Download Glycoxidation of biological macromolecules: A critical

Glycobiology vol. 24 no. 11 pp. 979–990, 2014
doi:10.1093/glycob/cwu057
Advance Access publication on June 19, 2014
REVIEW
Glycoxidation of biological macromolecules: A critical
approach to halt the menace of glycation
Saheem Ahmad1,2, M Salman Khan2, Firoz Akhter2,
Mohd Sajid Khan1,2, Amir Khan3, J M Ashraf4,
Ramendra Pati Pandey5, and Uzma Shahab1,6,7
2
Department of Biosciences, Integral University, Lucknow, India; 3Glocal
School of Life Sciences, Glocal University, Saharanpur, Uttar Pradesh, India;
4
Department of Biotechnology, School of Biotechnology, Yeungnam
University, Yeungnam, Republic of Korea; 5Nano-Biotech Lab, Department of
Zoology, Kirorimal College, University of Delhi, Delhi, India; and 6Department
of Biochemistry, Central Drug Research Institute, Lucknow, India
Received on November 3, 2013; revised on May 29, 2014; accepted on June 12,
2014
Glycation is the result of covalent bonding of a free amino
group of biological macromolecules with a reducing sugar,
which results in the formation of a Schiff base that undergoes
rearrangement, dehydration and cyclization to form a more
stable Amadori product. The final products of nonenzymatic
glycation of biomacromolecules like DNA, proteins and lipids
are known as advanced glycation end products (AGEs). AGEs
may be generated rapidly or over long times stimulated by
distinct triggering mechanisms, thereby accounting for their
roles in multiple settings and disease states. Both Schiff base
and Amadori glycation products generate free radicals resulting in decline of antioxidant defense mechanisms and can
damage cellular organelles and enzymes. This critical review
primarily focuses on the mechanistic insight of glycation and
the most probable route for the formation of glycation
products and their therapeutic interventions. Furthermore,
the prevention of glycation reaction using therapeutic drugs
such as metformin, pyridoxamine and aminoguanidine (AG)
are discussed with special emphasis on the novel concept of the
bioconjugation of these drugs like, AG with gold nanoparticles
(GNPs). At or above 10 mM concentration, AG is found to be
toxic and therefore has serious health concerns, and the study
warrants doing this novel bioconjugation of AG with GNPs.
This approach might increase the efficacy of the AG at a
reduced concentration with low or no toxicity. Using the
concept of synthesis of GNPs with abovementioned drugs, it is
assumed that toxicity of various drugs which are used at high
doses can be minimized more effectively.
1
To whom correspondence should be addressed: Tel: +91-9452677867; Fax: +91522-2890809; e-mail: [email protected] (S.A.); Tel: +91-522-2890730;
Fax: +91-5222890809; e-mail: [email protected] (M.S.K.); Tel: +919450612013; Fax: +91-5222257539; e-mail: [email protected] (U.S.)
7
Present address: Department of Biochemistry, King George Medical
University, Lucknow, U.P., India.
Keywords: advanced glycation end products / antiglycation /
gold nanoparticle / oxidative stress / therapeutic intervention
Introduction
The story of glycation reaction was started way back in the year
1912 when Louise Camille Maillard first described the glycation reaction after whom the reaction is also known as the
Maillard reaction (Maillard 1912). Glycation is the process
whereby sugars bind to the free amino residues of proteins,
lipids and DNA macromolecule. Sugars and other reactive carbonyl compounds bind spontaneously to nucleophilic amino
groups of amino acids and proteins in a nonenzymatic process.
Reducing sugars, such as glucose in basic solutions and lipids
by β-oxidation or peroxidation generate formyl (an aldehyde)
and ketone groups. Aldehydes and ketones have a highly polarized carbonyl (C=O) group, the oxygen atom of which is electronegative and may react with nucleophiles in proteins and
other biomolecules like, DNA and lipids. Under high glucose
load (hyperglycemic condition), these biomolecules undergo a
nonenzymatic glycation reaction leading to the formation of a
complex series of compounds known as the advanced glycation
end products (AGEs). This, in turn, results in the deprivation of
the functions of the biological macromolecules by altering their
structural conformation.
Figure 1 schematically represents the probable pathway of
reaction of biomacromolecules with reducing sugars to form
protein AGEs, advanced lipoxidation end products (ALEs) and
DNA advanced glycation end products (DNA-AGEs). Glycation
and oxidative stress are closely linked and are often referred to as
“glycoxidation” process which is believed to be involved in the
complications associated with several disorders including diabetes, cardiovascular disease and Alzheimer’s disease, in addition
to various forms of cancer (Aldini et al. 2013).
Glycation of biomacromolecule
DNA glycation
When DNA reacts with sugars in vitro at a physiological temperature, the formation of DNA-bound AGEs is observed (Mustafa
et al. 2012; Ahmad et al. 2014). Glycation of DNA has shown to
considerably alter the structure of DNA macromolecule and it
leads to depurination, strand breaks and mutations such as insertions, deletions and transposition (Ahmad, Ahmad, et al. 2011;
Ahmad, Moinuddin, et al. 2011). Therefore, DNA-AGEs could
contribute to the loss of genomic integrity, which occurs during
© The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected]
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Fig. 1. Schematic representation of probable pathway of macromolecules reacting with reducing sugars to form AGEs/ALEs and DNA-AGEs, respectively.
This Figure was adapted from our published research paper in the Elsevier journal “International Journal of Biological Macromolecules” (2013), 58:206–210.
The permission is automatically granted to the authors/corresponding authors of the paper as per Elsevier STM Permission Guidelines (2012).
aging and may contribute to the age-related complications.
More detailed studies on the stability and dynamics of DNA
showed that glycation leads to partial unwinding and/or fragmentation of the double helix (Mustafa et al. 2012). Wuenschell
et al. (2010) investigated the mutagenic potential of the predominant DNA-glycation adduct carboxy ethyl deoxygunaosine
(CEdG) and exhibited that CEdG within the template DNA and
the corresponding triphosphate possess different syn/anti conformations during replication which influence base pairing preferences. Oxidative modifications within the DNA lead to
reduced gene expression (Nagai et al. 2010). We have shown in
the recent past that genotoxicity and immunogenicity are incurred in DNA and proteins by carcinogens and reactive
oxygen species (ROS) as well (Moinuddin et al. 2012; Shahab,
Ahmad, et al. 2012; Shahab, Moinuddin, et al. 2012; Shahab
et al. 2013). Moreover, most recently, our research group has
also shown that glycation-induced oxidative stress leads to
the modification of DNA macromolecule and results in alteration of its structure (Akhter et al. 2013). The structural
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perturbations in the DNA macromolecules are the consequence
of the genotoxic effect of the glycation reaction (Ahmad,
Moinuddin, et al. 2011).
The structural pathway for the formation of DNA bases
Amadori products is shown in Figure 2. In vitro incubation of
DNA with glucose, fructose and glucose-6-phosphate led to
UV absorbance and fluorescence changes, indicating that DNA
undergoes nonenzymatic browning reaction (Ahmad, Ahmad,
et al. 2011; Ahmad, Moinuddin, et al. 2011). So far, it has
been shown that among all DNA bases, deoxyguanosine exhibited the highest glycation rate with reactive carbonyl species
(RCS) (Li et al. 2008). Therefore, free guanosine, guanine or
2′-deoxyguanosine were used in model incubations with sugar
or RCS to identify the structure of possible DNA adducts.
N2-carboxyethyl-2′-deoxyguanosine (CEdG A,B) was established as a sensitive marker for DNA modifications by the
carcinogenic substance methylglyoxal (MG).
The role of DNA-glycation in vivo has been discussed in
great detail in our recent publication where we showed the
Glycation and its inhibition by nanoconjugation
Fig. 2. Mechanistic representation of glycation reaction between reducing sugars (ribose, glucose and deoxyribose) and adenine/guanine base.
presence of autoantibodies in type 1 and type 2 diabetes
patients against glycated human DNA (Ahmad et al. 2014).
Elevated levels of AGEs have been implicated in the pathological complications of diabetes, uremia, Alzheimer’s disease and
possibly cancer. CEdG adducts were specifically detected in a
human breast tumor and normal adjacent tissue at levels of 3–12
adducts/107 dG, suggesting that this lesion may be widely distributed in vivo which is an adduct of DNA glycation only.
Protein glycation
The protein glycation is an inevitable, nonenzymatic reaction
between reducing sugars and proteins, occurring in all living
systems. Although the reaction is slow, it is quite dynamic in
nature and starts with the formation of unstable Schiff base,
which undergoes a series of reactions leading to the formation of
heterogeneous molecules called AGEs (Thornalley et al. 1999).
Glucose and glucose-derived dicarbonyls such as glyoxal, MG,
glucosone and 3-deoxyglucosone (3-DG) are the major precursors
of AGEs. The levels of these precursors determine the formation
of different types of AGEs. The predominant AGE modifications
include fructosyl-lysine, carboxymethyl lysine (CML), carboxyethyl lysine (CEL) and pentosidine. AGEs are accumulated in
the body due to in vivo glycation as well as through intake of exogenous AGEs, which are mainly formed due to overheating of
foods and beverages (Faist and Erbersdobler 2001). Diabetes
promotes the formation of AGEs in vivo, thus, enhancing the
overall accumulation. AGEs cause cell damage at various levels,
namely (i) alteration of protein structure and function; (ii) protein
aggregation, fibril formation and protease resistance (Wei et al.
2012); (iii) aberrant signaling through interaction with the
RAGE and (iv) dysfunction of extracellular matrix. AGEs contribute substantially to the progression of diabetic complications,
including nephropathy, retinopathy, neuropathy; cardiovascular
diseases, cataract, accelerated aging, neurodegenerative diseases
and cancer.
Studies of protein glycation have focused on the reaction of
aldoses and ketoses, particularly glucose, with lysine residues
of proteins. The acyclic form of the monosaccharide reacts reversibly with the lysyl side chain of amino group to form an
initial Schiff base adducts. This exists mainly in the cyclic glycosylamine form (Neglia et al. 1983). AGEs are formed slowly
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throughout life and the concentrations of AGEs found represent
a lifelong accumulation of the glycation adducts. This applies
to chemically stable AGE residues formed on long-lived proteins. For example, CML, CEL and pentosidine residue accumulation on skin collagen (Shimasaki et al. 2011).
Various proteins and enzymes of clinical significance as well
as those involved in cellular processes such as glucose metabolism, bioenergetics, cell repair and stress response have been
affected by glycation. Plasma proteins especially human serum
albumin (HSA), immunoglobulins, apolipoprotein, fibrinogen
and transferrin are predominantly glycated and implicated in
various disease conditions (Zhang et al. 2008). Hemoglobin
undergoes extensive glycation and is an established biomarker
for diabetes (Lyons and Basu 2012). Likewise, early glycation
products of albumin could serve as markers for secondary complications of diabetes. Glycation of albumin decreases the antioxidant activity and binding capacity (Rondeau and Bourdon
2011). Similarly, AGE modified immunoglobulin G presents
unique neoepitopes, which elicit autoimmune response in
rheumatoid arthritis patients (Ahmad et al. 2012). Increased
glycation of apolipoproteins may play a role in the accelerated
development of atherosclerosis. Glycation of fibrinogen alters
the formation of fibrin network kinetics, which contributes to
decreased pore size and lysis rate of fibrin clots (Pieters et al.
2008). Transferrin glycation is associated with increased free
radical production, lipid peroxidation and decreased iron-binding
capacity (Van Campenhout et al. 2003). It has also been found
that glycation affects calcium signaling and calcium-dependent
processes. Human paraoxonase 1, a calcium-dependent esterase
responsible for metabolism of membrane lipid hydroperoxides,
is inactivated by glycation and implicated in coronary heart
disease (Mastorikou et al. 2008). Other proteins such as human
complement regulatory protein show reduced activity due to glycation, thereby promoting membrane attack complex formation
in the target organs of diabetic complications (Qin et al. 2004).
Glycation modification results in the diminished enzyme activity
of creatine kinase, alanine aminotransferase and cytoplasmic
aspartate aminotransferase aiding in the development of diabetic
complications (Beranek et al. 2001). Several intracellular enzymes
especially those involved in glucose metabolism have been
greatly affected by glycation modifications. Key enzymes such
as glyceraldehyde 3-phosphate dehydrogenase, bisphosphoglycerate mutase from erythrocytes and pancreatic glucokinase are
inactivated by glycation (Zhao et al. 2000). Increased glycation
of glycolytic enzymes leads to higher accumulation of carbonyls, which may further modify proteins. Other enzymes which
show loss of activity upon in vitro glycation include enolase,
nitric oxide synthase, catalase and Cu/Zn superoxide dismutase
(SOD1) (Pietkiewicz et al. 2009). In vitro glycation of Na-KATPase at different amino groups has shown differential catalysis
and cation binding, suggesting that glycation not only inhibits
enzyme activity but also modulates enzyme kinetics (Garner
et al. 1990). Interestingly, glycation-induced loss of functional
activity is compensated by increased gene expression. One of the
well-studied examples is the decreased functional activity of
glutathione system due to carbonyl stress, which is compensated
by increased expression of gamma-glutamylcysteine synthetase
enzyme (Miyahara et al. 2002). Nevertheless, targeting any of
the enzyme or protein involved in the nonenzymatic glycation
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may prevent their ultimate structure consequently their function
as well. The need of the hour is to stop this slow and steady glycation reaction with minimal or no toxicity. The approaches used
in the past have shown some deleterious effects on humans
undergoing trial in diabetic nephropathy patients against aminoguanidine (AG).
Lipoproteins glycation
In diabetes, hyperglycemia induces modification of plasma and
tissue proteins by nonenzymatic glycation, a gradual process
that culminates with the formation of irreversible AGE. AGE
accumulates particularly at sites of atherosclerotic lesions, but
the mechanisms whereby AGE contributes to diabetes-induced
accelerated atherogenesis are not fully understood. Low-density
lipoproteins (LDLs), either oxidized or glycated, are present in
the plasma and in the affected vasculature of diabetic patients
(Virella et al. 2003). Although there are several studies on the
effect of glycated proteins on vascular cells (Younis et al.
2008), only few data exist on the effect of irreversibly glycated
LDL (AGE-LDL) on endothelial cells. AGE interact with specific cellular receptors, the best characterized of which is the
receptor for AGE (RAGE). Interestingly, elevated levels of
AGE-LDL are present in the sera of euglycemic or normolipemic patients with atherosclerosis. AGE-LDL is present in the
vessel wall atheroma and exerts proatherogenic effects (Sima
and Stancu 2002; Hodgkinson et al. 2008).
It has been found that recognition of glycated LDL by
LDL receptor is impaired, while the uptake by monocytemacrophages are enhanced, which contributes to hyperlipidemia and accelerated foam-cell formation, respectively (Toma
et al. 2009).
It has been hypothesized that in diabetes, hyperglycemia and
the ensuing increased formation of AGE-LDL may directly
affect the vascular endothelium by activating RAGE, which in
turn may induce a series of changes leading to a prooxidant and
pro-inflammatory state, finally generating endothelial dysfunction characteristic for micro- and macroangiopathy. It has also
been reported that AGE-LDL induce in human endothelial cell
(HEC) an increased expression of RAGE, p22phox, p67phox
and NOX4, leading to an increase in NADPHox activity, and an
augmented expression of monocyte chemoattractant protein-1.
High glucose augments the effect of both nLDL and AGE-LDL
on HEC (Toma et al. 2009).
Moreover, the glycation of lipoproteins in diabetes was first
reported by Schleicher et al. (1981). It has been reported that in
healthy nondiabetic people the serum concentration of glycated
apolipoprotein B (apo B), although lower than in diabetic people
was on average 5 mg/dl, representing 4% of the total apo B
(the major component of the protein moiety of LDL) (Tames
et al. 1992). It has been reviewed the possibility that glycated
lipoproteins, including very-low-density lipoprotein, LDL and
also HDL could contribute to atherosclerosis. It has been consistently observed both in tissue culture and during in vivo turnover
studies that glycated LDL is not cleared by the physiological
LDL receptor (Wang et al. 1998). It thus has a slower catabolic
rate than nonglycated LDL. Glycation of LDL apo B involves
epitopes close to its receptor-binding site, suggesting that a
conformational change in the binding site influences recognition
Glycation and its inhibition by nanoconjugation
by LDL receptors. Glycated LDL is thus more likely to be
cleared by scavenger receptors on macrophages and endothelial
cells, to which its binding is not compromised by glycation, and
subclasses of scavenger receptors specific for AGEs have been
described (Schmidt et al. 1999). Furthermore, glycation and oxidation are by no means mutually exclusive naturally occurring modifications of LDL, because glycation itself generates free radicals
(glycoxidation) (Jenkins et al. 2004). Glycoxidated LDL is present
in the atheromatous plaque (Imanaga et al. 2000). It has, however,
been shown in vitro that prior oxidation is not essential for glycation of LDL to occur (Li et al. 1996).
Advanced glycation end products: source and target
AGEs are formed endogenously when the carbonyl groups of
reducing sugars nonenzymatically react with the free amino
groups on proteins, lipids and DNA. AGEs are generated in vivo
as a normal consequence of metabolism, but their formation is
accelerated under conditions of hyperglycemia, hyperlipidemia
and increased oxidative stress. Although glucose is relatively
slow in reacting with proteins, highly reactive dicarbonyl compounds (generated as a result of glucose autooxidation, lipid peroxidation and the interruption of glycolysis by reactive oxygen
species) are capable of rapid AGE formation. Dicarbonyls such
as glyoxal, MG and 3-DG interact with intracellular proteins
to form AGEs, and can also diffuse out of the cell and react
with extracellular proteins. Excessive AGE accumulation results
in significant cellular dysfunction by inhibiting communication
between cells, altering protein structure and interfering with lipid
accumulation within the arterial wall (Barlovic et al. 2010).
AGEs are well reported to bind to the RAGEs which activates nuclear factor kB, triggering oxidative stress, thrombogenesis, vascular inflammation and pathological angiogenesis
(Yamagishi et al. 2007), thereby contributing to many of the
long-term complications of diabetes. More recently, AGEs have
been implicated in the pathogenesis of type 2 diabetes by contributing to the development of insulin resistance and low-grade
inflammation known to precede the condition (Tahara et al.
2012). Apart from endogenous AGE formation, AGEs and
their precursors are also absorbed by the body from exogenous
sources such as cigarette smoke and through consumption of
highly heated processed foods. Browning of food during
cooking is used to enhance the quality, flavor, color and aroma
of the diet. This process (known as the Maillard reaction) generates large quantities of AGEs. Factors that enhance AGE formation in foods include high lipid and protein content, low water
content during cooking, elevated pH and the application of
high temperature over a short time period. More AGEs are generated in foods exposed to dry heat (grilling, frying, roasting,
baking and barbecuing) than foods cooked at lower temperatures for longer time periods in the presence of higher water
content (boiling, steaming, poaching, stewing or slow cooking)
(Uribarri et al. 2005). Kinetic studies have demonstrated that
10–30% of dietary AGEs consumed are intestinally absorbed
(Faist and Erbersdobler 2001), with only one-third of ingested
AGEs excreted in urine and feces. Plasma AGE concentration
appears to be directly influenced by dietary AGE intake and the
body’s capacity for AGE elimination (Delgado-Andrade et al.
2012). Low-AGE diets in animal studies have been shown to
reverse insulin resistance and chronic inflammation, inhibit
the progression of atherosclerosis and prevent experimental
diabetic nephropathy and neuropathy (Uribarri et al. 2007), but
whether these results can be translated to humans is uncertain.
Cross-sectional and case–control studies involving humans
with impaired renal function or diabetes have demonstrated
associations between elevated AGE intakes and serum biomarkers of oxidative stress, endothelial dysfunction, inflammation,
hyperlipidemia and hyperglycemia (Chao et al. 2010). AGEs
have also recently been implicated in the dysfunction and death
of pancreatic beta cells, leading to the hypothesis that excessive
AGE formation and oxidative stress possibly have a role in
the development of type 1 and type 2 diabetes (Coughlan et al.
2011). Low-AGE diets have been suggested as a possible
future therapeutic option for healthy individuals at risk for the
development of type 1 or type 2 diabetes (Vlassara and Striker
2011). Through reduced consumption of highly processed heattreated foods, dietary AGE restriction may represent a relatively
simple, noninvasive therapy for the effective treatment of many
of the metabolic disturbances attributed to excessive AGE
levels. This competent review might help to better understand
to stop the glycation menace either by dietary AGEs restriction
as reviewed here or by using novel therapeutic drugs and novel
bioconjugation approach discussed elsewhere.
Interrelations of ROS, RCS and AGEs
The nonenzymatic glycation of DNA or protein is the process
which links chronic hyperglycemia to a series of pathophysiological alterations and considered important in the development
of diabetes and the associated diseases (Ahmad, Shahab, et al.
2013). AGEs are direct pathogenic and accumulate in the
plasma, serum and tissues of patients in different diseases, e.g.
diabetes, end stage renal disease, cardiovascular, aging and
arthritis (Peppa et al. 2003).
The excess free radical production under hyperglycemic conditions originates from mitochondrial respiration, cytochrome
p450, xanthine oxidase, PKC dependent activation of NADH/
NADPH oxidase and RAGE-triggered cellular oxidant stress
(Bandeira et al. 2013). Under hyperglycemic conditions several
pathways gets activated, namely (i) autooxidation of glucose
which leads to the actual glycation reaction thus forming ROS
species, (ii) the generation of sorbitol pathway, (iii) activation
of PKC pathway by diacyl glycerol generation (DAG), (iv) activation of glucosamine and (v) mitochondrial pathway. All the
above pathways ultimately lead to the formation of ROS and
result in deleterious effects on protein, DNA and LDL macromolecule.
Figure 3 shows the free radical formation and the check points
where this slow and steady can be stopped. Furthermore, ROS,
within certain boundaries, is essential to maintain homeostasis.
Most recently, new sources of ROS generation have been reported
(Brieger et al. 2012). These ROS species are also generated in the
early and the advanced glycation processes and these species
have been shown to exhibit cytotoxicity (Figure 4). During the
rearrangement process of the glycation reaction there is also
the generation of free radicals like ·OH and O·2− (Ahmad,
Moinuddin, et al. 2011; Ahmad, Akhtar, et al. 2013).
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Fig. 3. Schematic representation of the formation of ROS and RNS under hyperglycemic condition: probable check points “×” to control the reaction.
Carbonyl stress is an imbalance of RCS production and carbonyl scavenging mechanisms, which originate from a multitude
of mechanistically related pathways, such as glycation, autooxidation of sugars, amino acid metabolism, lipid peroxidation and
UV damage (Sergei et al. 2008). The formation of RCS during
glycation reaction is shown in Figure 4. Generation of reactive
intermediate products is an important step in the glycation.
These compounds are known as α-dicarbonyls and include
3-DG, glyoxa and MG. 3-DG rapidly reacts with protein amino
groups to form AGE such as imidazolone, pyrraline and CML
(Jono et al. 2004). MG may be produced by nonenzymatic pathways from spontaneous decomposition of triose phosphates, autoxidation of carbohydrates and glucose degradation (Nagaraj
et al. 2002). In addition to reaction with arginine residues to form
imidazolone adducts, MG reacts with lysine residues in protein
to form CEL and the imidazolium cross-link, MG-lysine dimer.
On the other hand, production of GO in vivo under physiological
conditions can yield number of AGEs such as CML, pentosidine, glyoxal-lysine dimer and other nonfluorescent AGEs
(Nagai et al. 2012). α-Oxoaldehydes are metabolized and inactivated by enzymatic conversion to the corresponding aldonic
acids, catalyzed by the glutathione-dependent glyoxalase system
(Birkenmeier et al. 2010).
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Therapeutic intervention
Synthetic AGE inhibitors
The prevention of glycation reaction is one of the strategies to
reduce AGEs. Amadori product formation can be inhibited by
compounds that react with the reducing sugars, thereby inhibiting the reaction. The trapping of the reactive carbonyl intermediates formed in the first stage of Maillard reaction can be carried
out by using guanidine compounds such as AG. Aminoguanidine
was the first AGE inhibitor proposed to scavenge the dicarbonyl
compounds such as glyoxal, MG and 3-DG (Brownlee et al.
1986). Moreover, AG is an investigational drug for the treatment
of diabetic nephropathy that is no longer under development as a
drug. Numerous in vitro experiments and animal studies conducted on experimental diabetes with AG have shown the prevention of diabetes-induced deteriorations of cardiovascular structure
and function and of major long-term complications such as
nephropathy, retinopathy and neuropathy (Brownlee et al. 1986;
Hammes et al. 1991; Edelstein and Brownlee 1992). Owing to
safety concerns resulting from its additional effect, e.g. prooxidant
activities and inhibition of NO synthase (Suji and Sivakami
2006), it is currently unlikely that AG will be used to treat diabetic
complications (Turgut and Bolton 2010). Most of the studies were
comprised of the concentrations ranging from 10 to 100 mM and
Glycation and its inhibition by nanoconjugation
Fig. 4. Schematic representation of the formation of early and advanced glycation end products. Probable check points “×” to control the reaction
was found to be toxic therefore has serious health concerns.
Moreover, due to the toxic and prooxidant behavior of the AG,
further trials on AG were stopped because of this major apprehension. Moreover, the clinical phases in the AG treatment of patients
with type-1 diabetes were also ended due to serious complications
in those patients.
Another class of AGE inhibitors, “Amadorin” (the postAmadori inhibitors), inhibits the conversion of Amadori intermediates to AGE (Khalifah et al. 1999). The first Amadorin
identified was pyridoxamine (PM) that showed a great potential
for treatment of diabetic nephropathy. It inhibits AGE formation at different levels by scavenging carbonyl products of
glucose and lipid degradation, sequestering catalytic metal ions,
blocking oxidative degradation of Amadori intermediate and
trapping of ROS. Lalezari-Rahbar (LR) compounds are potent
Cu2+ chelators, which inhibit post-Amadori AGE formation
in vitro more efficiently than PM (Rahbar and Figarola 2003).
A lipophilic derivative of vitamin B1, benfotiamine, reduces
the accumulation of hexose and triose phosphates by shunting
these intermediates to pentose phosphate pathway and improving the activity of transketolase (Stracke et al. 2001).
Experimental animal model studies have shown that benfotiamine can reduce diabetic complications like nephropathy
and retinopathy (Hammes et al. 2003). Another approach
to reduce accumulation of AGE formation is to reverse the
process by AGE cross-link breakers such as N-phenacyl thiazolinium bromide and N-phenacyl-4,5-dimethylthiazolium
chloride (ALT-711/alagebrium). “RAGE blockers” comprise of
agents that trap AGE with soluble RAGE (sRAGE), block
RAGE and inhibit signal transduction mediated by AGE–RAGE.
Administration of recombinant sRAGE in animal models has
shown to suppress atherosclerosis, neuronal dysfunction and
diabetes (Park et al. 1998).
Novel AGE inhibitors: A link to gold nanoparticles
Aldose and ketose sugars were originally thought to be the sole
precursors of AGEs. Current research indicates that RCS generated from carbohydrate, lipid and amino acid metabolisms such
as MG, glyoxal, 3-DG and malondialdehyde are even more reactive and are potent precursors of AGE formation and protein
cross-linking (Bonnefont-Rousselot et al. 2000). Known AGE
inhibitors with renoprotective effects such as AG, PM and
OPB-9195 are thought to prevent AGE accumulation by interacting with these highly reactive RCS and acting as carbonyl
traps, thereby limiting oxidative damage to tissues. AG reacts
with α-dicarbonyls such as glyoxal, MG and 3-DG to form triazine derivatives, whereas PM was shown to interact and form
adducts with Glyoxal and MG (Lv et al. 2010). It has also been
suggested that the chelating activity of AGE inhibitors and
AGE breakers at therapeutic concentrations may contribute to
their inhibition of AGE formation and protection against development of diabetic complications (Nagai et al. 2012). Most
of the novel LR compounds analyzed show greater chelating
activities than PM and AG. LR-9, LR-59, LR-74 and LR-90
are potent chelators, with IC50 of 50–275 μM. Spectroscopic
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studies confirm the formation of inhibitor–copper complexes.
The study suggests that metal-catalyzed oxidation plays a critical
role in glucose-induced modifications of the collagen. Figure 4
shows the schematic representation of AGEs, ROS, RNS under
hyperglycemic condition and their therapeutic interventions along
with their check points.
Anti-glycation activity of gold nanoparticles (GNPs) was
first reported in year 2009 to inhibit the cataract formation as a
consequence of the glycation reaction (Singha et al. 2009). The
prevention of glycation of α-crystallin was done by conjugation
with GNPs. Formation of advanced glycosylic end products is
prevented by using bioconjugated GNPs, even if a strong glycating agent such as fructose is used. In addition, the nanoconjugation approach can provide some important information on
the structural distribution of any dynamic chaperone protein.
Because GNPs are biocompatible, their reported antiglycation
activity may have therapeutic medical implications.
In another study, the extent of nonenzymatic glycation of HSA
was monitored in order to estimate the formation of HSA-related
AGEs in the presence of 2 nm GNPs. Physiological concentrations of HSA and glyceraldehyde mixtures, incubated with
various concentrations of negatively charged 2 nm GNPs, resulted
in a lower reaction rate than mixtures without 2GNP. Moreover, increasing concentrations of GNPs exhibited a pronounced reduction in AGE formation (Seneviratne et al. 2012). Moreover, it
has also been suggested that combination of GNP, and antioxidants like Epigallocatechin gallate significantly accelerated diabetic cutaneous wound healing through angiogenesis regulation
and anti-inflammatory effects. This might be due to blockade of
RAGE by antioxidant agents and nanoparticles may restore effective wound healing in diabetic ulcer.
Furthermore apart from GNPs, silver nanoparticles (Ag-NPs)
have also shown to effectively reduce the menace of the glycation reaction. It has been determined the effects of Ag-NPs on
AGEs-induced endothelial cell permeability. The AGE-bovine
serum albumin (BSA) increased the dextran flux across a
PREC monolayer and Ag-NPs blocked the solute flux induced
by AGE-BSA. It was also demonstrated that Ag-NPs could
inhibit the AGE-BSA-induced permeability via Src kinase
pathway.
There are reports where researchers have proved that GNPs
alone (Seneviratne et al. 2012) and GNPs bioconjugated with
protein (Singha et al. 2009) can reduce the rate of nonenzymatic
modification of proteins responsible for glycation. The role of
GNPs in the targeted delivery of drugs is one of the most promising aspects. For the bioconjugation of drug with GNPs a
robust and stable protein, albumin was chosen as a capping
agent over GNPs. The role of albumin as a drug carrier for last
several years has emerged wonderfully because it does not only
provide the stability to the drugs but also improves the half-life
of drugs/active proteins/peptides. The conjugation was carried
out either by simple physical adsorption of the drugs onto
GNPs or via the use of alkanethiol linkers (Kratz 2008).
Biodistribution homogeneity, penetration via the hematoencephalic barrier and interaction with reticuloendothelial system
completely depends on the size of GNPs. The rapid reduction
in particle concentration in blood and their prolonged retention
in the organism is associated with the functioning of the hepatobiliary system. It takes 3–4 months for the accumulated
986
particles to be excreted from the liver and spleen. Also, available data allow for the reasonable conclusion that colloidal particles with a size of 3–100 nm are not toxic, provided that the
threshold dose does not exceed a value of the order of 1012 particles/mL (Dykman and Khlebtsov 2011). A huge number of
drugs have been successfully bioconjugated with GNPs and
have been approved for clinical trials. The GNPs have also
been used in multimodal delivery systems, when a GNP is
loaded with several therapeutic agents (both hydrophilic and
hydrophobic) and auxiliary agents, such as target molecules
and dyes for photodynamic therapy (Kim et al. 2009). There
are a large number of antitumor agents and antibiotics have
been bioconjugated with GNPs such as paclitaxel (Paciotti
et al. 2006), methotrexate (Chen et al. 2004), hemcytabin (Patra
et al. 2008), 5-fluorouracil (Agasti et al. 2009), doxorubicin
(Asadishad et al. 2010), vancomycin (Gu et al. 2003). The bioconjugation increased stability and efficacy up to 40% of all the
drugs used for bioconjugation. Therefore, it is argued that bioconjugation of AGE inhibitors with GNPs will definitely decrease the Ki substantially and hence doses and ultimately
toxicity. The internalization of nanoparticles is taken place by
receptor-mediated endocytosis (Chithrani et al. 2006), whereas
passive diffusion also plays an active role in the process of internalization. The regulation of internalization of nanoparticles
depends upon the interaction of nanoparticles with serum proteins which interact with different nanoparticles based on their
hydrophobic properties and impart them equal effective charge
irrespective of their initial charge characteristics. The internalization also depend on the size, shape, charge and surface functionalities which interact with cell surface receptors of GNPs
(Duncan et al. 2010).
In fact, proteins glycated to different extents showed the formation of nanoparticles of different size and eventually their
plasmon intensities were also different. This implied that glycated proteins cause some attenuation of the particle formation
that led to only smaller nanoparticle formation. One possible
example of such negative control on the particle size formation
may arise from proximity of glycation-prone sites on which
GNPs preferentially form on the protein surface. This as well as
other structural studies with nanoparticle protein conjugates,
prompted to explore the possibility of prevention of glycation
(Bhattacharya et al. 2007). The origin of such resistance against
glycation is intriguing. The amino acids containing the free
amino group (lysine) are potent sites for glycation in addition to
the N-terminal amino acid. On the other hand, GNPs competitively bind to these free amino groups. The observation that the
glycation will decrease upon masking of the free amino groups
(e.g. those residing on the lysine residues) may be compared
with the present observation (Hu et al. 2005). There is a strong
implication that the gold seeding process is favored at sites
where such free amino groups are present. That amino acid residues such as lysine may be specific targets (other than thiolcontaining residues like cysteine or methionine) may help in the
design of specific protein targets by GNPs.
The search for antiglycating agents is itself an important clinical issue, in that glycation is not confined to diabetic patients,
rather glycation leads to damage of several other physiologically
important proteins such as collagen, albumin and importantly
Hb. Few antiglycating agents have been already reported in the
Glycation and its inhibition by nanoconjugation
Table I. Bioconjugation of GNPs with different proteins and their association with different metabolic disorders
S. no.
Conjugation of Au with protein
Development of metabolic disorders
References
1.
2.
3.
4.
5.
6.
7.
8.
α-Crystallin
Plasma proteins and amino acids (Au–S or Au–NH2 bonds)
Tumor necrosis factor
Crystallin protein (masking of protein amine)
Collagen
Serum albumin
Trypsin, bovine serum albumin and transferrin
RAGE protein
Neurodegenerative diseases
Diabetes, cancer
Colon cancer
Alzheimer’s
Aging
Diabetes, Alzheimer’s
Diabetes, cancer, neurodegenerative diseases
Diabetic ulcer, inflammation
Singha et al. (2009)
Bhattacharya et al. (2007)
Rahim et al. (2014)
Singha et al. (2009)
Kim et al. (2012), Shimasaki et al. (2011)
Seneviratne et al. (2012)
Rahim et al. (2014)
Chen et al. (2012)
literature, and apparently a nontoxic agent like gold showing
antiglycating properties may itself have important clinical significance (Hipkiss 2000; Khan et al. 2013).
In the light of the above explanations, this review is aiming
to exploit its preventive effect on glycation by reducing the concentrations of the AG or other drugs showing toxicity at higher
concentrations but has antiglycation effect. These drugs might
be used for nanoconjugation using GNPs, thus reducing the
toxic concentration to minimal. The present concern on bioconjugation of AG with GNPs is the need of the hour, as this could
overcome the problem of side effects by increasing the efficacy
at the reduced doses.
To enhance activity of all the above novel drugs at reduced
dozes, such as LRs (LR-74, LR-90) and others including AG in
bioconjugation with GNPs, might prove to be more accurate
and specific novel inhibitor of DNA, protein and LDL glycation
at reduced doses. Table I enlists the bioconjugation of GNPs
with different proteins and their association with different metabolic disorders.
Future prospects
Since very few work has been done on AGEs inhibition using
nanoparticles as drug delivery system (Kim et al. 2012; Seneviratne
et al. 2012); therefore, it would be interesting to see the inhibition
of AGEs using various bioconjugated inhibitors (LR74, LR90 and
AG) with GNPs. In the light of above explanations, in general,
this study holds strong future prospects with the development
of new, more effective and more specific inhibitors. The inhibitors will be developed based on structure–activity relationship.
This study will help to identify the new targets for AGEs. Since
there are various diseases associated with glycation and its end products, such as diabetes, cancer, arthritis, atherosclerosis, ageing and
neurodegenerative disorders such as Alzheimer’s and Parkinson’s;
therefore, targeting a site could result in prevention or protection
against these drowning and dreaded diseases.
Conclusions
There is a considerable body of evidence implicating the formation and accumulation of AGEs as a major factor in the development of diabetic complications, atherosclerosis, Alzheimer’s
disease and the normal aging process. The significance of this
phenomenon becomes more evident where tight association
of lipoxidation reactions, overproduction of reactive oxygen
species and overgeneration of RCS with the process of AGE
formation are considered. Cellular damage by AGEs comes
from cross-linking and remodeling of structural proteins such
as collagens and metabolic enzymes which affects their physiological functions. Furthermore, tissue damage particularly in
vascular endothelial cells may originate by triggering of key
cell signaling systems and stimulation of inappropriate cellular
activities through secretion of cytokines and vascular cell adhesion molecules. Thus, therapeutic interventions should not only
target AGE formation but also AGE-protein cross-link formation. Considering the complexity of pathways and reactions
involved in AGE formation, it is not only the end products such
as AGE and ALE but also highly reactive carbonyl intermediates responsible for their formation that is toxic to the cells.
Therefore, it should be targeted in designing inhibitors that specifically react with each committed step and intermediate products of important pathways. Another factor to be considered is
the fact that glycoxidized proteins generate ROS and induce oxidative stress through the reaction with RAGE which activates and
shoot up the oxidative stress thus imbalancing the shift more
towards the damaging side. Also, ROS is generated by other reactions in the cascade of AGE formation such as MG and Schiff
base pathways leading to lipoxidation and oxidative damage to
cells. Therefore, strategies such as suppression of receptor
signaling pathways (e.g. RAGE antagonists), and the use of
antioxidants and α-oxoaldehyde scavengers will be helpful.
Nonetheless, compounds that possess both metal chelating and
carbonyl scavenging properties are ideal to inhibit both oxidative and carbonyl stresses. Such class of compounds may also
be effectors of AGE receptors such as RAGE that is involved in
cell signaling pathways. Unfortunately, from a large number of
naturally occurring and synthetic compounds reported previously as AGE inhibitors, only the mechanism of action of a few
compounds have been studied extensively to date. Unraveling
the mechanism(s) of action of these inhibitors is essential for
understanding the roles of AGE in the pathogenesis of a
number of age-related chronic diseases and to design more
effective therapeutic strategies for these diseases in the future.
Last but not the least, bioconjugated LR-74, LR-90 and AG
might prove to be novel inhibitor for glycation of DNA, proteins and LDL as very few studies has been performed till date
to stop/inhibit AGE formation using gold as a nanoparticle.
This kind of inhibition will be more accurate and precise with
reduced doses.
987
S Ahmad et al.
Abbreviations
AG, aminoguanidine; AGEs, advanced glycation end products;
Ag-NPs, silver nanoparticles; ALEs, advanced lipoxidation
end products; apo B, apolipoprotein B; BSA, bovine serum
albumin; CEdG, carboxy ethyl deoxygunaosine; CEL, carboxyethyl lysine; CML, carboxymethyl lysine; DAG, diacyl glycerol generation; DNA-AGEs, DNA advanced glycation end
products; GNPs, gold nanoparticles; HSA, human serum albumin;
HEC, human endothelial cell; LDLs, low-density lipoproteins; LR,
Lalezari-Rahbar; MG, methylglyoxal; PM, pyridoxamine; RAGE,
receptor for AGE; RCS, reactive carbonyl species; ROS, reactive
oxygen species; sRAGE, soluble RAGE
Acknowledgements
The authors are highly thankful to the Vice Chancellor of the
Integral University, Prof. Waseem Akhtar Sb. for the infrastructure support provided to the Department of Bio-Sciences.
Conflict of interest statement
None declared.
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