Yue Luo, Jianan Zhang Chi-Tang Ho*, Shiming Li*

a Department of Food Science, Rutgers University, NJ 08901, USA

b Hubei Key Laboratory of EFGI & RCU, Huanggang Normal University, Huanggang 438000, China

c School of Food Science and Engineering, South China University of Technology, Guangzhou 510640, China

Keywords:

Tea

Tea polyphenols

Reactive carbonyl species

Advanced glycation end product

Maillard reaction

A B S T R A C T

Tea as the most consumed beverage in the world has received enormous attention for its promoting health benefits.The deleterious effect of α-dicarbonyls and AGEs formed in Maillard reaction is also a longterm challenge.The connection between the two topics was the main aim of this review, to address and update the antiglycation effect and mechanism of tea and tea polyphenols.By analyzing recent publications,we have covered across chemistry models, cell lines and animal studies.Tea polyphenols, particularly catechins, showed outstanding antiglycation effect by trapping α-dicarbonyl compounds and impeding AGEs formation.Reduction of carbonyl stress brought alleviation to aging, diabetes, and collagen related diseases or complications through regulation of RAGE expression and subsequent MAPK and TGF-β pathway.Therefore, tea polyphenols can serve as promising natural candidates in the treatment and/or prevention of nephropathy, retinopathy, hepatopathy, hyperglycemia and obesity among others, by their potent antiglycation effect.Further studies need to address on aspects like exact mechanisms, solution of detection obstacles,balance of practical usage and harmful effects such as potential flavor damage and toxicity in food, to gain a comprehensive understanding of antiglycation activities of tea polyphenols and its actual application.

1.Introduction

Maillard reaction, found by French chemist Louis-Camille Maillard, is a chemical reaction between carbonyl groups of reducing sugars andN-terminal amine groups of amino acids, peptides or proteins [1].Primarily, studies of Maillard reaction were mainly focused on flavor generation and reduced nutritional value of amino acids and proteins.The physiological effects of Maillard reaction began to draw attention after the discovery of glycated hemoglobin in the blood of diabetic patients [2].

Since then, the potential pathogenic role of Maillard reaction has become a popular research direction, and mainly focused onα-dicarbonyl compounds (α-DC) and advanced glycation end products (AGEs).α-DCs and other reactive carbonyl compounds such as malondialdehyde and 4-hydroxy-2-nonenal fall into the category of reactive carbonyl species (RCS), but dominant RCS areα-DCs majorly including methylglyoxal (MGO) and glyoxal (GO).MGO,GO and other RCS are produced initially, and AGEs are finally yielded in the subsequent cascade process both in food and in the body.Nowadays, growing amount of evidences show thatα-DCs and AGEs are involved in pathogenesis of devastating aging- and diabetesrelated disorders and other various diseases, such as insulin resistance and metabolic syndrome, cancer growth, metastasis, Alzheimer’s disease, osteoporosis, and mainly cardiovascular and chronic kidney disease [3].Receptor for AGEs (RAGE) was suggested as a liaison between AGEs and diseases by the AGE-RAGE-reactive oxygen species (ROS) loop, resulting in subsequent activation of inflammation and release of ligands associated with deleterious physiological effects like tissue damage and lesion formation [4].

So far, synthetic AGE inhibitors can be classified into 3 types:i) reactive carbonyl trapping agents alleviating carbonyl stress;ii) metal-ion chelators suppressing glycoxidation; and iii) crosslink breakers against AGE crosslinks [5].Although some synthetic compounds demonstrated strong inhibitory activities against the formation of AGEs, or the effective breakage of the protein crosslinks caused by the Maillard reactionin vivo, they might also result in severe side effects.The most famous case is aminoguanidine (AG)which even reached phase III clinical trial.But the development of AG as a drug was terminated due to severe side effects including anemia, crescentic glomerulonephritis and kidney failure [6].Therefore, natural compounds with antiglycation effects would be better candidates for AGEs inhibition and possible safety profiles.

Tea, derived from leaf or bud ofCamellia sinensis, is classified into several major categories based on fermentation process: green tea (nonfermented), white tea (slight-fermented), oolong (semifermented), black tea (fermented) and dark tea (post-fermented) [7].Tea is the most consumed functional beverage around the world, and tea polyphenols have drawn enormous attention for their outstanding beneficial effects [8].Catechins, the major tea polyphenols, consist of 4 most abundant ones: (–)-epicatechin (EC), (–)-epicatechin-3-gallate(ECG), (–)-epigallocatechin (EGC), (–)-epigallocatechin-3-gallate(EGCG).Owning to their spectacular free radical scavenge ability and antioxidative capacity, tea catechins can prevent a variety of diseases by relieving oxidative stress and impeding the onset and progression of chronic pathological activities.Antioxidant, preventive effects of obesity, cardiovascular diseases, cancer, diabetes and associated complication, antiallergic, neuroprotective, gut health-promoting activities of tea have been well reported [9].Antiglycation effect of tea polyphenols is correlated and entangled with aforementioned biological activities.Therefore, this review aims to provide a collective analysis of recent studies focusing on tea polyphenols and antiglycation effect towards AGEs to better understand current progress and propound perspectives.

2.Reactive carbonyl species (RCS) and AGEs formation pathways

RCS and AGEs can be formed exogenously in food processing and endogenouslyin vivo.Exogenous formation primarily comes from Maillard reaction while endogenous formation mainly results from glycolysis [10].Maillard reaction is a complex cascade reactions,basically consisting of three phases [11].As shown in Fig.1 [12,13],α-DCs including the most well-known MGO, GO, 1-deoxyglucosone(1-DG), and 3-deoxyglucosone (3-DG) can be formed by Hodge and Namiki pathways.At the initial stage, the carbonyl group of reducing sugars reacts with the amino group of amino acids, peptides or proteins, forming a Schiff base which will successively generate glyoxal/glycolaldehyde by Namiki pathway and 1-DG or 3-DG by Hodge pathway with preceding Amadori products formation.Once Amadori products are generated, further rearrangement could contribute to the formation of AGEs like pentosidine andNε-carboxymethyllysine (CML) [14].

Fig.1 Dietary and endogenous formation pathways of DCs and AGEs.

In addition to Maillard reaction,α-DCs can be formed by various alternative pathways.Sugar autoxidation and lipid peroxidation are two other common reasons for MGO and GO formation in foods [11].As forin vivo, glycolysis plays the dominant role with other diverse pathways like glucose autoxidation, polyol pathway, ketone metabolism, and lipid peroxidation.Glycolysis is a spontaneous and enzyme-involved reaction initiated by glucose degradation to form glyceraldehyde-3-phosphate (DA3P) and dihydroxyacetone phosphate(DHAP) with the participation of aldolase.During the interconversion of the two triose phosphates via triosephosphate isomerase, a small fraction of enediol intermediate can escape and lead to MG generation [13].Other triosephosphate esters can go through similar spontaneous decomposition mechanism to form MG [15].

Aside from aforementioned formation from Amadori compound,most AGEs are formed withα-DCs acting as precursors.α-DCs may further go through interconversion, for instance, MGO can be formed from 3-DG fragmentation.That contributes to the diversity of AGEs pool.As shown in Fig.1, various AGEs can be formed according to different precursors and detailed formation pathways were demonstrated in previous reviews [12,13].

3.Homeostasis of dietary and endogenous DCs and AGEs

As shown in Fig.2,α-DCs and AGEs are in a dynamic equilibrium state.Free dietaryα-DCs and AGEs can be absorbed and enter the body circulation system directly via simple diffusion while low-molecular weight peptide-bound AGEs via transporter proteins in intestine involving microbial metabolism, and high molecular weight AGEs cannot be metabolized nor absorbed thus directly excreted in feces [16].Apart from direct absorption, foods also provide monosaccharides and fatty acids as important sources of glycation precursors via abovementioned endogenous biological or chemical reactions, such as glucose autoxidation, lipid peroxidation, and cell metabolism.These glycation forming compounds mainly include monosaccharides and dicarbonyls/carbonyls, the well-known main precursors of AGEs.α-DCs can stay at free form or react with plasma and tissue proteins and generate corresponding AGEs in the plasma and tissues as storage sources of circulating pool of AGEs.During the whole process, oxidative stress should take into account, which is considered as an important promotor for AGEs accumulation due to its stimulation effect on the production of highly reactive MGO and GO [1].

Fig.2 Circulation scheme and health effects of α-DCs and AGEs.

It is noteworthy that most of these AGEs would be excreted by the urinary system directly or via endocytosis and partial proteolysis by hepatocytes and macrophages [17].Moreover, detoxifying enzymes targeting on RCS can lowerα-DCs built-up and suppress further AGEs formation.Glyoxalase 1 (GLO1) plays dominant detoxifying roles by converting DCs like MGO and GO to lactic or glycolic acid,respectfully [18].Others include DJ1/PARK7, NADPH-dependent aldoketo reductases (AKRs), aldehyde dehydrogenases, and endosomallysosomal system (particular enzymes cathepsin L and D) [10].The remaining AGEs in circulation may be accumulated in collagens and organs with limited metabolic capacity, mainly the lens, liver,kidney and bladder.The crosslink between accumulated AGEs and tissue proteins promotes protein aggregation and causes tissue stiffness [1].The accumulation tends to increase along with aging and impaired health conditions like renal disfunction and diabetes that lead to excretion difficulties and aggravated oxidative and carbonyl stress [14].This is also the reason why current researches ofα-DCs and AGEs centralize in models reflecting aging, diabetes, and collagen related diseases or complications, such as cardiovascular,renal, retinal, hectic and articular dysfunctions.

Numerically, about 10% of exogenous AGEs can get into the blood circulation, of which 1/3 is excreted out through the kidney while the other 2/3 accumulates in the body and then induces various diseases [19].Typically, endogenous concentrations of GO, MGO,and 3DG in healthy individuals are around 50-300 nmol/L in plasma and 1-4 nmol/L in cells [20].Up to 99% of the cellular MGO exists in reversibly bounded form with biopolymers and small-metabolite thiols and amines.MGO is considered as the mainα-DCs responsible for albumin glycation [21].Particularly, the contents of dietary MGO and AGEs and corresponding healthy eating recommendations are given by Cambridge University Press recently to reduce body’s AGE pool [22].

4.Antiglycation effects of tea and tea polyphenols

Tea polyphenols mainly consist of tea catechins and thea flavins.Tea catechins include (+)-catechin (C), EC, ECG, EGC, EGCG,and (-)-gallocatechin gallate (GCG).Theaflavins, existing in black tea, have 4 major isomers as theaflavin (TF-1), theaflavin-3-O-gallate (TF-2a), thea flavin-3’-O-gallate (TF-2b) and thea flavin-3,3’-digallate (TF-3).Chemical structures of catechins and thea flavins are shown in Fig.3 while the schematic diagram of main pathway of the antiglycation activity of tea polyphenol is shown in Fig.4.

Fig.3 Chemical structures of tea polyphenols, α-DCs, AGEs and MGO-EGCG adducts.A.Tea polyphenols; B.α-Dicarbonyls; C.AGEs.Green box-glyoxal derived; Blue box-methylglyoxal derived; Yellow box-3-DG derived.D.MGO-EGCG adducts.

Fig.4 Scheme diagram of main pathways of tea polyphenol antiglycation activity.

The antiglycation ability of these tea polyphenols are investigated in different kinds of models.Basically, discussion is concentrated on three big models: chemical models, cell study andin vivoresearch.Around 60% of the selected papers focus on chemical models, serving as preliminary researches of cell study andin vivostudies or as an attempt on application in food systems.Only a few papers use cell models while the rest around 30% conducted animal studies.

4.1 Chemical models

In chemical models, studies normally investigateα-DCs trapping capability or/and subsequent antiglycation effects, in terms of AGEs formation inhibition.Studies correlated to AGEs formation largely use chemical models involving proteins and hyperglycemic environment, of which bovine serum albumin (BSA), glucose and MGO are the most common ones.BSA is the most adopted for its low cost and high structural similarity to human serum albumin [23].Other amino compounds include lysine [24,25], alanine, human serum albumin (HSA) [26]and crystallin [27], while other hyperglycemic promotors include fructose [24,28], maltose [19], ribose [29]and dehydroascorbic acid [27].

Tea catechins have always been popular research targets for its ubiquitous and natural high concentration in tea leaves.Theα-DCs trapping capacity of different tea catechins are compared and results are list in Table 1.EGC is believed to have the best MGO trapping ability comparing to EC, ECG and EGCG [30].Whereas EGCG and C can efficiently reduce 90% of MGO level and 70% or 40% of GO level, respectively, showing better antiglycation effect than AG [19,31].The outstanding capacity comes from the active sites at positions 6 and 8 of the A ring of catechins, confirmed by several studies that detected and demonstrated the exact structure of EGCG-MGO, C/EC-MGO/GO adducts of by LC-MS/MS and NMR analysis [19,30].TF3 also showed considerable high inhibitory effect on MGO [30].

Table 1Antiglycation effect of tea polyphenols in chemical models.

Asides from the pure MGO model, more studies adopted aforementioned chemical models imitating proteins under hyperglycemic environment, including amino compounds like BSA and hyperglycemic promoter like glucose.Among these chemical models, mainly two groups based on proving logic exist: one only detects AGEs or specifically CML concentration with tea catechins addition while the other one also provides detection of carbonyls providing a more complete chain of evidence.

EGCG as well as its four flavoalkaloids from white tea possessed effective AGEs reducing capacity with IC50at a range of 10.3-25.3 μmol/L, which is much better than AG.This study discovered and isolated two novel flavoalkaloids therein:(?)-6-(5’’’-S)-N-ethyl-2-pyrrolidinone-epigallocatechin-O-gallate and (?)-6-(5’’’-R)-N-ethyl-2-pyrrolidinone-epigallocatechin-O-gallate [28].The result is aligned with previous research results showing EGCG, GCG and ECG decreased almost half of fluorescence AGEs concentration at 10 μmol/L [32].EC exhibited almost 10 times of AGEs inhibition capacity than AG with IC50at 0.19 mmol/L vs 1.67 mmol/L for AG [33].Besides individual compounds, tea extracts were investigated for reflection of actual consumption.Green tea and black tea extract reduced the fluorescence level of AGEs with IC50around 20 mmol/L [34].Polyphenol extract fraction (PEF) and theanine extract fraction (TEF) from decaffeinated tea dust reduced fluorescence AGEs significantly but were weaker than AG, possibly due to lower content of effective compounds in extract than pure AG of 5 and 10 mmol/L [35].

Additionally, several studies conducted both MGO and AGEs detection before and after addition of tea active compounds,providing more direct evidence of the contribution ofα-DCs scavenging ability to AGEs inhibition.C displayed better antiglycative effect than EC and AG with 90%/40% outstanding reduction of MGO/GO levels and 50% significant reduction of CML level [19].Similarly, GCG from black tea even showed 96.7% reduction of AGEs by trapping MGO and scavenging activity towards free radicals like O2– and –OH [25].Noteworthy,dehydroascorbic acid (DASA), the oxidized form of ascorbic acid,is also a RCS.It is believed that DASA plays an important role in protein glycation and AGEs formation, especially in lens.EGCG,EGC, ECG and EC demonstrated the antiglycation ability to reduce subsequent AGEs formation via significantly trapping DASA by 60%-80% in only 1 h, forming A ring C6 and C8-ascorbyl conjugates [27].

Besides pure chemical models, real or simulated food systems were adopted for guiding practical usage.EC was added into coconut milk and eliminated free CML effectively [36].The study proposed that the CML-EC conjugation could happen at B-ring with LC-MS/MS detection, however, lack of NMR analysis could not be enough evidence to convince the case.Comparing to the other tea catechins,EC also seems to eliminate AGEs efficiently in aqueous and alcoholic environment (20%,V/V) by trapping MGO and inhibition of enzymes likeα-amylase,α-glucosidase, andβ-glucosidase [37].Another study,employed a model in a real vinegar system, found that C with addition of small amount of iron could significantly lower AGEs concentration by reduction of 5-HMF formation and elimination of free radicals [29].Besides aqueous food models, two studies mimic bread model and found C and PEF could lower CML and fluorescence AGEs in the systems, respectively [35,38].Along with effective antiglycation results, one of them showed the addition of C impeded pyrazine formation and thus affected bread flavor [38], while the other one adding tea extract maintained pleasant sensory quality [35].As yet,consumers largely tend to choose food based on visual and sensory contribution.Though the addition of tea reactive compounds provides potential health benefits for antiglycation effects, maintaining or even improving sensory quality is still a big challenge and criteria should be achieved at the same time.

4.2 Cell lines

Several tea catechins were evaluated for antiglycative ability in cell studies, EGCG, EC, ECG (Table 2).EGCG is still the main research target.Cell lines include human retinal pigmented epithelial cells(HRPECs), human umbilical vein endothelial cells (HUVECs) [39],human embryonic kidney cells (HEK293), human mesangial cells(HMCs), and human chondrocytes.EGCG is proved to inhibit CML or AGEs formation effectively by trapping precursors like MGO.Along with phloretin from apple, 6-shagoal and gingerol from ginger,EGCG showed protective effect on HRPECs treated with MGO.The MGO-induced carbonyl stress was significantly reduced by suppressing RAGE expression.Nuclear factor-erythroid 2-realated factor (Nrf2) function was thus activated by translocation from cytosol to nucleus, and continuously induced expression of phase II detoxifying enzymes like heme oxygenase-1 (HO-1) [40].Diabetic nephropathy has always been a great concern and attracts research attention.Two related cell lines (HEK293 and HMCs) were selected and investigated, showing that EGCG and peroxisome proliferatoractivated receptor δ agonist (L-165041) actively attenuated AGE-induced renal cell inflammation and apoptosis.Specifically, EGCG significantly lowered expression of a major pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), and mRNA and protein expression of RAGE.Moreover, EGCG inhibited the activation of nuclear factor-κB (NF-κB) pathway and cell apoptosis induced by AGEs and increased superoxide dismutase levels which was down-regulated by AGEs [41].Osteoarthritis is promoted by aging with AGEs accumulation in chondrocytes, inducing production of proinflammatory cytokines and matric metalloproteinases (MMPs).EGCG significantly inhibited the gene expression and production of TNF-α and MMP-13 at least partially through suppression of p38- mitogen-activated protein kinase (MAPK) and JNK-MAPK activation in human chondrocytes.In addition to MAPK pathway,EGCG also inhibited NF-κB pathway by impeding AGE-induced degradation of inhibitory enzyme lκBαand nuclear translocation of NF-κB p65 [42].

Table 2Antiglycation effect of tea polyphenols in cell lines.

4.3 Animal models

As shown in Table 3, a few tea catechin compounds and tea extracts were chosen to study their antiglycation ability and potential health benefits using animal models.The animal models include male C57BLKS/J type 2 diabetic mice, male Sprague-Dawley rat with direct AGEs injection, male (albino) Wistar rats with streptozotocin injection, male C57BL/6J mice fed with high-fat diet, type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats andCaenorhabditis elegans, which related to (diabetic) nephropathy,retinopathy, hepatopathy, hyperglycemia and obesity.

Table 3Antiglycation effect of tea polyphenols in animal models.

C and EC have been proven to significantly reduce AGEs formation and accumulation in kidney and retina in a dose dependent manner, and to further ameliorate inflammation and renal dysfunction in type 2 diabetic mice and improved vascular apoptosis in exogenously AGE-injected rat model, respectively [27,33].Additionally, EGCG is also well studied in a diabetic nephropathy rat model for its therapeutic potential on renal damage.After 50-day administration of different dosages, EGCG-treated groups exhibited alleviated hyperglycemia, proteinuria and lipid peroxidation.Renal AGEs accumulation was largely suppressed.The expression of inflammatory enzymes iNOS and COX2 were down-regulated significantly in high dosage of EGCG (50 and/or 100 mg/kg), similar to their upstream regulators NF-κB and lκBα.The expression of RAGE in kidney cortex was slightly decreased while for transforming growth factor-β (TGF-β) and fibronectin protein were significantly reduced, indicating that EGCG has a potential in suppressing pathogenic conditions of diabetic nephropathy like mesangial hypertrophy and fibronectin synthesis [43].In addition to nephropathy, the antiglycation effect of EGCG on obesity C57BL/6J mice model was also conducted.High dosage of EGCG (75 mg/kg)effectively reduced the weight of liver, kidney and the overall weight almost down to as low-fat diet control group.Obesity-related physiological conditions were thus attenuated, including plasma glycose and insulin level.The AGEs levels were significantly reduced by EGCG treatment in both plasma and liver, followed by subsequent inhibition of RAGE expression, activation of Nrf2 translocation into nucleus and enhancement of HO-1 expression and GSH/GSSG ratio [44].In addition to tea catechins, another pure compound often found in tea called quercetin was also studied in a diabetic rat model.The administration of quercetin (10 mg/kg) to the diabetic nephropathy and cardiomyopathy induced rats significantly lowered AGEs levels in both heart and kidney, as well as serum biomarkers of heart(aspartate transaminase (AST), lactate dehydrogenase (LDH) and creatine kinase (CPK)) and kidney (cystatin C, creatinine albumin and urea) damage and inflammatory cytokines like interleulin-6 (IL-6)and TNF-α [45].

Aside from pure individual compounds, different kinds of tea extracts were also mentioned in literatures.Green tea extract was obtained by ethanol (95%, 1:10,m/V) extraction for 2 days with constant stir and then vacuum evaporation below 50 °C for ideal extraction of tea catechins.Then, the green tea extract(300 mg/kg/day) was administrated by gavage to streptozotocin diabetic rats to investigate its effect on myocardial collagen function [46].Green tea extract significantly reduced diabetes-induced alleviated blood glucose, glycated hemoglobin (HbA1c) and systolic blood pressure, and ameliorated heart-related marker enzymes (AST, LDH,CPK) by decreasing in serum and increasing in cardiac tissues.Regardless of stable myocardial collagen content, green tea extract can significantly decrease AGEs formation and suppress collagen crosslinking in diabetic rats, displaying its potential in fighting against diabetic cardiovascular complications like stiffness of myocardium.Matcha, a powder green tea, is a popularly drink or served as a food additive in products like ice cream and desserts in Asia.Matcha was administrated to type 2 diabetic OLETF rats by oral gavage at different dosages (50, 100, 200 mg/kg/day) for 16 weeks, to investigate its impact on the progression of renal and hepatic damage [47].As a result, matcha supplementation significantly decreased glucose,triglyceride and total cholesterol levels in serum, liver and kidney,together with renal fluorescence AGE, CML, CEL levels and RAGE expression.Instead of SREBP-1, hepatic SREBP-2 expression was increased to normal rat level through high dosage matcha treatment,indicating partial restoration of hepatic function relevant to cholesterol biosynthesis in diabetic rats.Besides green tea and matcha extract, pu-erh tea extract as a representative dark tea also draw attention of its antiglycation effect.On a BKS.Cg-+Leprdb/+Leprdb/J (db/db) mice model, pu-erh tea extract effectively attenuated diabetic nephropathy with reduced renal AGE levels mainly by trapping MGO.Ameliorated renal dysfunctions include suppressing albuminuria, serum creatinine, glomerular cell loss,mesangial expansion and IgG deposition [48].

Apart from rat/mice model,C.elegansis another excellent choice of genetic tools for its ease of availability and culture, and relatively short lifespan [49].Fuzhuan tea (FZT), one of the brick-style teas in China, is famous for unique flavor from controlled fermentation process using fugusEurotium cristatumand also for its health benefits on obesity and obesity-related conditions [50].FZT extract was attained by deionized water (100 °C) extraction and freeze drying, and then gave toC.elegans[51].The results showed that FTZ perturbed the lifespan-shortening consequence and alleviated detrimental effects of a high-sugar diet whereas exhibited no effect of lifespan-extending on a normal diet.The lifespan promotion and fat content reduction effect were counted on DAF-16/FOXO and the insulin/IGF-1 signaling (IIS) pathway while the AGEs stress relief is through SKN-1/Nrf and p38/MAPK pathway independent of DAF-16/FOXO and IIS pathway.

Surprisingly, unlike general results showing AGEs stress alleviating effects of tea catechin, there are a few studies underlined contrary effect at high dosage supply.High concentration of natural compounds containing a catechol group like EC and 4-methylcatechol increased CML concentration significantly (1 mmol/L in glycated HSA model), which was in a dose-dependent manner and largely decreased to inhibition effect at lower concentration [26].The CML enhancing effect was further confirmed in STZ-induced diabetic mice model.Oral administration of 500 mg/kg/day EC for 45 days enhanced CML accumulation in gastric epithelial cells.Similarly, in a study investigated the CML formation during black tea processing conditions, CML formation was enhanced in Lys + Glu + Fru model with addition of 1, 5, 10, 15, 20 mmol/L EGC, EGC and EGCG [24].Hydrogen peroxide generated from autoxidation of catechol compounds actively involves in CML formation by generation of hydroxyl radicals through Fenton reaction, because introduction of glutathione peroxidase effectively impeded the CML formation enhancing effect, indicating control of hydrogen peroxide plays an important role in CML accumulation [25].Further evidence demonstrated that the hydrogen peroxide itself enhanced CML formation in a dose-dependent manner and among natural catechol compounds, EGCG produced more hydrogen peroxide than EC and also enhanced CML formation more effectively [52].Other possible reason may be that the acidic environment used in the chemical model favored accumulation Amadori products and oxidation of fructoselysine, an ARP largely produced, may also be an important CML formation pathway [24,53].

In conclusion, results from these studies demonstrated that tea polyphenols, especially tea catechins, could significantly prevent AGEs formation by trapping precursors like MGO and scavenging free radicals.The inhibitory effect of AGEs reflects on various health benefits towards (diabetic) retinopathy, osteoarthritis, nephropathy,hepatopathy, cardiomyopathy and others.The possible mechanism involved in these cytoprotective effects could be mainly through controlling RAGE expression, along with MAPK and TGF-β pathways.Specific modulations include activation of Nrf2 and following enhancement of key detoxifying enzyme HO-1 expression against ROS in KEAP1-Nrf2-ARE pathway, down regulation of upstream regulators, NF-κB and lκBα and corresponding downstream inflammatory enzymes iNOS, COX2, IL-6, TNF-α and MMPs.

5.Application

Clearly, antiglycation effects were shown across all kinds of tea,from green tea to dark tea, mainly due to polyphenols.However, the practical usage of antiglycation effect of tea polyphenols should be considered carefully because dietary and pharmaceutical application have different criteria.For food supply, it is crucial to balance the potential antiglycative benefits and resulted flavor formed from the addition of tea polyphenols.As MGO and GO play critical roles in flavor formation in food products [11], the addition of tea polyphenols may possibly impact throughout flavor by its trapping effect.Supporting studies demonstrated that addition of tea catechins changed bread flavor by inhibition of pyrazine formation [38].At the same time, one study simulated actual addition of EGCG-enriched green tea extract in lactose-reduced ultrahigh temperature (UHT)treated milk and found epimerization of EGCG to GCG, a reduction of Arg-derived AGEs formation but an enhancement of Lys-derived AGEs accumulation during one-year storage, indicating its possibility out of a major pathway of inhibiting AGEs formation [54].Therefore,the addition of tea polyphenols may not perturb overall AGEs formation by trappingα-DCs in real food system, especially for high temperature treatment.Further studies should address directly on the impact of tea polyphenols towards other pathways like metal ions and oxidative reactions instead, and investigations should expand to various food systems with different processing methods in order to bring consolidation of whole recognition of actual antiglycation effect of tea polyphenols.

As for nutraceutical/pharmaceutical supplement, a big challenge is to improve bioavailability of tea catechins.It is well-known that tea polyphenols have relatively low bioavailability, over 90% of green tea polyphenols lost upon gastric and intestinal digestion [9].Application of nano technology successfully improved tea polyphenol bioavailability by promoting stability and facilitating absorption [55,56].Besides the intact form of tea polyphenols,metabolites also need more attention.Catechins tend to be catabolized into smaller molecular metabolites by intestinal microflora, and glucuronidation and sulfation are believed to promote solubility and bioaccessibility [57,58].However, to our best knowledge,currently very few investigations intend to directly relate improving intact tea polyphenol or their metabolites with antiglycation effect especially on AGEs formation.Though owning to low bioavailability,evidence showed that repeated and high dose administration of tea polyphenols is capable of elevating endogenous levels and inducing toxicity [59,60].Therefore, pharmacokinetic and toxicity of tea catechins/metabolites also need to be further evaluated for the dose regime responsible for prevention/trapping of AGEs.

6.Discussion and perspectives

6.1 Detection recommendations

Detection inconsistency brings difficulties to rapid, simple and accurate comparation among different effective compounds from different published results.For instance, even for merely fluorescence detection, the excitation and emission wavelengths vary noticeably.The obstacle of AGEs measurement has existed for decades and comes from heterogenous complex nature of chemical moieties and highly bounded forms hard to be released.Up to date,the detection still focuses on several representative AGEs like CML,pyrraline and pentosidine.CML was the first AGE identified and thus well-studied, however, other AGEs deserve more attention and investigation [61].It is beyond the capability to analyze all AGEs precisely at this point due to the impossible preparation of all AGEs standards economically and easily.Hence, development of a standard measurement protocol is expected in the near future as detection technology is rapidly arising nowadays.

6.2 Biological signaling pathways

As mentioned in section 4 and shown in Fig.4, the cytoprotective effects of tea and tea polyphenols are mainly from regulation of RAGE expression, particular MAPK and TGF-β pathway.Tea polyphenols effectively promote KEAP1-Nrf2 pathway and inhibit MAPK and TGF-β pathways so that to alleviate nephropathy,vasculopathy, proliferation, apoptosis, inflammation and angiogenesis.However, pathways related to other biological activities of tea polyphenols should also take into account to see its possibility of linkage to antiglycation activities, such as PI3K-Akt, Jak-STAT,AMPK, Wnt/β-catenin cell signaling pathways.More importantly,the exact pathways underlying the antiglycation activities of tea polyphenols remains unclear and require further elucidation and sufficient accumulation of proofs.

Overall, this review provided a strong indication of the potential development and application of tea polyphenols, especially catechins,to serve as suitable natural candidates in replacing artificial AGE-breakers for prevention and/or management of diseases and associated complications.

Conflict of interest

The authors declare that there is no conflict of interests.

Acknowledgement

This research reported in this paper are funded by Hubei Science and Technology Plan Key Project (G2019ABA100).