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Chemistry » Organic Chemistry » "Glycosylation", book edited by Stefana Petrescu, ISBN 978-953-51-0771-2, Published: September 26, 2012 under CC BY 3.0 license. © The Author(s).

Chapter 10

Plant-Derived Agents with Anti-Glycation Activity

By Mariela Odjakova, Eva Popova, Merilin Al Sharif and Roumyana Mironova
DOI: 10.5772/48186

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Plant-Derived Agents with Anti-Glycation Activity

Mariela Odjakova1, Eva Popova1, Merilin Al Sharif1 and Roumyana Mironova2

1. Introduction

1.1. Glycation and consequences

Glycation or the Maillard reaction is the non-enzymatic adduct formation between amino groups (predominantly the ε-amino group of lysine and the guanidine group of arginine) [1, 2] and carbonyl groups of reducing sugars or other carbonyl compounds. This reaction is subdivided into three main stages: early, intermediate, and late. In the early stage, glucose (or other reducing sugars such as fructose, pentoses, galactose, mannose, xylulose) react with a free amino group of biological amines, to form an unstable aldimine compound, the Shiff base. Then through an acid-base catalysis, this labile compound undergoes a rearrangement to a more stable early glycation product known as Amadori product [3]. Because the Maillard reaction is non-enzymatic, the variables which regulate its velocity in vivo are the glucose and protein concentrations, the half-life of the protein, its reactivity in terms of free amino groups, and the cellular permeability to glucose.

In the intermediate stage, via dehydratation, oxidation and other chemical reactions, the Amadori product degrades to a variety of reactive dicarbonyl compounds such as glyoxal, methylglyoxal, and deoxyglucosones which, being much more reactive than the initial sugars, act as propagators of the reaction, again reacting with free amino groups of biomolecules. In the late stage of the glycation process through oxidation, dehydratation and cyclization reactions, irreversible compounds, called Advanced glycation end products (AGEs) are formed. The AGEs are yellow-brown, often fluorescent and insoluble adducts that accumulate on long-lived proteins thus compromising their physiological functions [4]. Glycation of proteins can interfere with their normal functions by disrupting molecular conformation, altering enzymatic activity, reducing degradation capacity, and interfering with receptor recognition [5]. AGE-modified proteins lose their specific functions and undergo accelerated degradation to free AGEs such as 2-(2-furoyl)-4(5)-furanyl-1H-imidazole (FFI), imidazolone, N-ε-carboxy-methyl-lysine (CML), N-ε-carboxy-ethyl-lysine (CEL), glyoxal-lysine dimmer (GOLD), methyl-glyoxal-lysine dimer (MOLD), and others. Moreover, AGEs can also act as cross-linkers between proteins, resulting in the production of proteinase-resistant aggregates [6].

The formation of AGEs progressively increases with normal aging and age-dependent AGEs have been shown to accumulate in human cartilage, skin collagen and pericardial fluid [7]. Long-lived proteins such as lens crystallins and especially collagens contain numerous lysine, hydroxylysine and arginine residues, have a slow turn over, and are prone to age-related accumulation of glycation damage [8]. Besides accumulation during healthy aging, AGEs are formed at accelerated rates in diabetes [9]. They are markers and also important causative factors for the pathogenesis of diabetes [10], cataracts [11], atherosclerosis [12], diabetic nephropathy [13], and neurodegenerative diseases, including Alzheimer’s disease [14]. Three routes have been proposed for AGEs formation: 1) autoxidative pathway in which sugars give rise to reactive products by autoxidation, 2) Amadori rearrangement, and 3) from the Shiff base. Reactive oxygen species (ROS) in the presence of trace levels of catalytic redox-active transition metal ions also contribute to AGEs formation. The process includes oxidative steps and is therefore called glycoxidation [15].

Except these endogenous AGEs, humans are also exposed to exogenous AGEs which are ingested with food. Some approaches for food processing promote the Maillard reaction and the development of browning products [16]. The formation of Maillard reaction products (MRPs) depends on the processing temperature and duration, and is greatly accelerated by long exposure to heat [17]. Food treatments such as frying or baking have a greater impact on the formation of MRPs than boiling [18]. MRPs are inherent to Western diet [19] and fructose intake was largely elevated in recent years because of an increased consumption of soft drinks and processed foods. Fructose and its metabolites, can initiate the non-enzymatic fructosylation of proteins. Moreover, among the various physiological sugars, fructose undergoes a more rapid oxidative degradation and is a more potent protein glycating agent than glucose [20]. During chronic hyperglycemia, excessive glucose uptake in tissues also affects the key enzyme aldose reductase (AR) in the polyol pathway. This leads to the reduction of various sugars to sugar alcohols, such as glucose to sorbitol, followed by nicotinamide adenine dinucleotide (NADH)-dependent sorbitol dehydrogenase-catalyzed fructose production. Increased fructose formation in turns leads to the production of reactive carbonyl species which are key factors in AGEs formation [21]. Furthermore, sorbitol and its metabolites accumulate in the nerves, retina, kidney, and lens due to poor penetration across membranes and inefficient metabolism, resulting in the development of diabetic complications [22]. Advanced glycation end products formed inside the body or ingested with food can also interact with specific receptors and/or binding proteins thus activating a series of intracellular signalling pathways, which are implicated in diabetic complications. Interaction of AGEs with receptors for advanced glycation end products (RAGE) can trigger signaling events through p38 MAP Kinase, nuclear factor kappa-B (NF-κB), P21 Ras and Jak/STAT pathways. The cellular response can involve the overexpression of cell adhesion molecules such as vascular cell adhesion molecule-1(VCAM-1), and the production of cytokines (interleukin-2, interleukin-6 and tumor necrosis factor-α) and vascular endothelial growth factor (VEGF) [23-25]. Various studies have shown that diabetes mellitus is associated with an increased production of free radicals and also with a decrease in the antioxidant potential leading to oxidative stress. Thus, the disturbed balance between radical formation and radical neutralization leads to oxidative damage of cell components such as proteins, lipids, and nucleic acids [26]. During glycoxidative stress, NF-κB activates the production of TNF-α which in turn leads to enhanced ROS production. In such a way AGEs formation keeps the oxidative stress ongoing [27, 28].

ROS exert a multitude of effects. They are both harmful by-products and cellular messengers. As messengers, ROS are involved in a network of intracellular and intercellular communication pathways and that is why mitochondrial production of ROS plays a crucial role in the pathogenesis of type II diabetes, neurodegenerative and cardiovascular diseases [29]. It has been reported that direct exposure of endothelial cells to hyperglycaemic concentrations of glucose increases the formation of ROS. Activation of the enzyme NADPH oxidase is strongly implicated in this process [30]. NADPH oxidase may be activated through an increased diacylglycerol mediated activation of protein kinase C (PKC) [31]. High concentrations of glucose [32] and ROS [33] also have been reported to activate PKC. Since hyperglycaemia is responsible for a rise in the mitochondrial production of ROS, targeting antioxidants to mitochondria and increasing their overall antioxidant potential is expected to ameliorate diabetic symptoms [34]. In order to enhance the antioxidant capacity of the body, we must increase the exogenous intake of antioxidants or stimulate the endogenous synthesis of antioxidants such as superoxide dismutase and reduced glutathione. The inhibition of AR and advanced glycation end products formation is yet another mode for diabetes treatment, which is not dependent on the control of blood glucose, and would be useful in prevention of certain diabetic complications [35].

2. Therapeutic agents

Both synthetic compounds and natural products have been evaluated as inhibitors against the formation of advanced glycation end products (AGEs). The synthetic AGEs inhibitors so far discovered are divided into three classes: (a) carbonyl trapping agents which attenuate carbonyl stress; (b) metal ion chelators, which suppress glycoxidations; and (c) cross-link breakers that reverse AGE cross-links [9]. However, despite of their inhibitory capacities against the formation of AGEs, many synthetic inhibitors of AGEs formation were withdrawn from clinical trials due to relatively low efficacies, poor pharmacokinetics, and unsatisfactory safety [36, 37].

For exaple, aminoguanidine (AG), a nucleophilic hydrazine compound which prevents the formation of AGEs was withdrawn from the crucial phase III of clinical trials because of safety concerns and apparent lack of efficacy [38]. On the other hand natural products have been proven relatively safe for human consumption and many plant extracts have been tested for their ability to prevent AGEs formation [39]. Moreover, a number of plant-derived products have been shown to possess hypoglycemic, hypolipidemic as well as antioxidant properties [40]. Some important compounds such as phenolics [41, 42], oligo- and polysaccharides [43, 44], carotenoids [45, 46], unsaturated fatty acids [45, 46] and many others have been reported to possess anti-glycating activity. Thus, the daily consumption of dietary components, mainly from plant sources which have an antioxidant effect, is considered to be of potential benefit for prevention of diabetes and diabetic complications [47]. For example ethanol fractions of Melissa officinalis, L (Lemon balm) were shown to possess high inhibitory effect on the formation of advanced glycation end products in the late stage of the glycation process [48]. Green tea consumption (drinking) also significantly reduced the advanced glycation, the accumulation of AGEs and the cross-linking of tail tendon collagen in diabetes [49]. Moreover, phenolics, particularly flavonoids, are responsible for the anti-glycation activity of herbal infusions [50]. Another beverage consumed worldwide, the coffee, is also rich in phenolic compounds, mainly caffeoylquinic, p-coumaroylquinic, feruoylquinic and dicaffeoylquinic acids which inhibit protein glycation and dicarbonyl compounds formation [51]. Except polyphenols which constitute a major group of plant-derived compounds with anti-glycation activity, some amino acids [52-54], triterpenes and saponins [55, 56], polysaccharides and oligosaccharides [43, 44, 57, 58] were shown to decrease the AGEs formation. Taurine, a sulfur amino acid, was shown to reduce acrylamide production in potato chip models suggesting its potential use in food processing to decrease acrylamide formation [53]. Another amino acid, arginine, was shown to have an immunomodulatory effect and to inhibit AGEs formation in in vitro studies [54].

3. Polyphenols

The anti-glycation capacity of numerous medicinal herbs and dietary plants was comparable with [59], or even stronger than that of aminoguanidine [42, 60, 61-63]. Several studies have demonstrated that the anti-glycation activity correlates significantly with the phenolic content of the tested plant extracts [5, 50, 59, 64, 65]. Polyphenols are the most abundant dietary antioxidants, being common constituents of fruits, vegetables, cereals, seeds, nuts, chocolate, and beverages, such as coffee, tea, and wine. They have been shown to lead to many health benefits, such as prevention of cancer [66], neurodegenerative diseases [67], cardiovascular diseases [68] and diabetes [69].

Although polyphenols are chemically characterized as compounds with phenolic structural features, this group of natural products is highly diverse and contains several sub-groups of phenolic compounds. The diversity and the wide distribution of polyphenols in plants have led to different ways of categorizing these naturally occurring compounds. Polyphenols have been classified by the source of origin, biological function, and chemical structure. Also, the majority of polyphenols in plants exist as glycosides with different sugar units and with sugars acylated at different positions of the polyphenol skeletons [70]. According to the chemical structure of the aglycones, polyphenols are subdivided into the following groups:

1. Phenolic acids are among the most important non-vitamin antioxidant phytochemicals naturally present in almost all vegetables and fruits. Their biological activity is related to their lipophilicity and is influenced by the presence of ring substituent hydroxyl groups and, in the case of polyhydroxylated phenolic esters, by the length of the ester moiety [71]. Phenolic acids are non-flavonoid polyphenolic compounds which can be divided into two main types, benzoic acid and cinnamic acid derivatives based on C1–C6 and C3–C6 backbones (Figure 1) [70].


Figure 1.

Phenolic acids: Left, Benzoic acids; right, Cinnamic acids. Tsao R (2010).

Cinnamic acids and derivatives

Caffeic acid is a naturally occurring cinnamic acid, found in many vegetables and herbs, e.g. coffee, pear, basil, oregano and apple [72]. In 2009 Gugliucci et al. demonstrated that caffeic acid in Ilex paraguariensis extracts inhibits the generation of fluorescent AGEs in in vitro experiments [65]. Moreover, extracts from two Chrysanthemum species (C. morifolium R. and C. indicum L.) demonstrated marked inhibition of the formation of AGEs and CML in in vitro model systems [42]. The plant extracts inhibited the formation of total AGEs after one week of incubation in BSA/glucose and BSA/fructose systems. Furthermore, the inhibitory effect of the Chrysanthemum extracts at a concentration of 5.0 was stronger than that of AG at a concentration of 1 mM as a positive control. The active components in these plants were characterized by liquid chromatography-diode array detector-atmospheric pressure chemical ionization/mass spectrometry, which showed that C. indicum L. conatins large amounts of caffeic acic, as well as luteolin and kaemferol. The other Chrysanthemum species (C. morifolium R.) contains chlorogenic acid, flavonoid glucoside varieties, and apigenin [42]. Chlorogenic acids, esters formed between certain trans cinnamic acids and (-)-quinic acid, are the major phenolic compounds in coffee, strawberries, pineapple, apple, and sunflower. 5-caffeoylquinic acid (5-CQA) is the only chlorogenic acid commercially available and has been extensively studied due to its antioxidant activity. Chlorogenic acids are free radical and metal scavengers, and along with other biological activities they may interfere with glucose absorption and have been shown to modulate gene expression of antioxidant enzymes [73]. Coffee fractions, in which chlorogenic acids are the main compounds, have been shown to inhibit the formation of CML in a concentration-dependent manner. In addition polyphenols such as caffeoylquinic, p-coumaroylquinic, feruloylquinic and dicaffeoylquinic acids contributed to about 70% of the antioxidant capacity of the coffee fractions [51]. Notably, Ilex paraguariensis, like coffee, contains a high concentration of caffeic acid, mostly esterified as chlorogenic acids [65]. Large amounts of chlorogenic acid were identified also in Chrysanthemum morifolium R. [42].

Recently, Jang et al. (2010) isolated three quinic acid derivatives from ethyl acetate soluble extract of the leaves and stems of Erigeron annuus. The structures of these compounds were identified as 3-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid methyl ester, and 3,5-di-O-caffeoyl-epi-quinic acid. The last compound exhibited the most potent inhibitory activity against AGEs formation (IC50 value of 6.06 µM vs. 961 µM for AG) and prevented opacification of rat lenses, while 3-caffeoylquinic acid (a monocaffeoylquinic acid) was not effective. Two caffeoyl erigerosides and a sucrose ester also were more effective AGEs inhibitors than AG. This is the first report on 3,5-di-O-caffeoyl-epi-quinic acid as an inhibitor of RLAR (rat lens aldose reductase), AGEs formation, AGEs-BSA cross-linking, and cataractogenesis [62].

Ferulic acid (FA) is another cinnamic acid that occurs naturally and which is present in drinks and foods, e.g., rice, wheat, oats and some fruits and vegetables [58]. In 2002 Kikuzaki et al. reported that ferulic acid possesses free radical scavenging properties toward hydroxyl radicals, peroxynitrite and oxidized low-density lipoprotein in vitro [74]. It has been also shown that ferulic acid can bind human serum albumin (HSA) to form complexes [75]. This interaction led to a significant reduction of the HSA α-helix structure and caused structural changes to the protein providing unusual protective effects against protein oxidation. Silván et al. (2011) reported that the addition of ferulic acid reduces the formation of CML and fluorescent AGEs in vitro by nearly 90% [76]. It was shown that the presence of ferulic acid in samples containing proteins and fructose prevents the blocking of free amino groups by about 15% and 30% in soy glycinin and BSA glycation model systems, respectively. Based on previously published results, as well as on the latest findings regarding ferulic acid, Silván et al. (2011) concluded that FA might prevent AGE formation by some of the following ways: acting as an antioxidant, binding amino groups, and inhibiting sugar autoxidation and early Maillard Reaction Products (MRP) degradation [76]. However, the exact mechanism of anti-glycation by ferulic acid demands further investigations.

In 2011 Miroliaei et al. reported the presence of rosmarinic acid, a dimmer of caffeic acid, in Melissa officinalis L. extract. They demonstrated that treatment of BSA with this herb resulted in a profound prevention of structural changes caused by D-glucose keeping the protein molecule close to its native polar conformation. The extract has the potential to arrest changes in the α-conformers by concealing the glycation sites and lowering the extent of the solvent-accessible surface area, thereby producing barriers for cross β-structure formation. The behavior of the balm extract in this respect resembles that of molecular chaperones which block the hydrophobic surfaces of substrate proteins. Moreover, when albumin molecules were treated with glucose in the presence of balm extract, a lower affinity of glycated BSA for RAGE receptors was observed. Based on the above experimental data, researchers concluded that the herb extract, possessing chaperone-like activity, would afford a protective effect against AGE-induced toxicity by suppression of receptor signaling pathways (e.g. RAGE antagonists) [48]. Also, Ma et al. (2011) reported that rosmarinic acid, isolated from Salvia miltiorrhiza Bge, has a more potent inhibitory effect against the formation of AGEs in α-glucosidase (IC50 0.04 µM) than the positive control (AG with IC50 of 0.11 µM) [63].

Benzoic acid derivatives

Three derivatives of gallic acid: ethyl gallate, pentagalloyl glucose, and protocatechuic acid were isolated from ethyl acetate fraction of Rhus verniciflua extracts [77]. These gallic acid derivatives have been shown to inhibit recombinant human aldose reductase as well as the accumulation of advanced glycation endproducts in BSA-glucose model system.

In 2007 Ardestani et al. reported that the Cyperus rotundus extract (CRE) has a potent antioxidant activity and chelating properties. CRE inhibits high fructose-induced oxidative damage to protein in a dose-dependent manner by decreasing protein carbonyl (PCO) formation and preserving protein thiols from oxidation [59]. Recently, RP-HPLC analysis of C. rotundus revealed the presence of phenolic compounds such as gallic acid, p-coumaric acid (a typical cinnamic acid), and epicatechin (flavanol) [78]. Accordingly, the potent inhibitory activity of C. rotundus on AGEs formation and protein oxidation might be related to its polyphenolic content.

A new gallic acid-derivative, 7-O-galloyl-D-sedoheptulose (GS), was identified in Cornus officinalis (2007). This polyphenolic compound showed beneficial effect on the early stage of the diabetic kidney disease [79]. GS reduced renal glucose, AGE formation, and oxidative stress in diabetic rats. Moreover, GS did not show any toxicity at 20 and 100 mg, and reduced Maillard reaction-induced CML via the marked inhibition of mitochondrial lipid peroxidation. It also effectively ameliorates the increases in serum creatinine and urinary protein to nearly normal levels [80].

2. Flavonoids

Flavonoids have the C6–C3–C6 general structural backbone in which the two C6 units (Ring A and Ring B) are of phenolic nature (Figure 2)

Due to the hydroxylation pattern and variations in the chromane ring (Ring C), flavonoids can be further allocated to different sub-groups such as anthocyanins, flavan-3-ols, flavones, flavanones and flavonols. While the vast majority of the flavonoids have their Ring B attached to the C2 position of Ring C, in some flavonoids such as isoflavones and neoflavonoids, Ring B is connected at the C3 and C4 position of Ring C, respectively.

Since beans, particularly soybean, are a major constituent of the diet in many cultures, the role of isoflavones has, thus, great impact on human health [70]. Flavonoids are present in various kinds of vegetables, tea, and red wine [81]. Numerous flavonoids are well-known antioxidants, effective in trapping free radicals, and in such a way participating in maintaining the overall plant cell redox homeostasis [82]. The primary structure of flavonoids (three benzene rings with one or more hydroxyl groups) is the key factor determining their antioxidation capacity. The antioxidation activity may involve the ability of flavonoids to scavenge free radicals, chelation of transition metal ions, sparing of LDL associated antioxidants, and binding to macromolecules or interaction with other kinds of antioxidants [83].


Figure 2.

Flavonoid structures. Tsao R (2010).

The antioxidant activity of flavonoids has been demonstrated in many lipid systems. Therefore, they are speculated to have potential in atherosclerosis prevention [81]. The antioxidant capacity of flavonoids depends on both their structure and glycosylation pattern. Cuminum cyminum (CC), commonly known as Jeera, was found to contain 51.87% w/w flavonoids, which were proposed to be responsible for its antiglycation property. Researchers have shown that treatment of streptozotocin-diabetic rats with CC reduced the renal oxidative stress and AGEs accumulation by increasing the antioxidant defense and reducing the free radical induced lipid peroxidation. The antioxidant activity of superoxide dismutase, catalase and reduced glutathione, increased upon CC treatment. Further experiment revealed that the antihyperglycemic effect of CC may be due to protection of surviving pancreatic β cells, and increase in insulin secretion and glycogen storage [84].

Flavonoids are also abundant in honeys, and honeys rich in flavonoids, such as buckwheat honey, exhibited higher antioxidant activity than flavonoid-poorer honeys such as acacia honey [85]. Raw Millefiori honey, for example, is packed full of antioxidants [86-88]. In addition to the direct contribution to the radical scavenging activity, the polyphenolic content also influences the honey color. Conjugated systems of double bonds, such as those present in flavonoids, terpenes, isoprene units and long chain phenolic acids present in honey, constitute chromophores that absorb photons of visible light giving rise to colors ranging from yellow to brown. Several reports point out the positive and highly significant correlation between honey color, phenolic content and antioxidant activity [85, 87, 88].

Chalcones, though lacking the heterocyclic Ring C, are still categorized as members of the flavonoid family [70]. The chalcone butein isolated from ethyl acetate fraction of Rhus verniciflua proved to be a potent inhibitor of Recombinant Human ALR2 (rhALR2) with an IC50 value of 0.7 µM. Butein also strongly inhibits the advanced glycation end products accumulation in vitro. It has been reported that the hydroxyl groups at the 3’-, 4’-, 5-, and 7-positions of flavones increase their AGE inhibitory activities, whereas the methylation or glycosylation of the 3’- or 4’-hydroxyl group reduces this activity [89]. In agreement with this report, the open ring form of 3-, 4-, 2’-, and 4’-tetrahydroxylated flavone, butein, has an increased AGE inhibitory activity. From these results the conclusion could be drawn that the inhibitory effect of Rhus verniciflua, and especially of the ethyl acetate fraction on rhALR2, is possibly exerted by butein acting as an active component.

In apple trees (Malus domestica), the major sub-family of flavonoids is represented by dihydrochalcones, which are found in large amounts (up to 5% of dry weight) in leaves and in immature fruits [90]. Among the known dihydrochalcones, phloridzin and its aglycone, phloretin, are simple forms [91] and their biosynthesis in Malus has been recently described [92]. Bernonville et al. (2010), demonstrated the presence of phloridzin alone or in combination with two additional dihydrochalcones, identified as sieboldin and trilobatin [60]. Phloridzin was shown to inhibit glucose intestinal absorption and renal resorption, resulting in normalization of blood glucose and overall diminution of glycaemia in animal models [93]. Based on the results of the antioxidant assays and the fact that sieboldin was several folds more efficient than phloridzin in inhibiting AGE formation (10-fold lower IC50 than phloridzin and 40-fold lower IC50 (0.2 mM) than AG), a role for sieboldin in inhibiting the formation of intermediate glycation products is suggestive [60].


Isoflanones have their ring B attached to the C3 position of ring C. They are mostly found in the leguminous family of plants [70]. Soy products and soybeans are particularly abundant sources of isoflavones which have both antioxidant and phytoesterogenic activities that may contribute to their potential anticarcinogenic and cardioprotective effects [94-96]. High soybean consumption has been implicated in the longevity of the Japanese [97]. Genistein and daidzein are the two main isoflavones in soy along with glycetein, biochanin A and formononetin [98]. In 2009 Hsieh et al. reported that soy isoflavones supplementation significantly and dose-dependently decreased the concentration of protein carbonyls in the liver, kidney and brain in D-galactose treated mice. Soy isoflavones administration effectively attenuate oxidative damage and improve parameters related to aging and Alzheimer’s disease [99].

Puerarin (daidzein-8-C-glucoside) is an isoflavone glycoside isolated from the root of Pueraria lobata and has various pharmacological effects, including anti-hyperglycemic and anti-allergic properties [100-102]. Additionally, puerarin has been reported to effectively inhibit advanced glycation end products formation which is one of the typical risk factors for diabetic complications [103]. In 2010 Kim et al. reported that puerarin administration to mouse mesanglial cells increased heme oxygenase-1(HO-1) protein levels in a dose-dependent manner [104]. This enzyme participates in conversion of heme to biliverdin, which is rapidly metabolized to bilirubin, a potent antioxidant [105]. Moreover, puerarin treatment was able to enhance the phosphorylation of protein kinase C δ-subunit which primarily regulates the expression of HO-1, which in turn inhibited AGE-induced inflammation in mouse mesanglial cells.

Flavones, Flavonols, Flavanones and Flavanonoles

These flavonoid subgroups are the most common and almost ubiquitous throughout the plant kingdom. (Figure 3)


Figure 3.

Flavones, Flavonols, Flavanones and Flavanonoles. Tsao R (2010).

Flavones and their 3-hydroxy derivatives flavonols, including their glycosides, methoxides, and other acylated products, make this the largest subgroup among all polyphenols [70]. The most common flavonol aglicones, quercetin and kaemferol, alone have at least 279 and 347 different combinations, respectively [106-108].

Kaempferol is a well known anti-oxidant flavonol aglycone that possesses anti-inflammatory properties resulting from its ability to diminish the formation of reactive species (RS) [109]. Kaempferol was detected in plant extracts of two Chrysanthemum species [42] and Erigeron annuus [110]. Kaempferol causes the inhibition of the inducible nitric oxide synthase and cyclooxygenase-2 and the down-regulation of NF-κB pathway [111]. In 2010 Kim et al. demonstrated that the short-term feeding of aged rats with kaempferol modulated both AGE accumulation and RAGE expression which are dependent on NF-κB transcriptional activity. Furthermore, kaempferol suppressed age-related NF-κB activation and its pro-inflammatory genes through the suppression of AGE-induced NADPH oxidase activation [112]. Quercetin is another example of flavonol aglycone found in citrus fruit, buckwheat and onions. Many researchers examined the ability of quercitrin to protect against protein damage (AGEs formation) using in vitro model systems [77, 113]. Both quercetin and kaempferol together with kaempferol-3-O-rutinoside were reported as the main polyphenols present in crude extracts of aerial parts of Cassia auriculata. Ethyl acetate fraction of this medicinal plant showed radical scavenging activity and inhibition of lipid peroxidation. The guava leaves extracts also are a very good source of phenolic compounds such as gallic acid, ferrulic acid, quercetin and quercetin derived glycosides. The phenolic compounds of guava leaf extracts significantly decreased fasting blood glucose levels in streptozotocin-induced diabetic rats, decreased glycation products, lipid peroxidation and improved the antioxidant status in a dose-dependent manner [114]. Thus, the effect of guava leaves on glycation may be due to the different composition of the phenolic compounds. The latter also showed strong inhibitory effects on the glycation of albumin, especially quercetin exhibited over 95% inhibitory effect at a concentration of 100µ The anti-glycation activity of the aqueous extracts of guava was higher than that of AG and green tea polyphenols [115]. More interestingly, flavonoids with the 3′,4′-dihydroxy group (i.e., quercetin and quercitrin) demonstrated the highest inhibitory activity against AGEs formation after incubation at 37°C for 14 days, with IC50 values much lower than that of AG [111]. Besides quercetin, the flavonoid glycosides isoquercitrin (quercetin-3-β-glucopyranoside) and hyperin (quercetin-3-D-galactoside) are well-known antioxidants [116-118]. Isoquercitrin showed outstanding antioxidant activity in yeast cells by increasing the activity of superoxide dismutase (SOD) [118]. It also demonstrated free radical scavenging properties [119]. Marzouk et al. (2006) reported that hyperin strongly inhibited the formation of 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals [117] and lipid peroxidation, as well as the hydroxyl radical and superoxide anion generation [120]. Also, hyperin inhibits lipopolysaccharide (LPS)-induced nitric oxide (NO) production [120]. It is worth mentioning that isoquercitrin and hyperin showed a dose-dependent inhibitory activity against the formation of AGEs which was stronger than that of the AG positive control. Thereby, hyperin demonstrated a greater effect by inhibiting AGEs formation by 92% as compared to isoquercitrin, which inhibited the accumulation of AGEs by 89.6%.

In 2011 Manaharan et al. reported the presence of quercetin-3-O-β-D-galactopyranoside in ethanolic extracts of Peltophorum pterocarpum leaves as the major bioactive compound. Peltophorum pterocarpum leaf and bark extracts were shown to inhibit aldose reductase far better than the pure compound quercetin [121]. The plant leaf and bark extracts were found to be about 28-fold and 56-fold more effective than quercetin, respectively in inhibiting aldose reductase which points to their potential use in hyperglycemia treatment. Also, the HPLC profiles of the active ethyl acetate fraction from Nelumbo nucifera leaves indicated the presence of quercetin 3-O-b-D-glucopyranoside and quercetin 3-O-b-D-glucuronopyranoside. In terms of N. nucifera’s antioxidant effect, the leaf extract exhibited potent antioxidant capacities in the DPPH and total ROS assay. The leaf extracts also showed remarkable inhibitory activities on RLAR and AGE formation [35].

Quercetin-3-O-rutinoside (Rutin), a common dietary flavonoid is an established antioxidant. It is found in fruits, vegetables and plant-derived beverages such as tea and wine [122]. Gut microflora in the large intestine metabolize rutin to a variety of compounds that include quercetin and phenol derivatives such as 3,4-dihydroxyphenylacetic acid (DHPAA), 3,4-dihydroxytoluene (DHT), 3-hydroxyphenylacetic acid (HPAA), and 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid, HVA) [122-124]. Rutin metabolites, particularly those that include vicinal hydroxyl groups in their structure such as 3,4-dihydroxyphenylacetic acid (DHPAA) and 3,4-dihydroxytoluene (DHT), are powerful inhibitors of the formation of CML and fluorescent derivatives (370-440 nm and 335-385 nm) in histone H1 caused by ADP-ribose. The plasma concentrations of these rutin metabolites are expected to effectively neutralize the reported plasma concentrations of glyoxal and methylglyoxal [125]. Rutin was also found to inhibit the formation of glycation products in collagen type I induced by glucose in vitro [126] and to be an effective inhibitor of lipoprotein glycation by increasing the resistance of LDL to HG/Cu (II)-mediated oxidation [127].

In 2009 Tsuji-Naito et al. reported that apigenin (4’,5, 7-trihydroxyflavone) in C. indicum L. is a minor flavonoid aglycone, although apigenin in C. morifolium R. is the main component of the plant extract which inhibits AGEs accumulation. Large amounts of another flavone – luteolin (2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-chromenone) were found in C. indicum L [42]. Apigenin, luteolin, apigenin-7-O- β -D-glucuronide methyl ester and apigenin-7-O- β -D-glucuronide were indentified in the ethyl acetate-soluble extract of flowers of Erigeron annuus [110]. This is the first report on apigenin-7-O-β-D-glucuronide and apigenin-7-O-β-D-glucuronide methyl ester having significant inhibitory activity towards aldose reductase and AGEs formation, which makes it worth to further study their potential for treatment of diabetic complications. The presence of luteolin together with maysin was also reported in the silk of Zea mays. These flavonoids are abundant in corn silk and in vitro glycation studies demonstrated their role in inhibiting AGE formation with luteolin being exceptionally active [61].

Hispidulin is a flavone compound from Artemisia campestris ssp. glutinosa [128], while vitexin (apigenin-8-C-glucoside) and isovitexin (apigenin-6-C-glucoside) are flavone C-glucosides, which have been identified in mung bean extract. The use of A. campestris has been recommended in Tunisian folk medicine for their antivenom [129], anti-inflammatory, antirheumatic and antimicrobial activities [130]. Recent studies provide for the first time data on the effect of an ethyl-acetate fraction from A. capillaries on the oxidative stress and antioxidant enzymes in high-fat diet induced obese and type 2 diabetic mice [131]. In 2010 Sefi et al. demonstrated that administration of an aqueous extract of A. campestris to diabetic rats increased significantly serum insulin levels, reduced serum glucose level by 60% (p < 0.001) and tended to bring the glucose value to near normal after 21 days. The ability of A. campestris extracts to reduce the blood glucose level could be attributed to a stimulation of langerhans islets, to an improvement of the peripheral sensitivity to remnant insulin, and to the strong antioxidant properties of the plant compounds [132].

Vitexin and isovitexin have been identified in other plants, such as bamboo leaves [133] and pigeonpea leaves [134]. Their anti-glycation activity could be attributed to their free radical scavenging and/or metal ion trapping activities, as they failed to directly trap reactive carbonyl species, such as methylglyoxal [64].

The number of flavanones, and their 3-hydroxy derivatives (flavanonols, which are also referred to as dihydroflavonols) identified in the last 15 years has significantly increased. Some flavanones have unique substitution patterns, e.g., prenylated flavanones, furanoflavanones, pyranoflavanones, benzylated flavanones, giving a large number of substituted derivatives of this subgroup [135]. A new compound that was designated as 4`-O-[β -D-apiosyl (12)] - β -D-glucopyranosyl] - 5-hydroxyl-7-O-sinapylflavanone was isolated from Viscum album (European Mistletoe). This compound together with previously identified compounds in V. album, 5,7-dimethoxy-4`-O-β -D-glucopyranoside flavanone, 4`,5-dimethoxy-7-hydroxy flavanone and 5,7-dimethoxy-4`-hydroxy flavanone, showed a potent anti-glycation activity, i.e. 72.5% (IC50 = 199.85 ± 0.067 mM) as well as superoxide anion scavenging capacity. The antioxidant potential of 4`,5-dimethoxy-7-hydroxy flavanone (IC50 = 58.36 ± 2.9m M) was determined to be greater than that of rutin used as a standard [41]. Recently, Jang et al. (2010) isolated from the flowers of E. annuus a novel 2,3-dioxygenated flavanone, erigeroflavanone, which was also shown to possess a strong anti–AGE activity [110]. In addition, the presence of fustin (2-(3, 4-dihydroxyphenyl)-3,7-dihydroxy-2,3-dihydrochromen-4-one), a flavanonol together with quercetin, morin (flavonol), and butein was reported in an ethyl-acetate fraction of Rhus verniciflua. All these flavonoids, especially those with hydroxyl groups at the 3’-,4’-,5’-, and 7-positions have shown a significant inhibitory activity against AGE in in vitro experiments [77].

In 2007 two dihydroflavonol glycoside, engeletin and astilbin, were isolated from an ethyl acetate extract of the leaves of Stelechocarpus cauliflorus R.E. Fr. The inhibitory activity of engeletin against a recombinant human aldose reductase (IC50 value = 1.16 µM) was twice that of quercetin used as a positive control (2.48 µM), and 23 times greater than that of astilbin (26.7 µM). Engeletin was shown to inhibit the aldose reductase uncompetitively. On the other hand, in contrast to its inhibitory activity against AR, astilbin was more potent than engeletin in suppressing AGE formation. Moreover, astilbin was almost as potent as the positive control, quercetin, in inhibiting advanced glycation end-products accumulation. Interestingly, the only structural difference between engeletin and astilbin is the number of hydroxyl groups in the B ring. Of both compounds only astilbin has the catechol orientation. Both astilbin and taxifolin (2, 3-dihydro quercetin), its aglycone, have been demonstrated to protect against oxidative damage [136]. Therefore, the antioxidant flavonoids such as engeletin and astilbin are potentially useful for therapeutic prevention of diabetic complications resulting from AGEs accumulation [137].

Flavanols and procyanidins

Flavanols or flavan-3-ols are often called catechins (Figure 4). They differ from most flavonoids in that they do not have a double bond between C2 and C3, and there is no C4 carbonyl in ring C [70]


Figure 4.

Flavanols and procyanidins. Tsao R (2010).

Catechin is the isomer with trans configuration and epicatechin is the one with cis configuration. Each of these two configurations has two steroisomers, i.e., (+)-catechin, (−)-catechin, (+)-epicatechin and (−)-epicatechin. (+)-Catechin and (−)-epicatechin are the two isomers often found in food plants. Catechin and epicatechin can form polymers, which are often referred to as proanthocyanidins because an acid-catalyzed cleavage of the polymeric chains produces anthocyanidins [70]. The presence of catechins was reported in green tea, which is an excellent source of many polyphenol antioxidants [49]. The most important catechins of green tea are (-)-epicatechin (EC), (-)-epicatechin- 3-gallate (ECG), (-)-epigallocatechin (EGC) and (-)-epigallocatechin-3-gallate (EGCG) [138]. Nearly 80% of the extract of green tea is a mixture of catechins namely epigallocatechin (EGC), epicatechin (EC), epigallocatechin-3-gallate (EGCG) and epicatechin-3-gallate (ECG). The sum of EGC and EGCG weighed more than 70% of the catechin mixture in the green tea extract [49]. It was shown that green tea treatment of diabetic rats significantly reduced the blood glucose level. This antihyperglycemic effect may be linked to enhanced basal and insulin-stimulated glucose uptake in rat adipocytes [139], inhibition of the intestinal glucose transporter [140], and decreased expression of genes that control gluconeogenesis [141]. Green tea supplementation also reduced the accumulation of AGEs in diabetic rats as indicated by decreased collagen linked fluorescence [49]. In 2009 Rasheed et al. reported that EGCG significantly decreased AGE-stimulated gene expression and the production of TNFα and matrix metalloproteinase-13 (MMP-13) in human chondrocytes. The inhibitory effect of EGCG on the AGE-BSA-induced expression of TNFα and MMP-13 was mediated at least in part via suppression of p38-MAPK and activation of JNK. In addition, EGCG inhibited the phosphorylating activity of IKKβ kinase in an in vitro assay and also the AGE-mediated activation and DNA binding activity of NF-κB by suppressing the degradation of its inhibitory protein IκBα in the cytoplasm [142]. EGCG has also been shown to prevent intracellular AGEs formation and the production of proinflammatory cytokines in monocytes under hyperglycemic conditions [143]. EGCG is capable of trapping reactive dicarbonyl species, such as methylglyoxal and glyoxal, as demonstrated by Ho and coworkers in 2007 [144]. Data from HPLC-DAD demonstrated that EGCG was able to bind lipoproteins and to enhance the antioxidant and antiglycation properties of LDL [145].

Proanthocyanidins are traditionally considered to be condensed tannins and depending on the interflavanic linkages, oligomeric proanthocyanidins can have A-type structure in which monomers are linked through C2–O–C7 or C2–O–C5 bonding, or B-type in which C4–C6 or C4–C8 bonds are common (Figure 4) [70]. Catechin and epicatechin procyanidin B2 (a dimer-type proanthocyanidin) isolated from cinnamon bark extract have been shown to possess a significant MGO trapping activitiy, with procyanidin B2 demonstrating the strongest inhibition of AGE formation among proanthocyanidins isolated from cinnamon bark [146]. All these flavonoids potently inhibited (more than 50%) the formation of pentosidine and CML [147] with procyanidin B2 showing the highest inhibition capacity (almost 80%) on the CML formation. Proanthocyanidins could further abate the MGO mediated formation of cross-links in creatine kinase in a dose-dependent manner. They also exerted various protective effects on glucose consumption impaired by high MGO concentrations through potential interaction with proteins involved in insulin signaling pathways [147]. Proanthocyanidin B-4 and two more nitrogen containing flavonoids were identified for the first time in Actinidia arguta [148]. The N-containing flavonoids comprise a very small class of natural products, which have been only rarely isolated from natural sources. The 1H- and 13C-NMR spectral data revealed that these newly isolated compounds are 6- and 8-(2- pyrrolidinone-5-yl)-(-)-epicatechins, which may be produced by condensation between (-)-epicatechin and 5-hydroxypyrrolidin-2-one under acidic conditions. Proanthocyanidin B-4 and the two novel compounds showed a significant activity against AGEs formation with IC50 values for proanthocyanidin B-4 of 10.1 µM, which is lower than that of the well known glycation inhibitor AG [148].

Geraniin, an ellagitannin, is the major tannin in Geranium thunbergii. It was also identified as the major bioactive compound in an ethanolic Nephelium lappaceum L. rind extract [149]. Previous studies have shown that N. lappaceum rind extract exhibits high anti-oxidant activity [150]. In 2011 Palanisamy et al. reported the ability of geraniin to scavenge free radicals and to possess in vitro hypoglycemic activity [149]. Geraniin is also an excellent inhibitor of carbohydrate hydrolysing enzymes (α-glucosidase and α-amylase) – superior to the positive control acarbose (carbohydrate hydrolysis inhibitor). It was far more effective in preventing polyol and advanced glycation endproducts formation as compared to the positive controls quercetin and green tea which reveals geraniin as an ideal candidate for the management of hyperglycemia in diabetic individuals [149].

4. Other phenolic compounds

A stilbene glucoside - 2,3,5,4’-tetrahydroxystilbene 2-O-β-D-glucoside (THSG) is a natural compound with strong antioxidative and anti-inflammatory properties, which has been reported as the major bioactive compound from Polygonum multiflorum Thunb., a traditional Chinese herbal tea [151,152]. It was shown to efficiently inhibit the formation of AGEs in a dose-dependent manner by trapping reactive MGO under physiological conditions (pH 7.4, 37°C) [153]. More than 60% of MGO was trapped by THSG within 24 hours and THSG was much more effective than resveratrol and its methylated derivative pterostilbene (two major bioactive stilbenes) [153]. In 2011 Chompoo et al. isolated two previously described compounds from Alpinia zerumbet, namely 5,6-dehydrokawain (DK) and dihydro-5,6-dehydrokawain (DDK) which are kawalactones. DK and DDK were present in all six different parts of the plant but rhizomes had higher inhibitory activity against AGEs formation than the other parts [154]. А previous study also provided data about the antioxidant acitivities of DDK present in leaves and rhizomes of A. zerumbet [155]. Among the compounds isolated from Alpinia zerumbet rhizomes, DK had the strongest inhibitory activity against BSA glycation with IC50 value of 15.9 µM. DK has been also shown to inhibit human platelet aggregation and to possess anti-inflamatory and cancer chemoprotective therapeutic properties [156].

5. Terpenes, carotenoids and polyunsaturated fatty acids

A terpene, 8(17),12-Labdadiene-15,16-dial (labdadiene) was isolated for the first time from the rhizome of Alpinia zerumbet together with 5,6-dehydrokawain (DK) and dihydro-5,6-dehydrokawain (DDK) [154]. In contrast to DK which strongly inhibited AGEs formation in BSA labdadiene markedly suppressed the fructosamine adduct formation with IC50 = 51.1 µg/mL. Labdadiene was also more efficient than DK in inhibiting glycation-induced protein oxidation and the formation of α-dicarbonyl compounds, at first place preventing glyoxal accumulation. It is possible that the aldehyde groups of labdadiene have a significant role in inhibiting AGEs formation. These aldehyde groups may compete with sugars for Schiff’s bases formation and/or limit the amount of amines available for glucose attachment. The fructosamine assay revealed that labdadiene has strong activity when compared to rutin and quercetin used as positive controls, although the inhibitory mechanism of labdadiene is likely to differ from that of rutin and quercetin [154].

The ability of microalgal extracts to inhibit AGEs formation differs from that of many other plant species and is not promoted by phenolic compounds. There is a weak correlation between the antiglycative activity and the total phenolic content of several microalgae as demonstrated by the very small correlation coefficient. For example, in total AGEs inhibition, the value of R2 was 0.035 for ethyl acetate fractions of green microalgae Chlorella [45]. In microalgae, a wide range of antioxidants can be produced such as carotenoids, polyunsaturated fatty acids and polysaccharides [157]. HPLC and gas chromatography (GC) analysis revealed that carotenoids, especially lutein in Chlorella and unsaturated fatty acids, mainly of linoleic acid, arachidonic acid and eicosapentaenoic acid in Nitzschia laevis contributed to the strong antiglycative capacities of these species [45]. The green microalga Chlorella zofingiensis accumulates primary carotenoids such as lutein and β-carotene to protect the cells from oxidative damage [158]. Results showed that lutein and some unsaturated fatty acids effectively inhibited the formation of both total AGEs and specific AGEs in vitro in a dose-dependent manner. For lutein, at the concentration of 0.8, the inhibitory efficacy was comparable to or even higher than the effect of 1 mM AG solution [45]. It is noteworthy that if the amount of primary carotenoids is not enough, secondary carotenoids (i.e. astaxanthin, canthaxanthin and adonixanthin) are generated to diminish the excessive oxidative stress. The green microalga Chlorella zofingiensis is known as a natural source of astaxanthin, a red ketocarotenoid that is a potent anti-oxidant. It acts as the major secondary carotenoid and over 90% of the astaxanthin is in the form of mono- and di-esters [158]. The antioxidant activity of astaxanthin is an order of magnitude higher than that of other carotenoids such as zeaxanthin, lutein, canthaxanthin and β-carotene, and 100 times higher than the antioxidant activity of a-tocopherol [159]. It was shown that under heterotrophic conditions the colour of C. zofingiensis gradually changed from green to red, indicating the accumulation of astaxanthin within algal cells. C. zofingiensis extracts and especially the red one are suggested to scavenge hydroxyl radicals and/or to chelate transition metals. Seven major fractions were obtained from astaxanthin-rich extract of C. zofingiensis. HPLC results revealed that they are astaxanthin diester, astaxanthin monoester, adonixanthin ester, free astaxanthin, free adonixanthin, lutein and zeaxanthin, and neoxanthin. The astaxanthin diester was found to be the most potent antiglycative compound among all fractions [46].

Several unsaturated fatty acids showed inhibitory activity against AGEs formation. Although palmitoleic and oleic acid were involved in the inhibition of pentosidine formation, the main contributors were linoleic acid, arachidonic acid, and eicosapentaenoic acid [45].

Hydrophobic compounds which also display antioxidant and hypoglycemic activities, such as oleanolic and ursolic acid, were observed in non-polar extracts from medicinal herbs [160]. Ursolic acid and its isomer, oleanolic acid, are triterpenoid compounds found across the vegetal kingdom that have anti-inflammatory, anti-arthritic, cytostatic, antiproliferative, and hepato-protective effects in mice, as well as membrane stabilizing properties [161-163]. One of the major components of yerba maté (Ilex paraguariensis) is oleanolic acid (OA) [65]. It has been reported that oleanolic acid has hypoglycemic and hypolipidemic effects in diabetic rats [164]. Oleanolic acid or ursolic acid (UA) intake at 0.1 or 0.2% increased the content of both acids in the kidney, dose-dependently decreased plasma glucose, HbA1c, renal Nε-(carboxymethyl)lysine, urinary glycated albumin and urinary albumin levels. OA or UA intake significantly reduced renal pentosidine and decreased AR activity. The triterpens have been shown also to elevate plasma insulin levels and renal creatinine clearance as well as to decrease renal sorbitol and fructose concentrations [55].

Arjunolic acid (2,3,23-trihydroxyolean-12-en-28-oic acid, AA), a natural pentacyclic triterpenoid saponin isolated from the bark of Terminalia arjuna, is well known to display various biological functions, including antioxidative [165], antifungal [166], hepatoprotective [167], and antibacterial activities [168]. AA plays a protective role against hepatotoxicity induced by environmental toxins such as drugs and chemicals. AA was shown to be effective in preventing the formation of reactive oxygen species (ROS), reactive nitrogen species (RNS), HbA1c, AGEs, and oxidative stress signaling cascades. AA also has been reported to protect against poly (ADP-ribose) polymerase (PARP)-mediated DNA fragmentation. Treatment with AA both before and after diabetes, on the other hand, prevented the NO signaling pathways and thereby brought the affected organs back to their physiological state. AA treatment was effective in preventing the phosphorylation of IκBα and NF-κB p65. Aslo, treatment with AA could prevent the hyperglycemia-induced phosphorylation of extracellular signal-regulated kinase (ERK) and p38. It was observed that the antidiabetic as well as antioxidant properties of AA were comparable to those of insulin [56].

6. Polysaccharides

In recent years a lot of attention has been paid to polysaccharides because of their unique biological activities [169]. Yang et al. (2009) have confirmed the presence of high quantity of polysaccharides in longan pericarp tissues (Dimocarpus longan Lour.) Polysaccharides of longan fruit pericarp (PLFP) have been found to be strong radical scavengers [170]. It is hypothesized that there is a link between the antioxidant and anti-glycative properties of PLFP. On the other hand, polysaccharides are composed of monosaccharides, which can compete with glucose for binding free amino groups in proteins thus lowering the effective concentration of glycation targets in proteins. This might be another pathway in which PLFP inhibits the formation of advanced glycation end products [44]. Moreover, it has been found that the molecular weight of the polysaccharide chain and the antioxidant activity of PLFP can be modified by ultrasonic treatment [44].

In 2009 Chen et al. reported on the ability of Ganoderma lucidum polysaccharides (GLP) to reduce lipid peroxidation and blood glucose levels in diabetic rats [171]. Administration of middle or high doses of GLP in diabetic mice significantly decreased blood glucose and HbA1c [43]. Blood cholesterol and triglyceride levels were also improved which could be ascribed to the reduced blood glucose levels [172]. GLP administration to diabetic rats further influenced the myocardial hydroxyproline as well as the soluble and insoluble myocardial collagen. After 16-week treatment of diabetic mice with GLP, the cross-linked and non-cross-linked collagens tended to decrease. The AGEs formation was also significantly reduced upon GLP treatment. In addition, the activities of antioxidant enzymes such as SOD, GSH-Px, and CAT from streptozotocin-treated diabetic rats were significantly enhanced after GLP administration [43]. Another study showed that all polysaccharides from pumpkin (Cucurbita moschata) (PPs) inhibited the formation of dicarbonyl compounds. Two of the ethanolic fractions isolated from pumpkin, PPIII and PPII, were proposed to be stronger inhibitors than AG. PPIII was shown to have 65% inhibitory effect at а concentration of 50µM. PPs also inhibited the aldose reductase in a dose-dependent manner [57]. Least but not last, the anti-glycative activity of PPs increased with a decrease in their molecular weight.

7. Other anti-glycative compouds

The major biochemical constituents of Withania somnifera roots are steroidal alkaloids and steroidal lactones from the class called withanolides [173]. To date, up to 19 withanolide derivatives have been isolated from Withania roots [174]. Recently, Withania and its active components were shown to scavenge free radicals and to inhibit lipid peroxydation [175]. Withania have been reported to suppress AGE linked fluorescence of rat’s tail tendon collagen, which was explained by its antioxidant and free radical scavenging effect [176].

Melanoidins are another class of antioxidants receiving attention in recent years. These polymeric brown compounds formed in the last stage of the Maillard reaction were supposed to be involved in the color and flavor development of thermally-processed foods. They are present in food and beverages such as coffee, beer, traditional balsamic vinegar, cocoa and bread [177-179]. It seems that during coffee roasting phenolic compounds are involved in the Maillard reaction to partially form the brown, water soluble polymers known as coffee melanoidins. Physiological studies indicated that some of the coffee effects arise not from caffeine but from melanoidins [51, 180]. The high molecular weight compound (HMWC) fraction of coffee was shown to inhibit BSA glycation by acting as radical scavenger and Fe-chelator in the post-Amadori phase of the reaction and by inhibiting the production of dicarbonyl reactive compounds during glucose autoxidation [51]. Verzelloni et al. (2011) noted that this fraction is rich in melanoidins and concluded that melanoidins could be mainly responsible for the anti-glycative activity of the HMWC fraction. Also, the presence of proteins and chlorogenic acids, incorporated in the melanoidins’ structure, has been reported [51].

Interestingly, the total phenolic content and honey color are predictive markers of the antioxidant activity in honey [85]. The radical-scavenging activity of honey was higher in honeys with high phenolic content and of darker color [181]. On the other hand, the color of honey may also result from non-enzymatic browning (the Maillard reaction) [182]. The brown, carbohydrates based melanoidin polymers have been shown to possess strong antioxidant activity [183]. It is thought that one of the possible mechanisms by which MRPs may act as both antioxidants and antibacterial agents, is their metal-chelating activitiy [184].

In 2010 Ye et al. uncovered the inhibitory effect of fermentation byproducts on AGE formation [185]. Japanese distilled spirit can be prepared from starchy substances, such as rice, barley and sweet potato. Recycled distilled residues (DRs) of rice and barley spirit as well as their vinegars inhibited the formation of Nε(carboxymethyl)lysine (CML), a major AGE in BSA model system. The high protein levels together with free lysines and arginines present in DRs of rice and barley spirits raise the possibility that these proteinaceous ingredients inhibit AGEs formation by competing with BSA for the glycation reaction. However, the low protein content in DRs of sweet potato spirit, which is accompanied by strong anti-glycation activity, argues against the above suggestion. Distilled residues and their derived vinegars are extremely complex mixtures containing caffeic acid as the dominant phenolic constituent and hence further investigations are required to elucidate the anti-glycative mechanism of DRs [185].

Vitamins and some trace elements such as zinc and selenium are also a part of the human antioxidant defence system which must be delivered by diet. For example, treatment with vitamin E prevents renal hypertrophy in streptozotocin diabetic rats [186]. Similarly, a combination of vitamins E and C administered for 12 weeks decreased lipid peroxidation and augmented the activities of antioxidant enzymes in the kidneys of stretozotocin diabetic rats. The treatment also reduced urinary albumin excretion, decreased kidney weight and reduced the thickness of the glomerular basement membrane [187]. Tocotrienol, a component of vitamin E that may accumulate more effectively in membranes than α-tocopherol [188], was shown to ameliorate experimental nephropathy in STZ-diabetic rats [189]. Pyridoxamine (PM), one of three natural forms of vitamin B6, was also reported to inhibit the Maillard reaction and PM application in diabetic nephropathy has now progressed to a phase III clinical trials. PM inhibits post-Amadori steps of the Maillard reaction by sequestering catalytic metal ions and blocking the oxidative degradation of Amadori intermediates [190]. Besides vitamin E and PM, α-lipoic acid (ALA) also possesses a strong antioxidant properties [191]. In rat soleus muscle, inhibition of glycogen synthesis and acceleration of glucose oxidation, have been correlated with the uncoupling effect of this acid. Thus, ALA may regulate glucose metabolism in muscles in a way which does not mimic the action of insulin. It has been reported that after long-term incubation in cell culture, ALA behaves as an antioxidant, whereas after short-term incubation and quick uptake by cultured cells it may act as a pro-oxidant. By acting as an antioxidant, ALA reduces oxidative stress and the formation of AGEs and improves insulin sensitivity in skeletal muscles and liver.

Recently, the effect of citric acid on the pathogenesis of diabetic complications has been reported. Citrate, a natural, dietary chelator found in citrus fruits [192], is widely used in food products as a preservative and to enhance tartness. Oral administration of citric acid to diabetic rats delayed the development of cataracts, inhibited the accumulation of AGEs such as Nε-(carboxyethyl) lysine (CEL) and CML in lens proteins. Citric acid also inhibited the development of nephropathy (albuminuria) and significantly reduced ketonemia in diabetic rats [193]. On the other hand, the administration of citric acid did not affect blood glucose or HbA1c but decreased the concentration of AGEs in lens. Since citrate did not directly inhibit the formation of CEL from acetol, most probably the inhibition of CEL formation by citric acid is secondary to the inhibition of ketogenesis.

AGEs and carbonyl accumulation have been shown to decrease in Zn-co-incubated samples containing BSA and glucose [194]. Zn also inhibited glycation and β-aggregation in BSA-containing samples. It has been suggested that during the glycation reaction, Zn prevented the β-sheet formation in albumin by promoting the native α-sheet conformation. The protection of thiol groups, which has been observed in Zn-containing samples, could be explained through one of the following three mechanisms: (1) direct binding of Zn to the thiols, (2) steric hindrance as a result of binding to other protein sites in close proximity to the thiol group or (3) a conformational change resulting from binding to another site on the protein [195].

8. Conclusion

Considering that AGEs are believed to act as major pathogenic propagators in many human diseases, and especially in diabetes and its complications, it is of great interest to identify anti-glycative substances and to examine their mode of action. The current review provides examples for the anti-glycation activity of plant-derived substances which target the essential stages of glycation through i) antiglycemic or hypoglycemic action, ii) inhibition of Amadori products formation or intervention in the post-Amadori phase of the reaction, iii) inhibition of the formation of AGEs precursors (oxidation products of sugars and early MRPs), and iv) reduction of AGEs cross-linking. This anti-glycation activity correlates with the phenolic content of the plant extracts although there is a wide range of others, nonphenolic compounds such as terpens, carotenoids, polyunsaturated fatty acids, polysaccharides, withanolides, and melanoidins which demonstrate a high potential to reduce the non-enzymatic protein glycosylation. The plant-derived anti-glycative comounds appear attractive candidates for the development of new generation therapeutics for treatment of diabetic complications and prophylaxis of aging, and point to the importance of an antioxidant-rich diet, as part of the overall diabetes management strategy.


This work was supported by grant DID02-31/09 from National Science Fund.


1 - Baynes JW, Watkins NG, Fisher CI, Hull CJ, Patrick JS, Ahmed MU, Dunn JA, Thorpe SR1989The Amadori product on protein: structure and reactions. Prog Clin Biol Res 3044367
2 - L. Bry, P. C. Chen, D. B. Sacks, 2001Effects of hemoglobin variants and chemically modified derivatives on assays for glycohemoglobin. Clin Chem 472153163
3 - Neglia CI, Cohen HJ, Garber AR, Ellis PD, Thorpe SR, Baynes JW1983C NMR investigation of nonenzymatic glucosylation of protein. Model studies using RNase A. J Biol Chem. 2581427914283
4 - A. Lapolla, P. Traldi, D. Fedele, 2005Importance of measuring products of non-enzymatic glycation of protein. Clin Biochem. 38103115
5 - Hsieh CL, Yang MH, Chyau CC, Chiu CH, Wang HE, LinYC, ChiuWT, Peng RY2007Kinetic analysis on the sensitivity of glucose- or glyoxal-induced LDL glycation to the inhibitory effect of Psidium guajava extract in a physiomimic system. BioSystems 88(1-2): 92-100
6 - S. Kikuchi, K. Shinpo, M. Takeuchi, S. Yamagishi, Z. Makita, N. Sasaki, K. Tashiro, 2003Glycation-a sweet temper for neuronal death. Brain Res. Rev. 41306323
7 - A. Simm, J. Wagner, T. Gursinsky, N. Nass, I. Friedrich, R. Schinzel, E. Czeslik, R. E. Silber, R. J. Scheubel, 2007Advanced glycation endproducts: A biomarker for age as an outcome predictor after cardiac surgery? Exp Gerontol. 427668675
8 - M. Brownlee, A. Cerami, H. Vlassara, 1988Advanced glycosylation end products in tissue and biochemical basis of diabetic complications. New Engl. J. Med. 3182013151321
9 - V. P. Reddy, A. Beyaz, 2006Inhibitors of the Maillard reaction and AGE breakers as therapeutics for multiple diseases. Drug Discov Today 11(13-14): 646-654
10 - N. Ahmed, 2005Advanced glycation endproducts-role in pathology of diabetic complications. Diabetes Res Clin Pract. 671321
11 - Stitt AW2005The maillard reaction in eye diseases. Ann N Y Acad Sci 1043582597
12 - J. M. Forbes, L. T. Yee, V. Thallas, M. Lassila, R. Candido, K. A. Jandeleit-Dahm, M. C. Thomas, W. C. Burns, E. K. Deemer, S. R. Thorpe, ME Allen. T. J. Cooper, 2004Advanced Glycation End Product Interventions Reduce Diabetes-Accelerated Atherosclerosis. Diabetes 53718131823
13 - Y. Yamamoto, T. Doi, I. Kato, H. Shinohara, S. Sakurai, H. Yonekura, T. Watanabe, K. M. Myint, A. Harashima, M. Takeuchi, S. Takasawa, H. Okamoto, N. Hashimoto, M. Asano, H. Yamamoto, 2005Receptor for advanced glycation end products is a promising target of diabetic nephropathy. Ann. N.Y. Acad. Sci. 1043562566
14 - T. Jono, T. Kimura, J. Takamatsu, R. Nagai, K. Miyazaki, T. Yuzuriha, T. Kitamura, S. Horiuchi, 2002Accumulation of imidazolone, pentosidine and N(epsilon)-(carboxymethyl)lysine in hippocampal CA4 pyramidal neurons of aged human brain. Pathol. Int. 529563571
15 - I. Boušová, D. Vukasović, D. Juretić, V. Palička, J. Dršata, 2005Enzyme activity and AGE formation in a model of AST glycoxidation by D-fructose in vitro. Acta Pharm. 55107114
16 - Ames JM1998Applications of the Maillard reaction in the food industry. Food Chem 624431439
17 - J. Hardy, M. Parmentier, J. Fanni, 1999Functionality of nutrients and thermal treatments of food. Proc Nutr Soc 583579585
18 - Chao PC, Hsu CC, Yin MC2009Analysis of glycative products in sauces and sauce-treated foods. Food Chem 113262266
19 - C. Delgado-Andrade, I. Seiquer, P. Navarro, F. J. Morales, 2007Maillard reaction indicators in diets usually consumed by adolescent population. Mol Nutr Food Res 51341351
20 - W. Zhao, P. S. Devamanoharan, S. D. Varma, 2000Fructose-mediated damage to lens α-crystallin: prevention by pyruvate. Biochim Biophys. Acta 15002161168
21 - T. Kawai, I. Takei, M. Tokui, O. Funae, K. Miyamoto, M. Tabata, T. Hirata, T. Saruta, A. Shimada, H. Itoch, 2010Effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy in patients with type 2 diabetes, in relation to suppression of Nε- carboxymethyl lysine. J Diabetes Complications 246424432
22 - Ramana KV, Srivastava SK2010Aldose Reductase: A Novel Therapeutic Target for Inflammatory Pathologies. Int J Biochem Cell Biol 4211720
23 - E. Boulanger, M. P. Wautier, J. L. Wautier, B. Boval, Y. Panis, N. Wernert, P. M. Danze, P. Dequiedt, 2002AGE binds to mesothelial cells via RAGE and stimulate VCAM-1 expression. Kidney Int 611148156
24 - E. Boulanger, N. Grossin, M. P. Wautier, R. Taamma, J. L. Wautier, 2007Mesothelial RAGE activation by AGEs enhances VEGF release and potentiates capillary tube formation. Kidney Int 712126133
25 - Schmidt AM, Yan SD, Yan SF, Stern DM2001The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responces. J. Clin. Invest 1087949955
26 - M. Naziroğlu, P. Butterworth, 2005Protective effects of moderate exercise with dietary vitamin C and E on blood antioxidative defense mechanism in rats with streptozotocin-induced diabetes. Can J Appl Physiol. 302172185
27 - Q. Zhang, J. M. Ames, R. D. Smith, J. W. Baynes, T. O. Metz, 2009A perspective on the Maillard reaction and the analysis of protein glycation by mass spectrometry: probing the pathogenesis of chronic disease. J Proteome Res 82754769
28 - A. L. Wang, A. Yu, H. Qi, X. A. Zhu, M. Tso, 2007AGEs mediates expression and secretion of TNF alpha in rat retinal microglia. Exp Eye Res 845905913
29 - B. Halliwell, 2009The wanderings of free radical. Free Radic Biol Med 465531542
30 - L. Li, G. Renier, 2006Activation of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase by advanced glycation end products links oxidative stress to altered retinal vascular endothelial growth factor expression. Metabolism 551115161523
31 - T. Inoguchi, P. Li, F. Umeda, H. Y. Yu, M. Kakimoto, M. Imamura, T. Aoki, T. Etoh, T. Hashimoto, M. Naruse, H. Sano, H. Utsumi, H. Nawata, 2000High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C-dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes 491119391945
32 - L. Xia, H. Wang, S. Munk, J. Kwan, H. J. Goldberg, I. G. Fantus, C. I. Whiteside, 2008High glucose activates PKC-zeta and NADPH oxidase through autocrine TGF-beta 1 signaling in mesanglial cells. Am. J. Physiol. 295(6): F1705F1714
33 - Lee EY, Chung CH, Kim JH, Joung HJ, Hong SY2006Antioxidants ameliorate the expression of vascular endothelial growth factor mediated by protein kinase C in diabetic podocytes. Nephrol. Dial. Transplant. 21614961503
34 - M. Edeas, 2009Anti-oxidants, controverses et perspectives: comment expliquer I’echec. J. Soc Biol 2033271280
35 - H. A. Jung, Y. J. Jung, N. Y. Yoon, da. M. Jeong, H. J. Bae, D. W. Kim, D. H. Na, J. S. Choi, 2008Inhibitory effects of Nelumbo nucifera leaves on rat lens aldose reductase, advanced glycation end products formation, and oxidative stress. Food Chem Toxicol 461238183826
36 - K. Kawanishi, H. Ueda, M. Moriyasu, 2003Aldose reductase inhibitors from the nature. Curr Med Chem. 101513531374
37 - S. Manzanaro, J. Salva, J. A. de la Fuente, 2006Phenolic marine natural products as aldose reductase inhibitors. J Nat Prod. 691014851487
38 - Thornalley PJ2003Use of aminoguanidine (Pimagedine) to prevent the formation of advanced glycation endproducts. Arch Biochem Biophys 41913140
39 - Lee GY, Jang DS, Lee YM, Kim JM, Kim JS2006Naphthopyrone glucosides from the seeds of Cassia tora with inhibitory activity on advanced glycation end products (AGEs) formation. Arch Pharm Res. 297587590
40 - V. T. Vasu, H. Modi, J. V. Thaikoottathil, S. Gupta, 2005Hypolipidaemic and antioxidant effect of Enicostemma littorale Blume aqueous extract in cholesterol fed rats. J. Ethnopharmacol. 101(1-3): 277-282
41 - M. I. Choudhary, S. Maher, A. Begum, A. Abbaskhan, S. Ali, A. Khan, Atta-ur. Shafique-ur-Rehman-Rahman, 2010Characterization and antiglycation activity of phenolic constituents from Viscum album ( European Mistletoe). Chem Pharm Bull (Tokyo) 587980982
42 - K. Tsuji-Naito, H. Saeki, M. Hamano, 2009Inhibitory effects of Chrysanthemum species extracts on formation of advaced glycation end products. Food Chem. 1164854859
43 - G. Meng, H. Zhu, S. Yang, F. Wu, H. Zheng, E. Chen, J. Xu, 2011Attenuating effects of Ganoderma lucidum polysaccharides on myocardial collagen cross-linking relates to advanced glycation end product and antioxidant enzymes in high-fat-diet and streptozotocin-induced diabetic rats. Carbohydrate Polymers 841180185
44 - B. Yang, M. Zhao, Y. Jiang, 2009Anti-glycated activity of polysaccharides of longan (Dimocarpus longan Lour.) fruit pericarp treated by ultrasonic wave Food Chem 1142629633
45 - Z. Sun, X. Peng, J. Liu, K. Fan-W, M. Wang, F. Chen, 2010Inhibitory effect of microalgal extracts on the formation of advanced glycation endproducts (AGEs). Food Chem. 1201261267
46 - Z. Sun, J. Liu, X. Zeng, J. Huangfu, Y. Jiang, M. Wang, Chen, F(2011Astaxanthin is responsible for antiglycoxidative properties of microalga Chlorella zofingiensis. Food Chem. 126416291635
47 - R. Yazdanparast, A. Ardestani, S. Jamshidi, 2007Experimental diabetes treated with Achillea santolina: Effect on pancreatic oxidative parameters.J. Ethnopharmacol. 11211318
48 - M. Miroliaei, S. Khazaei, S. Moshkelgosha, M. Shirvani, 2011Inhibitory effects of Lemon balm (Melissa officinalis, L.) extract on the formation of advanced glycation end products. Food Chem. 1292267271
49 - Babu PV, Sabitha KE, Shyamaladevi CS2008Effect of green tea extract on advaced glycation and cross-linking of tail tendon collagen in streptozotocin induced diabetic rats. Food Chem Toxicol. 461280285
50 - Ho SC, Wu SP, Lin SM, Tang YL2010Comparison of anti-glycation capacities of several herbal infusions with that of green tea. Food Chem. 1123768774
51 - E. Verzelloni, D. Tagliazucchi, D. Rio, L. Calani, A. Conte, 2011Antiglycative and antioxidative properties of coffee fractions. Food Chem. 124414301435
52 - Huang JS, Chuang LY, Guh JY, Yang YL, Hsu MS2008Effect of taurine on advanced glycation end products-induced hypertrophy in renal tubuar epithelial cells. Toxicol Appl Pharmacol. 2332220226
53 - Shin DC, Kim CT, Lee YC, Choi WJ, Na YJ2010Reduction of acrylamide by taurine in aqueous and potato chip model systems. Food Res Int 43513561360
54 - Huang KH, Pai MH, Wu CH, Liu JJ, Yeh SL(2010Supplemental dietary arginine reduces renal RAGE expression and oxidative damage in rats with streptozotocin-induced type 2 diabetes.e-SPEN 5(2): e77e84. Available:
55 - Wang ZH, Hsu CC, Huang CN, Yin MC2010Anti-glycative effect of oleanolic acid and ursolic acid in kidney of diabetic mice. Eur J Pharmacol. 628(1-3):255-260
56 - P. Manna, J. Das, J. Ghosh, P. C. Sil, 2010Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IkappaBalpha/NF-kappaB, MAPKs, and mitochondria-dependent pathways: Prophylactic role of arjunolic acid. Free Radic Biol Med. 481114651484
57 - X. Wang, L. S. Zhang, L. L. Dong, 2010Inhibitory effect of polysaccharides from pumpkin on advanced glycation end-products formation and aldose reductase activity. Food Chem. 1201261267
58 - J. Wang, B. Sun, Y. Cao, Y. Tian, 2009Protein glycation inhibitory activity of wheat bran feruoyl oligosaccharides. Food Chem. 1122350353
59 - A. Ardestani, R. Yazdanparast, 2007Cyperus rotundus suppresses AGE formation and protein oxidation in a model of fructose-mediated protein glycoxidation. Int J Biol Macromol. 415572578
60 - Bernonville. T. Dugé de, S. Guyot, J. P. Paulin, M. Gaucher, L. Loufrani, D. Henrion, S. Derbré, D. Guilet, P. Richomme, J. F. Dat, M. N. Brisset, 2010Dihydrochalcones: Implication in resistance to oxidative stress and bioactivities against advanced glycation end-products and vasoconstriction. Phytochemistry 714443452
61 - D. A. Farsi, C. S. Harris, L. Reid, S. A. Bennett, P. S. Haddad, L. C. Martineau, J. T. Arnason, 2008Inhibition of Non-enzymatic Glycation by Silk Extracts from a Mexican Land Race and Modern Inbred Lines of Maize (Zea mays). Phytother. Res. 22108112
62 - DS Yoo. N. H. Jang, N. H. Kim, Y. M. Lee, C. S. Kim, J. Kim, J. H. Kim, J. S. Kim, 2010Di-O-caffeoyl-epi-quinic acid from the leaves and stems of Erigeron annuus inhibits protein glycation, aldose reductase, and cataractogenesis. Biol Pharm Bull 332329333
63 - Ma H. Y. Gao, H. Y. Sun, L. Huang, J. Xu, X. M. Wu, L. J. , 2011Constituents with α-glucosidase and advanced glycation end-product formation inhibitory activities from Salvia miltiorrhiza Bge. J Nat Med. 6513742
64 - X. Peng, Z. Zheng, K. W. Cheung, F. Shan, G. X. Ren, S. F. Chen, M. Wang, 2008Inhibitory effect of mung bean extract and its constituents vitexin and isovitexin on the formation of advanced glycation endproducts. Food Chem. 1062457481
65 - A. Gugliucci, D. H. Bastos, J. Schulze, M. F. Souza, 2009Caffeic and chlorogenic acids in Ilex paraguariensis extracts are the main inhibitors of AGE generation by methylglyoxal in model proteins. Fitoterapia 806339344
66 - K. R. Landis-Piwowar, C. Huo, D. Chen, V. Milacic, G. Shi, T. H. Chan, Q. P. Dou, 2007A Novel Prodrug of the Green Tea Polyphenol (−)-Epigallocatechin-3-Gallate as a Potential Anticancer Agent Canser Res. 6743034310
67 - S. Mandel, O. Weinreb, T. Amit, B. H. Youdim, 2004Cell signaling pathways in the neuroprotective actions of the green tea polyphenol (-)-epigallocatechin-3-gallate: implications for neurodegenerative diseases. J. Neurochem 88615551569
68 - J. A. Vinson, J. Proch, P. Bose, S. Muchler, P. Taffera, D. Shuta, N. Samman, G. A. Agbor, 2006Chocolate Is a Powerful ex Vivo and in Vivo Antioxidant, an Antiatherosclerotic Agent in an Animal Model, and a Significant Contributor to Antioxidants in the European and American Diets. J Agric Food Chem 5480718076
69 - R. A. Kowluru, M. Kanwar, 2007Effects of curcumin on retinal oxidative stress and inflammation in diabetes. Nutr Metab. 4:8
70 - R. Tsao, 2010Chemistry and Biochemistry of Dietary Polyphenols. Nutrients 212311246
71 - My. Moridani, H. Sconbie, A. Jamshidzadeh, P. Salehi, Brien. P. J. O’, 2001Caffeic acid, chlorogennic acid, and dihydrocaffeic acid metabolism: glutathione conjugate formation. Drug Metab Dispos 2914321439
72 - Clifford MN1999Chlorogenic acids and other cinnamates-nature, occurrence and dietary burden. J Sci Food Agric 793362372
73 - S. M. Fiuza, C. Gomes, L. J. Teixeira, da. Giro, M. T. Cruz, M. N. Cordeiro, N. Milhazes, F. Borges, M. P. Marques, 2004Phenolic acid derivatives with potential anticancer properties--a structure-activity relationship study. Part 1: methyl, propyl and octyl esters of caffeic and gallic acids. Bioorg Med Chem. 121335813589
74 - H. Kikuzaki, M. Hisamoto, K. Hirose, K. Akiyama, H. Taniguchi, 2002Antioxidant properties of ferulic acid and its related compounds. J Agric Food Chem 50721612168
75 - J. Kang, Y. Liu, M. X. Xie, S. Li, M. Jiang, Y. D. Wang, 2004Interactions of human serum albumin with chlorogenic acid and ferulic acid. Biochim Biophys Acta 16742205214
76 - J. M. Silván, S. H. Assar, C. Srey, Castillo. M. Dolores del, J. M. . Ames, 2011Control of the Maillard reaction by ferulic acid. Food Chem 1281208213
77 - Lee EH, Song DG, Lee JY, Pan CH, Um BH, Jung SH2008Inhibitory Effect of the Compounds Isolated from Rhus verniciflua on Aldose Reductase and Advanced Glycation Endproduct. Biol Pharm Bull. 31816261630
78 - C. Proestos, N. Chorianopoulos, G. J. E. Nychas, M. Komaitis, 2005RP-HPLC analysis of the phenolic compounds of plant extracts. Investigation of their antioxidant capacity and antimicrobial activity. J. Agric. Food Chem.5311901195
79 - N. Yamabe, K. S. Kang, Y. Matsuo, T. Tanaka, T. Yokozawa, 2007Identification of Antidiabetic Effect of Iridoid Glycosides and Low Molecular Weight Polyphenol Fractions of Corni Fructus, a Constituent of Hachimi-jio-gan, in Streptozotocin-Induced Diabetic Rats. Biol. Pharm. Bull. 30712891296
80 - N. Yamabe, K. S. Kang, C. H. Park, H. Tanaka, T. Yokozawa, 2009O-Galloyl-D-sedoheptulose Is a Novel Therapeutic Agent against Oxidative Stress and Advanced Glycation Endproducts in the Diabetic Kidney. Biol. Pharm. Bull. 324657664
81 - J. Terao, Y. Kawai, K. Murota, 2008Vegetable flavonoids and cardiovascular disease. Asia Pac. J. Clin. Nutr. 17(S1): 291-293
82 - I. Hernández, L. Alegre, F. Van Breusegem, S. Munné-Bosch, 2009How relevant are flavonoids as antioxidant in plants? Trends Plant Sci 143125132
83 - Fraga CG2007Plant polyphenols : how to translate their in vitro antioxidant actions to in vivo conditions. IUBMB Life 59(4-5):308-315
84 - Jagtar AG, Patil PB2010Antihyperglycemic activity and inhibition of advanced glycation end product formation by Cuminum cyminum in streptozotocin induced diabetic rats. Food Chem Toxicol 48(8-9):2030-2036
85 - J. Bertoncelj, U. Doberšek, M. Jamnik, T. Golob, 2007Evaluation of the phenolic content, antioxidant activity and colour of Slovenian honey. Food Chem. 1052822828
86 - M. Blasa, M. Candiracci, A. Accorsi, M. P. Piacentini, M. C. Albertini, E. Piatti, 2006Raw Millefiori honey is packed full of antioxidants. Food Chem 97217222
87 - L. Estevinho, A. P. Pereira, L. Moreira, L. G. Dias, E. Pereira, 2008Antioxidant and antimicrobial effects of phenolic compounds extracts of Northeast Portugal honey. Food Chem Toxicol 461237743779
88 - N. Gheldof, N. J. Engeseth, 2002Antioxidant capacity of honeys from various floral sources based on the determination of oxygen radical absorbance capacity and inhibition of in vitro lipoprotein oxidation in human serum samples. J Agric Food Chem 501030503055
89 - H. Matsuda, T. Wang, H. Managi, M. Yoshikawa, 2003Structural requirements of flavonoids for inhibition of protein glycation and radical scavenging activities. Bioorg. Med. Chem. 1153175323
90 - I. Pontias, D. Treutter, J. P. Paulin, M. N. Brisset, 2008Erwinia amylovora modifies phenolic profiles of susceptible and resistant apple through its type III secretion system. Physiol. Plant. 1323262271
91 - Williams AH1964Dihydrochalcones; their occurrence and use as indicators in plant chemical taxonomy. Nature 202824825
92 - C. Gosh, H. Halbwirth, J. Kuhn, S. Miosic, K. Stich, 2009Biosynthesis of phloridzin in apple (Malus domestica Borkh). Plant Sci. 1762223231
93 - J. R. Ehrenkranz, N. G. Lewis, C. R. Kahn, J. Roth, 2005Phlorizin: a review. Diabetes Metab. Res. Rev. 2113138
94 - Messina MJ, Loprinzi CL2001Soy for breast cancer survivors: a critical review of the literature. J. Nutr. 131 (11), 30955-31085
95 - Omoni AO, Aluko RE2005Soybean foods and their benefits: potential mechanisms of action. Nutr. Rev. 638272283
96 - G. Rimbach, C. Boesh-Saadatmandi, J. Frank, D. Fuchs, U. Wenzel, H. Daniel, W. L. Hall, Peter. D. Weinberg, 2008Dietary isoflavones in the prevention of cardiovascular disease- A molecular perspective. Food Chem. Toxicol. 46413081319
97 - H. Sho, 2001History and characteristics of Okinawan longevity food. Asia Pac J Clin Nutr. 102159164
98 - W. M. Mazur, J. A. Duke, K. Wahala, S. Rasku, H. Adlercreutz, 1998Isoflavonoids and lignans in legumes: Nutritional and heath aspects in Humans. J.Nutr. Biochem 9193200
99 - Hsieh HM, Wu WM, Hu ML2009Soy isoflavones attenuate oxidative stress and improve parameters related to aging and Alzheimer’s disease in C57BL/6J mice treated with D-galactose. Food Chem Toxicol. 473625632
100 - Hsu FL, Lin IM, Kuo DH, Chen WC, Su HC, Cheng JT2003Antihyperglycemic effect of puerarin in streptozotocin-induced diabetes rats. J. Nat. Prod. 666788792
101 - F. L. Xiong, X. H. Sun, L. Gan, X. L. Yang, H. B. Xu, 2006Puerarin protects rat pancreatic islets from damage by hydrogen peroxide. Eur. J. Pharmacol. 529(1-3): 1-7
102 - Xu XH2003Effects of puerarin on fatty superoxide in aged mice induced by D-galactose. Chin. J. Chin. Master. Med. 2816669
103 - Kim J., Lee YM, Lee GY, Jang DS, Bae KH, Kim JS2006Constituents of the Root of Pueraria lobata inhibit formation of advanced glycation end products (AGEs) Arch. Pharm. Res. 2910821825
104 - Kim KM, Jung DH, Jang DS, Kim YS, Kim JM, Kim HN, Surh YJ, Kim JS2010Puerarin suppresses AGEs-induced inflammation in mouse mesangial cells: A possible pathway through the induction of heme oxygenase-1 expression. Toxicol Appl Pharmacol 2442106113
105 - Alam, Cook JL2003Transcriptional regulation of the heme oxygenase-1 gene via the stress response element pathway. Curr. Pharm. Des. 93024992511
106 - R. Tsao, J. Mc Callum, 2009Chemistry of flavonoids. In: de la Rosa L, Alvarez-Parrilla E, González-Aguilar G, editors. Fruit and Vegetable Phytochemicals: Chemistry, Nutritional Value and Stability. Blackwell Publishing: Ames, IA, USA, 131153
107 - K. M. Valant-Vetschera, E. Wollenweber, 2006Flavones and Flavonols. In: Andersen ØM, Markham KR, editors. Flavonoids: Chemistry, Biochemistry and Applications. CRC Press/Taylor & Francis Group: Boca Raton, FL, USA, 617748
108 - C. Williams, 2006Flavone and flavonol O-glycosides. In: Andersen ØM, Markham KR, editors. Flavonoids: Chemistry, Biochemistry and Applications. CRC Press/Taylor & Francis Group: Boca Raton, FL, USA, 749856
109 - M. Blonska, Z. P. Czuba, W. Krol, 2003Effect of flavone derivatives on interleukin-1beta (IL-1beta) mRNA expression and IL-1beta protein synthesis in stimulated RAW 264.7 macrophages. Scand J Immunol 572162166
110 - Yoo NH, Jang DS, Yoo JL, Lee YM, Kim YS, Cho JH, Kim JS2008Erigeroflavanone, a Flavanone Derivative from the Flowers of Erigeron annus with Protein Glycation and Aldose Reductase Inhibitory Activity. J Nat Prod. 71713715
111 - V. García-Mediavilla, I. Crespo, P. S. Collado, A. Esteller, S. Sánchez-Campos, MJ González. Tuñón-Gallego, J. , 2007The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur J Pharmacol 557(2-3):221-229
112 - Kim JM, Lee EK, Kim DH, Yu BP, Chung HY2010Kaempferol modulates pro-inflammatory NFκ-B activation by suppressing advanced glycation endproducts-induced NADPH oxidase. American Aging Association 322197208
113 - H. Y. Kim, J. M. Lee, T. Yokozawa, K. Sakata, S. Lee, 2011Protective activity of flavonoid and flavonoid glycosides against glucose-mediated protein damage. Food Chem 126892895
114 - S. Soman, AA Indira. M. Rauf, C. . Rajamanickam, 2010Antioxidant and Antiglycative Potential of Ethyl Acetate Fraction of Psidium guajava Leaf Extract in Steptozotocin-Induced Diabetic Rats. Plant Foods Hum Nutr 654386391
115 - Wu JW, Hsieh CL, Wang HY, Chen HY2009Inhibitory effect of guava (Psidium guajava L.) leaf extracts and its active compounds on the glycation process of protein. Food Chem 1137884
116 - Marzouk MS, Moharram FA, El Dib RA, El-Shenawy SM, Tawfike AF2009Polyphenolic profile and bioactivity study of Oenothera speciosa Nutt. aerial parts. Molecules 14414561467
117 - Marzouk MS, Moharram FA, Haggag EG, Ibrahim MT, Badary OA(2006Antioxidant flavonol glycosides from Schinus molle. Phytother Res. 203200205
118 - Silva C., Raulino RJ, Cerqueira DM, Mannarino SC, Pereira MD, Panek AD, Silva JFM, Menezes FS, Eleutherio ECA2009In vitro and in vivo determination of antioxidant activity and mode of action of isoquercitrin and Hyptis fasciculate. Phytomedicine 168761767
119 - S. Panda, A. Kar, 2007Antidiabetic and antioxidative effects of Annona squamosa leaves are possibly mediated through quercetin-3O-glucoside. BioFactors 31(3-4): 201-210
120 - S. Lee, H. S. Park, Y. Notsu, H. S. Ban, Y. P. Kim, K. Ishihara, N. Hirasawa, S. H. Jung, Y. S. Lee, S. S. Lim, E. H. Park, K. H. Shin, T. Seyama, J. Hong, K. Ohuchi, 2008Effects of hyperin, isoquercitrin and quercetin on lipopolysaccharide-induced nitrite production in rat peritoneal macrophages. Phytother Res. 221115521556
121 - T. Manaharan, L. L. Teng, D. Appleton, C. H. Ming, T. Masilamani, U. D. Palanisamy, 2011Antioxidant and antiglycemic potential of Peltophorum pterocarpum plant parts. Food Chem 129413551362
122 - J. Winter, L. H. Moore, V. R. Dowell, V. D. Jr Bokkenheuser, 1989C-ring cleavage of flavonoids by human intestinal bacteria. Appl. Environ. Microbiol. 55512031208
123 - A. Braune, M. Gütschow, W. Engst, M. Blaut, 2001Degradation of quercetin and luteolin by Eubacterium ramulus. Appl Environ Microbiol 671255585567
124 - H. Schneider, R. Simmering, L. Hartmann, H. Pforte, M. Blaut, 2000Degradation of quercetin-3-glucoside in gnotobiotic rats associated with human intestinal bacteria. J. Appl. Microbiol. 89610271037
125 - S. Pashikanti, D. R. de Alba, G. A. Boissonneault, D. Cervantes-Laurean, 2010Rutin metabolites: Novel inhibitors of nonoxidative advanced glycation end products. Free Radic Biol Med 485656663
126 - D. Cervantes-Laurean, D. D. Schramm, E. L. Jacobson, I. Halaweish, G. G. Bruckner, G. Boissonneault, GA(2006Inhibition of advanced glycation end product formation on collagen by rutin and its metabolites. J. Nutr. Biochem. 178531540
127 - Wu CH, Lin JA, Hsieh WC, Yen GC2009Low-Density-Lipoprotein (LDL)-Bound Flavonoids Increase the Resistance of LDL to Oxidation and Glycation under Pathophysiological Concentrations of Glucose in Vitro. J Agric Food Chem. 571150585064
128 - M. Hurabielle, J. Eberle, M. Paris, 1982Flavonoids of Artemisia campestris, ssp. glutinosa. Planta. Med. 462124125
129 - A. Memmi, G. Sansa, I. E. I. Rjeibi, M. Ayeb, N. Srairi-Abid, Z. Bellasfer, A. Fekhih, 2007Use of medicinal plants against scorpionic and ophidian venoms. Arch. Inst. Pasteur. Tunis. 84(1-4): 49-55
130 - B. Behmanesh, G. A. Heshmati, M. Mazandarani, M. B. Rezaei, A. R. Ahmadi, E. O. Ghaemi, Nosrat. S. Bakhshandeh, 2007Chemical composition and antibacterial activity from essential oil of Artemisia sieberi Besser subsp. Sieberi in North of Iran. Asian J. Plant. Sci. 63562564
131 - Hong JH, Lee IS2009Effects of Artemisia capillaris ethyl acetate fraction on oxidative stress and antioxidant enzyme in high-fat diet induced obese mice. Chem. Biol. Interact. 179(2-3): 88-93
132 - M. Sefi, H. Fetoui, M. Makni, N. Zeghal, 2010Mitigating effects of antioxidant properties of Artemisia campestris leaf extract on hyperlipidemia, advanced glycation end products and oxidative stress in alloxan-induced diabetic rats. Food Chem Toxicol. 4819861993
133 - Y. Zhang, B. Bao, B. Lu, Y. Ren, X. Tie, Y. Zhang, 2005Determination of flavone C-glucosides in antioxidant of bamboo leaves (AOB) fortified foods by reversed-phase high-performance liquid chromatography with ultraviolet diode array detection. Journal of Chromatography A 1065177185
134 - Y. Fu, Y. Zu, W. Liu, C. Hou, L. Chen, S. Li, X. Shi, M. Tong, 2007Preparative separation of vitexin and isovitexin from pigeonpea extracts with macroporous resins. Journal of Chromatography A 11392206213
135 - Grayer RJ, Veitch NC2006Flavanones and dihydroflavonols. In: Andersen ØM, Markham KR, editors. Flavonoids: Chemistry, Biochemistry and Applications. CRC Press/Taylor & Francis Group: Boca Raton, FL, USA, 9181002
136 - H. Haraguchi, Y. Mochida, S. Sakai, H. Masuda, Y. Tamura, K. Mizutani, O. Tanaka, W. H. Chou, 1996Protection against oxidative damage by dihydroflavonols in Engelhardtia chrysolepis. Biosci. Biotechnol. Biochem. 606945948
137 - L. Wirasathien, T. Pengsuparp, R. Suttisri, H. Ueda, M. Moriyas, K. Kawanishi, 2007Inhibitors of aldose reductase and advanced glycation end-products formation from the leaves of Stelechocarpus cauliflorus R.E.Fr. Phytomedicine 14546550
138 - McKay DL, Blumberg JB2002The role of tea in human health: an update. J. Am. Coll. Nutr. 211113
139 - Wu LY, Juan CC, Ho LT, Hsu YP, HwangLS(2004Effect of green tea supplementation on insulin sensitivity in Sprague-Dawley rats. J. Agr. Food Chem. 523643648
140 - Y. Kobayashi, M. Suzuki, H. Satsu, S. Arai, Y. Hara, K. Suzuki, Y. Miyamaoto, Shimizu, M(2000Green tea polyphenols inhibit the sodium dependent glucose transporter of intestinal epithelial cells by a competitive mechanism. J. Agr. Food Chem. 481156185623
141 - Waltner-Law ME, Wang XL, Law BK, Hall RK, NawanoM(2002Epigallocatechin gallate, a constituent of Green tea represses hepatic glucose production. J. Biol. Chem. 277383493334940
142 - Z. Rasheed, A. N. Anbazhagan, N. Akhtar, S. Ramamurthy, F. R. Voss, T. M. Haqqi, 2009Green tea polyphenol epigallocatechin-3gallate inhibits advanced glycation end product-induced expression of tumor necrosis factor-α and matrix metalloproteinase-13 in human chondrocytes. Arthritis Res Ther 11(3):R71
143 - Wu CH, Wu CF, Huang HW, Jao YC, Yen GC2009Naturally occurring flavonoids attenuate high glucose-induced expression of proinflammatory cytokines in human monocytic THP-1 cells. Mol Nutr Food Res 538984995
144 - S. Sang, X. Shao, N. Bai, C. Y. Lo, C. S. Yang, C. T. Ho, 2007Tea polyphenol (-)- epigallocatechin-3-gallate: A new trapping agent of reactive dicarbonyl species. Chem Res Toxicol 201218621870
145 - Wu CH, Yeh CT, Yen GC2010Epigallocatechin gallate (EGCG) binds to low-density lipoproteins (LDL) and protects them from oxidation and glycation under high-glucose conditions mimicking diabetes. Food Chem 1213639644
146 - X. Peng, K. W. Cheng, Ma J. Chen, B. Ho, C. T. Lo, C. Chen, F. Wang, M. , 2008Cinnamon Bark Proanthocyanidins as Reactive Carbonyl Scavengers To Prevet Formation of Advanced Glycation Endproducts. J Agric Food Chem 5619071911
147 - X. Peng, Ma J. Chao, J. Sun, Z. Chang, R. C. C. Tse, I. Li, E. T. S. Chen, F. Wang, M. , 2010Beneficial Effects of Cinnamon Proanthocyanidins on the Formation of Specific Advanced Glycation Endproducts and Methylglyoxal-Induced Impairment on Glucose Consumption. J Agric Food Chem 5866926696
148 - DS Lee. G. Y. Jang, Y. M. Lee, Y. S. Kim, H. Sun, D. H. Kim, J. S. Kim, 2009Flavan-3-ols Having a γ-Lactam from the Roots of Actinidia arguta Inhibit the Formation of Advanced Glycation End Products in Vitro. Chem Pharm Bull. 574397400
149 - U. Palanisamy, L. Ling, T. Manaharan, D. Appleton, 2011Rapid isolation of geraniin from Nephelium lappaceum rind waste and its anti-hyperglycemic activity. Food Chem 1272127
150 - U. Palanisamy, H. M. Cheng, T. Masilamani, T. Subramaniam, L. T. Ling, A. K. Radhakrishnan, 2008Rind of the rambutan, Nephelium lappaceum, a potential source of natural antioxidants. Food Chem 10915463
151 - X. Wang, L. Zhao, T. Han, S. Chen, J. Wang, 2008Protective effects of 2,3,5,4’-tetrahydroxystilbene-2O-β-D-glucoside, an active component of Polygonum multiflorum Thunb, on experimental colitis in mice. Eur. J. Pharmacol. 578(2-3): 339-348
152 - L. Lv, X. Gu, J. Tang, C. T. Ho, 2007Antioxidant activity of stilbene glycoside from Polygonum multiflorum Thunb in vivo. Food Chem. 104416781681
153 - L. Lv, X. Shao, L. Wang, D. Huang, C. T. Ho, S. Sang, 2010Stilbene Glucoside from Polygonum multiflorum Thunb.: A Novel Natural Inhibitor of Advanced Glycation End Product Formation by Trapping of Methylglyoxal. J. Agric. Food Chem. 58422392245
154 - J. Chompoo, A. Upadhyay, W. Kishimoto, T. Makise, S. Tawata, 2011Advanced glycation end products inhibitiors from Alpinia zerumbet rhizomes. Food Chem 129709715
155 - AA Xuan. T. D. Elzaawely, S. Tawata, 2007Essential oils, kava pyrones and phenolic compounds from leaves and rhizomes of Alpinia zerumbet (Pers.) B.L. Burtt & R.M.Sm. and their antioxidant activity. Food Chem 1032486494
156 - I. Jantan, S. M. Raweh, M. Sirat, S. Jamil, Yasin. Y. H. Mohd, J. Jalil, J. A. Jamal, 2008Inhibitory effect of compounds from Zingiberaceae species on human platelet aggregation. Phytomedicine 154306309
157 - F. Chen, 1996High cell density culture of microalgae in heterotrophic growth. Trends in Biotechnology 1411421426
158 - E. Bar, M. Rise, M. Vishkautsan, S. Arad, 1995Pigment and structural changes in Chlorella zofingiensis upon light and nitrogen stress. J Plant Pysiol 1464527534
159 - W. Miki, 1991Biological functions and activities of animal carotenoids. IJPAC 63141146
160 - Hsieh CL, Peng CH, Chyau CC, Lin YC, Wang HE, Peng RY2007Low-density lipoprotein, collagen, and thrombin models reveal that Rosemarinus officinalis L. exhibits potent antiglycative effects. J Agric Food Chem 55828842891
161 - B. Saraswat, P. K. Visen, D. P. Agarwal, 2000Ursolic acid isolated from Eucalyptustereticornis protects against ethanol toxicity in isolated rat hepatocyes. Phytother Res143163166
162 - S. Martin-Aragón, Heras. B. de Las, M. I. Sanchez-Reus, J. Benedi, 2001Pharmacological modification of endogenous antioxidant enzymes by ursolic acid on tetrachloride-induced liver damage in rats and primary cultures of rat hepatocytes. Exp Toxicol Pathol 53(2-3):199-206
163 - R. Saravanan, P. Viswanathan, V. P. Kodukkur, 2006Protective effect of ursolic acid on ethanol-mediated experimental liver damage in rats. Life Sci 787713718
164 - D. Gao, Q. Li, Y. Li, Z. Liu, Y. Fan, Z. Han, J. Li, Li, K(2007Antidiabetic potential of oleanolic acid from Ligustrum lucidum Ait. Can J PhysiolPharmacol. 851110761083
165 - P. Manna, M. Sinha, P. Pal, P. C. Sil, 2007Arjunolic acid, a triterpenoid saponin, ameliorates arsenic-induced cyto-toxicity in hepatocytes. Chem. Biol. Interact. 1703187200
166 - P. Masoko, L. K. Mdee, L. J. Mampuru, J. N. Eloff, 2008Biological activity of two related triterpenes isolated from Combretum nelsonii (Combretaceae) leaves. Nat. Prod. Res. 221210741084
167 - P. Manna, M. Sinha, P. C. Sil, 2007Protection of arsenic-induced hepatic disorder by arjunolic acid. Basic Clin. Pharmacol. Toxicol. 1015333338
168 - JD Abou. Djoukeng-Mansour, E. Tabacchi, R. Tapondjou, A. L. Bouda, H. Lontsi, D. , 2005Antibacterial triterpenes from Syzygium guineense (Myrtaceae). J. Ethnopharmacol. 101(1-3):283-286
169 - Schepetkin IA, Quinn MT2006Botanical polysaccharides: Macrophage immunomodulation and therapeutic potential. Int Immunopharmacol 63317333
170 - B. Yang, MM Shi. J. Zhao, G. P. Cheng, N. Ruenroengklin, Y. M. Jiang, 2008Variations in water-soluble saccharides and phenols in longan fruit pericarp after drying. Journal of Food Process Engineering 3116677
171 - X. P. Chen, Y. Chen, S. B. Li, Y. G. Chen, J. Y. Lan, L. P. Liu, 2009Free radical scavenging of Ganoderma lucidum polysaccharides and its effect on antioxidant enzymes and immunity activities in cervical carcinoma rats. Carbohydrate Polymers 772389393
172 - Jain SK, Rains JL, Croad JL2007Effect of chromium niacinate and chromium picolinate supplementation on lipid peroxidation, TNF-alpha, IL-6, CRP, glycated hemoglobin, triglycerides, and cholesterol levels in blood of streptozotocin-treated diabetic rats. Free Radic Biol Med 43811241131
173 - M. Ganzera, M. I. Choudhary, I. A. Khan, 2003Quantitative HPLC analysis of withanolides in Withania somnifera. Fitotherapia 74 (1-2):68-76
174 - J. Zhao, N. Nakamura, M. Hattori, T. Kuboyama, C. Tohda, K. Komatsu, 2002Withanolide derivatives from the roots of Withania somnifera and their neurite outgrowth activities. Chem. Pharm. Bull. (Tokyo) 506760765
175 - B. Jayaprakasam, G. A. Strasburg, M. G. Nair, 2004Potent lipid peroxidation inhibitors from Withania somnifera fruits. Tetraherdron 601331093121
176 - V. P. Babu, A. Gokulakrishnan, R. Dhandayuthabani, D. Ameethkhan, C. V. Kumar, M. I. Ahamed, 2007Protective effect of Withania somnifera (Solanaceae) on collagen glycation and cross-linking. Comp Biochem Physiol. Part B147308313
177 - R. C. Borrelli, V. Fogliano, 2005Bread crust melanoidins as potential prebiotic ingredients. Mol Nutr Food Res 497673678
178 - Rufian-Henares JA, Morales FJ2007Angiotensin-I converting enzyme inhibitory activity of coffee melanoidins. J Agric Food Chem 55414801485
179 - D. Tagliazucchi, E. Verzelloni, A. Conte, 2008Antioxidant properties of traditional balsamic vinegar and boiled must model systems. Eur Food Res Technol 2273835843
180 - Z. Cao, X. Chen, E. Chang, J. Du, 2009Effective Components of Chinese Herbal Compound Decoction and Maillard reaction. Clin J Integr Med. 153224228
181 - K. Brudzynski, D. Miotto, 2011The relationship between the content of Maillard reaction-like products and bioactivity of Canadian honeys. Food Chem 1243869874
182 - N. Turkmen, F. Sari, E. S. Poyrazoglu, Y. S. Velioglu, 2006Effects of prolonged heating on antioxidant activity and color of honey. Food Chem 954653657
183 - Morales FJ, Jiménez-Perez SJ2004Peroxyl radical scavenging activity of melanoidins in aqueous systems. Eur Food Res Technol 2186515520
184 - H. Einarsson, B. G. Snygg, C. Eriksson, 1983Inhibition of bacterial growth by Maillard reaction products. J Agric Food Chem 31510431047
185 - X. J. Ye, T. B. Ng, R. Nagai, 2010Inhibitory effect of fermentation byproducts on formation of advanced glycation end-products. Food Chem 121410391045
186 - Kim SS, Gallaher DD, Csallany AS2000Vitamin E and probucol reduce urinary lipophilic aldehydes and renal enlargement in streptozotocin-induced diabetic rats. Lipids 351112251237
187 - K. Kedziora-Kornatowska, S. Szram, T. Kornatowski, L. Szadujkis-Szadurski, J. Kedziora, G. Bartosz, 2003Effect of vitamin E and vitamin C supplementation on antioxidative state and renal glomerular basement membrane thickness in diabetic kidney. Nephron. Exp. Nephrol. 95(4):e134e143
188 - Y. Yoshida, Y. Saito, L. S. Jones, Y. Shigeri, 2007Chemical reactivities and physical effects in comparison between tocopherols and tocotrienols: physiological significance and prospects as antioxidants. J. Biosci. Bioeng. 1046439445
189 - A. Kuhad, K. Chopra, 2009Attenuation of diabetic nephropathy by tocotrienol: involvement of NFkB signaling pathway. Life Sci. 84(9-10): 296-301
190 - Voziyan PA, Hudson BG2005Pyridoxamine: The many virtues of a Maillard Reaction inhibitor. Ann N Y Acad Sci 1043807816
191 - N. Dicter, Z. Madar, O. Tirosh, 2002Alpha-lipoic acid inhibits glycogen synthesis in rat soleus muscle via its oxidative activity and the uncoupling of mitochondria. J. Nutr. 1321030013006
192 - Penniston KL, Nakada SY, Holmes RP, Assimos, DG2008Quantitative assessment of citric acid in lemon juice, lime juice, and commercially-available fruit juice products. J Endourol. 223567570
193 - R. Nagai, M. Nagai, S. Shimasaki, J. W. Baynes, Y. Fujiwara, 2010Citric acid inhibits development of cataracts, proteinuria and ketosis in streptozotocin (type 1) diabetic rats. Biochem Biophys Res Commun. 3931118122
194 - Tupe RS, Agte VV2010Role of zinc along with ascorbic acid and folic acid during long-term in vitro albumin glycation. Br J Nutr 1033370377
195 - Powell SR2000The antioxidant properties of zinc. J Nutr 130(5S Suupl): 1447S-1454S