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Plant-Derived Agents with Anti-Glycation Activity

Authors:
  • Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences
Chapter 10
© 2012 Odjakova et al., licensee InTech. This is an open access chapter distributed under the terms of the
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Plant-Derived Agents
with Anti-Glycation Activity
Mariela Odjakova, Eva Popova,
Merilin Al Sharif and Roumyana Mironova
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/48186
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
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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
Plant-Derived Agents with Anti-Glycation Activity 225
(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
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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:
Plant-Derived Agents with Anti-Glycation Activity 227
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 mg.ml-1 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
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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
Plant-Derived Agents with Anti-Glycation Activity 229
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
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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
Plant-Derived Agents with Anti-Glycation Activity 231
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].
Isoflavones
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
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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
Plant-Derived Agents with Anti-Glycation Activity 233
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 100µg.ml-1. 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-
Glycosylation
234
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
Plant-Derived Agents with Anti-Glycation Activity 235
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].
Glycosylation
236
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
Plant-Derived Agents with Anti-Glycation Activity 237
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
Glycosylation
238
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
Plant-Derived Agents with Anti-Glycation Activity 239
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 mg.ml-1,
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
Glycosylation
240
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)
Plant-Derived Agents with Anti-Glycation Activity 241
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
Glycosylation
242
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-
Plant-Derived Agents with Anti-Glycation Activity 243
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.
Author details
Mariela Odjakova*, Eva Popova and Merilin Al Sharif
Department of Biochemistry, Faculty of Biology, Sofia University, Bulgaria
Roumyana Mironova
Roumen Tsanev Institute of Molecular Biology at the Bulgarian Academy of Sciences, Bulgaria
Acknowledgement
This work was supported by grant DID02-31/09 from National Science Fund.
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... AGE adducts can interact with proteins and affect their normal functions and/or degrade to free AGEs and produce proteinase-resistant aggregates by forming cross-links between amino acids. [11,12] AGEs accumulate in various body tissues, including the dermis, amyloid plaques, coronary atheroma, renal cortex, basement membrane, cartilage, cardiac muscle, lungs and the liver. Therefore, increasing AGE levels in plasma has been associated with a broad range of diseases including diabetes, Alzheimer's disease, rheumatoid arthritis, atherosclerosis, etc. [13,14] Some exogenous causes have been identified as sources of AGEs including diet and smoking. ...
... Fried, baked or processed food can form AGEs during food processing which are then ingested into the human body. [12] Food with high contents of fat and protein including cheese, meat and eggs contains high levels of AGEs. Tobacco is another contributor; reactive glycation products found in tobacco smoke and extracts can react with proteins to form AGEs. [15] The signalling pathway in which AGEs enter into the cells was proposed to involve several cell surface receptors including macrophage scavenger receptors (MSR) type II, oligosaccharyl transferase-48 (OST-48), 80K-H phosphoprotein, galectin-3 (AGE-R3) and the receptor for AGEs (RAGE). ...
... [27] Types, properties and biological effects of AGEs AGEs are often fluorescent stable molecules with yellow to brown colour. [12] They remain permanently in the cells without being destroyed or secreted. They can neither be recognised, destroyed by proteasomes nor be released from the cells in which they accumulate. ...
Article
Objectives Ageing is a major cause of multiple age-related diseases. Several mechanisms have been reported to contribute to these abnormalities including glycation, oxidative stress, the polyol pathway and osmotic stress. Glycation, unlike glycosylation, is an irregular biochemical reaction to the formation of active advanced glycation end-products (AGEs), which are considered to be one of the causes of these chronic diseases. This study provides a recent and comprehensive review on the possible causes, mechanisms, types, analytical techniques, diseases and treatments of the toxic glycation end products. Key findings Several mechanisms have been found to play a role in generating hyperglycaemia-induced oxidative stress including an increase in the levels of reactive oxygen species (ROS), increase in the levels of AGEs, binding of AGEs and their receptors (RAGE) and the polyol pathway and thus have been investigated as promising novel targets. Summary This review focuses on the key mechanisms attributed to cumulative increases of glycation and pathological RAGE expression as a significant cause of multiple age-related diseases, and reporting on different aspects of antiglycation therapy as a novel approach to managing/treating age-related diseases. Additionally, historical, current and possible future antiglycation approaches will be presented focussing on novel drug delivery methods.
... Till date more than 8000 polyphenolic compounds have been identified [90] and are classified according to their chemical structure into the following as phenolic acids, flavonoid, stilbenes and lignans [91], coumarins and curcuminoids (Fig. 3). ...
... Phenolic acids are aromatic secondary metabolites and are widely distributed throughout the plant kingdom and their phenolic structure contain one or more carboxylic group. These are the most important non-flavonoid as well as non-vitamin antioxidants present in plants [91]. They have diverse functions and are found to involve in plant-microbe symbiosis or interactions. ...
... ferulic acid etc. [91]. These compounds are major polyphenols found in coffee, pineapple, strawberries, rice, wheat, oats etc. Cinnamic acid and its derivatives have been linked with prevention and management of diabetes and its complications because of its several mechanism of actions such as stimulation of insulin secretion, improvement of pancreatic β-cell functionality, inhibition of hepatic gluconeogenesis, enhanced glucose uptake, increased insulin signaling pathway, delay of carbohydrate digestion and glucose absorption, inhibition of protein glycation and insulin fibrillation [94]. ...
Article
Full-text available
Advanced glycation end products (AGEs) are naturally occurring biomolecules formed by interaction of reducing sugars with biomolecules such as protein and lipids etc., Long term high blood sugar level and glycation accelerate the formation of AGEs. Unchecked continuous formation and accumulation of AGEs are potential risks for pathogenesis of various chronic diseases. Current mode of antidiabetic therapy is based on synthetic drugs that are often linked with severe adverse effects. Polyphenolic compounds derived from plants are supposed to inhibit glycation and formation of AGEs at multiple levels. Some polyphenolic compounds regulate the blood glucose metabolism by amplification of cell insulin resistance and activation of insulin like growth factor binding protein signaling pathway. Their antioxidant nature and metal chelating activity, ability to trap intermediate dicarbonyl compounds could be possible mechanisms against glycation and AGEs formation and hence, against AGEs induced health complications. Although, few species of polyphenolic compounds are being used in in vitro trials and their in vivo study is still in progress, increasing the area of research in this field may produce a fruitful approach in management of overall diabetic complications.
... These compounds have been also reported to promote health benefits by reducing the risk of diabetes and its complications such as catechins, procyanidins, caffeic acid, chlorogenic acid, p-coumaric acid, berberine, quercetin, o-coumaric acid, ferulic acid, protocatechuic acid, quercetin, and gallic acid (Aryaeian et al., 2017;Chen et al., 2019;Omar et al., 2016;Choi et al., 2011;Ormazabal et al., 2018;Yang and Kang, 2018;Abdel-Moneim et al., 2017). Furthermore, many phenolic compounds in plant food were also found to have antioxidant activity and the ability to resist the reaction of protein glycation (Ishioka et al., 2015;Odjakova et al., 2012). This can be seen when the antioxidant activities of gallic acid, p-coumaric acid, and rutin were tested by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) free radical and the ferric reducing antioxidant power (FRAP) assays as shown in a research work of Ouffai et al. (2021). ...
Article
Full-text available
Diabetes mellitus is the most common non-infective disease characterized by hyperglycemia (high level of blood glucose). Formation of advanced glycation end products (AGEs) in long termed-hyperglycemia and oxidative stress are the key factors to accelerate diabetic complications. To screen potential candidates for treating diabetes, total phenolic content, total flavonoid content, antioxidant activity from crude extracts of some Thai edible plants were primarily assessed, and the inhibiting potential of diabetes and its complications provided from some of these plants were evaluated in terms of their inhibitory activities of α-amylase, α-glycosidase, and AGEs formation. The highest amounts of phenolic and flavonoid compounds were found in the ethanolic extract of Caesalpinia mimosoides (S20, 12.63 ± 1.70 mg GAE/g DW) and Glochidion hirsutum (S8, 3.02 ± 0.25 mg CE/g DW), respectively. The highest antioxidant activity was found in Schinus terebinthifolius Raddi (S26, 217.94 ± 32.30 μg AAE/g DW) whereas the highest inhibitory activities of α-amylase and α-glycosidase were obtained from Basella alba L. (S11, IC50 = 0.21 ± 0.01 mg/ml) and S. terebinthifolius (S26, IC50 = 0.05 ± 0.02 mg/ml) respectively. The inhibitory effects of AGEs formation were studied in vitro using two model systems: BSA-glucose and BSA-methylglycoxal (MGO). The extracts of Glochidion hirsutum (Roxb.) Voigt (S8, IC50 = 0.20 ± 0.01 mg/ml) and Polygonum odoratum Lour. (S13, IC50 = 0.03 ± 0.01 mg/ml) exhibited the inhibitory activity of AGEs formation derived from glucose (BSA-glucose system) stronger than aminoguanidine (AG) (0.26 ± 0.00 mg/ml), which is a common AGEs formation inhibitory drug. By BSA-MGO assay, the inhibition of some selected extracts in this study (G. hirsutum, G. sphaerogynum, and S. terebinthifolius with IC50 = 0.11 ± 0.01, 0.11 ± 0.01, and 0.10 ± 0.00 mg/ml, respectively) were slightly less efficient than AG (the IC50 = 0.06 ± 0.00 mg/ml). These results indicated that some selected Thai edible plants in this present study provided potential applications towards the prevention of diabetes and their complications via the inhibitory of α-amylase, α-glycosidase, AGEs formation, and oxidative stress. This fundamental information would be important for alternative drug discovery and nutritional recommendations for diabetic patients.
... They help inhibit AGEs generation and act as free radicals and metal scavengers (Yeh et al. 2017). They block free amino acid residues, thus reducing the incidence of glycation (Odjakova et al. 2012). IFA has been seen to lower plasma glucose concentration in diabetic rat models. ...
Article
Glycation refers to carbonyl group condensation of the reducing sugar with the free amino group of protein which forms Amadori products and advanced glycation end products (AGEs). These AGEs alter protein structure and function by configuring a negative charge on the positively charged arginine and lysine residues. Glycation plays a vital role in the pathogenesis of metabolic diseases, brain disorders, aging, and gut microbiome dysregulation with the aid of three mechanisms: 1) formation of highly reactive metabolic pathway-derived intermediates which directly affect protein function in cells, 2) the interaction of AGEs with its associated receptors to create oxidative stress causing the activation of transcription factor NF-κB, and 3) production of extracellular AGEs hinders interactions between cellular and matrix molecules affecting vascular and neural genesis. Therapeutic strategies are thus required to inhibit glycation at different steps, such as blocking amino and carbonyl groups, Amadori products, AGEs-RAGE interactions, chelating transition metals, scavenging free radicals, and breaking crosslinks formed by AGEs. The present review focused on explicitly elaborating the impact of glycation-influenced molecular mechanisms in developing and treating non-communicable diseases.
... Glycation process occurs through oxidation, dehydration and cyclization reactions, and irreversible compounds, called advanced glycation end products (AGEs). During healthy aging, AGEs are formed at accelerated rates in diabetes, and also as causative factors for pathogenesis of diabetes, neurodegenerative disease, and cataracts [120]. ...
Article
Full-text available
A cataract is a condition that causes 17 million people to experience blindness and is the most significant cause of vision loss, around 47.9%. The formation of cataracts is linked to both the production of reactive oxygen species (ROS) and the reduction of endogenous antioxidants. ROS are highly reactive molecules produced by oxygen. Examples of ROS include peroxides, super-oxides, and hydroxyl radicals. ROS are produced in cellular responses to xenobiotics and bacterial invasion and during mitochondrial oxidative metabolism. Excessive ROS can trigger oxidative stress that initiates the progression of eye lens opacities. ROS and other free radicals are highly reactive molecules because their outer orbitals have one or more unpaired electrons and can be neutralized by electron-donating compounds, such as antioxidants. Examples of natural antioxidant compounds are vitamin C, vitamin E, and beta-carotene. Numerous studies have demonstrated that plants contain numerous antioxidant compounds that can be used as cataract preventatives or inhibitors. Natural antioxidant extracts for cataract therapy may be investigated further in light of these findings, which show that consuming a sufficient amount of antioxidant-rich plants is an excellent approach to cataract prevention. Several other natural compounds also prevent cataracts by inhibiting aldose reductase and preventing apoptosis of the eye lens.
... Oral hypoglycemic agents containing benzoic acid derivatives have recently been introduced for the treatment of type 2 diabetes. They can help to mitigate the formation of AGEs, as well as glucose levels and oxidative stress [273]. Furthermore, they have been shown to restore natural amounts of serum creatinine and urinary proteins. ...
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Non-enzymatic reaction involving carbonyl of reducing sugars and amino groups in proteins produces advanced glycation end products (AGEs). AGE accumulation in vivo is a crucial factor in the progression of metabolic and pathophysiological mechanisms like obesity, diabetes, coronary artery disease, neurological disorders, and chronic renal failure. The body's own defense mechanism, synthetic inhibitors, and natural inhibitors can all help to prevent the glycation of proteins. Synthetic inhibitors have the potential to suppress the glycation of proteins through a variety of pathways. They could avoid Amadori product development by tampering with the addition of sugars to the proteins. Besides which, the free radical scavenging and blocking crosslink formation could be another mechanism behind their anti-glycation properties. In comparison with synthetic substances, naturally occurring plant products have been found to be comparatively non-toxic, cheap, and usable in an ingestible form. This review gives a brief introduction of the Maillard reaction; formation, characterization and pathology related to AGEs, potential therapeutic approaches against glycation, natural and synthetic inhibitors of glycation and their probable mechanism of action. The scientific community could get benefit from the combined knowledge about important molecules, which will further guide to the design and development of new pharmaceutical compounds.
... In the Plectranthus genus, common triterpenes have been isolated, such as UA (Lukhoba et al., 2006) OA (Dellar et al., 1996), betulin, and betulinic acid. Triterpenic acids exhibit important biological and pharmacological activities, including anti-inflammatory, antimicrobial, antiviral, cytotoxic, and cardiovascular effects (Lin et al., 2002;Odjakova et al., 2012). UA (Lukhoba et al., 2006) and OA (Dellar et al., 1996) are isomeric triterpenic acids that only differ in the position of the Frontiers in Pharmacology | www.frontiersin.org ...
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Ethnopharmacological Relevance: Plectranthus genus ( Lamiaceae family) contain several species with acknowledged ethnopharmacological uses, such as, for gastrointestinal and respiratory-related problems, due to their anti-inflammatory, antibacterial and antifungal properties. The bioactivity of isolated medicinal compounds from this genus justifies the increased interest in recent times for species of Plectranthus , placing them in the spotlight for natural product drug development. Aim of the study: To the best of our knowledge, this is the first review on the biological activities of Plectranthus ecklonii Benth. As such, the aim of this review was three-fold: 1) to summarize the chemical compounds isolated from P. ecklonii ; 2) to collate the biological activities and mechanisms of action of these compounds from in vitro studies; and 3) to evaluate the documented uses and potential applications of this species, in order to postulate on the direction of pharmaceutical uses of this species. Materials and methods: An extensive database retrieval was performed using the electronic databases Web of Science, PubMed, Google Scholar and ScienceDirect. The search criteria consisted of the keywords “ Plectranthus ecklonii ”, “ Plectranthus ecklonii + review”, “ Plectranthus ecklonii + diterpenes” or “ Plectranthus ecklonii + abietanes”, “ ecklonii + parviflorone D”, searched individually and as combinations. Eligibility criteria were set out and titles in English, Portuguese and Spanish were reviewed, with all references included dating from 1970 to 2021. A total of 169 papers were selected and included. Chemical structures were drawn using ChemDraw 20.0, CID numbers were searched in PubChem and the PRISMA diagram was created using PowerPoint 2012. Results: To date, a total of 28 compounds have been isolated from P. ecklonii , including diterpenes, triterpenes, flavonoids, and hydroxycinnamic acids. Most focused on the antimicrobial action of its constituents, although compounds have demonstrated other bioactivities, namely antioxidant, anti-inflammatory and antitumor. The most recent studies emphasize the diterpenoids, particularly parviflorone D, with the help of nanotechnology. Conclusions: The widespread ethnobotanical and traditional uses of P. ecklonii can be scientifically justified by a range of biological activities, demonstrated by isolated secondary metabolites. These bioactivities showcase the potential of this species in the development of economically important active pharmaceutical ingredients, particularly in anticancer therapy.
... The selection of extraction mode has an impact on biological activity too. All the antidiabetic models showed that methanol extracts of all parts at ambient temperature exhibited potent antidiabetic activity, which may be attributed due to the presence of higher flavonoids and terpenoids contents (Hanhineva et al., 2010;Odjakova et al., 2012;Al-Ishaq et al., 2019). The polyphenolic and tannins may also exhibit a synergic effect at ambient temperature. ...
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Context: The extraction mode plays a key role in extracting a particular type of pharmacologically active compounds that can be isolated as leads to develop novel therapeutic molecules. Aims: To evaluate the impact of extraction mode on extract yield, phytochemicals constituents, and antidiabetic activity of different parts of the Calotropis procera. Methods: The different parts extracts were prepared by maceration and Soxhlet extraction. The resulting extracts were subjected to determining phytochemical constituents and antidiabetic activity using in vitro models (inhibition of alpha-amylase, glucose uptake by yeast cell, and inhibition of non-enzymatic Hb-glycation). Result: The yield of extracts was higher in Soxhlet extraction in both solvents compared to maceration. Likewise, methanol extract of all the parts prepared by Soxhlet extraction exhibited higher contents of total polyphenols and tannins (430.2 ± 0.99 and 228.3 ± 3.8, respectively). On the other hand, total flavonoids and terpenoids were more in all parts prepared by maceration. The extract of flower and stem prepared by maceration exhibited 64.87 ± 0.720%, 70.32 ± 0.75%, and 56.86 ± 0.13% antidiabetic activity in alpha-amylase enzyme, non – enzymatic Hb glycation inhibition, and glucose enhancement in yeast, respectively (p<0.05) as compared to standards. The IC50 of alpha-amylase inhibitory assay and non-enzymatic Hb-glycation was 600 µg/mL and 420 µg/mL, respectively, and EC50 for glucose uptake assay was 400 µg/mL. Conclusions: This study revealed that maceration extracts with higher flavonoid and terpenoid content have higher antidiabetic action than Soxhlet extracts. This study will assist in the future for the isolation of antidiabetic compounds from the plant.
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The fortification of yogurt with natural herbs to improve its nutritional and health benefit are an emerging trend. Hot infusions of Nyctanthes abo-tristis flowers are a traditionally used herb against diabetes. This study was designed to develop a novel yogurt fortified (FY) with 3, 3.5, and 6% N.arbor-tristis flower extract (NFE) to determine its suitability as a fortifier en route to innovative functional products. Upon fermentation, the highest sensory scores were obtained for the 3.5% NFE-FY with 11-, 6-, 3-fold higher antiglycation (NFE- IC50: 28.04 ± 1.13 μg/mL and 3.5% NFE-FY IC50: 46.80 ± 0.92 μg/mL) activity, free radical scavenging potentials, and total phenolic content, respectively. An improvement of texture profile values was observed in 3.5% NFE-FY compared to the control with 3.00 ± 0.1% fat, 3.88 ± 0.23% crude protein, 77.94 ± 0.09 moisture, 14.97 ± 0.27 total soluble solids, and 0.7637 ± 0.03 ash. The 3.5%NEF-FY also exhibited a longer shelf life and less microbial growth than the control. The GC-MS analysis of the NFE indicated the presence of phytochemicals essential for the observed bioactivity. The results confirmed that the N.arbor-tristis flower extract increased the overall quality of the yogurt and tested bioactivity. NFE-FY could be used in yogurt production to optimize the health benefits with improved functional characteristics to prevent diet-driven glycation activity.
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Proteins undergo continuous changes under the action of various intrinsic and extrinsic factors, leading to alteration of several intracellular metabolic pathways and the development of various clinical disorders. Non-enzymatic glycosylation is one of the main factors responsible for the progression of diabetic complications and the aging process. Although there are currently many effective therapies in the prevention and treatment of these diseases, in the last decade, there has been an increasing trend of replacing synthetic drugs by natural compounds, in order to reduce the side effects that may occur and the production costs. It is well known that aspirin (acetylsalicylic acid) inhibits the glycation process of serum proteins by acetylating N-terminal amino groups and lysine residues in their structure. Therefore, the main purpose of our research was to analyze the non-enzymatic glycation and fructation process of hemoglobin through spectrometric and electrophoretic techniques, in order to reveal how this process could influence the three-dimensional structure and biological function of the protein, and the effect of some natural aspirin-like compounds on the peroxidase and esterase activity of hemoglobin during fructose and glucose binding. In this way, a preliminary phytochemical characterization of a bark extract of white willow (Salix alba) was performed in order to evaluate the content of total phenolics, flavonoids, and salicylic derivatives, as well as the antioxidant activity. Then, human erythrocytes isolated from whole peripheral blood were incubated with different concentrations of fructose/glucose (10, 50, 100 mM) and S. alba extract for 5, 7, 10 and 14 days. The results obtained from the THz spectra confirmed that fructose was more reactive than glucose, so the glycation process took place more slowly than fructation. Also, the presence of S. alba extract showed an antiglycosylating effect, but not a total inhibition of the glycation process. In addition, enzymatic determinations proved that willow bark extract restored the peroxidase and esterase activities to the control levels. Our data indicated that salicylic compounds can be successfully used as substitutes for aspirin, one of the main synthetic compounds with anti-inflammatory and anti-glycosylating roles. Salicin, salicylic acid and other salicylic compounds possess strong antioxidant properties, which give them the ability to participate in the glycosylation process to block the formation of advanced glycation end products (AGEs).
Article
Tea is an important dietary source of flavanols and flavonols. In vitro and animal studies provide strong evidence that tea polyphenols may possess the bioactivity to affect the pathogenesis of several chronic diseases, especially cardiovascular disease and cancer. However, the results from epidemiological and clinical studies of the relationship between tea and health are mixed. International correlations do not support this relationship although several, better controlled case-referent and cohort studies suggest an association with a moderate reduction in the risk of chronic disease. Conflicting results between human studies may arise, in part, from confounding by socioeconomic and lifestyle factors as well as by inadequate methodology to define tea preparation and intake. Clinical trials employing putative intermediary indicators of disease, particularly biomarkers of oxidative stress status, suggest tea polyphenols could play a role in the pathogenesis of cancer and heart disease.
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This paper summarises the occurrence in foods and beverages of the cinnamic acids, their associated conjugates and transformation products. Quantitative data are lacking for some commodities known to contain them, but it is clear that for many people coffee will be the major source. The daily dietary intake of total cinnamates may vary substantially from almost zero to perhaps close to 1 g. The data relating to their absorption and metabolism are presented along with a consideration of their possible in vivo effects. Data for true bioavailability are incomplete: in particular it is not clear whether availability differs markedly with the form of the conjugate, and whether as a consequence some dietary sources may be superior to others. (C) 2000 Society of Chemical Industry.
Chapter
By 1975, some 360 flavone and flavonol glycosides were known to occur in the plant kingdom (Harborne and Williams, 1975). In the following five years, this number doubled so that some 720 structures were listed in our first supplement (Harborne and Williams, 1982). The pace of discovery during 1981–1985 has not slowed down and we now list at the end of this book nearly a thousand substances. This is a conservative estimate in the sense that a number of partly characterized glycosides, which probably differ in mode of linkage or in the type of sugar configuration from those reported here, have been described but are not included in our lists. It is to be regretted that some investigators still do not characterize their glycosides with the necessary rigour to establish the structures unambiguously. As before, the term ‘glycoside’ is used in its widest sense and we include here flavones and flavonols which are acylated and sulphated as well as glycosylated.
Chapter
In this chapter, emphasis is given to the natural distribution of flavones and flavonols occurring in the free state. The relevant data are compiled in Tables 7.1–7. 7. In all, these tables list over 200 flavones and almost 300 flavonols with simple hydroxyl (or methoxyl) substitution patterns (Tables 7.1 and 7.2), thus stressing the earlier observation that flavonols predominate over flavones. Further, these tables contain more than 160 compounds with extra substituents (including compounds shown in Figs 7.3 and 7.4). Since the data for the previous edition (Wollenweber, 1982a) were compiled, some 40 flavones and 50 flavonols of the usual type have been reported as novel natural products (Tables 7.1 and 7.2), and some 50 novel flavonoids with extra substituents have also been added (Tables 7.3–7.7 and Figs 7.3 and 7.4).
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The rind of rambutan, which is normally discarded was found to contain extremely high antioxidant activity when assessed using several methods. Although having a yield of only 18%, the ethanolic rambutan rind extract had a total phenolic content of 762 +/- 10 mg GAE/g extract, which is comparable to that of a commercial preparation of grape seed extract. Comparing the extract's pro-oxidant capabilities with vitamin C, alpha-tocopherol, grape seed and green tea, the rind had the lowest pro-oxidant capacity. In addition. the extract at 100 mu g/ml was seen to limit oxidant-induced cell death (DPPH at 50 mu M) by apoptosis to an extent similar to that of grape seed. The extracts were not cytotoxic to normal mouse fibroblast cells or splenocytes while the powderised rind was seen to have heavy metals contents far below the permissible levels for nutraceuticals. Our study for the first time reveals the high phenolic content, low pro-oxidant capacity and strong antioxidant activity of the extract from rind of Nephelium lappaceum. This extract, either alone or in combination with other active principles, can be used in cosmetic, nutraceutical and pharmaceutical applications. (c) 2007 Elsevier Ltd. All rights reserved.