two categories. One category involves the analysis of AGEs in food20 and the assessment of factors and mechanisms that affect AGE production in food,18 the bioavailability of AGEs in the diet, and the effects of AGE intake on health.4 The other category involves analyzing AGEs in vivo,5,11,21,22 exploring the possible pathogenesis of AGEs in vivo6−10 and in vivo AGE generation, metabolism, and clearance mechanisms,4,10,12 and investigating 2067
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including cell metabolism, glucose autoxidation, and lipid peroxidation, can produce glycation compounds. These glycation compounds can react with plasma proteins and tissue proteins to generate plasma and tissue AGEs, which are important sources of AGEs in the circulation system. However, most of these AGEs can be removed by the urinary system3,4,13,14,16 or via endocytosis of hepatocytes and macrophages.4,27 The rest of the circulating AGEs in the body may accumulate in the organs and tissues (mainly the liver, kidney, and bladder). Given the limited metabolic capacity of organisms, the amount of AGEs that accumulate in organs and tissues increases with increasing age. Of note, dietary patterns, digestive system status, and intestinal bacteria are important factors that influence the content of food-derived AGEs and glycation compounds in the body.3,15,16,18,26 The interactions between these factors are complex, and more studies are needed to help clarify the relationship between dietary AGEs and disease.
result of the different methods of AGE−BSA preparation in different laboratories, it is difficult to systematically discuss and compare relevant studies. In addition, most studies do not provide AGE−BSA chemical analysis results, and the experimental analysis data regarding the presence of free AGEs or microbial contaminants, such as lipopolysaccharides (LPS), greatly reduce the reference value of AGE−BSA studies. Of note, in recent years, the effects of high glycation stress caused by the specific metabolic mode of cancer cells and AGE accumulation in the tumor microenvironment on the development of cancer have received considerable attention.8 Of these studies, the most basic physiological studies on cancer cells explored the effects of AGE−BSA or AGE precursors. Numerous studies have used both high and low heat-processed foods to design high or low AGE diets and to explore the association of AGEs in the diet with disease development.4,12 Given that the source of food-derived AGEs in the body is digested food, it is not useful to link the AGE content of the food to the physiological effects caused by ingestion of the food. In addition, heat processing not only produces AGEs but also produces numerous highly reactive substances, such as heterocyclic amines (HCAs). Therefore, the results of the relevant research cannot be entirely attributed to the role of AGEs in food.
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AGES: A THREAT OR BENEFIT TO HUMAN HEALTH? Physiological Role of AGEs. The physiological effects of AGEs can be simply divided into two categories. (1) AGEs promote protein cross-linking and can act as bridging molecules of different peptide chains in proteins to promote protein aggregation or tissue stiffness, causing proteins and tissues to lose their original function. This aspect of the physiological role of AGEs is often discussed in cardiovascular disease associated with diabetes and chronic kidney disease, aging, skin diseases, and neurodegenerative diseases. (2) Protein-bound AGEs can activate cell membrane receptors, such as RAGE, oligosaccharyl transferase complex protein 48 (OST-48, generally known as AGER1), 80 KH protein (AGER2), and galectin-3 (AGER3), to directly promote ROS generation and affect cell physiology. Given the positive correlation between RAGE activation and numerous diseases, there is a wealth of research regarding the interaction of AGEs with RAGE and its role in disease.7−9 However, not all AGE protein adducts can bind to RAGE and activate specific cellular pathways.28 Only CML or Nεcarboxyethyllysine (CEL) protein adducts bind to RAGE and cause the activation of specific cellular signaling pathways.29 Effects of AGEs on Human Health. As shown in Figure 3, through the physiological functions described above, in vivo AGEs enhance oxidative stress, affect immune balance, promote chronic inflammation, cause tissue damage, change the functional properties of tissue proteins, promote protein aggregation, and further induce the occurrence of numerous diseases or accelerate disease progression.7−12,30 However, the differences in physiological effects induced by free AGEs and protein-bound AGEs have not yet been completely elucidated. The relationship of AGE structures and their bioactivities, the number of AGE residues, and the structures of glycated proteins with the biological activity of AGE protein adducts has not been clarified. Therefore, to clearly understand the effects of in vivo AGEs on disease and health, more research is needed to establish the relationship of AGE physicochemical properties with AGE disease bioactivity. Melanoidins, a group of Maillard reaction products, may involve AGEs and AGE protein adducts.3,4 Numerous studies confirm that melanoidins in food may have potential beneficial effects on health because melanoidins have potential tumor growth inhibition and antimutation, antioxidative, and intestinal microflora regulatory effects.31 However, most studies do not
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AGE HOMEOSTASIS Source of Body AGEs. AGE accumulation in the body can be derived from two main sources: the glycation of proteins in the body and dietary uptake. Key factors affecting protein glycation in vivo include oxidative stress and the types of glycation agents and proteins. Glycation agents include glucose, fructose, and dicarbonyl/carbonyl compounds with higher activities, of which the former has less reactivity compared to the latter. Most scholars agree that dicarbonyl/carbonyl compounds are the main precursors of AGEs. These highly active AGE precursors may result from protein degradation, glycolysis, lipid oxidation, glucose autoxidation, and other freeradical-induced molecular lysis reactions (Figure 1A). Oxidative stress promotes the production of highly reactive glycation agents, such as MG and GO, to further enhance the rate of protein glycation in the body.17−19 Oxidative stress is thus often considered an important promoter of the accumulation of large amounts of glycated proteins in the body. In addition, free AGEs in the diet can enter the circulatory system directly from the intestine through simple diffusion, whereas peptide-bound AGEs can enter the body via transporter proteins.26 Glycation may lead proteins to be resistant to digestive enzymes. This not only affects the nutritional value of the protein but may cause changes in intestinal microbiota as a result of glycated protein with high molecular weight that is difficult to digest and absorb, thus accumulating in the stool.3,15,26 Mechanisms Involved in Circulating AGE Homeostasis. As shown in Figure 2, the amount of AGEs observed in the body is the consequence of a dynamic equilibrium among various reactions. Most of the low-molecular-weight foodderived AGEs are excreted via the kidneys, whereas foodderived AGEs with high molecular weight that cannot be metabolized and absorbed into the body are excreted in stool.3,4,13,14,16 In addition, monosaccharides (especially fructose and glucose) and fatty acids derived from foods are important sources of glycation compounds in the body. Many monosaccharides are glycation compounds, and many biochemical reactions involving fatty acids and monosaccharides, 2068
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standard AGE preparation, precise AGE analysis, digestion and intestinal microbial effects, and adjusting nutrition loss and concerning effects of non-AGE products derived from heat processing in test samples should be considered. Of note, many scholars have recently started to explore the interaction among dietary AGEs, microbiota, immunomodulation, circulating AGEs, and the extent of disease, which will further explain the impact of AGEs on health and open a new chapter in AGE research.
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AUTHOR INFORMATION
Corresponding Author
*Telephone: 886-4-2287-9755. Fax: 886-4-2285-4378. E-mail:
[email protected]. ORCID
Gow-Chin Yen: 0000-0001-9538-4219 Author Contributions †
Jer-An Lin and Chi-Hao Wu contributed equally to this work.
Notes
The authors declare no competing financial interest.
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Figure 3. AGE-induced biological effects and correlated diseases.7−12,30
REFERENCES
(1) Maillard, L. C. Action of amino acids on sugars. Formation of melanoidins in a methodical way. Compt. Rend. 1912, 154, 66−68. (2) Rahbar, S.; Blumenfeld, O.; Ranney, H. M. Studies of an unusual hemoglobin in patients with diabetes mellitus. Biochem. Biophys. Res. Commun. 1969, 36, 838−843. (3) AlJahdali, N.; Carbonero, F. Impact of Maillard reaction products on nutrition and health: Current knowledge and need to understand their fate in the human digestive system. Crit. Rev. Food Sci. Nutr. 2017, 1−14. (4) Poulsen, M. W.; Hedegaard, R. V.; Andersen, J. M.; de Courten, B.; Bugel, S.; Nielsen, J.; Skibsted, L. H.; Dragsted, L. O. Advanced glycation endproducts in food and their effects on health. Food Chem. Toxicol. 2013, 60, 10−37. (5) Ahmed, M. U.; Thorpe, S. R.; Baynes, J. W. Identification of Nεcarboxymethyllysine as a degradation product of fructoselysine in glycated protein. J. Biol. Chem. 1986, 261, 4889−4894. (6) Nagai, R.; Matsumoto, K.; Ling, X.; Suzuki, H.; Araki, T.; Horiuchi, S. Glycolaldehyde, a reactive intermediate for advanced glycation end products, plays an important role in the generation of an active ligand for the macrophage scavenger receptor. Diabetes 2000, 49, 1714−1723. (7) Manigrasso, M. B.; Juranek, J.; Ramasamy, R.; Schmidt, A. M. Unlocking the biology of RAGE in diabetic microvascular complications. Trends Endocrinol. Metab. 2014, 25, 15−22. (8) Lin, J. A.; Wu, C. H.; Lu, C. C.; Hsia, S. M.; Yen, G. C. Glycative stress from advanced glycation end products (AGEs) and dicarbonyls: An emerging biological factor in cancer onset and progression. Mol. Nutr. Food Res. 2016, 60, 1850−1864. (9) Soman, S.; Raju, R.; Sandhya, V. K.; Advani, J.; Khan, A. A.; Harsha, H. C.; Prasad, T. S.; Sudhakaran, P. R.; Pandey, A.; Adishesha, P. K. A multicellular signal transduction network of AGE/RAGE signaling. J. Cell Commun. Signal 2013, 7, 19−23. (10) Byun, K.; Yoo, Y.; Son, M.; Lee, J.; Jeong, G. B.; Park, Y. M.; Salekdeh, G. H.; Lee, B. Advanced glycation end-products produced systemically and by macrophages: A common contributor to inflammation and degenerative diseases. Pharmacol. Ther. 2017, 177, 44−55. (11) Weli, H. K.; Akhtar, R.; Chang, Z.; Li, W. W.; Cooper, J.; Yang, Y. Advanced glycation products’ levels and mechanical properties of vaginal tissue in pregnancy. Eur. J. Obstet. Gynecol. Reprod. Biol. 2017, 214, 78−85. (12) Dietary AGEs and Their Role in Health and Disease; Uribarri, J., Ed.; CRC Press: Boca Raton, FL, 2017.
clarify the impact of molecular weight, molecular structure, or AGE residue content in the mode of action of melanoidins. Therefore, these studies will not be helpful to clarify the physiological characteristics of AGEs. The integration of the above discussion leads to the inference that AGEs have the potential to endanger health, but this needs to be verified in more detailed studies.
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FUTURE PERSPECTIVES Numerous studies have demonstrated the association of in vivo AGE protein adducts with disease and health. Despite the potential of AGEs to highly endanger health and advance the disease process, numerous controversies exist regarding the physiological impact of AGEs because the relationship between the physicochemical properties and biological activities of AGEs remains unclear. Furthermore, most AGE study designs did not explore or compare the biochemical and structural characteristics of free AGEs and AGE protein adducts and their contribution to the metabolic uptake and physiological effects of AGEs. Instead, these studies exclusively focused on evaluating the effects of carbohydrate-modified protein (such as AGE−BSA, AGE−HSA, AGE−casein, and fructose-modified egg whites) or Maillard-reaction-product-rich food (such as bread crust and heat-processed foods) on diseases via in vivo and in vitro experiments. Given that related studies have not fully elucidated the physiological roles of AGEs, designing a better experimental platform to explore the relationship between AGEs and diseases is a direction that scholars in relevant fields should focus on. Different scholars also have different opinions on the types of compounds covered by AGEs. Therefore, the conclusions drawn by different studies are not necessarily based on the same substance. In the future, scholars in AGE-related fields should unify the definition of AGEs and establish a standard experimental platform to evaluate the physicochemical properties and biological activities of AGEs to break through the bottleneck of AGE research at this stage and clarify the physiological role of AGEs. With regard to the design of relevant experimental platforms, 2069
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Journal of Agricultural and Food Chemistry (13) Scheijen, J. L. J. M.; Hanssen, N. M. J.; van Greevenbroek, M. M.; Van der Kallen, C. J.; Feskens, E. J. M.; Stehouwer, C. D. A.; Schalkwijk, C. G. Dietary intake of advanced glycation endproducts is associated with higher levels of advanced glycation endproducts in plasma and urine: The CODAM study. Clin. Nutr. 2017, DOI: 10.1016/j.clnu.2017.03.019. (14) Delgado-Andrade, C.; Tessier, F. J.; Niquet-Leridon, C.; Seiquer, I.; Pilar Navarro, M. Study of the urinary and faecal excretion of Nε-carboxymethyllysine in young human volunteers. Amino Acids 2012, 43, 595−602. (15) Martinez-Saez, N.; Fernandez-Gomez, B.; Cai, W.; Uribarri, J.; del Castillo, M. D. In vitro formation of Maillard reaction products during simulated digestion of meal-resembling systems. Food Res. Int. 2017, DOI: 10.1016/j.foodres.2017.09.056. (16) DeChristopher, L. R. Perspective: The paradox in dietary advanced glycation end products research-The source of the serum and urinary advanced glycation end products is the intestines, not the food. Adv. Nutr. 2017, 8, 679−683. (17) Wu, C. H.; Huang, S. M.; Lin, J. A.; Yen, G. C. Inhibition of advanced glycation endproduct formation by foodstuffs. Food Funct. 2011, 2, 224−234. (18) Lund, M. N.; Ray, C. A. Control of Maillard reactions in foods: Strategies and chemical mechanisms. J. Agric. Food Chem. 2017, 65, 4537−4552. (19) Engelen, L.; Stehouwer, C. D.; Schalkwijk, C. G. Current therapeutic interventions in the glycation pathway: Evidence from clinical studies. Diabetes, Obes. Metab. 2013, 15, 677−689. (20) Zhang, G.; Huang, G.; Xiao, L.; Mitchell, A. E. Determination of advanced glycation endproducts by LC-MS/MS in raw and roasted almonds (Prunus dulcis). J. Agric. Food Chem. 2011, 59, 12037−12046. (21) Ikeda, K.; Nagai, R.; Sakamoto, T.; Higashi, T.; Jinnouchi, Y.; Sano, H.; Matsumoto, K.; Yoshida, M.; Ueda, S.; Horiuchi, S.; Araki, T. Immunochemical Approaches to AGE-StructuresCharacterization of Anti-AGE Antibodies. In The Maillard Reaction in Foods and Medicine; O’Brien, J., Nursten, H. E., Crabbe, M. J. C., Ames, J. M., Eds.; Woodhead Publishing: Cambridge, U.K., 2005; pp 310−315, DOI: 10.1533/9781845698447.7.310. (22) Horiuchi, S.; Araki, N.; Morino, Y. Immunochemical approach to characterize advanced glycation end products of the Maillard reaction. Evidence for the presence of a common structure. J. Biol. Chem. 1991, 266, 7329−7332. (23) Gómez-Ojeda, A.; Jaramillo-Ortíz, S.; Wrobel, K.; Wrobel, K.; Barbosa-Sabanero, G.; Luevano-Contreras, C.; de la Maza, M. P.; Uribarri, J.; del Castillo, M. D.; Garay-Sevilla, M. E. Comparative evaluation of three different ELISA assays and HPLC-ESI-ITMS/MS for the analysis of Nε-carboxymethyl lysine in food samples. Food Chem. 2018, 243, 11−18. (24) Gerrits, E. G.; Lutgers, H. L.; Kleefstra, N.; Graaff, R.; Groenier, K. H.; Smit, A. J.; Gans, R. O.; Bilo, H. J. Skin autofluorescence: A tool to identify type 2 diabetic patients at risk for developing microvascular complications. Diabetes Care 2008, 31, 517−521. (25) Raghav, A.; Ahmad, J.; Alam, K.; Khan, A. U. New insights into non-enzymatic glycation of human serum albumin biopolymer: A study to unveil its impaired structure and function. Int. J. Biol. Macromol. 2017, 101, 84−99. (26) Hellwig, M.; Bunzel, D.; Huch, M.; Franz, C. M.; Kulling, S. E.; Henle, T. Stability of individual Maillard reaction products in the presence of the human colonic microbiota. J. Agric. Food Chem. 2015, 63, 6723−6730. (27) Zhuang, A.; Yap, F. Y.; Bruce, C.; Leung, C.; Plan, M. R.; Sullivan, M. A.; Herath, C.; McCarthy, D.; Sourris, K. C.; Kantharidis, P.; Coughlan, M. T.; Febbraio, M. A.; Hodson, M. P.; Watt, M. J.; Angus, P.; Schulz, B. L.; Forbes, J. M. Increased liver AGEs induce hepatic injury mediated through an OST48 pathway. Sci. Rep. 2017, 7, 12292. (28) Indurthi, V. S.; Leclerc, E.; Vetter, S. W. Interaction between glycated serum albumin and AGE-receptors depends on structural changes and the glycation reagent. Arch. Biochem. Biophys. 2012, 528, 185−196.
(29) Xue, J.; Rai, V.; Singer, D.; Chabierski, S.; Xie, J.; Reverdatto, S.; Burz, D. S.; Schmidt, A. M.; Hoffmann, R.; Shekhtman, A. Advanced glycation end product recognition by the receptor for AGEs. Structure 2011, 19, 722−732. (30) Teodorowicz, M.; van Neerven, J.; Savelkoul, H. Food Processing: The influence of the Maillard reaction on immunogenicity and allergenicity of food proteins. Nutrients 2017, 9, 835. (31) Langner, E.; Rzeski, W. Biological properties of melanoidins: A review. Int. J. Food Prop. 2014, 17, 344−353.
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