Introduction
Today, age-related chronic inflammatory diseases like type 2 diabetes mellitus and
cardiovascular diseases represent major health problems [1]. The prevalence of those conditions is exponentially increasing as the population
ages [2]. Therefore, prevention is of the highest importance and has a medical and economic
impact. Not surprisingly, future strategies are focusing on the identification of
individuals at risk for developing chronic complications using novel biomarkers for
pathophysiological pathways (i.e., to improve risk prediction) [2]. Various mechanisms have been proposed to explain the causes for the initiation
and progression of chronic diseases, and on a biochemical level, experimental and
histological data suggest that protein glycation-formation of AGEs, correlates with
many pathological complications [3], [4], [5]. The term glycation is defined as the spontaneous, nonenzymatic reaction of glucose
or other reducing sugars with an amino group of proteins, lipids, and nucleic acids
[6]. Protein glycation occurs predominantly on lysine, arginine, and N-terminal residues of proteins. It involves series of complex reactions, and it is
considered a post-translational modification of proteins found in biological systems
[6], [7]. In particular, AGEs are complex, heterogeneous, sugar-derived protein modifications
that have been implicated in the pathogenesis of diabetic complications, Alzheimerʼs
disease, and the process of normal aging [8], [9], [10]. Additionally, important physiological glycating agents apart from glucose are dicarbonyl
metabolites, particularly GO, MGO, and 3-DG [11].
The classical pathway (Hodge pathway) for AGEs formation can be generally subdivided
into 3 stages: initiation, propagation, and an advanced stage ([Fig. 1]). AGEs formation usually takes several days to several weeks to complete due to
the lack of enzymatic catalysis during the process. In the first step (initiation),
reducing sugars (aldoses and ketoses) react with amino groups via a nucleophilic addition,
resulting in aldimines and ketoimines (Schiff bases). Subsequently, through acid-base
catalysis, the unstable and reversible Schiff base undergoes Amadori or Heyns rearrangements,
resulting in 1-amino-deoxyketosyl or 2-amino-deoxyaldos-2-yl adducts (relatively stable
Amadori or Heyns products) [12], [13], [14]. During the propagation phase, the Amadori products can be transformed (within weeks)
into reactive dicarbonyl products. They initiate glycation by
undergoing further nonoxidative dehydration and rearrangement reactions to dicarbonyl
compounds, including 3-DG, GO, and MGO. While 3-DG is formed by nonoxidative rearrangement
and hydrolysis of Amadori product ([Fig. 1]), MGO and GO can be produced in several additional pathways (see further). Alternatively,
Amadori products can generate amines through metal-ion-mediated catalysis and oxidation,
while the glycosyl group is dehydrated to form deoxyglucosone (DG). Further on, these
early glycation products are highly prone to oxidative (glycoxidation) and nonoxidative
degradation, cleavage, and covalent binding, leading to a heterogeneous group of stable
compounds and cross-linking of proteins, commonly called AGEs. In particular, the
advanced stage is characterized by intermolecular or intramolecular heterocyclic cross-linking
and fragmentation that occurs in the protein molecules, leading to protein denaturation
and irreversible damage.
Fig. 1 General scheme of the Advanced Glycation Endproducts (AGEs) formation pathway (Hodge
pathway) going through Schiff base and Amadori product formation. However, AGEs can
be formed by pre- and post-Amadori product reactions, and in such a way that the Amadori
product is not a precursor. Alternatively, the reactive dicarbonyl species can be
formed directly from Schiff base degradation (Namiki pathway) or through the metal-catalyzed
autoxidation of reducing sugar (Wolff pathway).
Meanwhile, AGEs can also be formed from Amadori products directly through rearrangement
under both oxidative and nonoxidative conditions. In the oxidative pathway (Namiki
pathway), the unstable initial products (Schiff bases) can be directly converted to
oxoaldehydes (glycoxidation) [15]. Additionally, the Wolff pathway describes the metal-catalyzed autoxidation of reducing
sugars that leads to AGEs formation [16], [17]. The products from both pathways are dicarbonyl intermediates (MGO, GO, 3-DG) and
free radicals. Moreover, the oxidation of polyunsaturated fatty acids (lipoxidation
pathway) can also lead to GO or MGO formation, apart from the general ALEs. AGEs can
be formed by pre- and post-Amadori product reactions, and in such a way that the Amadori
product is not a precursor. Therefore, AGEs are generated in both the early and late
stages of glycation processes. Nevertheless, the
concept of early and advanced glycation adducts simplifies the whole process but
ensures a possibility of classifying the different glycation products [6].
Pathophysiological Role of AGEs
AGEs formation takes place under normal physiological conditions, but the equilibrium
can be shifted in a state of hyperglycemia [25]. Therefore, they are referred to sometimes as glycotoxins because they can be toxic
to the body when present for a prolonged period [26]. Most AGEs accumulate with age in long-lived tissue proteins like lens crystallins
and collagen due to their slow formation rate [27], [28]. Despite a belief that AGEs accumulate only on long-lived extracellular proteins,
rapid extracellular AGEs formation on short-lived proteins and intracellular AGEs
formation by reactive dicarbonyl compounds have recently become major topics of research
interest [28]. In general, the pathophysiological effects of AGEs can be related to several mechanisms
of action: (i) oxidative stress; (ii) carbonyl stress; and (iii) interaction
with RAGE on the cell surface [29], [30], [31]. To begin with, oxidative stress can lead to the damage of various cell components
and the activation of specific signaling pathways like nuclear factor-κB (NF-κB) ([Fig. 3]). In general, the hypothesis of cellular damage (to cardiac muscle and neuronal
cells) associated with age-related diseases and explained by excessive oxidative stress
was formulated a long time ago. However, novel pharmaceutical targets have been characterized
lately, opening new research challenges. A relatively new field of interest is carbonyl
stress, an imbalance of RCS production and carbonyl scavenging mechanisms. An important
step in the glycation reaction is the generation of reactive intermediate products
during all stages and pathways of glycation. For example, Schiff bases are highly
prone to oxidation and free
radical generation, which lead to the formation of RCS such as GO, MGO, and 3-DG.
Compared to ROS, these aldehydes are more stable and diffuse within or even escape
from the cell and attach to targets far away from their site of formation. The phenomenon
accelerates in diabetes and glycemia. Through the generation of ROS and RCS, AGEs
contribute to tissue injury by alteration of extracellular matrix structures through
the formation of protein cross-links and alteration of intracellular short-lived proteins
like metabolic enzymes and mitochondrial protein complexes [32]. Inside cells, the impact of glycation is countered by the high turnover and short
half-life of many cellular proteins. Long-lived extracellular proteins, however, accumulate
glycation adducts with age. Extracellular degraded glycated proteins are recognized
by specific receptors [33]. Multiple receptor independent and dependent pathways linking AGEs
to cellular and tissue dysfunction have been proposed [34]. So far, it is well-understood that the interaction between AGE-modified proteins
and RAGEs on the cell surface induces the overproduction of ROS and inflammatory mediators,
which leads to cellular disorder in biological systems [35]. The receptors are weakly expressed in vascular cells, smooth muscle cells, fibroblasts,
and monocyte/macrophages. The link between RAGE and its ligands triggers a cascade
of intracellular events, followed by the transcription of a range of genes involved
in different biological systems, as well as other reactions such as the induction
of oxidative stress ([Fig. 3]). All of these reactions lead to a series of functional changes that participate
in neurological and vascular complications (micro- and macrovasculopathies) in diabetes,
metabolic syndrome, etc. [23], [36]. There is a considerable body of evidence that the formation and accumulation of
AGEs are implicated as a major factor in the progression of various pathological conditions,
such as atherosclerosis, diabetic retinopathy, nephropathy, neuropathy, wound healing,
and Alzheimerʼs disease (see [Fig. 3]).
Fig. 3 Pathophysiological significance of protein glycation. Interaction of AGEs with RAGE
causing oxidative stress and initiating inflammation cascade that involves NF-κB activation; IL-2, IL-6, TNF-α synthesis; and cross-linking formation which lead to the development of micro- and
macrovasculopathies implicated in atherosclerosis, diabetic nephropathy, retinopathy,
neuropathy, and wound healing.
Hyperglycemia results in an accumulated amount of AGEs in the blood vessels, which
induces proliferation of smooth muscle cells, thickening of the intima (plaque formation
and sedimentation), and rigidity and stiffness of the vessels. Moreover, AGEs stimulate
foam cell formation by lipid and protein glycosylation. The LDLs are not discarded
in the normal way and then accumulate in the monocytes to form foam cells. The reason
for this is that the LDL receptor does not recognize the glycated LDLs. The AGE-RAGE
complex induces atherosclerosis by enhanced expression of VCAM-1 on the endothelial
cells and the production of cytokines. As a result, VCAM-1 promotes the adhesion of
the monocytes to the endothelial cells. Then, the monocytes differentiate into macrophages
that transform into foam cells by lipid uptake. Generally, pathological glycation
of collagen is the major cause of tissue dysfunction due to cross-linking that could
cause decreased elasticity and increased
thickness and rigidity of the vessel lumen. As a result, the vascular damage associated
with diabetes is the key for microvascular complications like neuropathy, nephropathy,
and retinopathy [37]. The AGE-RAGE complex increases the production of cytokines (IL-2, IL-6) and growth
factors (TNF-α) ([Fig. 3]) that are responsible for the development of macrovascular complications like generalized
atherosclerotic plaques. Additionally, during the glycoxidative stress, NF-κB activates the production of TNF-α, which leads to enhanced ROS production; in other words, AGEs formation continues
oxidative stress ([Fig. 3]) [32].
Retinopathy is the major cause of blindness in diabetic patients. The accumulation
of AGEs leads to thickening of the capillary basement membrane, enhanced permeability
of the capillaries, and apoptosis of pericytes. Hyperglycemia stimulates an excessive
expression of RAGE on pericytes and endothelial cells, causing deterioration of the
pericytes. The loss of pericytes is the clinical expression of retinopathy. Moreover,
a high level of AGEs in retinal cells includes the expression of vascular endothelial
growth factor, which destroys the blood-retinal barrier, and microvascular hyper-permeability,
which finally leads to blindness or poor vision [38].
Diabetic nephropathy, which is considered the most life-threatening condition in diabetic
patients, is associated with basal membrane thickening and decreased filtration [39]. The sedimentation of proteins in the glomerular space plays a significant role
in the reduction of filtration. AGEs stimulate an extreme RAGE expression that encourages
cell inflammation signaling pathways, such as NF-κB activation, as well as the generation of cytokines and growth factors. The TGF-β increases the synthesis of collagen matrix components, which leads to the greater
thickness of the basement membrane, increased vascular permeability, and reduced barrier
activity [40]. Further evidence for glomerular injuries comes from immunohistochemical studies
that have identified several AGEs such CML, pyrraline, and pentosidine in renal tissues
of diabetic patients [41].
In general, diabetes can affect the central, peripheral, and autonomic systems. The
manifestation of diabetic neuropathy can be characterized by functional abnormalities
(reduced blood flow) and structural changes like axonal degeneration, fiber demyelination,
and neuronal apoptosis. Particularly, AGEs react with plasma proteins like IgM and
IgG to activate the demyelination of the peripheral neurons. The complex AGE-RAGE
induces ROS formation and several intercellular signaling pathways. ROS promotes both
AGEs formation and AGEsʼ quenching of NO. Consequently, the NO level in the cells
is decreased, which results in nerve ischemia (lack of oxygen) and then nerve dysfunction
[42].
Wound healing in diabetic patients is hindered by the AGE-RAGE complex, which stimulates
the production of pro-inflammatory factors resulting in collagen degradation [43].
The increased number of AGEs can cause extensive cross-linking, oxidative stress,
and neuronal cell death representing the neuropathological and biochemical characteristics
of Alzheimerʼs disease, hampering the function of proteins or tissues [44].
AGEs Inhibitors
Today, there is an increased interest in agents with antiglycation activity that could
play a key role in the prevention and amelioration of AGE-mediated health problems.
The currently known AGEs inhibitors can be generally divided into 2 groups: synthetic
compounds and natural products.
Synthetic compounds
According to a previous review that investigated the current clinical therapies with
anti-AGEs effects, the applied agents can be summarized in several groups ([Table 2]) [28]. The inhibition of free radical generation, which is derived from glycation processes
and inhibition of protein modification, is considered a mechanism of antiglycation
activity. Much data have shown that typical antioxidants/nutrients such as (5) vitamin
B1 (thiamine) and (4) B6 (pyridoxamine) inhibit in vitro and in vivo AGEs formation [51]. Another preventive or therapeutic approach is to use nucleophilic anti-RCS molecules
such as (1) aminoguanidine, pyridoxamine, or (7) metformin. They could inhibit AGEs,
remove RCS, and prevent the interaction of AGEs with RAGE. Despite the reported inhibitory
capacity against AGEs formation, many synthetic inhibitors have been withdrawn from
clinical trials
due to relatively low efficacy, poor pharmacokinetics, and unsatisfactory safety
[52].
Table 2 Synthetic inhibitors of AGEs formation based on their mechanism of action or their
chemical structure.
|
Drug class
|
Compound
|
Stage of glycation
|
Mechanism of action
|
References
|
|
Specific AGEs inhibitors and AGEs breakers
|
 
(1) Aminoguanidine
|
late stage
|
Trapping α-dicarbonyl intermediates by nucleophilic reaction (carbonyl-scavenging activity).
|
[89], [91], [95], [96], [97], [98], [99]
|
(2) Alagebrium chloride (ALT-711)
|
late stage
|
Chemical cleavage of the carbon-carbon bond in α-dicarbonyl-containing cross-linked structures.
|
[28], [45], [97]
|
(3) N-phenacylthiazolium bromide (PTB)
|
late stage
|
Reacting with and cleaving covalent AGEs-derived protein cross-links.
|
[45]
|
|
B vitamins and synthetic derivatives of B vitamins
|
(4) Pyridoxamine (vitamin B6)
|
late stage
|
Blocking the oxidative degradation of glucose-derived Amadori intermediates by binding
catalytic metal ions interferes with the post-Amadori oxidative reactions or quenching
dicarbonyl compounds.
|
[91], [100], [101]
|
(5) Thiamine pyrophosphate, benfotiamine (synthetic derivative)
|
late stage
|
Benfotiamine shunts the triose glycolytic intermediates toward the reductive pentose
pathway.
|
[40], [91], [97], [102]
|
|
Aldose reductase inhibitors
|
(6) Epalrestat
|
multistage inhibitor
|
Trapping 3-DG and inhibiting the CML formation.
|
[28], [103]
|
|
Glucose-lowering medications
|
(7) Metformin
|
multistage inhibitor
|
Trapping MGO and other dicarbonyls.
|
[91], [104], [105]
|
|
Blood pressure-lowering medications
|
Calcium antagonists
|
(8) Amlodipine
|
late stage
|
Radical scavenging properties, inhibiting the production of dicarbonyl precursors
by chelation of metal ions, and blocking hydroxyl radicals at the pre-Amadori step.
|
[106]
|
|
ACE inhibitors
|
(9) Captopril
|
late stage
|
Inhibiting the formation of fluorescent AGEs (pentosidine).
|
[92], [107]
|
|
AIIRIs
|
(10) Olmesartan
|
late stage
|
Inhibiting the formation of fluorescent AGEs (pentosidine).
|
[92]
|
|
Lipid-lowering medications
|
(11) Simvastatin
|
late-stage
|
Antioxidant properties, consequently decreasing the lipid peroxidation and the AGEs
production.
|
[28]
|
|
Medications against rheumatic diseases
|
(12) Methotrexate
|
late stage
|
Decreasing serum and urinary pentosidine levels.
|
[28]
|
|
Weight-reduction therapies
|
(13) Orlistat
|
late stage
|
Decreasing the level of serum AGEs, urinary pentosidine, and serum CML.
|
[28]
|
|
NSAIDs
|
(14) Diclofenac
|
early stage
|
Blocking sugar attachment to proteins due to noncovalent binding.
|
[48], [91], [92]
|
(15) Acetylsalicylic acid
|
early stage
|
Blocking the attachment of reducing sugars to proteins due to acetylating the free
amino groups.
|
[45], [91]
|
|
Antidiabetic thiazolidinedione
|
(16) Pioglitazone
|
early stage
|
Inhibiting glycation and AGEs formation due to direct interaction between the hydrazine
nitrogen atom of pioglitazone and a carbonyl group; antioxidant effects.
|
[46], [89], [108]
|
|
Agents against diabetes-induced peripheral vascular diseases
|
(17) Pentoxifylline
|
early stage
|
Moderate activity for inhibiting glycation related to antioxidant properties.
|
[91]
|
Natural products
Current studies attempt to search for effective phytochemical compounds from dietary
plants, fruits, and herbal medicines to inhibit AGEs formation [53]. In the past 3 decades, there has been a significant increase in the anti-AGEs agents
from natural origin. The rate of scientific publications tripled during this time.
In the current review, the references were selected by a search of papers retrieved
using Web of Science for the period 1990 – 2019 and the keywords “natural products”
and “AGEs” ([Fig. 5]).
Fig. 5 Publication frequency in the research of natural products as potential inhibitors
of AGEs over the period 1990 – 2019. The database used was Web of Science and the
search terms were: “natural products” and “AGEs”, which reviled a total count of 4.251
publications.
Considering the toxic or side effects of synthetic molecules in clinical trials, natural
products can be more promising candidates as potent AGEs inhibitors. Phytochemicals
exhibit several antiglycation mechanisms, including effects on glucose metabolism,
amelioration of oxidative stress, scavenging of dicarbonyl species, and up/down-regulation
of gene expression [54]. So far, some plant extracts and their phenolic ingredients have been evaluated
for activity against AGEs formation and also for their antioxidant activity [55]. Therefore, natural products with strong inhibitory properties on AGEs formation
have great potential for further investigation as preventive drugs against AGE-associated
diseases and disorders [45]. However, it remains unknown whether phytochemicals possess protective effects against
glycotoxin-induced damage. While the anti-AGEs activity of a wide variety of
synthetic molecules has already been evaluated, the chemodiversity of natural
products such as secondary metabolites of vegetal origin still needs to be thoroughly
explored [56]. Many plant products and their active constituents have been reported for the prevention
and treatment of various pathological conditions in the human body: various plant
extracts ([Table 3]), fractions, or pure compounds ([Table 4]) have been heavily tested for inhibiting AGEs formation [26].
Table 3 Medicinal plant extracts inhibiting AGEs formation.
|
Plant
|
Extract
|
Antiglycation activity
|
Reference
|
|
Allium sativum skin
|
50% ethanolic extract
|
Inhibiting AGEs formation in an in vitro BSA/fructose assay. Strong antioxidant and free-radical scavenging properties.
|
[26], [59]
|
|
Alpinia zerumbet rhizome
|
Hexane
|
Inhibiting the Amadori products formation and trapping reactive dicarbonyl compounds.
|
[109]
|
|
Apocynum venetum L. (Apocynaceae) leaves
|
water
|
Antioxidant properties and protection against glucose-mediated protein modification
in vitro.
|
[110], [111]
|
|
Aralia taibaiensis root bark
|
n-butanol
|
Inhibiting AGEs formation in vitro: BSA/glucose, Gk-peptide/
ribose, and hemoglobin-δ glucose assay.
|
[66]
|
|
Astragalus membranaceus L. (Fabaceae) roots
|
methanol
|
Hypoglycemic effect, decreasing the aldose reductase and increasing the insulin level.
Additionally, inhibiting the CML and pentosidine formation.
|
[112]
|
|
Calendula officinalis L. (Asteraceae) whole plant
|
methanol
|
Inhibiting protein glycation in BSA/glucose in vitro assay, potent antioxidant activity.
|
[113]
|
|
Camellia sinensis leaves
|
water
|
Inhibiting AGEs formation in the BSA/MGO and BSA/ribose models by trapping α-dicarbonyl compounds. Reducing the post-prandial hyperglycemia.
|
[26], [62]
|
|
Chrysanthemum sp.
flowers
|
water
|
Inhabiting CML and pentosidine formation in an in vitro BSA/
glucose (fructose) assay by free radical and metal scavenging.
|
[57]
|
|
Cinnamomum verum bark
|
ethyl acetate
|
Inhibiting CML and pentosidine formation. Mimicking insulin activity.
|
[26], [54]
|
|
Citrus sinensis seeds;
Citrus reticulata × C. sinensis peels
C. reticulata × Citrus paradisis peels
|
water; 80% methanol
|
Inhibiting AGEs formation in BSA/glucose assay; HSA/MGO assay. Potent free radical
scavenging activity.
|
[114], [115]
|
|
Cuminum cyminum seeds
|
methanol
|
Inhibiting AGEs formation in BSA/fructose assay.
|
[67]
|
|
Curcuma longa L. (Zingiberaceae)
rhizome
|
methanol
|
Inhibiting free radicals and HbA1c formation; antioxidant effect, hypoglycemic effect, and preventing lipid peroxidation.
|
[116], [117]
|
|
Empetrum nigrum L. (Ericaceae)
fruit
|
80% ethanol
|
Inhibiting the formation of fluorescent AGEs in a concentration-dependent manner,
potent radical scavenging activity.
|
[118]
|
|
Erigeron annuus leases and stems
|
methanol
|
Inhibition of RLAR (rat lens aldose reductase), AGEs formation, AGEs/BSA cross-linking,
and cataractogenesis.
|
[58]
|
|
Garcinia mangostana
pericarp
|
water
|
Inhibiting the formation of pentosidine.
|
[63]
|
|
Garcinia subelleptica (Clusiaceae) leaves
|
ethyl acetate
|
Inhibiting protein glycation in several in vitro models: BSA/
glucose experiment, fructosamine adduct, and α-dicarbonyl compounds formation.
|
[82]
|
|
Glycyrrhiza glabra L. (Fabaceae)
roots
|
methanol
|
Inhibiting AGEs formation through radical scavenging properties. Antioxidant and hypoglycemic
activity.
|
[119]
|
|
Hypericum perforatum L. (Hypericaceae)
aerial part
|
methanol
|
Free radical scavenging activity, inhibiting lipid peroxidation, and inhibiting the
advanced glycation in a BSA/glucose assay.
|
[120]
|
|
Ilex paraguariensis leaves and stems
|
water
|
Inhibition of the free-radical-mediated conversion of Amadori products to AGEs.
|
[26], [60]
|
|
Juglans regia L. (Juglandaceae)
bark
|
methanol
|
Inhibiting protein glycation in BSA/glucose in in vitro assay, antioxidant activity.
|
[113]
|
|
Knoxia valerianoides Thovel ex Pitards (Rubiaceae)
root
|
methanol
|
In vitro inhibition of AGEs formation in BSA/fructose and glucose assay, and inhibition of
rat lens aldose reductase activity.
|
[99], [121]
|
|
Matricaria recutita L. (Asteraceae)
leaves
|
70% methanol extract
|
Potent inhibition on the rat lens aldose reductase, AGEs formation, and reactive oxygen
species.
|
[122]
|
|
Melissa officinalis L. (Lamiaceae) leaves
|
water
|
Inhibiting the pentosidine formation in BSA/fructose model. Improving tissue damage
in blood vessels and skin elasticity.
|
[123]
|
|
Mentha arvensis L. (Lamiaceae)
leaves
|
water
|
Reduction of fructosamine formation, dicarbonyl compounds formation, and glycated
albumin; free radical scavenging activity.
|
[124]
|
|
Nigella sativa L. (Ranunculaceae) Seeds
|
water
|
Scavenging reactive carbonyl and oxygen species.
|
[125]
|
|
Origanum majorana leaves
|
methanol
|
Inhibiting AGEs formation in vitro (BSA/glucose assay, BSA/MGO assay, Amadori screening assay, glycation of hemoglobin)
and in streptozotocin-induced diabetic rats.
|
[64]
|
|
Panax ginseng L. (Araliaceae)
root
|
different solvents: water, 70% ethanol, 55% ethanol
|
Reducing AGEs formation through alleviating oxidative stress.
|
[45], [126]
|
|
Polygonum multiflorum Thunb. (Polygonaceae)
root
|
80% ethanol
|
Scavenging free radicals, inhibiting lipid peroxidation, and protein glycation.
|
[127]
|
|
Punica granatum L. (Lythraceae)
fruit
|
fruit juice
|
Antiglycation effect through inhibiting the α-amylase and α-glucosidase, and metal chelating activity.
|
[128], [129]
|
|
Rhus verniciflua Stokes. (Anacardiaceae)
bark
|
ethanol
|
Inhibiting aldose reductase and AGEs formation in a BSA/glucose assay, potent antioxidant
activity.
|
[130]
|
|
Rosmarinus officinalis leaves
|
50% ethanolic extract
|
Inhibiting AGEs formation in an in vitro BSA/fructose assay. Potent antioxidant and antiglycation activity.
|
[26], [59], [61]
|
|
Solanum lycopersicum L. (Solanaceae)
fruit
|
tomato paste
|
Inhibiting glucose autoxidation and trapping reactive dicarbonyl compounds.
|
[26], [54], [131]
|
|
Thymus vulgaris
whole plant
|
methanol
|
Inhibiting AGEs formation in a BSA in vitro model; fructosamine formation detected through the reduction of NBT.
|
[65]
|
|
Trigonella foenum-graeceum L. (Fabaceae) seeds
|
70% ethanolic extract
|
Hypoglycemic and antioxidant effect, decreasing the lipid peroxidation.
|
[132]
|
|
Vaccinium spp. (Ericaceae)
leaves
|
ethanol
|
Inhibiting Amadori product formation and trapping reactive dicarbonyl compounds.
|
[133]
|
|
Vitis vinifera L. (Vitaceae) skin
|
water
|
Scavenging free radicals and dicarbonyl species.
|
[134]
|
Table 4 Pure compounds inhibiting AGEs formation presented according to the classification
of plant secondary metabolites.
|
Classification
|
Compound
|
Antiglycation activity
|
Reference
|
|
Stilbenes
|
(18) resveratrol
|
Inhibiting AGEs formation in BSA/fructose, BSA/MGO, arginine/MGO models. A competitive
inhibitor of α-amylase and α-glucosidase.
|
[135]
|
|
Chalcones
|
(19) curcumin
|
Inhibiting AGEs formation through trapping MGO, modulating the RAGE expression, and
interfering with the NF-κB pathway.
|
[69]
|
|
(20) phloridzin
|
Inhibiting the absorption of glucose in the small intestines and the renal resorption,
resulting in an overall decrease of hyperglycemia in animal models. Additional anti-inflammatory
activity, antioxidant properties, and anti-AGEs effect in BSA/glucose in vitro model.
|
[136], [137]
|
|
Phenolic acids
|
(21) rosmarinic acid, (22) carnosic acid
|
Efficiently inhibit AGEs formation in part by decreasing glycation and by reducing
the level of reactive precursors (such as methylglyoxal) for glycation.
|
[61]
|
|
(23) 7-
O
-galloyl-D-sedoheptulose
|
Reduced renal glucose, AGEs formation, and oxidative stress in diabetic rats, showing
a beneficial effect on the early stages of diabetic kidney disease.
|
[73]
|
|
(24) caffeic acid
|
Inhibiting AGEs formation in the in vitro BSA/glucose model, decrease the expression of proinflammatory mediators. In general,
prevents and delays vascular dysfunction in diabetes.
|
[138]
|
|
(25) ellagic acid
|
Preventing in vivo accumulation of AGEs (CML) and ameliorating renal changes in diabetic rats.
|
[139], [140]
|
|
(26) vanillic acid
|
Inhibiting reactive dicarbonyl intermediates (MGO), ROS formation, and CML formation,
and consequently, preventing the development of diabetic neuropathy.
|
[141]
|
|
(27) chlorogenic acid
|
Inhibiting the AGEs cross-linking to collagen in an AGE-ELISA assay and dicarbonyl
intermediates (MGO).
|
[142]
|
|
(28) ferulic acid
|
Preventing glucose-, fructose-, and ribose-induced protein glycation, as well as MGO-induced
protein glycation and oxidative protein damage in BSA.
|
[143]
|
|
Kavalactones
|
(30) kawain and methysticine
|
Inhibiting protein glycation in BSA/glucose assay.
|
[74]
|
|
Coumarins
|
(31) umbelliferone
|
Inhibiting α-glucosidase and the pancreatic amylase; as a result, decreasing the postprandial
hyperglycemia. Inhibiting α-dicarbonyl compounds formation.
|
[144]
|
|
Flavanols
|
(33) (+)-catechin
|
Greater antiglycation activity due to carbonyl scavenging and antioxidant activity.
|
[111]
|
|
(34) (−)-epicatechin
|
Trapping ROS and RCS (e.g., MGO).
|
[145]
|
|
(35) (−)-epicatechin gallate
|
Suppressing the carbonylation and the formation of amyloid cross-β structures of BSA and the AGEs formation through a BSA/fructose model, additionally
trapping MGO.
|
[146]
|
|
(36) (−)-epigallocatechin-3-gallate
|
Decreasing the AGE-stimulated gene expression and production of TNF-α, and AGE-mediated activation of NF-κB.
|
[147]
|
|
Flavones
|
(37) luteolin
|
Potent inhibitor on the early stage of protein glycation (δ-Glu assay), preventing the HbA1c formation.
|
[47]
|
|
(38) apigenin
|
Inhibiting AGEs formation through trapping MGO, suppressing the production of ROS
and inflammatory cytokines and adhesion molecules.
|
[148]
|
|
(39) diosmin
|
Decreasing glycosylated hemoglobin and increasing hemoglobin and plasma insulin.
|
[149]
|
|
(40) vitexin
|
Inhibiting AGEs formation in an in vitro BSA/glucose and BSA/MGO assays because of trapping dicarbonyl intermediates and free
radical scavenging capacity.
|
[150]
|
|
Flavanones
|
(41) naringenin
|
Inhibiting AGEs formation in an in vitro BSA/MGO assay.
|
[151]
|
|
(42) plantagoside
|
Inhibiting protein glycation and, in physiological conditions, protein cross-linking
glycation.
|
[78]
|
|
(43) liquiritin
|
Increasing the AGEs-reduced superoxide dismutase activity, decreasing RAGE expression,
and blocking NF-κB activation. Consequently, has a protective effect on AGEs-induced endothelial dysfunction.
|
[152]
|
|
Flavonols
|
(44) kaempferol
|
Effect on the intermediate stage of AGEs formation by trapping MGO.
|
[79]
|
|
(45) quercetin
|
Inhibit AGEs formation via chelating metal ions, trapping MGO, and trapping ROS. The activity was more potent
than aminoguanidine.
|
[80], [81]
|
|
(46) hyperoside
|
Inhibiting AGEs-induced upregulation of RAGE.
|
[153]
|
|
(47) rutin
|
Metal chelating properties. Inhibiting pentosidine formation in collagen/glucose model.
|
[154]
|
|
(48) myricetin
|
Decreasing insulin resistance. Demonstrates anti-inflammation, anti-oxidative stress,
anti-aldose reductase, anti-nonenzymatic glycation, and anti-hyperlipidemic activity.
|
[155]
|
|
Anthocyanins
|
(49) cyanidin 3-
O
-Glc
|
Inhibiting dicarbonyl compounds and reducing fructosamine formation, affecting the
initiation and the intermediate state of protein glycation. Potent ROS scavenging
activity.
|
[156]
|
|
PMFs
|
(50) 5-
O
-demethyl nobiletin
|
Inhibiting protein glycation in several in vitro models: BSA/glucose experiment, fructosamine adduct, and α-dicarbonyl compounds formation.
|
[82]
|
|
Biflavonoids
|
(51) amentoflavone
|
Inhibiting protein glycation in an in vitro assay using fluorescent measurement.
|
[83]
|
|
Naphthoquinones
|
(52) juglone
|
Inhibiting prolyl-isomerase-1 (regulating the protein function through post phosphorylation),
which acts against vascular oxidative stress, endothelial dysfunction, and inflammation.
|
[157]
|
|
Anthraquinones
|
(53) emodin
|
Inhibiting fructose-, MGO-, and glyoxal-induced HAS. The antiglycation effect is due
to the binding capacity and stabilization of the HAS protein structure.
|
[158]
|
|
Tannins
|
geraniin
|
Inhibiting α-glucosidase and α-amylase, which leads to decreased postprandial hyperglycemia. Anti-AGEs activity
through inhibiting the aldose reductase in vitro.
|
[84]
|
|
Terpenes
|
(54) thymol
|
Inhibiting AGEs formation in a BSA/MGO model by trapping dicarbonyl intermediates
and free radicals.
|
[159]
|
|
3-O-[α-L-arabinofuranosyl-(1 – 4)-β-D-glucuronopyranosyl]-oleanolic acid
|
Inhibiting protein glycation in several in vitro models: BSA/glucose experiment, Gk-peptide ribose, and hemoglobin-δ-gluconolactone assay.
|
[85]
|
|
astragaloside V
|
Inhibiting the CML and pentosidine formation in an in vitro BSA/ribose model. A promising candidate for preventing diabetic complications.
|
[112]
|
|
ginsenoside Rb1
|
Improving insulin resistance, having anti-obesity, anti-hyperglycemic, and anti-diabetic
effect by inhibiting protein glycation, the aldose reductase activity.
|
[160]
|
|
(55) oleanolic acid
|
Inhibiting fructosamine and α-dicarbonyl compounds formation due to potent antioxidant activity and trapping MGO.
Binding to lysine and arginine residues of the BSA prevents the attachment of the
BSA to sugars.
|
[161]
|
|
(56) ursolic acid
|
Inhibiting AGEs formation by attenuating the aldose reductase and sorbitol dehydrogenase
activity–the 2 major enzymes in the polyol pathway.
|
[162]
|
|
Alkaloids
|
(57) berberine
|
Preventing microvascular complications in diabetes due to protective effect on high
glucose-induced endothelial dysfunction in vitro with increased NO and endothelium-dependent vasodilatation.
|
[163]
|
Plant extracts
Chrysanthemum morifolium Ramat. (Asteraceae) contains a large amount of (27) chlorogenic acid, flavonoid glucoside,
and aglycone varieties–for example, (38) apigenin. Chrysanthemum indicum L. (Asteraceae) is a rich source of (24) caffeic acid, luteolin, and (44) kaempferol.
The 2 Chrysanthemum species extracts demonstrated strong inhibition of AGEs formation, in particular,
CML and pentosidine in the BSA/glucose (fructose) assay [57]. The inhibitory effects of Chrysanthemum extracts at a concentration of 5 mg/ml were stronger than aminoguanidine at a concentration
of 1 mM, which was used as a positive control.
The ethyl acetate-soluble fraction of the stem and leaves extract of Erigeron annuus L. (Asteraceae) contains quinic acid derivatives such as 3,5-di-O-caffeoyl-epi-qunic acid, which showed an IC50 of 6.06 µM in the BSA/glucose assay (while the IC50 of aminoguanidine was 961 µM) and prevented opacification of rat lenses [58].
Cinnamon (Cinnamomum verum J. Presl, Lauraceae), a traditional spice, has been shown to attenuate the symptoms
of metabolic syndrome such as insulin resistance, hyperglycemia, increased protein
glycation, and inflammation. It was found that the ethyl acetate extract from the
bark containing (33) catechin, (34) epicatechin, and procyanidin B2 inhibited CML
and pentosidine formation. Additionally, the presence of catechins was proven to reduce
MGO to the physiological level [26], [54].
S-ethylcysteine and S-propylcysteine in garlic (Allium sativum L., Amaryllidaceae) extract are strong antioxidants and free radical scavengers,
inhibiting CML formation and the plasma HbA1c (glycated hemoglobin) [26], [45]. In an in vitro BSA/fructose model, the IC50 of the extract was 16.8 µg/ml and lower than that of aminoguanidine at 27.7 µg/ml
[59].
Ilex paraguariensis A. (Aquifoliaceae) (maté) contains a high level of antioxidants that have been proven
in in vitro models to inhibit the second phase of the glycation reaction, namely, the free radical-mediated
conversion of Amadori products to AGEs [26], [45]. In another study, it was shown that I. paraguariensis and its main component, chlorogenic acid, inhibited fructose formation of AGEs with
amino acids at conditions compatible with those in the digestion system. The value
for the maté tea was 83% inhibition at 50 µg/ml concentration, and for caffeic and
chlorogenic acid, the IC50 was 0.9 mM [60].
Rosmarinus officinalis L. (Lamiaceae), which mainly contains (21) rosmarinic acid, (22) carnosic acid, and
carnosol, possesses antioxidant activity and antiglycation properties comparable to
aminoguanidine [26]. An in vitro BSA/glucose model revealed that rosmarinic acid and carnosic acid at 400 µg/ml inhibit
fluorescent AGEs by 90%, and CML and CEL by 82.7% and 75.2% and 71.4% and 64.2%, respectively.
Moreover, the addition of 400 µg/ml rosmarinic acid and carnosic acid inhibited fluorescent
AGEs by more than 90%, both in the BSA/GO and BSA/MGO models; the formation of CML
by 64.9% and 53.9% in the BSA/GO assay; and CEL by 28.9% and 24.3% in BSA/MGO assay,
respectively [61].
Camellia sinensis L. (Theaceae), which is a rich source of (−)-epigallocatechin 3-O-gallate (EGCG) and (−)-epicatechin 3-O-gallate (ECG), has strong antioxidant properties and inhibits the accumulation of
CML and CEL and the activation of RAGE [26]. In the glucose-glycated BSA models, the addition of green tea extract reduced the
fluorescence intensity by 64.6% (while 72.8% for aminoguanidine). Also, the green
tea extract was proven to inhibit α-glucosidase and α-amylase, resulting in delayed postprandial hyperglycemia [62].
The exocarp 80% aqueous methanol extracts from Citrus reticulata Blanco × Citrus sinensis L. (Rutaceae) and Citrus reticulata × Citrus paradisis Macfad. decreased AGEs formation by lowering the levels of carbonyl compounds in
adipocyte cells in vitro
[54].
A standardized extract from Ginkgo biloba L. (Ginkgoaceae) (EGb 761) containing 24% flavonoids and 6% terpenoids was proven
to inhibit the RAGE activation in microvascular endothelial cells induced by hypoxic
and hypoglycemic conditions [26].
The fruit of Garcinia mangostana L. (Clusiaceae) (mangosteen) contains catechins, procyanidins, anthocyanin, and xanthones,
such as α-mangostin. A study investigating the effect of mangosteen pericarp extract on the
elasticity of the skin suggested that the water-soluble polyphenols in the water extract
from mangosteen inhibit oxidation, resulting in the inhibition of the pentosidine
formation in vivo and in vitro
[63]. Oral administration of water extract of mangosteen at 100 mg/day to volunteer patients
for 3 months reduced the serum pentosidine content and the skin autofluorescence intensity,
improving the total skin condition.
The methanolic extract of the leaves of Origanum majorana L. (Lamiaceae) showed inhibition of AGEs formation in vitro and in streptozotocin-induced diabetic rats [64]. Besides the antioxidant activity of the extract, the in vitro studies demonstrated inhibition of protein glycation (IC50 = 0.310 ± 0.054 mg/ml in the BSA/glucose assay) and trapping abilities against RCS
such as methylglyoxal (IC50 = 0.190 ± 0.028 mg/ml). Treatment of streptozotocin-diabetic mice with the Origanum majorana extract and glibenclamide (as a positive control) for 28 days showed beneficial effects
on renal metabolic disorders including glucose levels and AGEs formation as compared
to the diabetic control and the positive control.
The methanol extract of Thymus vulgaris L. (Lamiaceae) containing the flavonoids (45) quercetin, eriodictyol, 5,6,4′-trihydroxy-7,8,3′-trimethoxyflavone,
and cirsilineol suppressed the levels of AGEs formation measured through a fluorescent
assay (82% AGEs inhibition at 1 mg/ml methanolic extract) [65].
Aralia taibaiensis L. (Araliaceae) showed particularly potent inhibition of the late glycation and the
formation of AGEs. The antiglycation properties were addressed to the triterpenoid
saponin content in the n-butanol extract [66]. The results from testing 1 mg/ml of the extract showed 77.44% inhibition in the
hemoglobin-δ/glucose assay (while the value for the 50 mM aminoguanidine was 20.17%); 77.63% in
the BSA/glucose assay (while the value for the 50 mM aminoguanidine was 76.52%); and
68.19% in the Gk-peptide/ribose assay (while the value for the 50 mM aminoguanidine
was 65.11%). The mechanism of action of the plant extract could be explained by scavenging
free radicals, reducing oxidative damage, enhancing insulin sensitivity, and regulating
the enzymes related to glucose metabolism.
The widely consumed aromatic food spice cumin (Cuminum cyminum L., Apiaceae) showed antiglycation properties in the BSA/fructose intrinsic fluorescence
assay. The seedsʼ flavor constituents, such as sesquiterpenoids, monoterpenoids, and
chalcone derivatives, demonstrated a potent role in this biological effect in the
in vitro assay (AGEs inhibition > 50% vs. 35%, respectively, and for aminoguanidine as a positive
control) [67].
Isolated natural compounds
In this review, the selection of the enlisted and discussed pure compounds from medicinal
plants ([Fig. 6]) is according to the established classification of plant secondary metabolites.
Fig. 6 Chemical structures of natural products with AGEs inhibiting properties presented
based on the classification of plant secondary metabolites.
Resveratrol (18), a natural antioxidant found in grapes, has been described to inhibit
AGEs-induced proliferation and collagen synthesis in vascular smooth muscle [68].
Additionally to its antioxidant and anti-inflammatory properties, (19) curcumin was
reported to be a potent inhibitor of AGEs formation and cross-linking of collagen
in diabetic rats [69]. It prevented the accumulation of AGE-collagen in diabetic animals; also, Hu et
al. reported trapping of MGO by curcumin in cell-free systems and human umbilical
vein endothelial cells (HUVECs). Thus, curcumin may prevent MGO-induced endothelial
dysfunction by directly trapping MGO [26], [70]. Another study found that additional mechanisms in how curcumin abolished AGEs-induced
effects were through modulating the RAGE expression and interfering with the NF-κB pathway. In conclusion, curcumin is a potential protective agent against AGEs formation
and AGEs-induced disruption through several mechanisms of action [71].
Phenolic acids are among the most widely distributed plant nonflavonoid phenolic compounds
that can exert antioxidant activity by scavenging hydroxyl radicals and acting as
chain-breaking and reducing agents [72]. They can be divided into 2 main types: benzoic acid and cinnamic acid derivatives.
Examples of cinnamic acid derivatives are caffeic acid, chlorogenic acid, (28) ferulic
acid, and rosmarinic acid, while the benzoic acid derivatives include compounds derived
from gallic acid.
Rosmarinic acid (21) and (22) carnosic acid are 2 commercially available active constituents
of rosemary extract that can possess anti-AGEs properties in in vitro models: BSA/glucose, BSA/glyoxal, and BSA/methylglyoxal assay [61]. In the BSA/glucose assay, 400 µg/ml rosmarinic acid reduced AGEs formation by 97.4%,
while with 50 µg/ml carnosic acid, the inhibition rate was 3 times higher. Rosmarinic
acid decreased the MGO formation when added at concentrations higher than 25 µg/ml
and did not show an effect on GO concentration at the levels lower than 50 µg/ml.
A gallic acid derivative, (23) 7-O-galloyl-D-sedoheptulose, isolated from Cornus officinalis L. (Cornaceae), significantly reduced the expression of RAGE in type 2 db/db mice
(20 or 100 mg/kg body weight/day, per os, administered every day for 6 weeks) and decreased the fluorescent AGEs and ROS in
the liver, as well as the expression of oxidative stress- and inflammation-related
proteins [73].
Silymarin (29), a flavonolignan obtained from Silybum marianum L. (Asteraceae), has shown, in addition to its free-radical scavenging properties,
in vitro inhibitory effects on the late-stage glycation and subsequent cross-linking [26].
Kavalactones, (30) DL-kawain and methysticine, are a class of lactone compounds isolated
from Alpinia zerumbet Pers. (Zingiberaceae) and used in the preparation of traditional food in the Okinawan
islands. They are thought to contribute to the longevity of the people in this region
[74]. The prevention of AGEs formation was investigated by the BSA/glucose assay where
both kawain (IC50 = 43.5 ± 1.2 µM) and methysticine (IC50 = 45.0 ± 1.3 µM) inhibited the process significantly better than aminoguanidine (IC50 = 231.0 ± 11.5 µM).
Mangiferin (32)–a major xanthone glucoside in the roots of Anemarrhena asphodeloides Bunge (Asparagaceae) traditionally used in Chinese medicine–has been reported for
its antidiabetic and anti-inflammatory effects in a diabetic cardiomyopathy rat model.
Mangiferin reduced AGEs production and expression of RAGE, preventing the release
of inflammatory cytokines and inhibiting the accumulation of ROS [75].
Flavonoids have been extensively investigated as AGEs inhibitors. In general, it is
difficult to draw a clear line between the structural characteristics of flavonoids
for inhibition of protein glycation and radical scavenging activities. However, Matsuda
et al. suggested the following statements can be made about potential AGEs inhibitors:
(1) an increasing number of hydroxyl groups in position 3′, 4′, 5, 7 is associated
with increased inhibitory activity; (2) flavones are more active than the corresponding
flavonols, flavanones, and isoflavones; (3) methylation or glycosylation of the 4′-hydroxyl
group of flavones, flavonols, and flavanones reduces activity; (4) methylation or
glycosylation of the 3-hydroxyl group of flavonols tends to increase activity; (5)
glycosylation of the 7-hydroxyl group of flavones and isoflavones reduces activity
[76]. During the past few decades, a vast number of flavonoids have been reported to
possess
promising antiglycation activity.
Significant inhibition of AGEs formation by (33) (+)-catechin–a major metabolite of
lotus seedpod oligomeric procyanidins–was demonstrated in a study by Wu et al. The
anti-glycation properties of the compound were related to its potent activity of trapping
dicarbonyl intermediates (IC50 value 0.049 ± 0.019 mg/ml; scavenging MGO activity 78.25 ± 2.99%) and its antioxidant
capacities [77].
Plantagoside (42) (5,7,4′,5′-tetrahydroxyflavone-3′-O-glucoside) and its aglycone (5,7,3′,4′,5′-pentahydroxyflavone) obtained from the
50% ethanolic extract of Plantago major L. (Plantaginaceae) seeds were proven to inhibit both the formation of AGEs in physiological
conditions and protein cross-linking glycation. The fluorometric BSA assay reported
IC50 1.2 µM for plantagoside and IC50 18.0 µM for the aglycone, which was 83- and 5.5-times stronger, respectively, than
the one with aminoguanidine (IC50 100.0 µM) used as a positive control [78]. Additionally, 18.0 µM plantagoside was identified to inhibit AGEs formation at
the physiological level.
Kaempferol (44), the well-known antioxidant flavonol aglycone, was detected to inhibit
the early stages of AGEs formation by scavenging MGO in physiological conditions,
forming mono-MGO and di-MGO adducts. The data showed that MGO was trapped up to 60%
by 0.25 mM aminoguanidine (although the inhibitory activity was not dose-dependent),
in contrast to the same concentration of kaempferol, where the remaining MGO decreased
significantly to 32% in a dose-dependent manner [79].
Quercetin (45) is another example of a flavonol aglycone that was proven to inhibit
MGO-mediated AGEs formation as well as glucose- and ribose-mediated AGEs formation
[80]. One hundred µM exhibited 50% inhibition of MGO, which was the highest result among
other polyphenols tested in the assay such as (−)-epicatechin, gallic acid, hesperetin,
(47) rutin, and kaempferol. Another study compared the antiglycation properties of
quercetin and aminoguanidine, the generally used positive control in various fluorescent
assays: hemoglobin-δ-gluconolactone (δ-Glu) assay, MGO/HSA (human serum albumin), GO/HSA, and Gk-peptide
(N-acetyl-glycyl-lysine methyl ester)/ribose tests [81]. In the GO/HSA, 500 µM quercetin inhibited almost 75% of the post-Amadori glycation,
while 10 mM of aminoguanidine reached 72.5% inhibition. In the Gk-peptide/ribose assay,
which is used to evaluate the inhibiting properties of the
compound against cross-linking, 200 and 500 µM quercetin inhibited 61.5% and
69.6% of the late glycation products over 14 days. As for aminoguanidine, the 62%
inhibition in the same test was achieved in a concentration of 10 mM.
In an in vitro screening assay, (47) rutin exhibited a significant inhibitory effect at the intermediate
stage of AGEs formation by trapping MGO with an IC50 value of 71.8 µM [26].
PMFs, particularly (50) 5-O-demethyl nobiletin isolated from the chloroform fraction of Citrus depressa Hayata (Rutaceae) peel, had significantly higher AGEs inhibitory activity (IC50 = 64.2 ± 3.6 µM) than aminoguanidine (IC50 = 484.3 ± 7.3 µM) measured in vitro through fluorimetric methods [82].
Amentoflavone (51), a biflavonoid isolated from the methanol leaves extract of Calophyllum flavoramulum Hend. &Wyatt-Sm. (Calophyllaceae), was found to possess potent anti-AGEs activity
in vitro: IC50 = 0.05 mM, while the activity of quercetin, used as a reference compound, was moderately
strong: IC50 = 0.5 mM [83]. Amentoflavone can exert its anti-AGEs activity through various mechanisms like
radical scavenging and chelation of divalent metal ions as well as trapping dicarbonyl
species.
Geraniin, the main ellagitannin in the crude extract from Nephelium lappaceum L. (Sapindaceae) peels, is an effective inhibitor of the carbohydrate enzymes α-glucosidase and α-amylase; therefore, it has the potential to interrupt carbohydrate digestion and
the absorption of glucose, resulting in suppressed postprandial hyperglycemia. Additionally,
in vitro studies proved its significant aldose reductase-inhibiting properties, consequently,
decreasing the formation of AGEs [84]. It has been demonstrated that geraniin has antioxidant, immune-modulation, antimicrobial,
and anticancer properties besides the promising therapeutic effects on hypertension,
cardiovascular diseases, and metabolic dysregulation.
Twelve triterpenoid saponins isolated from the extract of root bark of Aralia taibaiensis Z. Z. Wang & H. C. Zheng (Araliaceae), a plant frequently used for the treatment
of diabetes mellitus in traditional Chinese medicine, exhibited both antioxidant and
antiglycation properties. The activity against AGEs formation was detected through
the hemoglobin-δ-gluconolactone assay, BSA/glucose assay, and Gk-peptide/ribose assay, and it was
significantly higher for the 3-O-[α-L-arabinofuranosyl-(1 – 4)-β-D-glucuronopyranosyl]-oleanolic acid (TA24); 3-O-{β-D-glucopyranosyl-(1 – 2)-[β-D-glucopyranosyl-(1 – 3)]-β-D-glucuronopyranosyl}-oleanolic acid (TA21), and 3-O-{β-D- glucopyranosyl-(1 – 2)-[β-D-glucopyranosyl-(1 – 3)]-β-D-glucuronopyranosyl}-oleanolic acid 28-O-β-D-glucopyranosyl ester (TA9) [85].
Astragaloside V from the crude extract of Astragali Radix has shown inhibition of
the formation of CML and pentosidine in in vitro samples [26], [50], [86].
Other groups of compounds include anthraquinones, such as (53) emodine, and carotenoids,
especially lutein and β-carotene from the ethyl acetate fraction of the green microalgae Chlorella zofingiensis Donz. (Oocystaceae), that contribute to the strong antiglycation activity of this
species; unsaturated fatty acids such as linoleic acid, arachidonic acid, and eicosapentaenoic
acid from Nitzschia laevis Hassall (Bacillariaceae) were reported as inhibitors of glycation. Moreover, (56)
ursolic acid was suggested to play a significant role in patients with diabetes in
reducing hyperglycemia, hepatic glucose production, hyperlipidemia, and the influx
of glucose through the polyol pathway.
Considering that AGEs are major pathogenic propagators in many human diseases, and
especially in diabetes and its complications, it is of great importance to identify
anti-glycation substances and to examine their mode of action. It is important to
note that one AGE inhibitor will not act on all pathways; therefore, it is difficult
to accept the existence of a magic bullet. Nevertheless, the current review seeks
to address the lacuna in contemporary research for new potential drugs or lead compounds
with AGEs inhibiting properties. However, despite the tremendous efforts of many scientists
in the field, none of the discussed natural products or extracts have progressed to
clinical trials or even systematic preclinical studies. The reason for this can be
found in the current lack of validated analytical methods for the unambiguous determination
of AGEs inhibiting properties of particular candidates. Future work involving advanced
analytical techniques and suitable
sample preparation steps is expected to reveal the positive hits among plant
compounds as inhibitors of AGEs formation.
