The Complexity of Advanced Glycation End Products in Foods: Where

Technologies, North Carolina Agricultural and Technical State University, North Carolina. 4. Research Campus, 500 Laureate Way, Kannapolis, NC 28081, ...
1 downloads 0 Views 676KB Size
Download PDF
Perspective Cite This: J. Agric. Food Chem. 2018, 66, 1325−1329

pubs.acs.org/JAFC

Complexity of Advanced Glycation End Products in Foods: Where Are We Now? Yingdong Zhu, Hunter Snooks, and Shengmin Sang* Laboratory for Functional Foods and Human Health, Center for Excellence in Post-Harvest Technologies, North Carolina Agricultural and Technical State University, North Carolina Research Campus, 500 Laureate Way, Kannapolis, North Carolina 28081, United States ABSTRACT: Recent clinical trials indicate that consumption of dietary advanced glycation end products (AGEs) may promote the development of major chronic diseases. However, the outcomes of human studies have proven inconclusive as a result of estimates of the total AGE intake being taken with a single AGE in most of the studies. In this perspective, we summarized the major types of AGEs derived from proteins, nucleic acids, and phospholipids during food processing and suggested a panel of AGEs as markers to better measure the intake of total dietary AGEs in human studies. KEYWORDS: dietary AGEs, amino acids, chronic disease, dicarbonyls, Maillard reactions, nucleotides, phospholipids

A

nucleic acids give rise to various types of dietary AGEs during cooking. Intermolecular cross-linking between proteins, proteins and DNA, or proteins and lipids, induced by dicarbonyls, would further increase the complexity of dietary AGEs. It is unlikely that one single specific AGE is able to reflect the complexities of total AGEs in different diets. Determination of total AGE levels only based on CML contents, therefore, is prone to obscure differences of AGEs between two groups in human intervention studies, eventually leading to conflicting outcomes. The goal of this perspective is to summarize major types of AGEs derived from reactive proteins, nucleic acids, and phospholipids in cooked foods. We expect to emphasize that measurement of total AGEs based on CML alone may make evaluations of the effects of dietary AGE intake on risk factors of chronic diseases in human studies pointless.

dvanced glycation end products (AGEs) are a large, heterogeneous group of compounds that originated from the non-enzymatic Maillard reactions between reducing sugars and proteins, lipids, or nucleic acids1,2 and can be generated both in vitro and in vivo.3 The major precursors of AGEs generated during Maillard reactions are the reactive dicarbonyl species, with glyoxal (GO), methylglyoxal (MGO), and 3deoxyglucosone (3-DG) being the major species.4,5 Important sites of glycation are lysyl side chains, N-terminal amino groups, and arginyl guanidine groups of proteins, guanyl bases of nucleotides, and amino groups of phosphatidylethanolamine (PE) and phosphatidylserine (PS).5 It has been widely accepted that AGEs in vivo contribute to the pathogenesis of many chronic diseases, including diabetes and diabetic complications,6 neurodegenerative diseases,2 and cardiovascular and kidney diseases.7 Increasing evidence suggests dietary AGEs as important contributors to the AGE pool of the body, where they become indistinguishable from endogenous AGEs, in both structure and function.8 Recent systematic reviews in clinical trials indicate that consumption of dietary AGEs may promote risk factors associated with chronic diseases, including inflammation, oxidative stress, and insulin resistance.1,5,9 However, there are also studies showing no differences for circulating biomarkers of inflammation levels between interventions after high AGE consumption in both healthy adults10,11 and diabetic patients.12,13 Moreover, the studies that examined the effect of a high AGE diet on risk factors for type 2 diabetes in healthy populations10,14 and insulin resistance in diabetic patients12−14 were conflicting. As reviewed, all studies used cooking methods to generate differences in AGEs between diets.9 Total AGE levels in diets were evaluated mostly on the basis of the content of lysinederived AGE, N-ε-carboxymethyllysine (CML), which was quantified mainly by enzyme-linked immunosorbent assay (ELISA) and liquid chromatography−tandem mass spectrometry (LC−MS/MS) or estimated from an AGE database.5,9 CML was the first AGE detected in foods and usually used as a marker of AGEs in foods.15 Nevertheless, different diets rich in different compositions and amounts of proteins, lipids, and © 2018 American Chemical Society

■

LYSINE-DERIVED AGES ARE NOT THE ONLY DOMINATING AMINO-ACID-DERIVED AGES IN FOODS Many different types of amino-acid-derived AGEs have been found in foods, which were mainly tied to the glycation of lysine, arginine, and cysteine residues.15 The primary amino group in the side chains of lysine is the most reactive precursor amine in proteins; a large number of lysine-derived AGEs, therefore, can form during food processing. However, the AGEs that have been unambiguously identified and quantified in processed foods remains quite few.4 To date, the major lysinederived AGEs found include CML and N-ε-carboxyethyllysine (CEL), pyrraline in milk, pasta, and bakery products, pronyllysine in the crusts and crumbs of bread, and lysine dimers [glyoxal-lysine dimer (GOLD), methylglyoxal-lysine dimer (MOLD), and 3-deoxyglucosone-lysine dimer (DOLD)] in bakery products (Figure 1).4 Among them, CML is the most Received: Revised: Accepted: Published: 1325

December 19, 2017 January 26, 2018 January 29, 2018 January 29, 2018 DOI: 10.1021/acs.jafc.7b05955 J. Agric. Food Chem. 2018, 66, 1325−1329

Perspective

Journal of Agricultural and Food Chemistry

Figure 1. Structures of main dietary AGEs derived from amino acids. CML, N-ε-carboxymethyllysine; CEL, N-ε-carboxyethyllysine; GOLD, glyoxallysine dimer; MOLD, methylglyoxal-lysine dimer; DOLD, 3-deoxyglucosone-lysine dimer; MG-H1, N5-(4,5-dihydro-4-methyl-5-oxo-1H-imidazol-2yl)-L-ornithine; MG-H2, (αS)-α,2-diamino-4,5-dihydro-5-methyl-4-oxo-1H-imidazole-1-pentanoic acid; MG-H3, (αS)-α,2-diamino-4,5-dihydro-4methyl-5-oxo-1H-imidazole-1-pentanoic acid; G-H1, N5-(4,5-dihydro-5-oxo-1H-imidazol-2-yl)-L-ornithine; DG-H1, N5-[4,5-dihydro-5-oxo-4[(2S,3R)-2,3,4-trihydroxybutyl]-1H-imidazol-2-yl]-L-ornithine; CMC, S-(carboxymethyl)cysteine; GODIC, glyoxal-derived imidazolium crosslinking; MODIC, methylglyoxal-derived imidazolium cross-linking; and DODIC, 3-deoxyglucosone-derived imidazolium cross-linking.

molecules of MGO and arginine, was found only at low levels in milk products but was found in greater concentrations in bakery products (up to 1400 μmol/kg) compared to CML in the bakery products (up to 320 μmol/kg).5 This may lead to underestimation of the contents of AGEs in bakery products compared to milk if AGE concentrations are measured solely based on CML contents. Additionally, in the process of making coffee, up to 30% of arginine is modified to argpyrimidine, and argpyrimidine seems to be even more important and probably a more useful marker for AGEs than CML in coffee.5 Other arginine derivatives, pentosidine with 5−10 mg/kg of protein in roasted coffee and up to 35 mg/kg of protein in some bakery products as well as arginine cross-links [methylglyoxal-derived imidazolium cross-linking (MODIC), glyoxal-derived imidazolium cross-linking (GODIC), and 3-deoxyglucosone-derived imidazolium cross-linking (DODIC)] with 10−150 mg/kg of protein in bakery products also contribute to AGE pools in foods.5 Thus, to avoid measurement errors of total AGEs in diets, contents of arginine-derived AGEs may be considered as equally important as CML. The thiol side chains in cysteine residues are even more reactive nucleophiles to dicarbonyls than lysine and arginine under a condition of low pKa.17 It is reported that cysteine residues rapidly react with dicarbonyls to give rise to

widely studied and has been quantified mainly by ELISA in a large variety of foods prepared with different cooking methods, which have been used as a database to estimate AGE levels in many human studies. Reportedly, cooked pork, beef, and chicken (121 °C for 10 min) contained around 9.8, 13.4, and 8.2 mg/kg of free plus protein-bound CML, respectively.15 The levels of CEL in meat products have been shown to be close to CML.15 Pyrraline, a product of lysine and 3-DG, has been quantified in several foods, such as milk, bakery products, and pasta.4 Concentrations found ranged from 150 mg/kg of protein in sterilized milk up to 3700 mg/kg of protein in bread crusts, suggesting that pyrraline represents one of the quantitatively dominating AGEs in foods.4 However, unlike CML, little attention has been paid to CEL or pyrraline as markers to reflect total AGEs in human trials. The guanidino side chain of arginine is a target for glycation by dicarbonyls, such as MGO, GO, and 3-DG, forming respective arginine-derived AGEs, including MGO hydroimidazolones (MG-Hs), GO hydroimidazolones (G-Hs), 3DG hydroimidazolones (DG-Hs), and other derivatives (Figure 1). MG-Hs comprise the most prevalent arginine-derived AGEs in foods, which are formed as a mixture of three isomers (MGH1, MG-H2, and MG-H3) by arginine residues in protein with MGO.16 Interestingly, argpyrimidine, a product from two 1326

DOI: 10.1021/acs.jafc.7b05955 J. Agric. Food Chem. 2018, 66, 1325−1329

Perspective

Journal of Agricultural and Food Chemistry

Figure 2. Structures of major dietary AGEs derived from nucleotides and phospholipids. MG-dG, methylglyoxal-deoxyguanosine; G-dG, glyoxaldeoxyguanosine; CE-dG, N2-(1-carboxyethyl)-deoxyguanosine; CM-dG, N2-(1-carboxymethyl)-deoxyguanosine; CE-dA, N6-(1-carboxyethyl)deoxyadenosine; CM-dA, N6-(1-carboxymethyl)-deoxyadenosine; Amadori-PE, Amadori-phosphatidylethanolamine; CM-PE, N-(1-carboxymethyl)phosphatidylethanolamine; and CE-PE, N-(1-carboxyethyl)-phosphatidylethanolamine.

thiohemiacetal adducts,18 which, in the case of GO, is followed by an intramolecular Cannizzaro-type rearrangement to form a major stable product, S-(carboxymethyl)cysteine (CMC) (Figure 1).17 Protein-bound CMC is able to bear the harsh conditions of acid hydrolysis (e.g., 110 °C) used to hydrolyze the derivatized protein prior to analysis.17 The percentage conversion of thiol groups to CMC is substrate-dependent and ≤32%.17 CMC has recently been identified as an AGE both in vitro and in vivo.17,19 CMC appears to be a stable potential marker of glycation reactions on proteins, but its formation and contents in cooked foods have not yet been investigated. Furthermore, cysteine derivatives from other dicarbonyls, such as MGO and 3-DG, are unclear thus far. Other amino acids, such as histidine with an imidazole side chain and tryptophan with an indole side chain, can also be modified during protein glycation and glycoxidation reactions.17 As a matter of fact, N-terminal amino groups in all amino acids are able to act as nucleophiles and readily react with 1,2-dicarbonyls to form adducts.17 It is reasonable to hypothesize that glycation on the imidazole side chain of histidine, the indole side chain of tryptophan, and N-terminal amino groups in all amino acids in diets takes place during the cooking process. Thus, to more accurately evaluate intake of total AGEs in diets, contents of AGEs derived from lysine, arginine, and cysteine rather CML alone should be measured at the same time. In addition, more efforts to investigate AGEs derived from the imidazole side chain of histidine, the indole side chain of tryptophan, and N-terminal amino groups of all amino acids should be made in the future.

guanosine (G-dG), respectively (Figure 2), which can further rearrange to stable N2-(1-carboxyethyl)-deoxyguanosine (CEdG) and N2-(1-carboxymethyl)-deoxyguanosine (CM-dG) (Figure 2).22 The related adducts, N6-(1-carboxyethyl)deoxyguanosine (CE-dA) and N6-(1-carboxymethyl)-deoxyguanosine (CM-dA), have also been characterized (Figure 2).22 Among them, MG-dG, CE-dG, and G-dG were found to be the major nucleotide AGEs21 and have been detected in cultured cells and isolated peripheral mononuclear leucocytes by LC− MS/MS.23 On the other hand, nucleobases, nucleosides, and nucleotides are widely present in food products, especially for meat products, with concentrations up to grams per kilogram.24 Considerable amounts of nucleotide AGEs are supposed to be generated in foods as a result of high heat treatment. Regardless, the formation and contents of nucleotide AGEs in food has not yet been investigated. The possible contribution of nucleotide AGEs to total AGEs in diets is obviously underinvestigated in human intervention studies.

■

PHOSPHOLIPID AGES SHOULD BE ADDED TO THE DIETARY AGE POOL Amino residues of membrane lipids, such as phosphatidylethanolamine (PE) and phosphatidylserine (PS), are also targets for glycation. In vivo studies have already confirmed that PE is exposed to glycation under hyperglycemic conditions, yielding Amadori-PE (deoxy-D-fructosyl PE) (Figure 2) as the principal product.25 Plasma Amadori-PE levels were found to be 1.8−3.6 times higher in diabetic patients compared to healthy subjects.25 These early glycation products of PE can be further transformed to a wide spectrum of glycation end products of PE (AGE-PE), such as N-carboxymethyl-PE (CM-PE) and Ncarboxyethyl-PE (CE-PE) (Figure 2). CM-PE and CE-PE have also been detected in human erythrocytes and plasma by LC− MS/MS.26 On the other hand, numerous food matrices contain abundant contents of phospholipids (PLs), particularly for dairy products with PL levels ranging from 3.6 to 479.5 mg/100 g of product.27 Only a few studies, thus far, have confirmed the presence of Amadori products of PE and PS in milk powders by matrix-assisted laser desorption/ionization−mass spectrometry

■

POSSIBLE ROLE OF NUCLEOTIDE AGES IN FOODS IS UNDERINVESTIGATED The guanyl bases in nucleic acids can act as strong nucleophiles to attack dicarbonyls. Among DNA nucleobases, guanine was the most reactive with GO and MGO, followed by adenine and cytosine, and thymine did not react because it does not have a free amino group.20 Limited studies showed that dicarbonyl glycation of DNA forms nucleotide AGEs.21 MGO and GO reacted with deoxyguanosine to form reversible cyclic adducts, methylglyoxal-deoxyguanosine (MG-dG) and glyoxal-deoxy1327

DOI: 10.1021/acs.jafc.7b05955 J. Agric. Food Chem. 2018, 66, 1325−1329

Perspective

Journal of Agricultural and Food Chemistry (MALDI−MS).28 It is reasonable to hypothesize that abundant PLs lead to the formation of abundant glycated PLs in foods during heat treatment. However, contents of glycated PLs in foods have not yet been determined. Irrespective of varieties of PL AGEs, PL AGEs should be one part of the total AGEs in diets.

highly practicable based on a recent report regarding analysis of a few AGEs in almond samples.29 Furthermore, it is also critical to study the bioavailability and toxicity of each of the major AGEs to find out which AGEs are more bioavailable and/or toxic to human health. The synthesized AGE standards will this type of research as well.

■

■

CROSS-LINKS INDUCED BY DICARBONYLS ARE COMMON DIETARY AGES The bifunctional nature of dicarbonyls can lead to the formation of protein−protein, protein−DNA, and DNA− DNA cross-links.22 Cross-links between arginine and lysine (Figure 1), such as GODIC, MODIC, DODIC, glucosepan, and pentosidine, have been found in the milligrams per kilogram range in bakery products,5 of which MODIC and GODIC are the major food protein cross-links derived from MGO and GO, respectively. Other cross-links, such as DNA− protein cross-links and DNA−DNA cross-links, have also been found in vitro and in cultured cells,22 but whether these crosslinks are present in diets is not yet known.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] and/or [email protected]. ORCID

Shengmin Sang: 0000-0002-5005-3616 Funding

The authors are grateful for financial support from United States Department of Agriculture (USDA)−National Institute of Food and Agriculture (NIFA) Grant 2012-67017-30175 to Shengmin Sang. Notes

The authors declare no competing financial interest.

■

■

ESTABLISHMENT OF A PANEL OF AGE MARKERS FOR GLYCATION IN DIETS MAY IMPROVE ACCURACY OF TOTAL AGE MEASUREMENT IN HUMAN STUDIES The Maillard reaction extensively and readily occurs on proteins, nucleic acids, and phospholipids in foodstuffs while cooking. In particular, the free amino group in lysine, the guanidine group in arginine, the thiol group in cysteine, the guanyl base in nucleotides, and the amino residue in PLs are highly reactive targets for glycation, forming their respective AGEs, such as CML and CEL, MG-Hs and G-Hs, CMC, MGdG and G-dG, and Amadori-PLs, which represent major types of AGEs in foods. Markers of glycation in foods cannot be unique; therefore, using one specific AGE, derived from specific food components, to evaluate the total AGEs in diets is unlikely to exactly reflect the differences in AGE levels between a highAGE diet, low-AGE diet, and control in human intervention studies. We propose here that a panel of AGE markers, including CML and CEL from lysine, MG-H1 and G-H1 from arginine, CMC from cysteine, MG-dG and G-dG from nucleotides, and Amadori-PL from PLs, could be used to better estimate the intake of total dietary AGEs and eventually enhance the estimation of the effects of dietary AGE intake on risk factors of chronic diseases in human studies. Determination of a panel of AGE markers in commonly consumed human foods helps to establish more comprehensive databases regarding the levels of major types of AGEs in foodstuffs, which can serve as important references to estimate the intake of dietary AGEs in future studies. However, one of the main challenges in this area of research is that most of these free AGEs are not commercially available. To advance AGE research, the first step is to synthesize the major AGEs and then use them as standards to develop analytical methods to quantify them in foodstuffs. The panel of AGE markers (eight AGEs) mentioned above contain acid- or heat-labile AGEs, such as MG-H1 and G-H1 from arginine.4 Therefore, use of a cocktail from proteolytic enzymes for hydrolysis of protein-bound AGEs, instead of acid hydrolysis, is much more suitable for food sample preparation.29 Meanwhile, simultaneous determination and quantification of an AGE marker pool in foodstuffs, using the LC−MS/MS method, is

ABBREVIATIONS USED AGEs, advanced glycation end products; CE-dA, N6-(1carboxyethyl)-deoxyadenosine; CE-dG, N2-(1-carboxyethyl)deoxyguanosine; CEL, N-ε-carboxyethyllysine; CM-dA, N6-(1carboxymethyl)-deoxyadenosine; CM-dG, N2-(1-carboxymethyl)-deoxyguanosine; CML, N-ε-carboxymethyllysine; CMC, S(carboxymethyl)cysteine; 3-DG, 3-deoxyglucosone; DG-H1, N5-[4,5-dihydro-5-oxo-4-[(2S,3R)-2,3,4-trihydroxybutyl]-1Himidazol-2-yl]-L-ornithine; DOLD, 3-deoxyglucosone-lysine dimer; DODIC, 3-deoxyglucosone-derived imidazolium crosslinking; ELISA, enzyme-linked immunosorbent assay; G-dG, glyoxal-deoxyguanosine; G-H1, N5-(4,5-dihydro-5-oxo-1H-imidazol-2-yl)-L-ornithine; GO, glyoxal; GOLD, glyoxal-lysine dimer; GODIC, glyoxal-derived imidazolium cross-linking; LC−MS/MS, liquid chromatography−tandem mass spectrometry; MG-dG, methylglyoxal-deoxyguanosine; MG-H1, N5-(4,5dihydro-4-methyl-5-oxo-1H-imidazol-2-yl)-L-ornithine; MGH2, (αS)-α,2-diamino-4,5-dihydro-5-methyl-4-oxo-1H-imidazole-1-pentanoic acid; MG-H3, (αS)-α,2-diamino-4,5-dihydro4-methyl-5-oxo-1H-imidazole-1-pentanoic acid; MGO, methylglyoxal; MOLD, methylglyoxal-lysine dimer; MODIC, methylglyoxal-derived imidazolium cross-linking; PE, phosphatidylethanolamine; PL, phospholipid; PS, phosphatidylserine

■

REFERENCES

(1) Uribarri, J.; del Castillo, M. D.; de la Maza, M. P.; Filip, R.; Gugliucci, A.; Luevano-Contreras, C.; Macias-Cervantes, M. H.; Markowicz Bastos, D. H.; Medrano, A.; Menini, T.; Portero-Otin, M.; Rojas, A.; Sampaio, G. R.; Wrobel, K.; Wrobel, K.; Garay-Sevilla, M. E. Dietary advanced glycation end products and their role in health and disease. Adv. Nutr. 2015, 6, 461−473. (2) Salahuddin, P.; Rabbani, G.; Khan, R. H. The role of advanced glycation end products in various types of neurodegenerative disease: A therapeutic approach. Cell. Mol. Biol. Lett. 2014, 19, 407−437. (3) Tamanna, N.; Mahmood, N. Food processing and Maillard reaction products: Effect on human health and nutrition. Int. J. Food Sci. 2015, 2015, 526762. (4) Henle, T. Protein-bound advanced glycation endproducts (AGEs) as bioactive amino acid derivatives in foods. Amino Acids 2005, 29, 313−322. (5) Poulsen, M. W.; Hedegaard, R. V.; Andersen, J. M.; de Courten, B.; Bugel, S.; Nielsen, J.; Skibsted, L. H.; Dragsted, L. O. Advanced

1328

DOI: 10.1021/acs.jafc.7b05955 J. Agric. Food Chem. 2018, 66, 1325−1329

Perspective

Journal of Agricultural and Food Chemistry glycation endproducts in food and their effects on health. Food Chem. Toxicol. 2013, 60, 10−37. (6) Singh, V. P.; Bali, A.; Singh, N.; Jaggi, A. S. Advanced glycation end products and diabetic complications. Korean J. Physiol. Pharmacol. 2014, 18, 1−14. (7) Busch, M.; Franke, S.; Ruster, C.; Wolf, G. Advanced glycation end-products and the kidney. Eur. J. Clin. Invest. 2010, 40, 742−755. (8) Cai, W.; Gao, Q. D.; Zhu, L.; Peppa, M.; He, C.; Vlassara, H. Oxidative stress-inducing carbonyl compounds from common foods: Novel mediators of cellular dysfunction. Mol. Med. 2002, 8, 337−346. (9) Clarke, R. E.; Dordevic, A. L.; Tan, S. M.; Ryan, L.; Coughlan, M. T. Dietary advanced glycation end products and risk factors for chronic disease: A systematic review of randomised controlled trials. Nutrients 2016, 8, 125. (10) Harcourt, B. E.; Sourris, K. C.; Coughlan, M. T.; Walker, K. Z.; Dougherty, S. L.; Andrikopoulos, S.; Morley, A. L.; Thallas-Bonke, V.; Chand, V.; Penfold, S. A.; de Courten, M. P. J.; Thomas, M. C.; Kingwell, B. A.; Bierhaus, A.; Cooper, M. E.; de Courten, B.; Forbes, J. M. Targeted reduction of advanced glycation improves renal function in obesity. Kidney Int. 2011, 80, 190−198. (11) Uribarri, J.; Cai, W.; Pyzik, R.; Goodman, S.; Chen, X.; Zhu, L.; Ramdas, M.; Striker, G. E.; Vlassara, H. Suppression of native defense mechanisms, SIRT1 and PPARγ, by dietary glycoxidants precedes disease in adult humans; relevance to lifestyle-engendered chronic diseases. Amino Acids 2014, 46, 301−309. (12) Luévano-Contreras, C.; Garay-Sevilla, M. E.; Wrobel, K.; Malacara, J. M.; Wrobel, K. Dietary advanced glycation end products restriction diminishes inflammation markers and oxidative stress in patients with type 2 diabetes mellitus. J. Clin. Biochem. Nutr. 2013, 52, 22−26. (13) Vlassara, H.; Cai, W.; Crandall, J.; Goldberg, T.; Oberstein, R.; Dardaine, V.; Peppa, M.; Rayfield, E. J. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 15596−15601. (14) Uribarri, J.; Cai, W.; Ramdas, M.; Goodman, S.; Pyzik, R.; Chen, X.; Zhu, L.; Striker, G. E.; Vlassara, H. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: Potential role of AGER1 and SIRT1. Diabetes Care 2011, 34, 1610−1616. (15) Sun, X.; Tang, J.; Wang, J.; Rasco, B. A.; Lai, K.; Huang, Y. Formation of free and protein-bound carboxymethyllysine and carboxyethyllysine in meats during commercial sterilization. Meat Sci. 2016, 116, 1−7. (16) Wang, T.; Streeter, M. D.; Spiegel, D. A. Generation and characterization of antibodies against arginine-derived advanced glycation endproducts. Bioorg. Med. Chem. Lett. 2015, 25, 4881−4886. (17) Zeng, J.; Davies, M. J. Evidence for the formation of adducts and S-(carboxymethyl)cysteine on reaction of α-dicarbonyl compounds with thiol groups on amino acids, peptides, and proteins. Chem. Res. Toxicol. 2005, 18, 1232−1241. (18) Lo, T. W.; Westwood, M. E.; McLellan, A. C.; Selwood, T.; Thornalley, P. J. Binding and modification of proteins by methylglyoxal under physiological conditions. A kinetic and mechanistic study with Nα-acetylarginine, Nα-acetylcysteine, and Nα-acetyllysine, and bovine serum albumin. J. Biol. Chem. 1994, 269, 32299−32305. (19) Alt, N.; Carson, J. A.; Alderson, N. L.; Wang, Y.; Nagai, R.; Henle, T.; Thorpe, S. R.; Baynes, J. W. Chemical modification of muscle protein in diabetes. Arch. Biochem. Biophys. 2004, 425, 200− 206. (20) Li, Y.; Cohenford, M. A.; Dutta, U.; Dain, J. A. The structural modification of DNA nucleosides by nonenzymatic glycation: An in vitro study based on the reactions of glyoxal and methylglyoxal with 2′deoxyguanosine. Anal. Bioanal. Chem. 2008, 390, 679−688. (21) Fleming, T.; Rabbani, N.; Thornalley, P. J. Preparation of nucleotide advanced glycation endproducts−Imidazopurinone adducts formed by glycation of deoxyguanosine with glyoxal and methylglyoxal. Ann. N. Y. Acad. Sci. 2008, 1126, 280−282.

(22) Petrova, K. V.; Millsap, A. D.; Stec, D. F.; Rizzo, C. J. Characterization of the deoxyguanosine-lysine cross-link of methylglyoxal. Chem. Res. Toxicol. 2014, 27, 1019−1029. (23) Rabbani, N.; Shaheen, F.; Anwar, A.; Masania, J.; Thornalley, P. J. Assay of methylglyoxal-derived protein and nucleotide AGEs. Biochem. Soc. Trans. 2014, 42, 511−517. (24) Domínguez-Á lvarez, J.; Mateos-Vivas, M.; Rodríguez-Gonzalo, E.; García-Gómez, D.; Bustamante-Rangel, M.; Delgado Zamarreño, M.-M.; Carabias-Martínez, R. Determination of nucleosides and nucleotides in food samples by using liquid chromatography and capillary electrophoresis. TrAC, Trends Anal. Chem. 2017, 92, 12−31. (25) Miyazawa, T.; Nakagawa, K.; Shimasaki, S.; Nagai, R. Lipid glycation and protein glycation in diabetes and atherosclerosis. Amino Acids 2012, 42, 1163−1170. (26) Shoji, N.; Nakagawa, K.; Asai, A.; Fujita, I.; Hashiura, A.; Nakajima, Y.; Oikawa, S.; Miyazawa, T. LC−MS/MS analysis of carboxymethylated and carboxyethylated phosphatidylethanolamines in human erythrocytes and blood plasma. J. Lipid Res. 2010, 51, 2445− 2453. (27) Restuccia, D.; Spizzirri, U. G.; Puoci, F.; Cirillo, G.; Vinci, G.; Picci, N. Determination of phospholipids in food samples. Food Rev. Int. 2012, 28, 1−46. (28) Calvano, C. D.; De Ceglie, C.; Zambonin, C. G. Development of a direct in-matrix extraction (DIME) protocol for MALDI−TOF− MS detection of glycated phospholipids in heat-treated food samples. J. Mass Spectrom. 2014, 49, 831−839. (29) 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.

1329

DOI: 10.1021/acs.jafc.7b05955 J. Agric. Food Chem. 2018, 66, 1325−1329