Recent development of plant products with anti-glycation activity: a review

Abstract

Diabetes mellitus (DM) is an endocrine disorder characterized by chronic hyperglycemia, which results from an absolute or a relative deficiency of insulin or resistance to insulin. Hyperglycemia is increasingly linked to the pathogenesis of diabetic complications in individuals with long-duration diabetes. One of the inevitable consequences of hyperglycemia is the enhanced accumulation of advanced glycation end-products (AGEs), which are implicated in the pathogenesis of diabetes. Various natural products and their active constituents have reportedly been used for the treatment of diabetes and its complications. Some of these molecules are known to have anti-glycation activity. The search for novel anti-glycation agents from various sources is gaining a lot of importance. Attention has especially been focused on plants with an ethnopharmacological background and also on plants rich in triterpenoids and phenolics, which generally exhibit antioxidant and anti-glycation effects. Plant extracts or compounds obtained from them that possess both antioxidant and anti-glycation activities might have great therapeutic potential for treating diabetic complications. This review highlights the anti-glycation activities of phytochemicals, which will aid in the identification of lead molecules for the development of new anti-glycation drugs.

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Ashish A. Chinchansure

Ashish A. Chinchansure studied chemistry at the Swami Ramanand Teerth Marathwada University of Nanded, India between 2002 and 2007, where he obtained his Bachelor's and Master's degrees. He is currently carrying out research for his PhD studies at the CSIR-National Chemical Laboratory, India under the supervision of Dr Swati P. Joshi. His work comprises the extraction, isolation and characterization of secondary metabolites from plants belonging to the family Lamiaceae and the biological evaluation of natural products regarding important biological activities, viz. antimycobacterial, antiviral, anti-glycation, antimalarial and cytotoxicity studies.

Arvind M. Korwar

Arvind M. Korwar is a Research Associate at CSIR-National Chemical Laboratory, working with Dr Mahesh J. Kulkarni on post-translational modifications (PTM), especially advanced glycation end-products (AGEs) and their contribution to the progression of breast cancer and diabetes. He obtained a Master's in Biochemistry from Karnataka University, followed by a PhD in Biochemistry from the University of Pune, India in the year 2012. For his PhD, he studied luminal A subtype breast cancer and was instrumental in developing methods to identify and characterize AGE-modified proteins. His current research interests are in disease signaling pathways, histone/nuclear proteome (chemical) modifications and host–pathogen interaction.

Mahesh J. Kulkarni

Mahesh J. Kulkarni is a Senior Scientist at CSIR-National Chemical Laboratory, India. He obtained his PhD degree from the University of Agricultural Sciences, Bangalore, India. For the last 10 years, he has been working in the area of mass spectrometry and proteomics. The major focus of his research is to understand the role of advanced glycation end-products (AGEs) in the development of diabetic complications. The long-term goal is to identify a diagnostic marker for diabetic complications, identify drug targets and develop intervention strategies.

Swati P. Joshi

Swati P. Joshi is a Senior Principal Scientist in chemistry at the CSIR-National Chemical Laboratory in India. She obtained her PhD degree from CSIR-NCL, India. Her research activity involves the isolation and identification of new natural products and the identification of bioactive natural products for the development of new drugs and pest control agents. The main focus of her group is on the phytochemical analysis of plants from one of the biodiversity hotspots – Western Ghats – specifically, endemic and rare plants. Biological activities of interest are anticancer, antimycobacterial, antifungal, antiviral including anti-HIV, anti-glycation, antioxidant and antimalarial.

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1. Introduction

Diabetic patients are prone to develop complications such as retinopathy, cataract, neuropathy, atherosclerosis, nephropathy, embryopathy, and delayed healing of wounds. Hyperglycemia plays a key role in the pathogenesis of diabetes, as it results in prolonged exposure of plasma proteins to elevated blood glucose in diabetic patients with poor glycemic control.¹ As a consequence, the plasma proteins undergo glycation – chemical modification caused by glucose. Several plasma proteins, including hemoglobin, serum albumin and transferrin, have been shown to be glycated.² Glycation is a non-enzymatic reaction between the carbonyl group of reducing sugars and a free amino group of proteins, leading to the formation of a Schiff base, which is the first product of the glycation reaction that is relatively fast and highly reversible.² The next step involves conversion of a thermodynamically unstable Schiff base into a stable, reversible Amadori product. Proteins bearing an Amadori product are often referred to as glycated proteins or Maillard reaction products. Finally, the Amadori product undergoes a series of dehydration and fragmentation reactions, resulting in a variety of carbonyl compounds including methylglyoxal (MGO), glyoxal (GO), glucosones, 3-deoxyglucosone (3-DG) and so on.³ These carbonyl compounds are more reactive than the original sugar and act as reaction propagators, leading to the formation of advanced glycation end-products (AGEs) (Fig. 1).

Fig. 1 Formation of advanced glycation end-products (AGEs) and some of the phytochemicals known to inhibit glycation at different stages of AGEs formation.

The AGEs formed are known to be quite heterogeneous, depending on the glycating agent. For example, glyoxal-derived AGEs include carboxymethyl-lysine (CML) and glyoxal lysine dimer (GOLD), while methylglyoxal-derived AGEs are carboxyethyl-lysine (CEL), argpyrimidine, and methylglyoxal lysine dimers (MOLD), and 3-deoxyglucosone-derived AGEs are pyrraline and deoxyglucosone-derived lysine dimers (DOLD)³ (Fig. 2).

Fig. 2 Heterogeneous AGEs formed during glycation reaction.

The glycation reaction preferentially takes place at the ε-amino groups of lysine, arginine and histidine, while glycation-mediated protein crosslinking is more specific to arginine residues.⁴ Especially highly reactive dicarbonyl compounds, like glyoxal, deoxyglucosone or methylglyoxal, promote the formation of intracellular AGEs.^3,5 Various proteins, including collagen, interact with AGEs or reactive dicarbonyl compounds and form protein crosslinks.⁶ Quantitative analysis of AGEs has suggested that intracellular proteins are more heavily AGEs-modified than extracellular proteins.⁷ AGEs are associated with the pathogenesis of several diseases, as they affect the target cells in three different ways, as depicted in Fig. 3.⁸

Fig. 3 Formation of intracellular AGEs and the mechanisms through which they cause cell damage.

(1) AGE modification of intracellular proteins leads to their altered structure and function. Intracellular glucose undergoes auto-oxidation to produce reactive dicarbonyl compounds, which react with proteins, lipids and nucleic acids, leading to the formation of AGEs. Dihydroxyacetone phosphate (DHAP) formed during glycolysis is converted to MGO, which can react with proteins to produce AGEs. Most glycolytic intermediates are also potential precursors of AGEs.⁹ (2) AGE modification of extracellular matrix (ECM) components and their interaction with other ECM components and cell receptors lead to a range of altered cellular processes and phenotypes. (3) Binding of AGE-modified plasma proteins to the receptor for AGE (RAGE) activates a downstream signaling cascade, leading to nuclear translocation of transcription factors such as NF-κB, specificity protein-1 (SP-1), activator protein-1 (AP-1) and nuclear factor interleukin-6 (NF-IL6), and contributes to various cellular processes including pro-inflammatory response, overexpression of RAGE and generation of reactive oxygen species (ROS), etc. (Fig. 3).

AGEs play a crucial role in the development of a variety of diabetic complications. Increased production of AGEs and their accumulation lead to increased oxidative stress, contributing to vascular complications in diabetes.^10–12 Thus, agents that inhibit the formation of AGEs have therapeutic potential in alleviating glycation-associated diseases. Compounds with combined anti-glycation and antioxidant properties may offer better therapeutic potential.^13,14 Therefore, inhibition of glycation by plant-derived natural compounds would offer great therapeutic potential and possibly help in minimizing the pathogenesis of secondary complications of diabetes.

1.1 Advanced glycation end-product (AGE) inhibitors

The wide occurrence of AGE-associated diseases has led to efforts to identify and develop AGE inhibitors that suppress the formation of AGEs. Historically, aminoguanidine (AMG) was the first AGE inhibitor explored in clinical trials. AMG is a nucleophilic agent that traps reactive carbonyl intermediates such as MGO, GO, and 3-DG to form relatively non-toxic adducts. However, this drug was not ultimately approved for commercial production because of its side effects observed in phase III clinical trials in patients with diabetes. Nevertheless, AMG has provided strong evidence that inhibition of AGE formation by trapping reactive carbonyl species could be a reasonable therapeutic approach for the treatment of diabetes complications. AMG is now being used as a prototype for obtaining new anti-glycation molecules.¹⁵

Glycation can be inhibited at various steps leading to AGE formation. Schiff base/Amadori product formation is the first step in the glycation reaction where intervention can be carried out. Various inhibitors are known to act at this stage of the reaction, e.g. amines, polyamines, and small peptides.^16–18 Some known natural products, like gallic acid (61), (+)-catechin (42) and quercetin (20), inhibit Amadori product formation.¹⁹ Furthermore, glycated proteins can be chemically deglycated or transglycated by highly nucleophilic compounds such as hydrazine derivatives. Hydralazine, an antihypertensive and vasodilator, acts as a potent transglycating agent.²⁰ Certain molecules can inhibit or prevent glycation by modifying or blocking amino acid side chains. For example, acetylsalicylic acid prevents protein glycation by transferring an acetyl group to lysine, and the acetylated lysine cannot react with glucose.²¹ Natural products with an ability to acetylate proteins could be potential glycation inhibitors.

Post-Amadori reaction inhibitors, also called Amadorins, inhibit the conversion of the Amadori product to AGEs.²² Pyridoxamine (PM), or vitamin B6, was the first Amadorin to be identified and showed great potential for the treatment of diabetic nephropathy.²³ Reactive dicarbonyl compounds such as GO, MGO and 3-DG are involved in protein crosslinking and AGE formation. Some molecules are able to inhibit AGE formation by trapping such dicarbonyl compounds. These include AMG, OPB-9195 [(±)-2-isopropylidenehydrazono-4-oxothiazolidin-5-ylacetanilide], etc. Metformin, an analog of AMG and a popular antihyperglycemic drug, also traps dicarbonyl compounds.^24,25 Amongst natural products, 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) (68) and 4,6,7-trihydroxy-2-methoxy-8-(3-methylbut-2-enyl)phenanthren-1,1′-4′,6′,7′-trihydroxy-2′-methoxy-8′-(3-methylbut-2-enyl)phenanthrene (71), isolated from Polygonum multiflorum²⁶ and Prosthechea michuacana²⁷ respectively, exhibit in vitro inhibition of AGEs by trapping reactive MGO. Natural flavonoids, like luteolin (12), apigenin (14), myricetin (35) and silymarin (38), also exhibit these properties. Another approach to reducing AGE levels is by using crosslink breakers such as N-phenacylthiazolium bromide (PTB) and N-phenacyl-4,5-dimethylthiazolium chloride (ALT-711/alagebrium), which break AGE crosslinks.²⁸ Oxidative stress promotes the glycation reaction and acts synergistically to increase the accumulation of AGEs.²⁹ It also upregulates the expression of RAGE, which is the principal receptor in AGE-induced pathogenesis.³⁰ The AGE–RAGE interaction results in ROS production and activation of a pro-inflammatory pathway. Thus, reducing oxidative stress may inhibit AGE formation. Many plant-derived products, especially dietary antioxidants, are known to possess anti-glycation activity.³¹ Molecules that block AGE–RAGE interaction or decrease RAGE expression are also important in reducing AGE-induced harmful effects. FPS-ZM1 was confirmed to be a potent RAGE blocker with a high affinity constant.³² RAGE expression is downregulated by angiotensin receptor blockers such as losartan, telmisartan, etc.³³ Many phytomolecules act at more than one stage of the glycation process and have greater potential to control this process. The discovery of molecules from natural sources that inhibit glycation at various stages would immensely help in the treatment and management of glycation-associated diseases (Fig. 1).

1.2 Phytochemicals with anti-glycation activity

Many natural products, particularly plant products, have been proven relatively safe for human consumption and many plant extracts have been evaluated for their ability to prevent AGE formation. There has been enormous interest in the development of alternative medicines for oxidative stress and related disorders. Many plant products and their active constituents have reportedly been used for the treatment of diabetes and diabetic complications. Diets rich in fruit and vegetables have been found to offer protection against degenerative diseases, due to the presence of bioactive substances. These substances exert specific effects on biological targets, including anti-glycation activity.³⁴ Compounds with antioxidant activity, such as polyphenols, have been proven to exhibit anti-glycation effects at physiological concentrations, although there are reports indicating that their anti-glycation capacity depends on the model system employed. Plant materials comprising many hydrophobic compounds such as the saponins of ursolic and oleanolic acid exhibit antioxidant and hypoglycemic activities. Such hydrophobic compounds exhibiting anti-glycation behaviour are present in non-polar extracts of many medicinal plants.³⁵ The search for anti-glycation and antioxidant agents from various sources is gaining a lot of importance. Attention has been especially focused on plants rich in triterpenoids and phenolics which generally exhibit antioxidant and anti-glycation effects. Natural extracts or compounds that possess both antioxidant and anti-glycation activities might have great therapeutic potential for treating diabetic complications.

A number of plants and plant products have been shown to exhibit anti-glycation activity.^36,37 Attempts have been made in the present review to highlight recent work on the anti-glycation potential of phytochemicals. Plant products, including extracts, fractions and phytochemicals, with broad-spectrum anti-glycation activity are shown in Table 1. Some biologically important phytochemicals, particularly terpenoids and polyphenols, which have been studied extensively for their antioxidant and anti-glycation activities are shown in Table 2. These compounds exhibiting anti-glycation activity represent potential leads for the development of new anti-glycation agents.

Table 1 Plants and plant products with anti-glycation activity

Sr no.	Plant (family) common name	Extract, active ingredient	Activity
1	Acanthopanax senticosus (Araliaceae)	Roots – saponin extract	Antioxidant and anti-glycation properties^88
2	Achyrocline satureioides (Asteraceae) macela	Water extract	Anti-glycation activity – prevents MGO-induced inhibition of plasminogen and antithrombin III^113
3	Actinidia arguta (Actinidiaceae) kiwifruit	Roots – proanthocyanidin B4 (46)	Inhibition of AGE formation with IC50 10.1 μM (ref. 67)
4	Aegle marmelos (Rutaceae) bael	Fruit pulp – methanolic extract	Antiperoxidative, free radical-scavenging and potential inhibitor of enzymes related to carbohydrate digestion (α-amylase and α-glucosidase)^101
		Leaf chloroform extract – limonene (1)	Extract – antidiabetic, anti-glycation and antioxidant activities, prevents kidney damage and establishment of cataracts; 1 – potent anti-glycation activity; non-toxic at the concentration used^136
5	Aframomum danielli (Zingiberaceae) alligator pepper	80% acetone extract	Anti-glycation and antioxidant activity (IC50 0.125 μg mL^−1)^105
6	Allium cepa (Liliaceae) onion	Ethanol extract	Anti-glycation and antioxidant activities^104
7	Allium fistulosum (Liliaceae) Welsh onion	Ethanol extract	Anti-glycation and antioxidant activities^104
8	Allium sativum (Liliaceae) garlic	Aged garlic extract	In vitro inhibition of the formation of AGEs and the formation of glycation-derived free radicals^137
		Ethanol extract	Anti-glycation and antioxidant activities^104
9	Aloe sinkatana (Liliaceae) aloe	Methanol and ethyl acetate extracts – 2,8-dihydroxy-6-(hydroxymethyl)-1-methoxyanthracene-9,10-dione (72)	Extracts – inhibitory effect on early-stage protein glycation; 72 – inhibitory effects against glucose-induced AGEs^76
10	Alpinia zerumbet (Zingiberaceae) variegated shellflower	Rhizomes – dihydro-5,6-dehydrokawain (60)	Inhibitory activity against BSA glycation, IC50 15.9 μM, inhibits human platelet aggregation, anti-inflammatory and cancer chemoprotective properties^71
		Rhizome – labdadiene (2)	Potent anti-glycation agent, IC50 51.06 μg mL^−1; inhibits AGE formation at three different steps in the pathway – could be used to prevent glycation-associated complications in diabetes^37,39
11	Anthemis nobilis (Asteraceae) Roman chamomile	Extract	Anti-glycation effect^111
		Mixed herbal extract (MHE)	Double-blind, placebo-controlled, parallel-group study to assess the anti-glycation effect – improvement in the symptoms related to quality of life (QOL), inhibits the generation of CML and AGEs^97
12	Antidesma madagascariense (Euphorbiaceae)	Aqueous extract, n-butanol fractions	Antioxidant and anti-glycation activities comparable to those of AMG with no apparent cytotoxicity^98
13	Aralia taibaiensis (Araliaceae)	Root bark – saponin extract	Anti-glycation and antioxidant properties^88
		Root bark extract – triterpenoid saponins	Antioxidant and anti-glycation properties – synergistic effect^138
		Root bark – 3-O-{β-D-glucopyranosyl-(1→2)-[α-D-arabinofuranosyl-(1→4)]-β-D-glucuronopyranosyl}-oleanolic acid-28-O-β-D-glucopyranosyl ester (4), 3-O-{β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-glucuronopyranosyl}-oleanolic acid 28-O-β-D-glucopyranosyl ester (5), 3-O-{β-D-glucopyranosyl-(1→3)-[α-D-arabinofuranosyl-(1→4)]-β-D-glucuronopyranosyl}-oleanolic acid 28-O-β-D-glucopyranosyl ester (6), 3-O-{β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-glucuronopyranosyl}-olean-11,13(18)-diene-28-oic acid-28-O-β-D-glucopyranosyl ester (7), 3-O-{β-D-glucopyranosyl-(1→3)-[α-D-arabinofuranosyl-(1→4)]-β-D-glucuronopyranosyl}-olean-11,13(18)-diene-28-oic acid-28-O-β-D-glucopyranosyl ester (8)	Moderate effects on anti-glycation and antioxidant activities for the treatment of diabetes^42
14	Artocarpus lakoocha (Moraceae) Monkey jack	Heartwood – oxyresveratrol (67)	Anti-glycation (IC50 2.0 mg mL^−1 – five times higher than that of AMG); antioxidant activity (IC50 0.1 mg mL^−1 by DPPH method and 0.43 mg mL^−1 by TBARS method – nearly twice as strong as those of resveratrol)^75
		Heartwood – ethanol extract	Antioxidant and anti-glycation effect (IC50 3.20 mg mL^−1) – could be developed for use in anti-aging cosmetics^96
		Heartwood extract – phytooxyresveratrol (67)	Anti-aging properties – anti-glycation and free radical-scavenging activities^139
15	Asparagus officinalis (Liliaceae) asparagus	Roots – saponin extract	Anti-glycation and antioxidant properties^88
16	Azadirachta indica (Meliaceae) neem, nimb	Leaves – chloroform and methanol extracts	Improves hyperlipidemia and hyperinsulinemia in STZ-induced diabetic rats^89
17	Boswellia sacra (Burseraceae) salvi	Resin – methanol extract fractions	Anti-glycation and antioxidant activities^90
18	Byrsonima crassifolia (Malpighiaceae) nanche	Fruits and seeds – hexane, chloroform and methanol extracts	Inhibitory activity against AGEs formation, IC50 ranging from 94.3 to 138.7 mg mL^−1; antihyperglycemic properties after 4 h of a single oral dose to normoglycemic and STZ-induced severely diabetic rats; can also improve hyperlipidemia and hyperinsulinemia^114
19	Calendula officinalis (Asteraceae) pot marigold	Methanol extract	In vitro anti-glycation and antioxidant activity^92
20	Camellia sinensis (Theaceae) tea plant, chai	Leaf ethanol extract	Antioxidant and anti-glycation effect (IC50 0.04 mg mL^−1) – could be developed for use in anti-aging cosmetics^96
		Green tea extract	Effect on formation of AGEs and AGE crosslinks in collagen in STZ-induced diabetic rats^107
21	Capsicum annuum (Solanaceae) chillies	Seed and pericarp – 70% ethanol extract	Glycation inhibition, anti-α-glucosidase and anti-tyrosinase activities; antioxidant activities^108
22	Cassia tora (Fabaceae) wild senna	Seeds – naphthopyrone glucosides	Inhibitory activity on AGEs formation^118
23	Centella asiatica (Umbelliferae) Mandukaparni	Purified extract	Anti-glycation and anti-inflammatory activities^93
24	Chrysanthemum indicum (Asteraceae) shevanti	Corolla water extract – luteolin (12), kaempferol (13), caffeic acid (52)	Corolla used to treat eye and inflammatory disease; inhibition of the formation of AGEs in BSA/glucose (fructose) systems^46
25	Chrysanthemum morifolium (Asteraceae) florist's chrysanthemum	Corolla water extract – apigenin (14), chlorogenic acid (55), flavonoid glycosides	Corolla used to treat eye and inflammatory disease; inhibition of the formation of AGEs in BSA/glucose (fructose) systems^46
26	Cinnamomum sp. (Lauraceae)	Bark extract – procyanidin B2 (44)	Inhibition of AGE formation by 80%; exerts various protective effects on glucose consumption impaired by high MGO concentrations^63
27	Cinnamomum zeylanicum (Lauraceae) cinnamon	Bark aqueous extract – (+)-catechin (42), (−)-epicatechin (43), procyanidin B2 (44)	Extract – in vivo increase in cellular glucose uptake; decrease in serum glucose, triglyceride, LDL cholesterol, and total cholesterol in diabetics; 42, 43, 44 – inhibitory effects on the formation of AGEs, antioxidant activities, trapping of reactive carbonyl species^62
28	Coffea arabica (Rubiaceae) Arabian coffee	Coffee fraction	Anti-glycation and antioxidative properties^109
29	Connarus ruber (Connaraceae) Danis Vine	Bark extract	Inhibition of dimerization of lysozyme by D-ribose, inhibition of melanin formation by B16 melanoma cells; DPPH radical-scavenging effect^126
30	Cordia platythyrsa (Boraginaceae) West African cordia	Methyl orsellinate (78)	In vitro anti-glycation activity^81
31	Cordia sinensis (Boraginaceae) grey-leaved cordia	Ethyl acetate-soluble fraction – kaempferol-3-O-β-D-glucopyranoside (28), kaempferide-3-O-β-D-glucopyranoside (29), kaempferol-3-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside (30), kaempferide-3-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside (31), quercetin-3-O-β-D-glucopyranoside (32), trans-caffeic acid (52), rosmarinic acid (53), methyl rosmarinate (54), protocatechuic acid (63)	Anti-glycation, anti-inflammatory and antioxidant activities^53
32	Coriandrum sativum (Umbelliferae) dhanne	Ethanol extract	Anti-glycation and antioxidant activities^104
33	Cornus officinalis (Cornaceae) dogwood	7-O-Galloyl-D-sedoheptulose (65)	Reduced renal glucose, AGE formation, and oxidative stress in diabetic rats; no toxicity at 20 and 100 mg (ref. 73)
34	Crataegus oxyacantha (Rosaceae) hawthorn	Extract	Anti-glycation effect^111
		Berry – mixed herbal extract (MHE)	Double-blind, placebo-controlled, parallel-group study to assess the anti-glycation effect – results suggest an improvement in the symptoms related to quality of life (QOL), inhibits the generation of CML and AGEs in individuals with abnormal sugar metabolism^97
35	Cratoxylum cochinchinense (Hypericaceae) yellow cow wood	Extract; YCT extract containing at least 90% mangiferin as active constituent	Extract – antioxidant activity; inhibition of the formation of AGEs; strong inhibition of hypochlorous acid-induced DNA damage; YCT – significantly higher activity in assays of phospholipid peroxidation and superoxide and peroxynitrite scavenging^127
36	Cuminum cyminum (Umbelliferae) cumin	Seeds – methanolic extract	Antihyperglycemic activity and inhibition of AGEs formation in STZ-induced diabetic rats^115
37	Cupressus sempervirens var. horizontalis (Cupressaceae) Mediterranean cypress	Branchlet and fruit essential oil	Anti-glycation and antioxidant properties^128
38	Curcuma longa (Zingiberaceae) turmeric	Ethanol extract	Anti-glycation and antioxidant activities^104
39	Cyperus rotundus (Cyperaceae) nut grass	Hydroalcoholic extract	Suppresses AGE formation and protein oxidation in BSA – fructose model^94
40	Dendrobium huoshanense (Orchidaceae)	Stem – polysaccharide (DHP-W2)	In vitro anti-glycation activity in dose- and time- dependent manner;^83 hypoglycemic and anti-cataract activities through inhibition of protein glycation^84
41	Dimocarpus longan (Sapindaceae) longan	Fruit pericarp – polysaccharides	Anti-glycation activity^85
42	Disterigma rimbachii (Ericaceae)	Leaves – ethanol extract	Potent inhibitor of AGEs^119
43	Duranta repens (Verbenaceae) golden dewdrop	Stem and bark – methanolic extract – (+)-5′-methoxyisolariciresinol (76), (−)-5′-methoxyisolariciresinol (77)	At 500 μg mL^−1, 8.9 and 44.6% inhibition, respectively, of AGEs; free radical-scavenging activities^80
44	Emblica officinalis (= Phyllanthus emblica) (Euphorbiaceae) Indian gooseberry	Fruit – methanol extract	α-Amylase and α-glucosidase inhibition, anti-glycation activity and antioxidant activity; significant inhibition of the oxidation of LDL under in vitro conditions^95
		Fruit – ethanol extract	Antioxidant and anti-glycation effect (IC50 0.02 mg mL^−1) – could be developed for use in anti-aging cosmetics^96
45	Eremurus persicus (Liliaceae) Serish	5,6,7-Trimethoxycoumarin (50)	Plant – used as an antidiabetic agent in Iranian traditional medicine; 50 – anti-glycation properties, at 3 mM 75% inhibition compared with 83% inhibition of the standard rutin^14
46	Erigeron annuus (Asteraceae) Eastern daisy fleabane	Flowers – erigeroflavanone (39)	Anti-glycation and aldose reductase inhibitory activity^59
47	Eulophia ochreata (Orchidaceae) golden-yellow eulophia	Tubers – methanolic and aqueous extracts	Plant – reported to manage diabetes in traditional medical systems; extracts – α-amylase inhibitory activity (IC50 0.87 and 1.25 mg mL^−1, respectively), antioxidant activity; aqueous extract –anti-glycation potential^129
48	Faujasiopsis flexuosa (Asteraceae)	Aqueous extract, n-butanol fraction	Anti-glycation activities (p < 0.05) comparable to AMG with no apparent cytotoxicity; antioxidant activity^98
49	Glycine max (Fabaceae) soybean	Soybean extract – isoflavone (48) coumestrol (51)	Binds with AGEs, AGE-scavenging activity^68
50	Houttuynia cordata (Saururaceae) lizard tail, heart-leaved houttuynia	Mixed herbal extract (MHE)	Double-blind, placebo-controlled, parallel-group study to assess the anti-glycation effect – improvement in the symptoms related to quality of life (QOL), inhibits the generation of CML and AGEs^97
		Extract	Anti-glycation effect^111
51	Hydnora johannis (Hydnoraceae)	Roots – 70% ethanol extract – (+)-catechin (42), protocatechuic acid (63)	In vitro anti-glycation and antioxidant properties^64
52	Ilex paraguariensis (Aquifoliaceae) mate	Water extract	Anti-glycation activity – prevents MGO-induced inhibition of plasminogen and antithrombin III^113
		Polyphenol-rich extract	In vitro inhibition of AGEs formation, potency comparable with extract of green tea and AMG^140
		Oleanolic acid (3), caffeic acid (52), 5-caffeoylquinic acid (55)	Anti-glycation effect^35
53	Iris loczyi (Iridaceae)	Whole plant ethanol extract – arborinone (9) 5,7-dihydroxy-2′,6-dimethoxyisoflavone (47)	α-Glucosidase inhibition and anti-glycation agent^43
54	Iris unguicularis (Iridaceae)	Rhizomes ethanol extract – kaempferol (13), 8-methoxyeriodictyol (23)	α-Glucosidase inhibition and anti-glycation agent^43
55	Juglans regia (Juglandaceae) walnut	Methanol extract	In vitro anti-glycation and antioxidant activities^92
56	Juniperus oblonga (Cupressaceae) Chatanah	Fruits and branches – essential oils	Anti-glycation and antioxidant activities^130
57	Mallotus philippensis (Euphorbiaceae) Kamala tree	Bark methanolic extract – bergenin (74)	Moderate anti-glycation activity (IC50 = 75.69 μM)^78
58	Malpighia emarginata (Malpighiaceae) acerola	Fruit extract	Anti-aging effects such as prevention of UV damage, anti-glycation effects, and enhancement of synthesis of type IV and type I collagens in human cultured fibroblasts^117
59	Melissa officinalis (Lamiaceae) lemon balm	Extract	Inhibitory effect on the formation of AGEs^120
60	Mentha piperita (Lamiaceae) peppermint	Ethanol extract	Anti-glycation and antioxidant activities^104
61	Morus alba (Moraceae) mulberry	Leaf – 50% ethanol extract	In vitro anti-glycation (IC50 16.4 μg mL^−1) and free radical-scavenging activity (IC50 61.7 μg mL^−1); 1 g kg^−1 for six weeks to STZ-induced diabetic rats – antihyperglycemic, antioxidant and anti-glycation effects in chronic diabetic rats – may be beneficial as food supplement for diabetics^131
62	Murraya koenigii (Rutaceae) curry leaf tree	Ethanol extract	Anti-glycation and antioxidant activities^104
63	Musa paradisiaca (Musaceae) banana	Inflorescence – methanolic extract, fractions	Anti-glycation activity (IC50 31.00 μg mL^−1); free radical-scavenging and anti-glycation activities; ethyl acetate fraction – DPPH method (IC50 9.80 μg mL^−1), 2,2′-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) method (IC50 13.5 μg mL^−1), superoxide radical-scavenging (IC50 26.40 μg mL^−1), hydroxyl radical-scavenging (IC50 19.71 μg mL^−1), nitric oxide radical-scavenging activity (IC50 25.73 μg mL^−1)^110
64	Myristica fragrans (Myristicaceae) nutmeg	80% acetone extract	Anti-glycation activity – IC50 0.20 μg mL^−1 and antioxidant activity IC50 0.10 μg mL^−1 (ref. 105)
65	Nelumbo nucifera (Nelumbonaceae) Indian lotus	Leaf extract	Antioxidant activity in the DPPH and total ROS assay; inhibitory activities on RLAR and AGE formation^99
66	Nepeta juncea (Lamiaceae)	Aerial parts – methanolic extract, fractions	Glycation inhibitory activity – n-hexane fraction 74.3%, chloroform fraction 72.4% and water fractions 64.7% inhibition^121
67	Nephelium lappaceum (Sapindaceae) rambutan	Rind extract – geraniin (73)	Antioxidant activity; free radical-scavenging activity; in vitro hypoglycemic activity; inhibition of carbohydrate-hydrolysing enzymes (α-glucosidase and α-amylase); effective in preventing polyol and AGEs formation^77
68	Ocimum tenuiflorum (=O. sanctum) (Lamiaceae) holy basil	Aqueous extract, n-butanol fractions	Antioxidant activity; anti-glycation activities comparable to AMG with no apparent cytotoxicity^98
69	Ophiopogon japonicus (Asparagaceae) monkey grass	Roots – saponin extract	Anti-glycation and antioxidant properties^125
70	Opuntia monacantha (Cactaceae)	Cladodes – polysaccharide aqueous extract	Inhibition of the formation of AGEs in time- and dose-dependent manner^86
71	Origanum majorana (Lamiaceae) sweet marjoram	Leaves – methanolic extract	In vitro inhibitory effects on the formation of AGEs; glycation inhibitory activity^132
72	Osbeckia octandra (Melastomataceae)	Leaf decoction	Used in the treatment of diabetes in Ayurvedic medicine; anti-glycation activity; antioxidant activity by ABTS and DPPH method^91
73	Osyris wightiana (Santalaceae) Popli	Aerial parts – nicotiflorin (kaempferol-3-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside or kaempferol-3-O-rutinoside) (30)	In vitro anti-glycation activity^54
74	Otostegia persica (Lamiaceae) golder	Aerial parts – 3′,7-dihydroxy-4′,6,8-trimethoxyflavone (22)	Plant used traditionally in Iran for the treatment of malaria, fever and diabetes; 22 at 3 mM 65% inhibition of glycation as compared to the standard inhibitor, rutin, with 83% inhibition^141
75	Panax notoginseng (Araliaceae) Himalayan ginseng	Roots – saponin extract	Anti-glycation and antioxidant properties^125
76	Passiflora alata (Passifloraceae) passion flower	Leaf hydroalcoholic extract	Antioxidant activities; in vivo iron-induced cell death, quantified by lactate dehydrogenase leakage, effective protection against protein damage induced by iron and glucose^133
77	Passiflora edulis (Passifloraceae) passion fruit	Leaf hydroalcoholic extract	Antioxidant activities; in vivo iron-induced cell death, quantified by lactate dehydrogenase leakage, effective protection against protein damage induced by iron and glucose^133
78	Passiflora manicata (Passifloraceae) red passion flower	Leaf – aqueous extract	In vitro and in vivo anti-glycation and antioxidant activities^134
79	Peltophorum pterocarpum (Fabaceae) copperpod	Leaves, bark – ethanol extract	Inhibition of aldose reductase^122
80	Petroselinum crispum (Apiaceae) parsley	Ethanol extract	Anti-glycation and antioxidant activities^104
81	Piper auritum (Piperaceae) eared pepper	Leaves – hexane extract	Antioxidant and anti-glycation activity^135
82	Plantago asiatica (Plantaginaceae) Asian plantain	Methanol extract – plantamajoside (56)	Extract – at 0.1 mg mL^−1, 41% inhibition of AGEs; 56 at 10 mM 95.2% in vitro anti-glycation activity as compared to 89.8% glycation inhibitory activity for AMG at 10 mM; antioxidant activity^15
83	Polygala tenuifolia (Polygalaceae) Chinese senaga root	Root bark – saponin extract	Anti-glycation and antioxidant properties^125
84	Polygonum multiflorum (Polygonaceae) many-flowered knotweed	2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (THSG) (68)	Inhibits the formation of AGEs in a dose-dependent manner by trapping reactive MGO under physiological conditions (pH 7.4, 37 °C); antioxidant, anti-inflammatory properties^26
		Roots – polysaccharide (PMP-1), polysaccharide (PMP-2)	Antioxidant activity, PMP-2 – suppression of AGEs formation^82
85	Prosthechea michuacana (Orchidaceae)	Bulbs – chloroform extract – α,α′-dihydro-3′,5′,2-trimethoxy-3-hydroxy-4-acetoxy-4′-isopentenylstilbene (69), 5-[2-(3-hydroxy-5-methoxyphenyl)ethyl]-2-methoxyphenol (gigantol) (70), 4,6,7-Trihydroxy-2-methoxy-8-(3-methylbut-2-enyl)phenanthren-1,1′-4′,6′,7′-trihydroxy-2′-methoxy-8′-(3-methylbut-2-enyl)phenanthrene (71)	Bulbs – used as anti-inflammatory agents; in vitro inhibition of AGEs^27
86	Psidium guajava (Myrtaceae) guava tree	Extract	Inhibitory effect in a physiomimic system on sensitivity of glucose or glyoxal-induced LDL glycation^142
		Leaf extract – quercetin (20), (+)-catechin (42), gallic acid (61)	Extract – at 50 mg mL^−1 95% inhibitory effect on the formation of α-dicarbonyl compounds; inhibitory effects on the production of Amadori products; 20, 42 and 61 at 100 mg mL^−1 over 95%, 80% and 80% inhibitory effects, respectively, on BSA glycation^19
		Leaf extract – phenolic compounds	Decrease in fasting blood glucose levels in STZ-induced diabetic rats; decreased glycation and lipid peroxidation products; improved the antioxidant status in a dose-dependent manner^143
87	Pterocarpus marsupium (Fabaceae) Indian kino tree	Bark extract	Anti-glycation and antioxidation, optical anti aging action against UV-B; acts to prevent hair loss as it suppresses glycation of hair follicle tissues^100
88	Punica granatum (Punicaceae) Pomegranate	Fruit juice – polysaccharide	Anti-glycation and antioxidant activity – can be used in delaying or preventing complications of diabetes and aging^87
89	Pueraria lobata (Fabaceae) kudzu	Root – puerarin (49)	Inhibit AGEs formation^69
90	Rhodiola rosea (Crassulaceae) golden root	Root extract	Anti-glycation activity^123
91	Rhus verniciflua (Anacardiaceae) lacquer tree	Extract – ethyl acetate fraction – ethyl gallate (62) protocatechuic acid (63) pentagalloyl glucose (64)	Inhibits recombinant human aldose reductase, accumulation of AGEs in BSA-glucose model system^72
		Extract – ethyl acetate fraction – butein (41)	A potent inhibitor of recombinant human ALR2 (rhALR2), IC50 0.7 μM; strongly inhibits AGEs accumulation in vitro^61
92	Rosa davurica (Rosaceae) Amur rose	Root methanol extract – (+)-catechin (42)	Extract and 42 – antioxidant activity in a DPPH radical-scavenging assay; dose-dependent inhibition of AGEs; extract – immunostimulatory activity in a pro-inflammatory macrophage assay^144
93	Rosmarinus officinalis (Lamiaceae) rosemary	Acetone extract, aqueous extract	Anti-glycation-related features, viz. At 0.1 mg mL^−1 suppression of relative electrophoretic mobility; at 1.3 mg mL^−1 anti-induction of conjugated dienes; at 0.5 mg mL^−1 inhibition of thiobarbituric acid reactive substances production and AGEs formation; at 0.1 mg mL^−1 blocks glucose incorporation; at 0.05 mg mL^−1 effective against antithrombin III^106
94	Salvia chloroleuca (Lamiaceae)	Methanol extract	Anti-glycation and antioxidant activities^103
95	Salvia miltiorrhiza (Lamiaceae) danshen	Rosmarinic acid (53)	α-Glucosidase and AGEs formation – inhibitory activities (IC50 0.04 μM as against AMG with IC50 of 0.11 μM)^145
96	Salvia mirzayanii (Lamiaceae)	Methanol extract	Anti-glycation and antioxidant activities^103
97	Salvia reuterana (Lamiaceae)	Aerial parts – methanol extract	Anti-glycation, antioxidant activity^13
98	Salvia santolinifolia (Lamiaceae)	Methanol extract	Anti-glycation and antioxidant activities^103
99	Saraca asoca (Caesalpiniaceae) Ashoka	Flowers	Flowers – widely used against diabetes in Himalayan tribes of India^146
		Flowers – flavonoid fraction	Inhibition of α-glucosidase, α-amylase and in vivo LDL oxidation – therapeutic potential as an antihyperglycemic agent^101
100	Solanum xanthocarpum (Solanaceae) Indian nightshade	Fruits – crude methanolic fraction	Anti-glycation activity^124
101	Stelechocarpus cauliflorus (Annonaceae) burahol	Leaves – engeletin (36), astilbin (37)	36 – inhibition of recombinant human aldose reductase, IC50 26.7 and 1.16 μM; suppressing AGE formation; 37 more potent than 36 (ref. 58)
102	Syzygium samarangense (Myrtaceae) pink wax apple	Fruit – vescalagin (75)	Protective effects against MGO-induced inflammation and carbohydrate metabolic disorder in rats^79
103	Tamarindus indica (Caesalpiniaceae) tamarind tree	Seed coat – ethanol extract	Antioxidant and anti-glycation effect (IC50 0.01 mg mL^−1) – could be developed for use in anti-aging cosmetics^96
104	Terminalia bellerica (Combretaceae) baheda	Fruit – methanol extract	α-Amylase and α-glucosidase-inhibiting and anti-glycation activities; antioxidant activity; significant inhibition of the oxidation of LDL under in vitro conditions^95
		Fruit – ethanol extract	Antioxidant and anti-glycation effect (IC50 0.02 mg mL^−1) – could be developed for use in anti-aging cosmetics^96
105	Terminalia chebula (Combretaceae) chebulic myrobalan, hirda	Fruit – aqueous extract – chebulic acid (66)	Preventive effects on AGEs-induced endothelial cell dysfunction^74
106	Teucrium polium (Lamiaceae) cat thyme	Extract – ethyl acetate fraction	In vitro suppression of the formation of AGEs and protein oxidation^94
		Aerial parts – apigenin (14), rutin (21)	Plant used in Iran as a drug to treat hyperglycemia, 14 and 21 – in vitro free radical-scavenging and anti-glycation activity; inhibitory effects on the production of AGEs from bovine serum albumin in the presence of glucose; prevents oxidative stress condition induced by STZ and increases insulin release in rat islets^56
107	Thymus vulgaris (Lamiaceae) common thyme	Ethanol extract	Anti-glycation and antioxidant activities^104
108	Vaccinium barandanum (Ericaceae)	Leaves – ethanol extract	Potent inhibitor of AGEs, IC50 4.2 – 16.2 μg mL^−1 (ref. 119)
109	Vaccinium consanguineum (Ericaceae)	Leaves – ethanol extract	Potent inhibitor of AGEs, IC50 4.2 – 16.2 μg mL^−1 (ref. 119)
110	Vaccinium gaultheriifolium (Ericaceae)	Leaves – ethanol extract	Potent inhibitor of AGEs, IC50 4.2 – 16.2 μg mL^−1 (ref. 119)
111	Vaccinium macrocarpon (Ericaceae) cranberry	Berries – phytochemical fractions	Inhibition of glycation of human hemoglobin and serum albumin by scavenging reactive carbonyls^147
112	Vaccinium poasanum (Ericaceae)	Leaves – ethanol extract	Potent inhibitor of AGEs, IC50 4.2 – 16.2 μg mL^−1 (ref. 119)
113	Vaccinium tonkinense (Ericaceae)	Leaves – ethanol extract	Potent inhibitor of AGEs, IC50 4.2 – 16.2 μg mL^−1 (ref. 119)
114	Vaccinium vitis-idaea (Ericaceae) cowberry	Berries – 80% ethanolic extract – quercetin-3-O-galactoside (33), cyanidin-3-O-galactoside (40), (+)-catechin (42)	Anti-glycation activities – IC50 2.86 μg mL^−1 (6.16 μM), 3.10 μg mL^−1 (6.40 μM) and 8.35 μg mL^−1 (28.75 μM), respectively; provides pharmacological validation for the traditional use of V. vitis-idaea as an antidiabetic remedy^57
115	Viola betonicifolia (Violaceae) arrowhead violet	Whole plant – 2,4-dihydroxy-5-methoxycinnamic acid (57)	Moderate anti-glycation activity (IC50 = 355 μM) similar to the standard rutin (IC50 = 294 μM); antioxidant activity – inhibition against DPPH free radicals with IC50 = 124 μM.^70
116	Viscum album (Fabaceae) European mistletoe	4′-O-[β-D-Apiosyl-(1→2)-β-D-glucosyl]-5-hydroxyl-7-O-sinapylflavanone (24), 5,7-dimethoxy-4′-O-β-D-glucopyranosylflavanone (25), 4′,5-dimethoxy-7-hydroxyflavanone (26), 5,7-dimethoxy-4′-hydroxyflavanone (27), 3-(4-acetoxy-3,5-dimethoxyphenyl)-2E-propenyl-β-D-glucopyranoside (58), 3-(4-hydroxy-3,5-dimethoxyphenyl)-2E-propenyl-β-D-glucopyranoside (59)	Anti-glycation activity, IC50 range 264.5–413.9 μM (ref. 51)
117	Vitis vinifera (Vitaceae) grapes	Extract	Anti-glycation effect^111
		Seed products	In vitro inhibition of the formation of AGEs^148
		Leaves – mixed herbal extract (MHE)	Double-blind, placebo-controlled, parallel-group study to assess the anti-glycation effect – improvement in the symptoms related to quality of life (QOL), inhibits the generation of CML and AGEs in individuals with abnormal sugar metabolism^97
		Red grape skin extract	Inhibition of AGEs^112
118	Withania somnifera (Solanaceae) ashwagandha, Indian ginseng	Withania	Suppression of AGE-linked fluorescence of rat's tail tendon collagen; antioxidant and free radical-scavenging activities^102
119	Zingiber officinale (Zingiberaceae) ginger, adrak, ale	Rhizome – ethyl acetate extract	DPPH radical-scavenging activity (IC50 4.59 μg mL^−1); at 5 μg mL^−1 enhances glucose uptake in cell lines; anti-glycation activity (IC50 290.84 μg mL^−1)^149
		Ethanol extract	Anti-glycation and antioxidant activities^104
		80% acetone extract	Antioxidant and anti-glycation activity (IC50 0.285 μg mL^−1)^105

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Table 2 Phytochemicals with anti-glycation activity

Sr. no.	Compound	Activity
1	Arjunolic acid (10)	Effective in preventing the formation of ROS, RNS, HbA1C, AGEs, and oxidative stress signaling cascades and offers protection against PARP-mediated DNA fragmentation – can provide evidence for its potential uses in diabetic patients^44
2	Baicalein (15)	At 50 mM in vitro gradual decrease in aspartate aminotransferase (AST) activity^47
3	Baicalin (16)	At 50 mM in vitro gradual decrease in aspartate aminotransferase activity^47
4	β-Carotene (11)	Inhibitory effects on the formation of AGEs; prevention of secondary structural changes in BSA due to thermal glycation^45
5	(+)-Catechin (42)	Protective activity against glycation, tryptophan damage, browning and main-chain fragmentation of proteins incubated with glucose^48
		Introduction into LDL particles protects the lipoprotein against glycotoxin-mediated adverse effects^49
6	(−)-Epicatechin (43)	Protective activity against glycation, tryptophan damage, browning, and main-chain fragmentation of proteins incubated with glucose^48
7	Epigallocatechin gallate (45)	Decreased AGE-stimulated gene expression; inhibits the AGE-mediated activation and DNA-binding activity of NF-κB by suppressing the degradation of its inhibitory protein IκBα in the cytoplasm^65
		Under hyperglycemic conditions, prevents intracellular AGEs formation and the production of pro-inflammatory cytokines in monocytes^66
		Limits LDL oxidation and glycation under high-glucose conditions mimicking diabetes^150
8	Hydroxycitric acid	At 2.5 mM in vitro gradual decrease in aspartate aminotransferase activity^47
9	7-Hydroxyflavone (17)	Protective activity against glycation, tryptophan damage, browning, and main-chain fragmentation of proteins incubated with glucose^48
10	Kaempferol (13)	Protective activity against glycation, tryptophan damage, browning, and main-chain fragmentation of proteins incubated with glucose^48
		Introduction into LDL particles protects the lipoprotein against glycotoxin-mediated adverse effects^49
		Short-term feeding of aged rats modulated AGE accumulation and RAGE expression; suppressed AGE-related NF-κB activation and its pro-inflammatory genes through the suppression of AGE-induced NADPH oxidase activation^52
11	Luteolin (12)	Introduction into LDL particles protects the lipoprotein against glycotoxin-mediated adverse effects^49
12	Morin (34)	Protective activity against glycation, tryptophan damage, browning, and main-chain fragmentation of proteins incubated with glucose^48
13	Myricetin (35)	Protective activity against glycation, tryptophan damage, browning, and main-chain fragmentation of proteins incubated with glucose^48
14	Naringenin (18)	Introduction into LDL particles protects the lipoprotein against glycotoxin-mediated adverse effects^49
		Protective activity against glycation, tryptophan damage, browning, and main-chain fragmentation of proteins incubated with glucose^48
15	Naringin (19)	Introduction into LDL particles protects the lipoprotein against glycotoxin-mediated adverse effects^49
16	Oligomeric procyanidins (44) (lotus seedpods)	In vitro anti-glycation activity^151
17	Oleanolic acid (3)	Blood glucose-lowering and weight loss effect in STZ-induced diabetic animals; in an insulin-resistant model it may promote insulin signal transduction and inhibit oxidative stress-induced hepatic insulin resistance and gluconeogenesis^40
		Anti-glycation effect in kidney of diabetic mice^41
18	Quercetin (20)	Protective activity against glycation, tryptophan damage, browning, and main-chain fragmentation of proteins incubated with glucose^48
		Introduction into LDL particles protects the lipoprotein against glycotoxin-mediated adverse effects^49
		In vitro protection against protein damage (AGEs formation)^55
19	Rutin (21)	Protective activity against glycation, tryptophan damage, browning, and main-chain fragmentation of proteins incubated with glucose^48
		In vitro inhibition of the formation of glycation products in collagen type I induced by glucose^152
		Introduction into LDL particles protects the lipoprotein against glycotoxin-mediated adverse effects^49
20	Silymarin (38)	12 Week administration in STZ-induced diabetic rats – effect on AGE formation and a specific ligand of a receptor for AGEs – supplementation may reduce the burden of AGEs in diabetics and may prevent resulting complications^57

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2. Plant products as anti-glycation agents

2.1 Terpenoids with anti-glycation activity

Terpenoids possess wide structural diversity and exhibit a broad spectrum of biological activities (Fig. 4). Wide structural variation has also been observed in phytochemicals with anti-glycation activity. In vivo studies showed a chloroform extract of Aegle marmelos leaves in streptozotocin (STZ)-induced diabetic rats for 60 days prevented kidney damage and other secondary complications. The extract, at 16 μg, inhibited protein glycation by 44.33%, pentosidine formation by 59.31%, and effectively inhibited protein carbonyl formation. Bio-guided fractionation revealed a monoterpene, limonene (1), as the bioactive component responsible for the anti-glycation activity. The extract also exhibited antioxidant activity in ferric-reducing and 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) assays (85.26% scavenging, IC₅₀ 26 μg mL⁻¹).³⁸

Fig. 4 Terpenoids with anti-glycation activity.

Labdane diterpene, labdadiene (2), isolated from the rhizomes of Alpinia zerumbet exhibited inhibitory activities on the formation of fructosamine adducts and α-dicarbonyl compounds with IC₅₀ 51.06 μg mL⁻¹ and this activity was found to be similar to that of the flavonoids quercetin (20) and rutin (21). These results indicate that 2 is a potent anti-glycation agent which was found to inhibit AGE formation and could be used to prevent glycation-associated complications in diabetes.³⁹

Triterpenoids of wide structural diversity have been reported to exhibit anti-glycation activity. Oleanolic acid (3), a pentacyclic triterpene carboxylic acid, along with two phenolic acids, caffeic acid (52) and chlorogenic acid (55) from Ilex paraguariensis, contributed to anti-glycation activity. The effect was found to be more potent than the anti-glycation effect of standard AMG, a well-known anti-glycation agent.³⁵ In another study, 3 exhibited a significant blood glucose-lowering and weight-reducing effect in STZ-induced diabetic models. In an insulin-resistant model, it promoted insulin signaling and inhibited oxidative stress-induced hepatic insulin resistance and gluconeogenesis.⁴⁰ Compound 3 has also been found to exhibit an anti-glycation effect in the kidney of diabetic mice.⁴¹

Glycoside esters of oleanolic acid, viz. 3-O-{β-D-glucopyranosyl-(1→2)-[α-D-arabinofuranosyl-(1→4)]-β-D-glucuronopyranosyl}-oleanolic acid 28-O-β-D-glucopyranosyl ester (4), 3-O-{β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-glucuronopyranosyl}-oleanolic acid 28-O-β-D-glucopyranosyl ester (5) and 3-O-{β-D-glucopyranosyl-(1→3)-[α-D-arabinofuranosyl-(1→4)]-β-D-glucuronopyranosyl}-oleanolic acid 28-O-β-D-glucopyranosyl ester (6), isolated from the root bark of Aralia taibaiensis, have been found to exhibit moderate anti-glycation and antioxidant activities, which correlate with the use of this plant in the treatment of diabetes. Two oleanolic acid glycosides with an 11,13-diene system, viz. 3-O-{β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-glucuronopyranosyl}-olean-11,13(18)-diene-28-oic acid 28-O-β-D-glucopyranosyl ester (7) and 3-O-{β-D-glucopyranosyl-(1→3)-[α-D-arabinofuranosyl-(1→4)]-β-D-glucuronopyranosyl}-olean-11,13(18)-diene-28-oic acid 28-O-β-D-glucopyranosyl ester (8), also exhibited the same activity.⁴² From the whole plant of Iris loczyi, arborinone (9), a pentacyclic triterpenoid, along with 5,7-dihydroxy-2′,6-dimethoxyisoflavone (47), was isolated, which inhibited the activity of α-glucosidase (a therapeutic target for the treatment of carbohydrate-mediated diseases) and had anti-glycation potential.⁴³ Arjunolic acid (10), a pentacyclic triterpenic acid responsible for the major bioactivity of Terminalia arjuna, a plant used as a heart tonic in Ayurveda, has been found to be effective in preventing the formation of HbA1c, ROS, AGEs, and oxidative stress signaling, and protecting against poly(ADP-ribose)polymerase (PARP)-mediated DNA fragmentation. This diverse biological activity can provide evidence for its potential uses in diabetic patients.⁴⁴

The tetraterpenoid β-carotene (11), which is a precursor of vitamin A, (a metabolite present in many plants) has been found to exhibit an inhibitory effect on the formation of AGEs and prevent secondary structural changes in BSA due to thermal glycation.⁴⁵

2.2 Flavonoids with anti-glycation activity

A number of flavonoids have been reported to exhibit promising anti-glycation activity (Fig. 5). The flavone luteolin (12) and flavonol kaempferol (13) were isolated from an extract of the corolla of Chrysanthemum indicum, along with the phenylpropenoic acid caffeic acid (52), as active principles responsible for inhibition of the formation of CML and other AGEs in in vitro studies with BSA/glucose (fructose) systems. Chrysanthemum species have been demonstrated to inhibit aldose reductase, suggesting that these plants have therapeutic benefits against diabetic disease. Apigenin (14), another biologically important flavone, along with chlorogenic acid (55) isolated from Chrysanthemum morifolium, has been reported to exhibit the same activity.⁴⁶ The introduction of luteolin (12) into low-density lipoprotein (LDL) particles is reported to offer protection against glycotoxin-mediated adverse effects. Two flavones, baicalein (15) and its glucuronic acid ester baicalin (16) obtained from the Chinese medicinal plant, Scutellaria baicalensis, at 50 mM, are reported to induce a gradual decrease in vitro in the activity of aspartate aminotransferase (AST), an enzyme associated with inflammation and myocardial infarctions.⁴⁷ 7-Hydroxyflavone (17) was also found to exhibit a protective effect against glycation, tryptophan damage, browning, and main-chain fragmentation of proteins incubated with glucose.⁴⁸

Fig. 5 Flavonoids with anti-glycation activity.

The dihydroflavone naringenin (18), its glycoside naringin (19), the flavonols kaempferol (13) and quercetin (20), and the flavonol glycosides rutin (21) and (+)-catechin (42) have also been reported to exhibit anti-glycation activities with varying inhibitory potentials.⁴⁹ Otostegia persica is used in Iranian traditional medicine for the treatment of malaria, fever and diabetes and from the aerial parts of this plant 3′,7-dihydroxy-4′,6,8-trimethoxyflavone (22) has been isolated as the active principle responsible for the glycation inhibitory activity. This flavone, at 3 mM concentration, exhibited 65% inhibition as compared with 83% inhibition obtained for rutin (21).⁵⁰ Like naringenin (18) and naringin (19), a few other dihydroflavones are also reported to exhibit a broad spectrum of anti-glycation activities. These include 8-methoxyeriodictyol (23), isolated from the rhizomes of Iris unguicularis with inhibitory activity against α-glucosidase,⁴³ and four dihydroflavones, 4′-O-[β-D-apiosyl-(1→2)-β-D-glucosyl]-5-hydroxy-7-O-sinapylflavanone (24), 5,7-dimethoxy-4′-O-β-D-glucopyranosylflavanone (25), 4′,5-dimethoxy-7-hydroxyflavanone (26) and 5,7-dimethoxy-4′-hydroxyflavanone (27) isolated from European mistletoe Viscum album with promising anti-glycation potential.⁵¹

Many flavonols and their glycoside derivatives are reported to exhibit anti-glycation activities. Kaempferol (13), as mentioned earlier, is reported to inhibit α-glucosidase and the formation of CML and other AGEs in BSA/glucose (fructose) systems.^43,46,48 Its protective activity was also observed in another study by its introduction into LDL particles to protect the lipoprotein against glycotoxin-mediated adverse effects.⁴⁹ Short-term feeding of 13 to aged rats was found to modulate AGE accumulation and RAGE expression.⁵² Kaempferol-3-glucoside (28), its 4′-methyl ether derivative (29), the diglycoside kaempferol-3-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside (30) and its 4′-methyl ether, kaempferide-3-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside (31), isolated from Cordia sinensis, were found to exhibit anti-glycation activity along with anti-inflammatory and antioxidant potential.⁵³ Nicotiflorin (kaempferol-3-rutinoside or kaempferol-3-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside) (30) isolated from Osyris wightiana has been found to be responsible for in vitro anti-glycation activity.⁵⁴

Quercetin (20) is an important flavonol with a broad spectrum of biological activities. Psidium guajava leaf extract inhibited glycation processes in an albumin/glucose model system and 20 was identified as one of the active principles with over 80% inhibitory effect. It has been found to exhibit a strong inhibitory effect on glycation of albumin – at 100 μg mL⁻¹ concentration >95% inhibition was observed.¹⁹ As mentioned earlier, kaempferol (13) and quercetin (20) also exhibited a protective effect against glycation⁴⁸ and provided in vitro protection against protein damage.⁵⁵ In another study, quercetin-3-glucopyranoside (32) was found to exhibit a broad range of bioactivities. It was isolated from Cordia sinensis as a potent anti-glycation agent and also exhibited anti-inflammatory and antioxidant properties.⁵³ Teucrium polium is used in Iran as a drug to treat hyperglycemia. From this plant, rutin (quercetin-3-O-rutinoside) (21) and the flavone apigenin (14) were isolated and confirmed as in vitro free radical-scavenging and anti-glycation agents. These two flavonoids also exhibited strong inhibitory effects on the formation of AGEs from BSA in the presence of glucose in terms of protein carbonyl formation and loss of protein thiols. They also prevented oxidative stress conditions induced by STZ and were found to increase insulin release.⁵⁶ Quercetin-3-O-galactopyranoside (33), obtained from an ethanol extract of berries of Vaccinium vitis-idaea, exhibited anti-glycation activity with IC₅₀ 2.86 μg mL⁻¹ (6.16 μM). The extract demonstrated concentration-dependent inhibition of AGE formation as shown by fluorometric detection of AGEs and immunodetection of CML adducts of albumin. These results demonstrated that the flavonoid components of the berry extract are potent anti-glycation agents and provided pharmacological validation for the traditional use of V. vitis-idaea as an antidiabetic remedy.⁵⁷ The flavanols morin (34) and myricetin (35), like other flavonoids, showed protective activity against glycation.⁴⁸ From the leaves of Stelechocarpus cauliflorus, two dihydroflavonols, viz. dihydrokaempferol-3-rhamnoside, engeletin (36), and dihydroquercetin-3-rhamnoside, astilbin (37), have been isolated which provided inhibition of recombinant human aldose reductase (IC₅₀ 1.16 μM and 26.7 μM, respectively). These two flavonols also exhibited suppression of AGE formation, astilbin being a more potent anti-glycation agent than engeletin.⁵⁸ Silymarin, a complex flavonoid (38), acts as a specific RAGE blocker and may reduce the burden of AGEs in diabetic patients. Silymarin (38) has also been identified as a novel antioxidant with anti-glycation properties in both in vitro and in vivo systems.⁵⁹ Erigeroflavanone (39), a novel 2,3-dioxygenated flavanone, exhibited inhibitory activity against protein glycation and aldose reductase.⁶⁰

The anthocyanin cyanidin-3-O-D-galactoside (40), isolated from an ethanolic extract of berries of V. vitis-idaea, exhibited anti-glycation activity with IC₅₀ 3.10 μg mL⁻¹ (6.10 μM).⁵⁷ The chalcone butein (41) obtained from an extract of Rhus verniciflua has been found to be a potent inhibitor of recombinant human aldehyde reductase 2 (rhALR2) with IC₅₀ 0.7 μM, and also provided in vitro inhibition of accumulation of AGEs.⁶¹

Catechins and their polymers proanthocyanidins are reported to exhibit broad-spectrum biological activities including anti-glycation activity (Fig. 6). An extract of Cinnamomum zeylanicum was reported to induce an increase in cellular glucose uptake and improved glucose metabolism and decreased triglycerides, LDL and total cholesterol in type 2 diabetes patients. C. zeylanicum bark extract has been reported to be effective in alleviation of diabetes through its antioxidant and insulin-potentiating activities. An aqueous extract of the bark exhibited an inhibitory effect on the formation of AGEs in a BSA/glucose model and (+)-catechin (42), (−)-epicatechin (43) and procyanidin B2 (44) were found to be responsible for these activities. Their anti-glycation potential was brought about by their antioxidant activities and was related to their abilities to trap reactive carbonyl species such as MGO. A preliminary study on the reaction between MGO and procyanidin B2 (44) revealed that the MGO-procyanidin B2 adduct showed great potential to be developed as an agent to alleviate diabetic complications.^62,63 (+)-Catechin (42) obtained from an ethanol extract of berries of V. vitis-idaea exhibited anti-glycation activity with IC₅₀ 8.35 μg mL⁻¹ (28.75 μM).⁵⁷

Fig. 6 Anthocyanins, chalcones, catechins and isoflavones with anti-glycation activity.

From the roots of Hydnora johannis, (+)-catechin (42) has been isolated as an active principle responsible for anti-glycation effects, having antioxidant properties (scavenging DPPH and ABTS radicals).⁶⁴ The introduction of (+)-catechin (42) and its gallate ester, epigallocatechin gallate (45), into LDL particles protects the lipoprotein against glycotoxin-mediated adverse effects.⁴⁹ Both (+)-catechin (42) and (−)-epicatechin (43) have exhibited protective activity against glycation.⁴⁸ Epigallocatechin gallate (45) also decreased AGE-stimulated gene expression, AGE-mediated activation and the DNA-binding activity of NF-κB.⁶⁵ Under hyperglycemic conditions, 45 prevented intracellular AGEs formation and the production of pro-inflammatory cytokines in monocytes.⁶⁶ Proanthocyanidin B4 (46) obtained from the roots of Actinidia arguta exhibited inhibitory activity against AGEs formation with IC₅₀ 10.1 μM.⁶⁷

An isoflavone, 5,7-dihydroxy-2′,6-dimethoxyisoflavone (47), has been isolated from Iris loczyi as an α-glucosidase inhibitor with promising anti-glycation activity.⁴³ An isoflavone from soybean extract (48), along with a coumarin, coumestrol (51), have been patented for their anti-glycation activity. These two compounds bind with advanced glycation end-products (AGE), especially glyceraldehyde-derived AGE-2, to inhibit their intestinal absorption, thereby preventing AGE-related disease.⁶⁸ The isoflavone glycoside puerarin (49), isolated from the roots of the Chinese medicinal plant Pueraria lobata, has been found to inhibit AGEs formation.⁶⁹

2.3 Phenylpropenoids with anti-glycation activity

A number of phenylpropenoids have shown anti-glycation activities (Fig. 7). The coumarin-5,6,7-trimethoxycoumarin (50) has been isolated as an anti-glycation agent from Eremurus persicus, a plant used as an antidiabetic agent in Iranian traditional medicine. In a study, at 3 mM concentration, 50 exhibited 75% inhibition as compared with 83% inhibition obtained for rutin (21), which was used as a reference anti-glycation agent.¹⁴ Moreover, the coumarin coumestrol (51) has been isolated from I. loczyi as an active component with anti-glycation activity.⁶⁸

Fig. 7 Phenylpropenoids with anti-glycation activity.

Caffeic acid (52), a phenylpropenoic acid, has been isolated as an active principle from the corolla of C. indicum.⁴⁶ In another study, caffeic acid (52), rosmarinic acid (53) and its methyl ester (54) were isolated from Cordia sinensis exhibiting anti-glycation activities with 69.2, 87.3 and 88.4% inhibition, respectively, as compared to 86.0% inhibition obtained for 21, which was used as a standard. These three phenylpropenoic acids also exhibited anti-inflammatory and antioxidant activities.⁵³ Caffeic acid (52) and its ester 5-caffeoylquinic acid (55) isolated from I. paraguariensis have been found to provide an anti-glycation effect stronger than that of AMG.³⁵ Compound 55 has also been isolated from C. morifolium as an active principle exhibiting inhibition of AGEs formation in BSA/glucose (fructose) systems.⁴⁶ A caffeic acid ester, plantamajoside (56), isolated from a methanol extract of Plantago asiatica has exhibited glycation inhibitory activity: at 0.1 μg mL⁻¹ concentration, 41% inhibition of AGE fluorescence. At 10 and 25 mM, it exhibited in vitro glycation-inhibiting and antioxidant activities, which were found to be higher than those of AMG evaluated at 10 and 25 mM concentrations.¹⁵ The cinnamic acid derivative 2,4-dihydroxy-5-methoxycinnamic acid (57) isolated from Viola betonicifolia exhibited moderate anti-glycation activity (IC₅₀ = 355 mM) comparable to that of the standard rutin (21) (IC₅₀ = 294 mM). It also exhibited antioxidant activity in a DPPH assay: inhibition of free radicals with IC₅₀ = 124 mM.⁷⁰

Two phenylpropenoic glycosides, 3-(4-acetoxy-3,5-dimethoxyphenyl)-2E-propenyl-β-D-glucopyranoside (58) and 3-(4-hydroxy-3,5-dimethoxyphenyl)-2E-propenyl-β-D-glucopyranoside (59), have been isolated as anti-glycation agents from V. album. From the same source, a flavone and flavone glycosides (24, 25 and 26), as mentioned earlier, have also been isolated as anti-glycation agents.⁵¹ A kawalactone, dihydro-5,6-dehydrokawain (60), was isolated from the rhizomes of Alpinia zerumbet and exhibited inhibitory activity against BSA glycation. It also inhibited human platelet aggregation and was found to possess anti-inflammatory and cancer chemoprotective properties.⁷¹

2.4 Phenolic compounds with anti-glycation activity

There are reports of phenolic acids and their esters with anti-glycation activities (Fig. 8), viz. gallic acid (61) (over 80% inhibitory effect on the glycation of albumin),¹⁹ ethyl gallate (62), protocatechuic acid (63) and pentagalloyl glucose (64) isolated from Rhus verniciflua with an inhibitory effect on recombinant human aldose reductase and the accumulation of AGEs.⁷² 7-O-Galloyl-D-sedoheptulose (65) isolated from Cornus officinalis led to reduced renal glucose, AGE formation, and oxidative stress in diabetic rats. It also reduced CML, serum creatinine and urinary protein to near-normal levels, with no toxicity at 20 and 100 mg.⁷³ Chebulic acid (66) isolated from fruits of Terminalia chebula displayed preventive effects on AGEs-induced endothelial cell dysfunction.⁷⁴

Fig. 8 Phenolic compounds with anti-glycation activity.

Recently, a number of natural stilbenoids such as resveratrol and its derivatives have been found to exhibit broad-spectrum biological activities, including anti-glycation activity. Oxyresveratrol (67) isolated from the heartwood of Artocarpus lakoocha has been found to exhibit anti-glycation activity with IC₅₀ 2.0 μg mL⁻¹ which was found to be five times higher than that of AMG. Compound 67 also exhibited strong antioxidant activity, nearly twice as strong as that of resveratrol.⁷⁵ THSG (2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside) (68) isolated from Polygonum multiflorum has been found to inhibit the formation of AGEs in a dose-dependent manner by trapping reactive MGO under physiological conditions (pH 7.4, 37 °C). It also exhibited antioxidant and anti-inflammatory properties.²⁶ Two dihydrostilbenoids, viz. α,α′-dihydro-3′,5′,2-trimethoxy-3-hydroxy-4-acetoxy-4′-isopentenylstilbene (69) and 5-[2-(3-hydroxy-5-methoxyphenyl)ethyl]-2-methoxyphenol (gigantol) (70), isolated from the bulbs of Prosthechea michuacana along with a phenanthrene dimer, 4,6,7-trihydroxy-2-methoxy-8-(3-methylbut-2-enyl)phenanthren-1,1′-4′,6′,7′-trihydroxy-2′-methoxy-8′-(3-methylbut-2-enyl)phenanthrene (71) exhibited in vitro inhibition of the formation of AGEs by trapping reactive MGO, potent anti-Amadorin activity and inhibitory activity against glycated hemoglobin, as well as protection against LDL oxidation.²⁷ An anthraquinone, 2,8-dihydroxy-6-(hydroxymethyl)-1-methoxyanthracene-9,10-dione (72), isolated from Aloe sinkatana exhibited inhibitory effects against glucose-induced AGEs.⁷⁶

A tannin, geraniin (73), obtained from the rind of Nephelium lappaceum exhibited in vitro hypoglycemic activity: inhibition of carbohydrate-hydrolysing enzymes (α-glucosidase and α-amylase) and prevention of polyol and AGEs formation, along with antioxidant and free radical-scavenging activities.⁷⁷ A galloyl glycoside, bergenin (74), has been isolated from the bark of Mallotus philippensis exhibiting moderate AGE inhibitory activity with IC₅₀ 75.69 μM.⁷⁸ An ellagitannin, vescalagin (75), isolated from the fruit of Syzygium samarangense provided a protective effect against methylglyoxal-induced inflammation and carbohydrate metabolic disorder in rats caused by an increase in γ-lactate and was found to retard AGE formation and prevent β-cell damage.⁷⁹

Two lignans, (+)-5′-methoxyisolariciresinol (76) and (−)-5′-methoxyisolariciresinol (77), were isolated from the stem and bark of Duranta repens and a study revealed that at 500 μg mL⁻¹ concentration these lignans exhibited 8.9 and 44.6% inhibition of AGEs, respectively, as compared to 34.3% inhibition obtained for AMG. These two lignans also exhibited free radical-scavenging activities.⁸⁰ Methyl orsellinate (78) isolated from Cordia platythyrsa exhibited in vitro anti-glycation activity.⁸¹

2.5 Polysaccharides with anti-glycation activity

Two polysaccharides, PMP-1 and PMP-2, have been obtained from the roots of Polygonum multiflorum. PMP-2 suppressed AGE formation while both polysaccharides exhibited strong antioxidant activities.⁸² A polysaccharide, DHP-W2, obtained from Dendrobium huoshanense stem has been found to exhibit in vitro anti-glycation activity in a dose- and time-dependent manner.⁸³ This polysaccharide also exhibited a hypoglycemic effect and anti-cataract activity through inhibition of protein glycation.⁸⁴ Polysaccharides obtained from the fruit pericarp of Dimocarpus longan exhibited anti-glycation activity.⁸⁵ Polysaccharides obtained from an aqueous extract of the cladodes of Opuntia monacantha have been found to inhibit the formation of AGEs in a time- and dose-dependent manner.⁸⁶ Polysaccharides obtained from the fruit juice of Punica granatum exhibited promising anti-glycation and antioxidant activity and these may be used in delaying or preventing complications of diabetes and aging.⁸⁷

2.6 Plant extracts with anti-glycation activity

A number of plant extracts have been studied and found to exhibit promising anti-glycation activity, and the isolation of active compounds from such plants can lead to the identification of lead molecules for the development of new anti-glycation drugs. Some of these extracts or purified extracts have been reported to exhibit other pharmacological properties such as antioxidant, anti-inflammatory, hypoglycemic and insulin resistance inhibitory activities, along with anti-glycation activity. Some of these extracts are prepared from plants used extensively in traditional systems of medicine such as Ayurveda and have the advantage of multiple biological activities, although the metabolites responsible for these activities have not yet been identified. These include: Asparagus officinalis,⁸⁸ Azadirachta indica,⁸⁹ Boswellia sacra,⁹⁰ Osbeckia octandra,⁹¹ Calendula officinalis,⁹² Centella asiatica,⁹³ Cyperus rotundus,⁹⁴ Emblica officinalis,^95,96 Houttuynia cordata,⁹⁷ Ocimum sanctum,⁹⁸ Juglans regia,⁹² Nelumbo nucifera,⁹⁹ Pterocarpus marsupium,¹⁰⁰ Punica granatum,⁸⁷ Saraca asoca,¹⁰¹ Tamarindus indica,⁹⁶ Terminalia bellerica^95,96 and Withania somnifera.¹⁰² Furthermore, Chinese traditional medicinal plants with promising anti-glycation activities include: Panax notoginseng,⁸⁸ Polygala tenuifolia,⁸⁸ Salvia chloroleuca, S. mirzayanii, S. santolinifolia¹⁰³ and S. reuteriana.¹³

Extracts of many plants used as spices, food additives and essential oils have also been found to exhibit a wide range of anti-glycation effects. These include: Allium cepa, Allium fistulosum, Coriandrum sativum, Curcuma longa, Mentha piperita, Murraya koenigii, Petroselinum crispum, Thymus vulgaris, Zingiber officinale,¹⁰⁴ Myristica fragrans¹⁰⁵ and Rosmarinus officinalis.¹⁰⁶ Extracts of some plants used as foods and nutraceuticals have also been found to display a wide range of anti-glycation activities. These include: Camellia sinensis,^96,107 Capsicum annuum,¹⁰⁸ Coffea arabica,¹⁰⁹ Musa paradisiaca¹¹⁰ and Vitis vinifera.^97,111,112

Some plant extracts exhibiting anti-glycation activity have been studied extensively and found to have a different mode of action. These include Achyrocline satureioides, which prevents MGO-induced inhibition of plasminogen, as well as antithrombin III.¹¹³ Other plants, such as Anthemis nobilis and Byrsonima crassifolia, display antihyperlipidemic and antihyperinsulinemic activity and inhibit AGEs formation;¹¹⁴ Cuminum cyminum exhibits antihyperglycemic activity and inhibits AGEs formation in STZ-induced diabetic rats;¹¹⁵ Dendrobium huoshanense displays hypoglycemic, anti-glycation and anti-cataract activities through inhibition of protein glycation;^83,84 Erigeron annuus exhibits inhibition of protein glycation, aldose reductase, cataractogenesis and AGEs;^59,116 and Malpighia emarginata displays anti-aging and anti-glycation activity and inhibits enhancement of the synthesis of type IV and type I collagens in human cultured fibroblasts.¹¹⁷

A number of plants with ethnopharmacological backgrounds have been evaluated for their anti-glycation activity. These include Cassia tora,¹¹⁸ Cordia platythyrsa,⁸¹ Crataegus oxyacantha,¹¹¹ Dimocarpus longan,⁸⁵ Disterigma rimbachii,¹¹⁹ Melissa officinalis,¹²⁰ Nepeta juncea,¹²¹ Peltophorum pterocarpum,¹²² Rhodiola rosea,¹²³ Solanum xanthocarpum,¹²⁴ and Vaccinium barandanum, V. consanguineum, V. gaultheriifolium, V. macrocarpon, and V. poasanum.¹¹⁹ A number of plant extracts have been found to exhibit promising anti-glycation activities. Although these plants have no strong ethnopharmacological status, further work on the isolation of their active principle(s) and evaluation for other pharmacological activities will lead to new findings in the area of anti-glycation activity and phytotherapy for the treatment of diabetic complications. These include: Acanthopanax senticosus,¹²⁵ Aframomum danielli,¹⁰⁵ Antidesma madagascariense,⁹⁸ Connarus ruber,¹²⁶ Cratoxylum cochinchinense,¹²⁷ Crataegus oxyacantha,⁹⁷ Cupressus sempervirens var. horizontalis,¹²⁸ Eulophia ochreata,¹²⁹ Faujasiopsis flexuosa, Juniperus oblonga,¹³⁰ Morus alba,¹³¹ Ophiopogon japonicus,¹²⁵ Origanum majorana,¹³² Passiflora alata and P. edulis,¹³³ Passiflora manicata¹³⁴ and Piper auritum.¹³⁵ The isolation of active principle(s) responsible for anti-glycation and other related biological activities will perhaps lead to new anti-glycation agents.

3. Summary

The current review describes the anti-glycation activity of plant-derived natural products, 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), (iv) reduction of crosslinking of AGEs and (v) blocking of RAGE. A number of plant extracts and plant products have been found to exhibit a wide range of anti-glycation activities. From quite a few of these, the active principle(s) responsible for this important biological activity have been identified and these were found to have wide structural diversity. Some of these lead compounds were found to act with diverse modes of action such as anti-glycation, tryptophan damage, browning, and main-chain fragmentation of proteins. Moreover, some of these lead molecules were found to possess other pharmacological properties such as antioxidant, anti-inflammatory, hypoglycemic and insulin resistance-inhibiting activities, which may contribute to the overall anti-glycation activity of the extract/purified extract. This anti-glycation activity correlates with the phenolic content of the plant extracts, although there is a wide range of other, non-phenolic compounds such as terpenoids, flavonoids, phenylpropenoids, polysaccharides, which have a high potential to reduce non-enzymatic protein glycosylation.

Some of these lead molecules can be adopted for the development of new anti-glycation drugs. In addition, some plant products, such as extracts/purified extracts representing compounds with wide structural diversity and hence responsible for diverse biological activities, have been found to exhibit promising anti-glycation properties. These plant products have a great potential to be developed as herbal drugs.

The plant-derived anti-glycation agents appear attractive candidates for the development of a new generation of therapeutics for the treatment of diabetic complications and aging. This review shows that a limited fraction of plants with ethnopharmacological backgrounds and a still smaller fraction from the huge biodiversity of plants have been investigated for this important pharmacological activity. More and more plant extracts and plant products will be studied for this important activity in the near future, which will lead to the isolation of novel anti-glycation phytomolecules. Extracts and plant products prepared from the unexplored biodiversity of plants will lead to new findings in the area of anti-glycation and phytotherapy for the treatment of diabetic complications.

4. Abbreviations

3-DG	3-Deoxyglucosone
ABTS	2,2′-Azinobis(3-ethylbenzothiazoline-6-sulfonic acid)
AFGP	1-Alkyl-2-formyl-3,4-glycosylpyrrole
AMG	Aminoguanidine
AGEs	Advanced glycation end-products
AST	Aspartate aminotransferase
BSA	Bovine serum albumin
CEL	Nε-(Carboxyethyl)lysine
CML	Nε-(Carboxymethyl)lysine
DM	Diabetes mellitus
DOLD	Deoxyglucosone-derived lysine dimer
DPPH	2,2-Diphenyl-1-picrylhydrazyl
FL	Fructosyl-lysine
GO	Glyoxal
GOLD	Glyoxal lysine dimer
HbA1c	Glycated hemoglobin
LDL	Low-density lipoprotein
MG-H1	Nε-(5-Hydro-5-methyl-4-imidazolon-2-yl)ornithine
MGO	Methylglyoxal
MM	Millimolar
MOLD	6-{1-[(5S)-5-Ammonio-6-oxido-6-oxohexyl]-4-methylimidazolium-3-yl}norleucinate (methylglyoxal lysine dimer)
MRPs	Maillard reaction products
NADPH	Nicotinamide adenine dinucleotide phosphate
NF-κB	Nuclear factor kappa-light-chain-enhancer of activated B cells
PARP	Poly(ADP-ribose) polymerase
PM	Pyridoxamine
PTB	N-Phenacylthiazolium bromide
RAGE	Receptor for advanced glycation end-products
rhALR2	Recombinant human ALR2
RLAR	Rat lens aldose reductase
RNS	Reactive nitrogen species
ROS	Reactive oxygen species
STZ	Streptozotocin
TBARS	Thiobarbituric acid reactive substances
THSG	2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside
TNFα	Tumor necrosis factor alpha
μM	Micromolar

Acknowledgements

Authors thank CSIR-Network project CSC0111 for financial support. AAC and AMK thank CSIR for research fellowship.

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