Role of Methylglyoxal in Alzheimer’s Disease

Abstract

Alzheimer’s disease is the most common and lethal neurodegenerative disorder. The major hallmarks of Alzheimer’s disease are extracellular aggregation of amyloid β peptides and, the presence of intracellular neurofibrillary tangles formed by precipitation/aggregation of hyperphosphorylated tau protein. The etiology of Alzheimer’s disease is multifactorial and a full understanding of its pathogenesis remains elusive. Some years ago, it has been suggested that glycation may contribute to both extensive protein cross-linking and oxidative stress in Alzheimer’s disease. Glycation is an endogenous process that leads to the production of a class of compounds known as advanced glycation end products (AGEs). Interestingly, increased levels of AGEs have been observed in brains of Alzheimer’s disease patients. Methylglyoxal, a reactive intermediate of cellular metabolism, is the most potent precursor of AGEs and is strictly correlated with an increase of oxidative stress in Alzheimer’s disease. Many studies are showing that methylglyoxal and methylglyoxal-derived AGEs play a key role in the etiopathogenesis of Alzheimer's disease.

1. Introduction

Alzheimer’s disease (AD) is the most common and lethal neurodegenerative disorder characterized by progressive neuronal loss and neuroinflammation in the brain and associated with progressive cognitive decline, memory impairment, and changes in behavior and personality, with rising incidence among elderly people. One of the pathological hallmarks of AD is neuritic plaques in the cerebral cortex and hippocampus. Amyloid (A), a 40–42 amino-acid peptide generated by proteolytic cleavages of the amyloid- protein precursor (APP) [1], is one of the main components of neuritic plaques. A is cytotoxic and capable of inducing oxidative stress and neurodegeneration [2, 3]. Another distinctive feature of AD is neurofibrillary tangles (NFTs), composed of bundles of paired helical filaments (PHFs) [4], mainly containing hyperphosphorylated microtubule-associated tau protein (MAP-tau) [5]. Under normal physiological conditions, tau promotes assembly and stability of microtubules and is thus involved in axonal transport [6, 7]. In AD, tau proteins aggregate forming fibrillar insoluble intracellular inclusions. The main processes involved in the etiology and pathogenesis of AD are reported in Figure 1.

Figure 1 

Classical processes participating in the etiology and pathogenesis of AD (modified from [131]).

The full understanding of the etiology and pathogenesis of AD has remained elusive, and more and more evidences are confirming that AD is a disease with numerous genetic and environmental contributing factors. Some years ago, it has been proposed that a chemical process known as glycation may contribute to both extensive protein cross-linking and oxidative stress in AD [8]. Nonenzymatic protein glycation is an endogenous process in which reducing sugars react with amino groups in proteins through a series of Maillard reactions forming reversible Schiff base and Amadori compounds, producing a heterogeneous class of molecules, collectively termed advanced glycation end products (AGEs) [9]. The -ketoaldehyde methylglyoxal (MG), formed endogenously as a by-product of the glycolytic pathway, by degradation of triosephosphates or nonenzymatically by sugar fragmentation reactions, is the most potent precursor of AGE formation [10]. MG is able to induce cellular damage, cross-linking of proteins, and glycation [11] playing an important role in the pathogenesis of many neurodegenerative diseases [12]. In AD, AGEs accumulate in neurons and astroglia and are also found associated with neuritic amyloid plaques and NFTs [13–16]. MG may also contribute to neurodegeneration triggering oxidative stress [17–19]. Oxidative stress is characterized by an imbalance between reactive oxygen species (ROS) production and the detoxifying endogenous system. There is accumulating evidence suggesting a key role of oxidative stress in the pathophysiology of AD [20–23]. A central role for oxidative stress by the activation of NADPH oxidase in astrocytes has been demonstrated as the cause of A-induced neuronal death [24] and of alterations in astrocyte mitochondrial bioenergetics that may in turn affect neuronal functioning and/or survival [25].

As oxidative stress and MG are closely interlinked, the role of MG and MG-induced production of AGEs and ROS in the development of AD is reviewed in this paper. In addition, the ability of MG to modulate detrimental redox signaling in AD has been considered.

2. Methylglyoxal Production

MG is a reactive intermediate of cellular metabolism, present ubiquitously in all cells. It is produced under both normal and pathological conditions via several different pathways, involving both enzymatic and nonenzymatic reactions [26]. The rate of MG formation depends on the organism, tissue, cell metabolism, and physiological conditions; therefore, MG plasma concentration reflects these factors. Plasmatic MG can be derived from exogenous sources, such as coffee, alcoholic beverages, and food [27, 28] and from endogenous sources: in situ formation in the plasma, release from cells, and loss from injured cells [29].

Since MG is ubiquitously present in living cells, almost all foods and beverages contain MG, as reviewed by Vistoli et al. [30]. The main sources of MG are represented by mono-, oligo-, and polysaccharides and lipids [31]. Several reactions and processes are involved in the accumulation of MG: autoxidation, photodegradation, and heating and prolonged storage are the main sources of MG as a degradation product in foodstuff [32–35]. Moreover, many microorganisms produce and release MG: fermentation can be a critical process increasing MG levels in alcoholic drinks and fermented foods [36]. MG is reported to originate also from environmental sources. Cigarette smoke is one of the combustion processes that can generate MG [37]; drinking water can contain MG due to the purification treatments [38]; rainwater can absorb MG from polluted air and transmits it to the soil [39].

Endogenously derived MG is formed during carbohydrate and lipid and amino acid metabolisms and involves both enzymatic and nonenzymatic reactions [40–43]. The enzymes that catalyze the reactions of MG synthesis are MG synthase, cytochrome P450 2E1, myeloperoxidase, and amino oxidase, participating in glycolytic bypass, acetone metabolism, and amino acid breakdown, respectively; nonenzymatic pathways include the spontaneous decomposition of dihydroxyacetone phosphate, the Maillard reaction, the oxidation of acetol, and lipid peroxidation [42].

The main pathway leading to MG is linked to carbohydrate metabolism and involves enzymatic and nonenzymatic degradation of the triosephosphate intermediates glyceraldehyde 3-phosphate and dihydroxyacetone-phosphate deriving from glycolysis [40, 44, 45]. It should be noted that triosephosphates originate not only from glycolytic processes but also from other routes of glucose metabolism (Entner-Doudoroff pathway, hexose monophosphate route) and from xylitol metabolism or the activity of glycerophosphate dehydrogenase, linking glycerol breakdown to MG production [40]. Dihydroxyacetone phosphate can be converted to MG by either spontaneous nonenzymatic elimination of the phosphate group or by the enzymatic contribution of MG synthase, an enzyme found in prokaryotic and mammalian systems [36, 46]. MG can also derive via the Maillard reaction in vivo under physiological conditions, similar to what is observed during food cooking and through the glycation of macromolecules and the autoxidation of carbohydrates [43].

MG production deriving from lipid metabolism is mainly linked to the acetone metabolism [47]. Acetone is derived from acetoacetate by myeloperoxidase activity and is converted to MG by the cytochrome P450 2E1 via acetol as intermediate [48]. In pathological conditions like ketosis and diabetic ketoacidosis, the oxidation of ketone bodies is likely to be an important source of MG [49]. In addition, triacylglycerol hydrolysis produces glycerol that can be transformed into MG through glycerolphosphate produced by a specific glycerol kinase [50]. Lipoperoxidation is another nonenzymatic process leading to MG formation [51, 52].

The catabolism of the aminoacids threonine and glycine (and partially tyrosine) can also generate MG through the aminoacetone intermediate [53–55]. This metabolic oxidative pathway is mediated by the enzyme semicarbazide sensitive amine oxidase (SSAO) and appears to be exacerbated in low coenzyme A states [56, 57].

3. Methylglyoxal Induced AGE Production

MG is able to induce protein glycation leading to the formation of AGEs [11] and is believed to be the most important source of AGEs. Glycation of proteins is a complex series of parallel and sequential reactions known as Maillard reaction [58]. Glycation starts with the reaction of glucose with lysine and leads to the formation of fructosyl-lysine (FL) and N-terminal amino acid residue-derived fructosamines while later stage reactions produce stable adducts [58]. It has been observed that FL degrades slowly to form AGEs [59] while MG reacts relatively rapidly with proteins to form AGEs [58], in particular MG is up to 20,000 times more reactive than glucose in glycation reactions [11]. MG reacts almost exclusively with arginine residues and to a lesser extent with lysine, cysteine, and tryptophan residues. The reaction of MG with arginine leads to the formation of cyclic imidazolone adducts (MG-H) [60] and other related structural isomers. MG-H is formed as three structural isomers: N-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), 2-amino-5-(2-amino-5-hydro-5-methyl-4-imidazolon-1-yl)pentanoic acid (MG-H2), and 2-amino-5-(2-amino-4-hydro-4-methyl-5-imidazolon-1-yl)pentanoic acid (MG-H3) [61]. These adducts can undergo other reactions; they can add a second MG molecule yielding either N-(4-carboxy-4,6-dimethyl-5,6-dihydroxy-1,4,5,6-tetrahydropyrimidine-2-yl)-L-ornithine (THP) [62] or argpyrimidine (N-(5-hydroxy-4,6-dimethylpyrimidine-2-yl)-l-ornithine) [63]. MG also reacts with lysine residues to form the -(1-carboxyethyl)-L-lysine (CEL) and -(1-carboxymethyl)-L-lysine (CML) adducts and the lysine dimer 1,3-di(-lysino)-4-methyl-imidazolium (MOLD) [64]. With one lysine and one arginine residue, MG forms 2-ammonio-6-(2-[(4-ammonio-5-oxido-5-oxopentyl) amino]-4-methyl-4,5-dihydro-1H-imidazol-5-ylidene amino) hexanoate (MODIC) [65]. MG can react also with cysteine residues giving reversible hemithioacetal adducts [66] and could spontaneously modify tryptophan residues yielding carboline derivatives [33].

In human serum albumin, the following concentrations of MG-derived AGEs were detected: MG-H1 2493 ± 87 mmol/mol protein; argpyrimidine 200 ± 40 mmol/mol protein; CEL 29.7 ± 1.8 mmol/mol protein; and MOL 5 ± 1 mmol/mol protein [67]. In cerebrospinal fluid of patients with amyotrophic lateral sclerosis, elevated levels of CML were reported [68], and the tissue levels of CML in cortical neurons and cerebral vessels were related to the severity of cognitive impairment in patients with cerebrovascular disease [69]. It has been demonstrated that MG is involved in the increased levels of AGEs observed in AD [70] and MG-derived AGEs such as CEL and MOLD and MG-derived hydroimidazolone have each been identified in intracellular protein deposits in neurofibrillary tangles [71] and cerebrospinal fluid [72].

4. Methylglyoxal Induced ROS Production

The production of ROS and reactive nitrogen species (RNS) during MG metabolism have been extensively depicted in some reviews [43, 73, 74] and a large body of literature describes the correlation among MG, AGEs, oxidative stress, and pathologies [40] such as diabetes [75], hypertension [76], aging [74, 77, 78], and neurodegeneration [13, 79].

Although the link between MG and free radicals has been investigated since the 1960s mainly by Szent-Gyorgyi [80, 81], only in 1993, the generation of ROS in a cellular system was described [82].

Free radicals and/or ROS and RNS can be produced during both the formation of MG and its degradation; the reactions involved in these processes could be summarized as follows. The enzymatic formation of MG from aminoacetone (catalyzed by SSAO) or from acetol (catalyzed by galactose oxidase) is coupled to hydrogen peroxide production [83, 84]; hydrogen peroxide is produced also when MG is converted to pyruvate by the action of the enzyme glyoxal oxidase [85, 86]. The autoxidation of aminoacetone to MG, mediated by metal ions such as and , is considered a source of carbon-centered radicals and superoxide [87, 88]; similarly, the nonenzymatic reaction from acetoacetate to MG produces ROS, in the presence of myoglobin, hemoglobin, manganese, cytochrome c, or peroxidase [89, 90].

MG, likewise for monosaccharide, undergoes autoxidation [91–93] and photolysis [94], resulting in ROS generation; these reactions involve superoxide, hydrogen peroxide, and hydroxyl radical [95].

As reported in [43] and [77], ROS production related to MG has been identified in a very wide range of cellular systems, for example, vascular smooth muscle cells (VSMCs), endothelial cells, rat hepatocytes, platelet, neurons, and so forth. We have recently demonstrated that MG induces ROS production in primary culture of rat cardiomyocytes [96].

Moreover, MG is able to increase the activity of prooxidant enzymes [97–99] and to reduce antioxidants, in particular glutathione (GSH) and its enzymes [17, 100, 101]. Since the glyoxalase system that degrades MG uses reduced glutathione as a cofactor [102], decreased antioxidants in turn impair the detoxification of MG, leading to further oxidative damage.

It has been reported, furthermore, that MG can modify Cu,Zn superoxide dismutase (SOD) by covalent cross-linking, releasing copper ions from the enzyme and inactivating it [103]. Other studies indicate that MG increases mitochondrial superoxide production [104, 105].

The correlation between ROS levels and MG concentration has been reported both in animals and cultured cells [43, 76, 77]. Commonly, in cell models, the administration of MG to the medium is followed by ROS level determination, that is often obtained by the 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) assay or, seldom, by other tests such as lucigenin-linked chemiluminescence assay [106].

As previously reported, MG is the most reactive endogenous carbonyl able to generate AGEs. AGEs also induce oxidative stress through several mechanisms. AGEs stimulate production of cytokines and growth factors [62, 66, 107–111]. Moreover, AGEs bind to the AGE receptor (RAGE) and scavenger receptors to induce oxidative stress in various cells including VSMCs, endothelial cells, and mononuclear phagocytes [112]. In endothelial cells, AGEs increase expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and increase activity of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) to increase oxidative stress [109, 113].

5. Methylglyoxal and Methylglyoxal-Derived AGE Deposits in AD

As both the extracellular A deposits and the intracellular NFTs have elevated stability and are long-lived proteins, they represent an ideal substrate for glycation [70]. It has been suggested that the insolubility and protease resistance of -amyloid plaques are caused by extensive AGE-covalent protein cross-linking [4, 16]. In 1994, Vitek et al. observed, for the first time, that plaque fractions of AD brains contained about 3-fold more AGE adducts than preparations from healthy, age-matched controls. They showed that the in vivo half-life of -amyloid is prolonged in AD, resulting in greater accumulation of AGE modifications which in turn may act to promote accumulation of additional amyloid [114]. An immunohistochemical study using a monoclonal antibody specific for AGE proteins showed extracellular AGE immunoreactivity in amyloid plaques in different cortical areas, in particular, primitive plaques, coronas of classic plaques and some glial cells in AD cortex were positive for AGEs [115]. More recently, Fawver et al. [14] stained AD brain tissue for AGEs, and similar to the previous findings, AGEs were colocalized with amyloid plaques. In addition, Ko et al. [116] showed that APP was upregulated by AGEs in vitro and in vivo, and AGEs modulate APP expression through ROS. To explore whether glycated A is more toxic than authentic A, Li et al. [117] treated 8-DIV embryonic hippocampal neurons with A or A-AGE for 24 h. They found that A-AGE was more toxic than A in decreasing cell viability, increasing cell apoptosis, inducing tau hyperphosphorylation, and reducing synaptic proteins. It has also been observed that MG is not only capable of increasing the rate of production of -amyloid -sheets, oligomers and protofibrils but also of increasing the size of the aggregates [13].

The 4 allele of the apolipoprotein E (ApoE) is known as an important susceptibility gene for AD [118, 119]. It has been demonstrated that ApoE is codeposited in senile plaques in brains of patients with AD [120] and ApoE4 carriers present a higher A deposition in the form of senile plaques than noncarriers [121, 122]. Interestingly, AGEs colocalized to a very high degree with ApoE and ApoE4 exhibited a 3-fold greater AGE-binding activity than the ApoE3 isoform [123]. The authors suggested that ApoE may participate in aggregate formation in the AD brain by binding to AGE-modified plaque components, which may explain why ApoE4 is associated with increased risk of AD.

As discussed above, AGEs can be localized intracellularly. Evidences have been provided that AGEs may accumulate in pyramidal neurons exhibiting a granular perikaryonal distribution in human brain whereas animals show a nuclear staining pattern [124]. It has been shown that AGEs accumulate in endosomal and lysosomal vesicles of pyramidal neurons in the hippocampus, the dentate gyrus, cortical layers III, V, and VI, and in entorhinal cortical layers II, III, V, and VI [125]. Interestingly, Wong et al. [126] observed colocalization of AGEs and inducible nitric oxide synthase (iNOS) in a few astrocytes in the upper neuronal layers in the early stage AD brains, while, in late AD brains, there was a much denser accumulation of astrocytes colocalized with AGEs and iNOS in the deeper and particularly upper neuronal layers. An immunohistochemical study showed that, in AD patients, the percentage of AGE-positive neurons (and astroglia) increases with the progression of the disease and those neurons which show diffuse cytosolic AGE immunoreactivity also contain hyperphosphorylated tau, suggesting a link between AGE accumulation and the formation of early neurofibrillary tangles [16]. Using specific AGE antibodies directed against CML, pyrraline, and hexitol-lysine it has been demonstrated that AGEs are colocalized with NFTs [15, 127, 128].

In AD patients, AGEs accumulate also in the cerebrospinal fluid (CSF), which is in close contact with the brain. An increased accumulation of Amadori products in all major proteins of CSF of AD patients including albumin, apolipoprotein E, and transthyretin has been observed [129]. Bär et al. [130] measured significantly elevated levels of CML in CSF of AD patients when compared to controls. In CSF protein, Ahmed et al. [72] observed an increased levels of CML residues in subjects with AD and in CSF ultrafiltrate; the concentrations of MG-derived hydroimidazolone free adducts were also increased.

6. Role of Methylglyoxal and Methylglyoxal-Derived AGEs in the Progression of AD

The process underlying AD is complex and involves many different features such as mitochondrial dysfunction, abnormal protein aggregation, inflammation, and excitotoxicity. Beeri et al. [132] conducted an interesting clinical study on 267 subjects, at least 75 years old, and cognitively intact at the beginning of the project. They demonstrated that the subjects with higher serum levels of MG had a faster rate of cognitive decline. Several potential mechanisms have been suggested to explain MG and MG-derived AGE neurotoxicity. Krautwald and Münch [70] suggested that AGEs contribute to the pathogenesis of AD in two different ways: cross-linking cytoskeletal proteins inducing neuronal dysfunction and death and accumulating on A deposits chronically activating micro- and astroglial cells, as widely underlined in the previous paragraph. Moreover, it has been observed that MG is a neurotoxic mediator of oxidative damage in the progression of AD and other neurodegenerative diseases [133]. The brain is highly susceptible to oxidative stress due to its high energy demand, high oxygen consumption, large amounts of peroxidizable polyunsaturated fatty acids, and low levels of antioxidant enzymes [134]. It is no wonder that ROS induced damage to biomolecules is widely reported in AD and increasing evidences suggest that oxidative stress plays a critical role in the disease [135]. As the impairment of mitochondrial function is the main source of ROS generation and also a major target of oxidative damage, mitochondrial dysfunction has been implicated in AD [136, 137]. de Arriba et al. [138] demonstrated that MG may seriously affect mitochondrial respiration and the energetic status of cells. In particular, they observed that MG increases intracellular ROS and lactate production in SH-SY5Y neuroblastoma cells and decreases mitochondrial membrane potential and intracellular ATP levels. SH-SY5Y neuroblastoma cells have been extensively used to study the effect of MG as they show greater sensitivity to MG challenge, due to a defective antioxidant and detoxifying ability [17]. Huang et al. [139] observed that MG induced Neuro-2A neuroblastoma cell line apoptosis via alternation of mitochondrial membrane potential and Bax/Bcl-2 ratio, activation of caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP). Moreover, they investigated the mechanisms behind MG-induced neuronal cell apoptosis demonstrating that MG activates proapoptotic mitogen-activated protein kinase (MAPK) signaling pathways (JNK and p38). This data is in agreement with the results of Chen et al. [140] that, using primary cultures of rat hippocampal neurons, demonstrated that MG increases the expression level of cleaved caspase-3 and decreases Bcl-2/Bax ratio. As activated caspase-3 immunoreactivity is elevated in AD and exhibits a high degree of colocalization with NFTs and senile plaque in AD brain, it has been suggested that activated caspase-3 may be a factor in functional decline [63].

AGEs exert direct toxicity to cells through predominantly apoptotic mechanisms. Yin et al. [141] investigated the effects of AGEs in SH-SY5Y cells and rat cortical neurons. They observed that AGEs induce cell death increasing intracellular ROS through the increase of NADPH oxidase activity. Moreover, endoplasmic reticulum stress was triggered by AGE-induced oxidative stress, resulting in the activation of C/EBP homologous protein (CHOP) and caspase-12 that consequently initiates cell death. Tau phosphorylation is strictly controlled by the coordinated activities of tau phosphatase(s) and tau kinase(s), and the hyperphosphorylation of tau in the AD brain might be due to the overactive protein kinases and/or inactivation of protein phosphatases [142, 143]. Tau can be phosphorylated by different protein kinases such as the members of the MAPK family (JNK, p38 and Erk1/2), GSK-3, and cyclin-dependent kinase 5 (cdk5), while protein phosphatase (PP) 2A plays a major role in regulating dephosphorylating of the hyperphosphorylated tau isolated from the AD brains [143–147]. Using wild-type mouse N2a cells, Li et al. [148] observed that MG induces tau hyperphosphorylation and activates GSK-3 and p38, while the simultaneous inhibition of GSK-3 or p38 could attenuate MG-induced tau hyperphosphorylation, suggesting an important roles of GSK-3 and p38 in the MG-induced NTFs formation. On the other hand, an interesting proteomic study demonstrated a decreased level of PP2 in SH-SY5Y cells subjected to MG-induced oxidative stress. Thus, it could be speculated that MG has a double role in inducing tau hyperphosphorylation: enhancing kinase activities and reducing phosphatase level. Besides hyperphosphorylation, it has been suggested that carbonyl-derived posttranslational modifications of neurofilaments may account for the biochemical properties of NFTs, likely as a result of extensive cross-links [149, 150]. Kuhla et al. [151], in an in vitro experiment, incubated wild-type and seven pseudophosphorylated mutant tau proteins with MG and observed the formation of PHF-like structures. Interestingly, MG formed PHFs in a concentration-dependent manner and this process could be accelerated by hyperphosphorylation.

7. Redox Signaling Modulated by Methylglyoxal in AD

As previously highlighted, MG cytotoxicity to tissue or cells is mainly mediated through an increase of oxidative stress and an induction of apoptosis. Oxidative stress is thought to play a causative role in the development of AD [152, 153]. Such stress is a typical activator of two important MAPK pathways in AD: the JNK and the p38 signaling pathways [154]. It has been suggested that the activation of the MAPK signaling pathways contributes to AD pathogenesis through different mechanisms including induction of apoptosis in neurons [155–158], activation of - and γ-secretases, [159, 160] and phosphorylation and stabilization of APP [161, 162]. Different studies have associated MG with MAPK pathways. In RAW 264.7 cells, MG stimulated the simultaneous activation of p44/42 and p38 MAPK and also stimulates the translocation to the cell membranes of another important protein kinase involved in cellular signaling: protein kinase C (PKC) [163]. Moreover, Pal et al. [164] indicated that MG stimulates iNOS activation by p38 MAPK-NF--dependent pathway and ROS production by ERK and JNK activation in sarcoma-180 tumor bearing mice.

Regarding the implications of MAPK signaling pathway in oxidative damage leading to apoptosis, it has been observed that MG is able to induce apoptosis in PC12 cells through the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin/gamma-glutamylcysteine ligase catalytic subunit (PI3K/Akt/mTOR/GCLc)/redox signaling pathway. Huang et al. [165] indicated that MG-induced Neuro-2A cell apoptosis was mediated through activation of the MAPK signaling pathway mediated by p38 and JNK. Recently, Heimfarth et al. [166] demonstrated that the exposure of slices of cerebral cortex and hippocampus of new born rats to mM MG induced ROS production and cytotoxicity. In particular, they showed that the signaling pathway mediated by ERK is totally implicated in the ROS-mediated cytotoxic damage as the initial blockage of MEK/ERK signaling pathway might be useful for the protection of cells from the high ROS levels. Additionally, they observed that p38MAPK and JNK pathway activation is related with ROS-independent mechanisms leading to reduced cell viability and apoptotic cell death.

Moreover, as it has been underlined in the previous paragraph, the MG activation of GSK-3 and p38 MAPK induces AD tau hyperphosphorylation [148].

8. Conclusions

Many scientific evidences revealed different important actions of MG on signal transduction, redox balance, and cell energetic status as well as homeostatic control of cellular function. Elevated MG levels induce AGEs and ROS production playing a role in AD by several mechanisms (Figure 2). AGEs extensively cross-link proteins in A deposits and neurofilaments exacerbating AD pathological hallmarks. In particular, AGEs cross-link proteins in A deposits making them more insoluble, protease resistant, and more toxic. MG induces tau hyperphosphorylation by enhancing kinase activities and reducing phosphatase level. Moreover, MG is a neurotoxic mediators of oxidative stress in the progression of AD and is capable of activating many redox signaling pathways leading to apoptosis and cellular dysfunction. Accumulation of AGEs further magnifies ROS production by inducing the glycation of important antioxidant enzymes and by providing precursor of oxidative stress. In conclusion, it can be reasonably supposed that cognitive decline associated with AD might be strongly linked to an increase in MG levels due to an oxoaldehyde detoxification impairment or an altered endogenous oxoaldehyde production. From a clinical point of view, the reduction of risk factors for pathologies such as diabetes, characterized by MG accumulation due to hyperglycemic conditions and impaired glucose metabolism [167], and the enhancement of MG scavenging system may provide new therapeutic opportunities to reduce the pathophysiological modifications associated with carbonyl stress in AD.

Figure 2 

Role of MG and MG-derived AGEs in AD.

Abbreviation List

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgments

This work was supported by MIUR-FIRB (Project RBAP11HSZS) and “Fondazione del Monte di Bologna e Ravenna” (Italy) (Cristina Angeloni and Silvana Hrelia).

References

1. H. Zheng and E. H. Koo, “Biology and pathophysiology of the amyloid precursor protein,” Molecular Neurodegeneration, vol. 6, no. 1, article 27, 2011. View at: Publisher Site | Google Scholar
2. D. M. Walsh, I. Klyubin, J. V. Fadeeva, M. J. Rowan, and D. J. Selkoe, “Amyloid-β oligomers: their production, toxicity and therapeutic inhibition,” Biochemical Society Transactions, vol. 30, no. 4, pp. 552–557, 2002. View at: Publisher Site | Google Scholar
3. D. T. Loo, A. Copani, C. J. Pike, E. R. Whittemore, A. J. Walencewicz, and C. W. Cotman, “Apoptosis is induced by β-amyloid in cultured central nervous system neurons,” Proceedings of the National Academy of Sciences of the United States of America, vol. 90, no. 17, pp. 7951–7955, 1993. View at: Google Scholar
4. A.-L. Bulteau, P. Verbeke, I. Petropoulos, A.-F. Chaffotte, and B. Friguet, “Proteasome inhibition in glyoxal-treated fibroblasts and resistance of glycated glucose-6-phosphate dehydrogenase to 20 S proteasome degradation in vitro,” The Journal of Biological Chemistry, vol. 276, no. 49, pp. 45662–45668, 2001. View at: Publisher Site | Google Scholar
5. P. S. Sachdev, L. Zhuang, N. Braidy, and W. Wen, “Is Alzheimer's a disease of the white matter?” Current Opinion in Psychiatry, vol. 26, no. 3, pp. 244–251, 2013. View at: Publisher Site | Google Scholar
6. D. W. Cleveland, S. Y. Hwo, and M. W. Kirschner, “Purification of tau, a microtubule associated protein that induces assembly of microtubules from purified tubulin,” Journal of Molecular Biology, vol. 116, no. 2, pp. 207–225, 1977. View at: Google Scholar
7. R. Brandt and G. Lee, “Functional organization of microtubule-associated protein tau. Identification of regions which affect microtubule growth, nucleation, and bundle formation in vitro,” The Journal of Biological Chemistry, vol. 268, no. 5, pp. 3414–3419, 1993. View at: Google Scholar
8. G. Münch, J. Thome, P. Foley, R. Schinzel, and P. Riederer, “Advanced glycation endproducts in ageing and Alzheimer's disease,” Brain Research Reviews, vol. 23, no. 1-2, pp. 134–143, 1997. View at: Publisher Site | Google Scholar
9. P. Ulrich and A. Cerami, “Protein glycation, diabetes, and aging,” Recent Progress in Hormone Research, vol. 56, pp. 1–21, 2001. View at: Publisher Site | Google Scholar
10. P. J. Thornalley, “Pharmacology of methylglyoxal: formation, modification of proteins and nucleic acids, and enzymatic detoxification—a role in pathogenesis and antiproliferative chemotherapy,” General Pharmacology, vol. 27, no. 4, pp. 565–573, 1996. View at: Publisher Site | Google Scholar
11. P. J. Thornalley, “Dicarbonyl intermediates in the Maillard reaction,” Annals of the New York Academy of Sciences, vol. 1043, pp. 111–117, 2005. View at: Publisher Site | Google Scholar
12. R. Ramasamy, S. J. Vannucci, S. S. D. Yan, K. Herold, S. F. Yan, and A. M. Schmidt, “Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation,” Glycobiology, vol. 15, no. 7, pp. 16R–28R, 2005. View at: Publisher Site | Google Scholar
13. K. Chen, J. Maley, and P. H. Yu, “Potential implications of endogenous aldehydes in β-amyloid misfolding, oligomerization and fibrillogenesis,” Journal of Neurochemistry, vol. 99, no. 5, pp. 1413–1424, 2006. View at: Publisher Site | Google Scholar
14. J. N. Fawver, H. E. Schall, R. D. P. Chapa, X. Zhu, and I. V. Murray, “Amyloid-beta metabolite sensing: biochemical linking of glycation modification and misfolding,” Journal of Alzheimer's Disease, vol. 30, no. 1, pp. 63–73, 2012. View at: Publisher Site | Google Scholar
15. R. J. Castellani, P. L. R. Harris, L. M. Sayre et al., “Active glycation in neurofibrillary pathology of Alzheimer disease: Nε-(Carboxymethyl) lysine and hexitol-lysine,” Free Radical Biology and Medicine, vol. 31, no. 2, pp. 175–180, 2001. View at: Publisher Site | Google Scholar
16. H.-J. Lüth, V. Ogunlade, B. Kuhla et al., “Age- and stage-dependent accumulation of advanced glycation end products in intracellular deposits in normal and Alzheimer's disease brains,” Cerebral Cortex, vol. 15, no. 2, pp. 211–220, 2005. View at: Publisher Site | Google Scholar
17. F. Amicarelli, S. Colafarina, F. Cattani et al., “Scavenging system efficiency is crucial for cell resistance to ROS-mediated methylglyoxal injury,” Free Radical Biology and Medicine, vol. 35, no. 8, pp. 856–871, 2003. View at: Publisher Site | Google Scholar
18. S. Kikuchi, K. Shinpo, F. Moriwaka, Z. Makita, T. Miyata, and K. Tashiro, “Neurotoxicity of methylglyoxal and 3-deoxyglucosone on cultured cortical neurons: synergism between glycation and oxidative stress, possibly involved in neurodegenerative diseases,” Journal of Neuroscience Research, vol. 57, no. 2, pp. 280–289, 1999. View at: Google Scholar
19. K. Shinpo, S. Kikuchi, H. Sasaki, A. Ogata, F. Moriwaka, and K. Tashiro, “Selective vulnerability of spinal motor neurons to reactive dicarbonyl compounds, intermediate products of glycation, in vitro: implication of inefficient glutathione system in spinal motor neurons,” Brain Research, vol. 861, no. 1, pp. 151–159, 2000. View at: Publisher Site | Google Scholar
20. D. A. Butterfield and C. M. Lauderback, “Lipid peroxidation and protein oxidation in Alzheimer's disease brain: potential causes and consequences involving amyloid β-peptide-associated free radical oxidative stress,” Free Radical Biology and Medicine, vol. 32, no. 11, pp. 1050–1060, 2002. View at: Publisher Site | Google Scholar
21. C. E. Cross, B. Halliwell, E. T. Borish et al., “Oxygen radicals and human disease. Davis conference,” Annals of Internal Medicine, vol. 107, no. 4, pp. 526–545, 1987. View at: Google Scholar
22. W. R. Markesbery, “Oxidative stress hypothesis in Alzheimer's disease,” Free Radical Biology and Medicine, vol. 23, no. 1, pp. 134–147, 1997. View at: Publisher Site | Google Scholar
23. A. Tarozzi, C. Angeloni, M. Malaguti, F. Morroni, S. Hrelia, and P. Hrelia, “Sulforaphane as a potential protective phytochemical against neurodegenerative diseases,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 415078, 10 pages, 2013. View at: Publisher Site | Google Scholar
24. A. Y. Abramov, L. Canevari, and M. R. Duchen, “β-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase,” Journal of Neuroscience, vol. 24, no. 2, pp. 565–575, 2004. View at: Publisher Site | Google Scholar
25. E. Motori, J. Puyal, N. Toni et al., “Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance,” Cell Metabolism, vol. 18, no. 6, pp. 844–859, 2013. View at: Publisher Site | Google Scholar
26. M. S. Silva, R. A. Gomes, A. E. Ferreira, A. P. Freire, and C. Cordeiro, “The glyoxalase pathway: the first hundred years... and beyond,” The Biochemical Journal, vol. 453, no. 1, pp. 1–15, 2013. View at: Publisher Site | Google Scholar
27. I. Nemet, L. Varga-Defterdarović, and Z. Turk, “Methylglyoxal in food and living organisms,” Molecular Nutrition and Food Research, vol. 50, no. 12, pp. 1105–1117, 2006. View at: Publisher Site | Google Scholar
28. J. Wang and T. Chang, “Methylglyoxal content in drinking coffee as a cytotoxic factor,” Journal of Food Science, vol. 75, no. 6, pp. H167–H171, 2010. View at: Publisher Site | Google Scholar
29. M. P. Kalapos, “Where does plasma methylglyoxal originate from?” Diabetes Research and Clinical Practice, vol. 99, no. 3, pp. 260–271, 2013. View at: Publisher Site | Google Scholar
30. G. Vistoli, D. De Maddis, A. Cipak, N. Zarkovic, M. Carini, and G. Aldini, “Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation,” Free Radical Research, vol. 47, no. S1, pp. 3–27, 2013. View at: Publisher Site | Google Scholar
31. J. Degen, M. Hellwig, and T. Henle, “1,2-dicarbonyl compounds in commonly consumed foods,” Journal of Agricultural and Food Chemistry, vol. 60, no. 28, pp. 7071–7079, 2012. View at: Publisher Site | Google Scholar
32. Y. V. Pfeifer, P. T. Haase, and L. W. Kroh, “Reactivity of thermally treated alpha-dicarbonyl compounds,” Journal of Agricultural and Food Chemistry, vol. 61, no. 12, pp. 3090–3096, 2013. View at: Publisher Site | Google Scholar
33. I. Nemet and L. Varga-Defterdarović, “Methylglyoxal-derived β-carbolines formed from tryptophan and its derivates in the Maillard reaction,” Amino Acids, vol. 32, no. 2, pp. 291–293, 2007. View at: Publisher Site | Google Scholar
34. S. Kuntz, S. Rudloff, J. Ehl, R. G. Bretzel, and C. Kunz, “Food derived carbonyl compounds affect basal and stimulated secretion of interleukin-6 and -8 in Caco-2 cells,” European Journal of Nutrition, vol. 48, no. 8, pp. 499–503, 2009. View at: Publisher Site | Google Scholar
35. J. P. Casazza, M. E. Felver, and R. L. Veech, “The metabolism of acetone in rat,” The Journal of Biological Chemistry, vol. 259, no. 1, pp. 231–236, 1984. View at: Google Scholar
36. R. A. Cooper, “Metabolism of methylglyoxal in microorganisms,” Annual Review of Microbiology, vol. 38, pp. 49–68, 1984. View at: Google Scholar
37. K. Fujioka and T. Shibamoto, “Determination of toxic carbonyl compounds in cigarette smoke,” Environmental Toxicology, vol. 21, no. 1, pp. 47–54, 2006. View at: Publisher Site | Google Scholar
38. V. Camel and A. Bermond, “The use of ozone and associated oxidation processes in drinking water treatment,” Water Research, vol. 32, no. 11, pp. 3208–3222, 1998. View at: Publisher Site | Google Scholar
39. T.-M. Fu, D. J. Jacob, F. Wittrock, J. P. Burrows, M. Vrekoussis, and D. K. Henze, “Global budgets of atmospheric glyoxal and methylglyoxal, and implications for formation of secondary organic aerosols,” Journal of Geophysical Research D, vol. 113, no. 15, Article ID D15303, 2008. View at: Publisher Site | Google Scholar
40. M. P. Kalapos, “Methylglyoxal in living organisms—chemistry, biochemistry, toxicology and biological implications,” Toxicology Letters, vol. 110, no. 3, pp. 145–175, 1999. View at: Publisher Site | Google Scholar
41. P. J. Beisswenger, S. K. Howell, R. G. Nelson, M. Mauer, and B. S. Szwergold, “α-oxoaldehyde metabolism and diabetic complications,” Biochemical Society Transactions, vol. 31, part 6, pp. 1358–1363, 2003. View at: Google Scholar
42. M. P. Kalapos, “Methylglyoxal and glucose metabolism: a historical perspective and future avenues for research,” Drug Metabolism and Drug Interactions, vol. 23, no. 1-2, pp. 69–91, 2008. View at: Google Scholar
43. M. P. Kalapos, “The tandem of free radicals and methylglyoxal,” Chemico-Biological Interactions, vol. 171, no. 3, pp. 251–271, 2008. View at: Publisher Site | Google Scholar
44. Q. Cui and M. Karplus, “Catalysis and specificity in enzymes: a study of triosephosphate isomerase and comparison with methyl glyoxal synthase,” Advances in Protein Chemistry, vol. 66, pp. 315–372, 2003. View at: Publisher Site | Google Scholar
45. J. P. Richard, “Mechanism for the formation of methylglyoxal from triosephosphates,” Biochemical Society Transactions, vol. 21, no. 2, pp. 549–553, 1993. View at: Google Scholar
46. R. A. Cooper, “[104] Methylglyoxal synthase,” Methods in Enzymology, vol. 41, pp. 502–508, 1975. View at: Publisher Site | Google Scholar
47. A. Dhar, K. Desai, M. Kazachmov, P. Yu, and L. Wu, “Methylglyoxal production in vascular smooth muscle cells from different metabolic precursors,” Metabolism: Clinical and Experimental, vol. 57, no. 9, pp. 1211–1220, 2008. View at: Publisher Site | Google Scholar
48. F. Y. Bondoc, Z. Bao, W.-Y. Hu et al., “Acetone catabolism by cytochrome P450 2E1: studies with CYP2E1-null mice,” Biochemical Pharmacology, vol. 58, no. 3, pp. 461–463, 1999. View at: Publisher Site | Google Scholar
49. Z. Turk, I. Nemet, L. Varga-Defteardarovic, and N. Car, “Elevated level of methylglyoxal during diabetic ketoacidosis and its recovery phase,” Diabetes and Metabolism, vol. 32, no. 2, pp. 176–180, 2006. View at: Publisher Site | Google Scholar
50. J.-Y. Jung, H. S. Yun, J. Lee, and M.-K. Oh, “Production of 1,2-propanediol from glycerol in saccharomyces cerevisiae,” Journal of Microbiology and Biotechnology, vol. 21, no. 8, pp. 846–853, 2011. View at: Publisher Site | Google Scholar
51. T. Shibamoto, “Analytical methods for trace levels of reactive carbonyl compounds formed in lipid peroxidation systems,” Journal of Pharmaceutical and Biomedical Analysis, vol. 41, no. 1, pp. 12–25, 2006. View at: Publisher Site | Google Scholar
52. H. Esterbauer, K. H. Cheeseman, and M. U. Dianzani, “Separation and characterization of the aldehydic products of lipid peroxidation stimulated by ADP-Fe²⁺ in rat liver microsomes,” The Biochemical Journal, vol. 208, no. 1, pp. 129–140, 1982. View at: Google Scholar
53. P. J. Thornalley, “The glyoxalase system in health and disease,” Molecular Aspects of Medicine, vol. 14, no. 4, pp. 287–371, 1993. View at: Publisher Site | Google Scholar
54. G. A. Lyles and J. Chalmers, “The metabolism of aminoacetone to methylglyoxal by semicarbazide-sensitive amine oxidase in human umbilical artery,” Biochemical Pharmacology, vol. 43, no. 7, pp. 1409–1414, 1992. View at: Publisher Site | Google Scholar
55. E. J. H. Bechara, F. Dutra, V. E. S. Cardoso et al., “The dual face of endogenous α-aminoketones: pro-oxidizing metabolic weapons,” Comparative Biochemistry and Physiology C, vol. 146, no. 1-2, pp. 88–110, 2007. View at: Publisher Site | Google Scholar
56. B. A. Callingham, A. E. Crosbie, and B. A. Rous, “Some aspects of the pathophysiology of semicarbazide-sensitive amine oxidase enzymes,” Progress in Brain Research, vol. 106, pp. 305–321, 1995. View at: Google Scholar
57. G. A. Lyles, “Mammalian plasma and tissue-bound semicarbazide-sensitive amine oxidases: biochemical, pharmacological and toxicological aspects,” International Journal of Biochemistry and Cell Biology, vol. 28, no. 3, pp. 259–274, 1996. View at: Publisher Site | Google Scholar
58. P. J. Thornalley, “Protein and nucleotide damage by glyoxal and methylglyoxal in physiological systems—role in ageing and disease,” Drug Metabolism and Drug Interactions, vol. 23, no. 1-2, pp. 125–150, 2008. View at: Google Scholar
59. P. J. Thornalley, A. Langborg, and H. S. Minhas, “Formation of glyoxal, methylglyoxal and 8-deoxyglucosone in the glycation of proteins by glucose,” The Biochemical Journal, vol. 344, part 1, pp. 109–116, 1999. View at: Publisher Site | Google Scholar
60. P. J. Thornalley, S. Battah, N. Ahmed et al., “Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry,” The Biochemical Journal, vol. 375, part 3, pp. 581–592, 2003. View at: Publisher Site | Google Scholar
61. N. Ahmed, P. J. Thornalley, J. Dawczynski et al., “Methylglyoxal-derived hydroimidazolone advanced glycation end-products of human lens proteins,” Investigative Ophthalmology and Visual Science, vol. 44, no. 12, pp. 5287–5292, 2003. View at: Publisher Site | Google Scholar
62. T. Oya, N. Hattori, Y. Mizuno et al., “Methylglyoxal modification of protein. Chemical and immunochemical characterization of methylglyoxal-arginine adducts,” The Journal of Biological Chemistry, vol. 274, no. 26, pp. 18492–18502, 1999. View at: Publisher Site | Google Scholar
63. I. N. Shipanova, M. A. Glomb, and R. H. Nagaraj, “Protein modification by methylglyoxal: chemical nature and synthetic mechanism of a major fluorescent adduct,” Archives of Biochemistry and Biophysics, vol. 344, no. 1, pp. 29–36, 1997. View at: Publisher Site | Google Scholar
64. E. B. Frye, T. P. Degenhardt, S. R. Thorpe, and J. W. Baynes, “Role of the Maillard reaction in aging of tissue proteins: advanced glycation end product-dependent increase in imidazolium cross-links in human lens proteins,” The Journal of Biological Chemistry, vol. 273, no. 30, pp. 18714–18719, 1998. View at: Publisher Site | Google Scholar
65. K. M. Bieme, D. Alexander Fried, and M. O. Lederer, “Identification and quantification of major maillard cross-links in human serum albumin and lens protein: evidence for glucosepane as the dominant compound,” The Journal of Biological Chemistry, vol. 277, no. 28, pp. 24907–24915, 2002. View at: Publisher Site | Google Scholar
66. T. W. C. Lo, M. E. Westwood, A. C. McLellan, T. Selwood, and P. J. Thornalley, “Binding and modification of proteins by methylglyoxal under physiological conditions: a kinetic and mechanistic study with Nα-acetylarginine, Nα- acetylcysteine, and Nα-acetyllysine, and bovine serum albumin,” The Journal of Biological Chemistry, vol. 269, no. 51, pp. 32299–32305, 1994. View at: Google Scholar
67. N. Ahmed, D. Dobler, M. Dean, and P. J. Thornalley, “Peptide mapping identifies hotspot site of modification in human serum albumin by methylglyoxal involved in ligand binding and esterase activity,” The Journal of Biological Chemistry, vol. 280, no. 7, pp. 5724–5732, 2005. View at: Publisher Site | Google Scholar
68. E. Kaufmann, B. O. Boehm, S. D. Süssmuth et al., “The advanced glycation end-product Nε-(carboxymethyl)lysine level is elevated in cerebrospinal fluid of patients with amyotrophic lateral sclerosis,” Neuroscience Letters, vol. 371, no. 2-3, pp. 226–229, 2004. View at: Publisher Site | Google Scholar
69. L. Southern, J. Williams, and M. M. Esiri, “Immunohistochemical study of N-epsilon-carboxymethyl lysine (CML) in human brain: relation to vascular dementia,” BMC Neurology, vol. 7, article 35, 2007. View at: Publisher Site | Google Scholar
70. M. Krautwald and G. Münch, “Advanced glycation end products as biomarkers and gerontotoxins—a basis to explore methylglyoxal-lowering agents for Alzheimer's disease?” Experimental Gerontology, vol. 45, no. 10, pp. 744–751, 2010. View at: Publisher Site | Google Scholar
71. T. Jono, T. Kimura, J. Takamatsu et al., “Accumulation of imidazolone, pentosidine and Nε-(carboxymethyl)lysine in hippocampal CA4 pyramidal neurons of aged human brain,” Pathology International, vol. 52, no. 9, pp. 563–571, 2002. View at: Publisher Site | Google Scholar
72. N. Ahmed, U. Ahmed, P. J. Thornalley, K. Hager, G. Fleischer, and G. Münch, “Protein glycation, oxidation and nitration adduct residues and free adducts of cerebrospinal fluid in Alzheimer's disease and link to cognitive impairment,” Journal of Neurochemistry, vol. 92, no. 2, pp. 255–263, 2005. View at: Publisher Site | Google Scholar
73. N. Taniguchi, M. Takahashi, H. Sakiyama et al., “A common pathway for intracellular reactive oxygen species production by glycoxidative and nitroxidative stress in vascular endothelial cells and smooth muscle cells,” Annals of the New York Academy of Sciences, vol. 1043, pp. 521–528, 2005. View at: Publisher Site | Google Scholar
74. K. M. Desai and L. Wu, “Free radical generation by methylglyoxal in tissues,” Drug Metabolism and Drug Interactions, vol. 23, no. 1-2, pp. 151–173, 2008. View at: Google Scholar
75. L. F. Dmitriev and V. N. Titov, “Lipid peroxidation in relation to ageing and the role of endogenous aldehydes in diabetes and other age-related diseases,” Ageing Research Reviews, vol. 9, no. 2, pp. 200–210, 2010. View at: Publisher Site | Google Scholar
76. T. Chang and L. Wu, “Methylglyoxal, oxidative stress, and hypertension,” Canadian Journal of Physiology and Pharmacology, vol. 84, no. 12, pp. 1229–1238, 2006. View at: Publisher Site | Google Scholar
77. I. Dhar and K. Desai, “Chapter 30. Aging: drugs to eliminate methylglyoxal, a reactive glucose metabolite, and advanced glycation endproducts,” in Pharmacology, L. Gallelli, Ed., 2012. View at: Publisher Site | Google Scholar
78. M. P. Kalapos, K. M. Desai, and L. Wu, “Methylglyoxal, oxidative stress, and aging,” in Aging and Age-Related Disorders, Oxidative Stress in Applied Basic Research and Clinical Practice, pp. 149–167, Humana Press, 2010. View at: Publisher Site | Google Scholar
79. X. Huang, F. Wang, W. Chen, Y. Chen, N. Wang, and K. von Maltzan, “Possible link between the cognitive dysfunction associated with diabetes mellitus and the neurotoxicity of methylglyoxal,” Brain Research, vol. 1469, pp. 82–91, 2012. View at: Publisher Site | Google Scholar
80. A. Szent-Gyorgyi, Bioelectronics: A Study in cellular regulations, Defense, and cancer, Academic Press, New York, NY, USA, 1968.
81. H. Kon and A. Szent Gyorgyi, “Charge transfer between amine and carbonyl,” Proceedings of the National Academy of Sciences of the United States of America, vol. 70, no. 11, pp. 3139–3140, 1973. View at: Google Scholar
82. M. P. Kalapos, A. Littauer, and H. De Groot, “Has reactive oxygen a role in methylglyoxal toxicity? A study on cultured rat hepatocytes,” Archives of Toxicology, vol. 67, no. 5, pp. 369–372, 1993. View at: Google Scholar
83. P. H. Yu, S. Wright, E. H. Fan, Z.-R. Lun, and D. Gubisne-Harberle, “Physiological and pathological implications of semicarbazide-sensitive amine oxidase,” Biochimica et Biophysica Acta, vol. 1647, no. 1-2, pp. 193–199, 2003. View at: Publisher Site | Google Scholar
84. J. M. Johnson, H. B. Halsall, and W. R. Heineman, “Redox activation of galactose oxidase: thin-layer electrochemical study,” Biochemistry, vol. 24, no. 7, pp. 1579–1585, 1985. View at: Google Scholar
85. P. J. Kersten and T. K. Kirk, “Involvement of a new enzyme, glyoxal oxidase, in extracellular H₂O₂ production by phanerochaete chrysosporium,” Journal of Bacteriology, vol. 169, no. 5, pp. 2195–2201, 1987. View at: Google Scholar
86. B. Leuthner, C. Aichinger, E. Oehmen et al., “A H₂O₂-producing glyoxal oxidase is required for filamentous growth and pathogenicity in Ustilago maydis,” Molecular Genetics and Genomics, vol. 272, no. 6, pp. 639–650, 2005. View at: Publisher Site | Google Scholar
87. Y. Hiraku, J. Sugimoto, T. Yamaguchi, and S. Kawanishi, “Oxidative DNA damage induced by aminoacetone, an amino acid metabolite,” Archives of Biochemistry and Biophysics, vol. 365, no. 1, pp. 62–70, 1999. View at: Publisher Site | Google Scholar
88. F. Dutra, F. S. Knudsen, D. Curi, and E. J. H. Bechara, “Aerobic oxidation of aminoacetone, a threonine catabolite: iron catalysis and coupled iron release from ferritin,” Chemical Research in Toxicology, vol. 14, no. 9, pp. 1323–1329, 2001. View at: Publisher Site | Google Scholar
89. C. C. C. Vidigal and G. Cilento, “Evidence for the generation of excited methylglyoxal in the myoglobin catalyzed oxidation of acetoacetate,” Biochemical and Biophysical Research Communications, vol. 62, no. 2, pp. 184–190, 1975. View at: Google Scholar
90. K. Takayama, M. Nakano, and K. Zinner, “Generation of electronic energy in the myoglobin catalyzed oxidation of acetoacetate to methylglyoxal,” Archives of Biochemistry and Biophysics, vol. 176, no. 2, pp. 663–670, 1976. View at: Google Scholar
91. T. Yamaguchi and K. Nakagawa, “Mutagenicity of and formation of oxygen radicals by trioses and glyoxal derivatives,” Agricultural and Biological Chemistry, vol. 47, no. 11, pp. 2461–2465, 1983. View at: Google Scholar
92. P. Thornalley, S. Wolff, J. Crabbe, and A. Stern, “The autoxidation of glyceraldehyde and other simple monosaccharides under physiological conditions catalysed by buffer ions,” Biochimica et Biophysica Acta, vol. 797, no. 2, pp. 276–287, 1984. View at: Publisher Site | Google Scholar
93. P. J. Thornalley, S. P. Wolff, M. J. Crabbe, and A. Stern, “The oxidation of oxyhaemoglobin by glyceraldehyde and other simple monosaccharides,” The Biochemical Journal, vol. 217, no. 3, pp. 615–622, 1984. View at: Google Scholar
94. R. Atkinson, W. P. L. Carter, K. R. Darnall, M. Winer, and J. N. Pitts, “A smog chamber and modeling study of the gas phase NOx—air photooxidation of toluene and the cresols,” International Journal of Chemical Kinetics, vol. 12, no. 11, pp. 779–836, 1980. View at: Publisher Site | Google Scholar
95. H. Nukaya, Y. Inaoka, H. Ishida et al., “Modification of the amino group of guanosine by methylglyoxal and other α-ketoaldehydes in the presence of hydrogen peroxide,” Chemical and Pharmaceutical Bulletin, vol. 41, no. 4, pp. 649–653, 1993. View at: Google Scholar
96. C. Angeloni, S. Turroni, L. Bianchi et al., “Novel targets of sulforaphane in primary cardiomyocytes identified by proteomic analysis,” PLoS ONE, vol. 8, no. 12, Article ID e83283, 2013. View at: Publisher Site | Google Scholar
97. T. Chang, R. Wang, and L. Wu, “Methylglyoxal-induced nitric oxide and peroxynitrite production in vascular smooth muscle cells,” Free Radical Biology and Medicine, vol. 38, no. 2, pp. 286–293, 2005. View at: Publisher Site | Google Scholar
98. C. Ho, P.-H. Lee, W.-J. Huang, Y.-C. Hsu, C.-L. Lin, and J.-Y. Wang, “Methylglyoxal-induced fibronectin gene expression through ras-mediated NADPH oxidase activation in renal mesangial cells,” Nephrology, vol. 12, no. 4, pp. 348–356, 2007. View at: Publisher Site | Google Scholar
99. R. A. Ward and K. R. McLeish, “Methylglyoxal: a stimulus to neutrophil oxygen radical production in chronic renal failure?” Nephrology Dialysis Transplantation, vol. 19, no. 7, pp. 1702–1707, 2004. View at: Publisher Site | Google Scholar
100. J. Nicolay, J. Schneider, O. Niemoeller et al., “Stimulation of suicidal erythrocyte death by methylglyoxal,” Cellular Physiology and Biochemistry, vol. 18, no. 4-5, pp. 223–232, 2006. View at: Publisher Site | Google Scholar
101. Y. S. Park, Y. H. Koh, M. Takahashi et al., “Identification of the binding site of methylglyoxal on gluthathione peroxidase: methylglyoxal inhibits glutathione peroxidase activity via binding to glutathione binding sites Arg 184 and 185,” Free Radical Research, vol. 37, no. 2, pp. 205–211, 2003. View at: Publisher Site | Google Scholar
102. P. J. Thornalley, “Glutathione-dependent detoxification of α-oxoaldehydes by the glyoxalase system: Involvement in disease mechanisms and antiproliferative activity of glyoxalase I inhibitors,” Chemico-Biological Interactions, vol. 111-112, pp. 137–151, 1998. View at: Publisher Site | Google Scholar
103. J. H. Kang, “Modification and inactivation of human Cu,Zn-superoxide dismutase by methylglyoxal,” Molecules and Cells, vol. 15, no. 2, pp. 194–199, 2003. View at: Google Scholar
104. N. Rabbani and P. J. Thornalley, “Dicarbonyls linked to damage in the powerhouse: glycation of mitochondrial proteins and oxidative stress,” Biochemical Society Transactions, vol. 36, part5, pp. 1045–1050, 2008. View at: Publisher Site | Google Scholar
105. M. G. Rosca, T. G. Mustata, M. T. Kinter et al., “Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation,” The American Journal of Physiology: Renal Physiology, vol. 289, no. 2, pp. F420–F430, 2005. View at: Publisher Site | Google Scholar
106. J. Du, H. Suzuki, F. Nagase et al., “Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process,” Free Radical Biology and Medicine, vol. 31, no. 4, pp. 469–478, 2001. View at: Publisher Site | Google Scholar
107. G. Basta, G. Lazzerini, M. Massaro et al., “Advanced glycation end products activate endothelium through signal-transduction receptor RAGE a mechanism for amplification of inflammatory responses,” Circulation, vol. 105, no. 7, pp. 816–822, 2002. View at: Publisher Site | Google Scholar
108. J. Chen, S. V. Brodsky, D. M. Goligorsky et al., “Glycated collagen I induces premature senescence-like phenotypic changes in endothelial cells,” Circulation Research, vol. 90, no. 12, pp. 1290–1298, 2002. View at: Publisher Site | Google Scholar
109. S. Kikuchi, K. Shinpo, M. Takeuchi et al., “Glycation—a sweet tempter for neuronal death,” Brain Research Reviews, vol. 41, no. 2-3, pp. 306–323, 2003. View at: Publisher Site | Google Scholar
110. M.-P. Wautier, O. Chappey, S. Corda, D. M. Stern, A. M. Schmidt, and J.-L. Wautier, “Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE,” The American Journal of Physiology: Endocrinology and Metabolism, vol. 280, no. 5, pp. E685–E694, 2001. View at: Google Scholar
111. M. E. Westwood and P. J. Thornalley, “Induction of synthesis and secretion of interleukin 1β in the human monocytic THP-1 cells by human serum albumins modified with methylglyoxal and advanced glycation endproducts,” Immunology Letters, vol. 50, no. 1-2, pp. 17–21, 1996. View at: Publisher Site | Google Scholar
112. P. J. Thornalley, “Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs,” Cellular and Molecular Biology, vol. 44, no. 7, pp. 1013–1023, 1998. View at: Google Scholar
113. A. Bierhaus, S. Chevion, M. Chevion et al., “Advanced glycation end product-induced activation of NF-κB is suppressed by α-lipoic acid in cultured endothelial cells,” Diabetes, vol. 46, no. 9, pp. 1481–1490, 1997. View at: Google Scholar
114. M. P. Vitek, K. Bhattacharya, J. M. Glendening et al., “Advanced glycation end products contribute to amyloidosis in Alzheimer disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 11, pp. 4766–4770, 1994. View at: Publisher Site | Google Scholar
115. T. Kimura, J. Takamatsu, N. Araki et al., “Are advanced glycation end-products associated with amyloidosis in Alzheimer's disease?” NeuroReport, vol. 6, no. 6, pp. 866–868, 1995. View at: Google Scholar
116. S.-Y. Ko, Y.-P. Lin, Y.-S. Lin, and S.-S. Chang, “Advanced glycation end products enhance amyloid precursor protein expression by inducing reactive oxygen species,” Free Radical Biology and Medicine, vol. 49, no. 3, pp. 474–480, 2010. View at: Publisher Site | Google Scholar
117. X. H. Li, L. L. Du, X. S. Cheng et al., “Glycation exacerbates the neuronal toxicity of beta-amyloid,” Cell Death and Disease, vol. 4, article e673, 2013. View at: Publisher Site | Google Scholar
118. H. M. Schipper, “Apolipoprotein E: implications for AD neurobiology, epidemiology and risk assessment,” Neurobiology of Aging, vol. 32, no. 5, pp. 778–790, 2011. View at: Publisher Site | Google Scholar
119. G. Bu, “Apolipoprotein e and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy,” Nature Reviews Neuroscience, vol. 10, no. 5, pp. 333–344, 2009. View at: Publisher Site | Google Scholar
120. Y. Namba, M. Tomonaga, H. Kawasaki, E. Otomo, and K. Ikeda, “Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease,” Brain Research, vol. 541, no. 1, pp. 163–166, 1991. View at: Publisher Site | Google Scholar
121. E. Kok, S. Haikonen, T. Luoto et al., “Apolipoprotein E-dependent accumulation of alzheimer disease-related lesions begins in middle age,” Annals of Neurology, vol. 65, no. 6, pp. 650–657, 2009. View at: Publisher Site | Google Scholar
122. T. Polvikoski, R. Sulkava, M. Haltia et al., “Apolipoprotein E, dementia, and cortical deposition of β-amyloid protein,” The New England Journal of Medicine, vol. 333, no. 19, pp. 1242–1247, 1995. View at: Publisher Site | Google Scholar
123. Y. M. Li and D. W. Dickson, “Enhanced binding of advanced glycation endproducts (AGE) by the ApoE4 isoform links the mechanism of plaque deposition in Alzheimer's disease,” Neuroscience Letters, vol. 226, no. 3, pp. 155–158, 1997. View at: Publisher Site | Google Scholar
124. G. Münch, B. Westcott, T. Menini, and A. Gugliucci, “Advanced glycation endproducts and their pathogenic roles in neurological disorders,” Amino Acids, vol. 42, no. 4, pp. 1221–1236, 2012. View at: Publisher Site | Google Scholar
125. J. J. Li, M. Surini, S. Catsicas, E. Kawashima, and C. Bouras, “Age-dependent accumulation of advanced glycosylation end products in human neurons,” Neurobiology of Aging, vol. 16, no. 1, pp. 69–76, 1995. View at: Publisher Site | Google Scholar
126. A. Wong, H.-J. Lüth, W. Deuther-Conrad et al., “Advanced glycation endproducts co-localize with inducible nitric oxide synthase in Alzheimer's disease,” Brain Research, vol. 920, no. 1-2, pp. 32–40, 2001. View at: Publisher Site | Google Scholar
127. V. Prakash Reddy, M. E. Obrenovich, C. S. Atwood, G. Perry, and M. A. Smith, “Involvement of Maillard reactions in Alzheimer disease,” Neurotoxicity Research, vol. 4, no. 3, pp. 191–209, 2002. View at: Publisher Site | Google Scholar
128. M. A. Smith, S. Taneda, P. L. Richey et al., “Advanced Maillard reaction end products are associated with Alzheimer disease pathology,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 12, pp. 5710–5714, 1994. View at: Publisher Site | Google Scholar
129. V. V. Shuvaev, I. Laffont, J.-M. Serot, J. Fujii, N. Taniguchi, and G. Siest, “Increased protein glycation in cerebrospinal fluid of Alzheimer's disease,” Neurobiology of Aging, vol. 22, no. 3, pp. 397–402, 2001. View at: Publisher Site | Google Scholar
130. K. J. Bär, S. Franke, B. Wenda et al., “Pentosidine and Nε-(carboxymethyl)-lysine in Alzheimer's disease and vascular dementia,” Neurobiology of Aging, vol. 24, no. 2, pp. 333–338, 2003. View at: Publisher Site | Google Scholar
131. L. Mucke, “Neuroscience: Alzheimer's disease,” Nature, vol. 461, no. 7266, pp. 895–897, 2009. View at: Publisher Site | Google Scholar
132. M. S. Beeri, E. Moshier, J. Schmeidler et al., “Serum concentration of an inflammatory glycotoxin, methylglyoxal, is associated with increased cognitive decline in elderly individuals,” Mechanisms of Ageing and Development, vol. 132, no. 11-12, pp. 583–587, 2011. View at: Publisher Site | Google Scholar
133. M. A. Lovell, C. Xie, and W. R. Markesbery, “Acrolein is increased in Alzheimer's disease brain and is toxic to primary hippocampal cultures,” Neurobiology of Aging, vol. 22, no. 2, pp. 187–194, 2001. View at: Publisher Site | Google Scholar
134. J. K. Andersen, “Oxidative stress in neurodegeneration: cause or consequence?” Nature Medicine, vol. 5, pp. S18–S25, 2004. View at: Publisher Site | Google Scholar
135. A. Nunomura, G. Perry, G. Aliev et al., “Oxidative damage is the earliest event in Alzheimer disease,” Journal of Neuropathology and Experimental Neurology, vol. 60, no. 8, pp. 759–767, 2001. View at: Google Scholar
136. R. H. Swerdlow, “Brain aging, Alzheimer's disease, and mitochondria,” Biochimica et Biophysica Acta, vol. 1812, no. 12, pp. 1630–1639, 2011. View at: Publisher Site | Google Scholar
137. P. F. Good, P. Werner, A. Hsu, C. W. Olanow, and D. P. Perl, “Evidence for neuronal oxidative damage in Alzheimer's disease,” The American Journal of Pathology, vol. 149, no. 1, pp. 21–28, 1996. View at: Google Scholar
138. S. G. de Arriba, G. Stuchbury, J. Yarin, J. Burnell, C. Loske, and G. Münch, “Methylglyoxal impairs glucose metabolism and leads to energy depletion in neuronal cells-protection by carbonyl scavengers,” Neurobiology of Aging, vol. 28, no. 7, pp. 1044–1050, 2007. View at: Publisher Site | Google Scholar
139. S.-M. Huang, H.-C. Chuang, C.-H. Wu, and G.-C. Yen, “Cytoprotective effects of phenolic acids on methylglyoxal-induced apoptosis in Neuro-2A cells,” Molecular Nutrition and Food Research, vol. 52, no. 8, pp. 940–949, 2008. View at: Publisher Site | Google Scholar
140. Y.-J. Chen, X.-B. Huang, Z.-X. Li, L.-L. Yin, W.-Q. Chen, and L. Li, “Tenuigenin protects cultured hippocampal neurons against methylglyoxal-induced neurotoxicity,” European Journal of Pharmacology, vol. 645, no. 1–3, pp. 1–8, 2010. View at: Publisher Site | Google Scholar
141. Q. Q. Yin, C. F. Dong, S. Q. Dong et al., “AGEs induce cell death via oxidative and endoplasmic reticulum stresses in both human SH-SY5Y neuroblastoma cells and rat cortical neurons,” Cellular and Molecular Neurobiology, vol. 32, no. 8, pp. 1299–1309, 2012. View at: Publisher Site | Google Scholar
142. F. Liu, Z. Liang, and C. X. Gong, “Hyperphosphorylation of tau and protein phosphatases in Alzheimer disease,” Panminerva Medica, vol. 48, no. 2, pp. 97–108, 2006. View at: Google Scholar
143. K. Iqbal, F. Liu, C.-X. Gong, A. C. del Alonso, and I. Grundke-Iqbal, “Mechanisms of tau-induced neurodegeneration,” Acta Neuropathologica, vol. 118, no. 1, pp. 53–69, 2009. View at: Publisher Site | Google Scholar
144. E. Planel, T. Miyasaka, T. Launey et al., “Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: implications for Alzheimer's disease,” Journal of Neuroscience, vol. 24, no. 10, pp. 2401–2411, 2004. View at: Publisher Site | Google Scholar
145. M. Hu, J. F. Waring, M. Gopalakrishnan, and J. Li, “Role of GSK-3β activation and α7 nAChRs in Aβ 1-42-induced tau phosphorylation in PC12 cells,” Journal of Neurochemistry, vol. 106, no. 3, pp. 1371–1377, 2008. View at: Publisher Site | Google Scholar
146. C. X. Gong, “Dephosphorylation of Alzheimer's disease abnormally phosphorylated tau by protein phosphatase-2A,” Neuroscience, vol. 61, no. 4, pp. 765–772, 1994. View at: Publisher Site | Google Scholar
147. J.-Z. Wang, C.-X. Gong, T. Zaidi, I. Grundke-Iqbal, and K. Iqbal, “Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B,” The Journal of Biological Chemistry, vol. 270, no. 9, pp. 4854–4860, 1995. View at: Publisher Site | Google Scholar
148. X. H. Li, J. Z. Xie, X. Jiang et al., “Methylglyoxal induces tau hyperphosphorylation via promoting AGEs formation,” NeuroMolecular Medicine, vol. 14, no. 4, pp. 338–348, 2012. View at: Publisher Site | Google Scholar
149. M. A. Smith, M. Rudnicka-Nawrot, P. L. Richey et al., “Carbonyl-related posttranslational modification of neurofilament protein in the neurofibrillary pathology of Alzheimer's disease,” Journal of Neurochemistry, vol. 64, no. 6, pp. 2660–2666, 1995. View at: Google Scholar
150. P. Cras, M. A. Smith, P. L. Richey, S. L. Siedlak, P. Mulvihill, and G. Perry, “Extracellular neurofibrillary tangles reflect neuronal loss and provide further evidence of extensive protein cross linking in Alzheimer disease,” Acta Neuropathologica, vol. 89, no. 4, pp. 291–295, 1995. View at: Publisher Site | Google Scholar
151. B. Kuhla, C. Haase, K. Flach, H. J. Luth, T. Arendt, and G. Munch, “Effect of pseudophosphorylation and cross-linking by lipid peroxidation and advanced glycation end product precursors on tau aggregation and filament formation,” J Biol Chem, vol. 282, no. 10, pp. 6984–6991, 2007. View at: Publisher Site | Google Scholar
152. M. T. Lin and M. F. Beal, “Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases,” Nature, vol. 443, no. 7113, pp. 787–795, 2006. View at: Publisher Site | Google Scholar
153. D. Praticò, “Oxidative stress hypothesis in Alzheimer's disease: a reappraisal,” Trends in Pharmacological Sciences, vol. 29, no. 12, pp. 609–615, 2008. View at: Publisher Site | Google Scholar
154. X. Zhu, H.-G. Lee, A. K. Raina, G. Perry, and M. A. Smith, “The role of mitogen-activated protein kinase pathways in Alzheimer's disease,” NeuroSignals, vol. 11, no. 5, pp. 270–281, 2002. View at: Publisher Site | Google Scholar
155. A. Chiarini, I. Dal Pra, M. Marconi, B. Chakravarthy, J. F. Whitfield, and U. Armato, “Calcium-sensing receptor (CaSR) in human brain's pathophysiology: Roles in late-onset Alzheimer's disease (LOAD),” Current Pharmaceutical Biotechnology, vol. 10, no. 3, pp. 317–326, 2009. View at: Publisher Site | Google Scholar
156. Y. Hashimoto, O. Tsuji, T. Niikura et al., “Involvement of c-Jun N-terminal kinase in amyloid precursor protein-mediated neuronal cell death,” Journal of Neurochemistry, vol. 84, no. 4, pp. 864–877, 2003. View at: Publisher Site | Google Scholar
157. C. A. Marques, U. Keil, A. Bonert et al., “Neurotoxic mechanisms caused by the alzheimer's disease-linked Swedish amyloid precursor protein. Mutation oxidative stress, caspases, and the JNK pathway,” The Journal of Biological Chemistry, vol. 278, no. 30, pp. 28294–28302, 2003. View at: Publisher Site | Google Scholar
158. B. Puig, T. Gómez-Isla, E. Ribé et al., “Expression of stress-activated kinases c-Jun N-terminal kinase (SAPK/JNK-P) and p38 kinase (p38-P), and tau hyperphosphorylation in neurites surrounding βA plaques in APP Tg2576 mice,” Neuropathology and Applied Neurobiology, vol. 30, no. 5, pp. 491–502, 2004. View at: Publisher Site | Google Scholar
159. E. Tamagno, M. Parola, P. Bardini et al., “β-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways,” Journal of Neurochemistry, vol. 92, no. 3, pp. 628–636, 2005. View at: Publisher Site | Google Scholar
160. C. Shen, Y. Chen, H. Liu et al., “Hydrogen peroxide promotes Aβ production through JNK-dependent activation of γ-secretase,” The Journal of Biological Chemistry, vol. 283, no. 25, pp. 17721–17730, 2008. View at: Publisher Site | Google Scholar
161. A. Colombo, A. Bastone, C. Ploia et al., “JNK regulates APP cleavage and degradation in a model of Alzheimer's disease,” Neurobiology of Disease, vol. 33, no. 3, pp. 518–525, 2009. View at: Publisher Site | Google Scholar
162. Z. Muresan and V. Muresan, “The amyloid-β precursor protein is phosphorylated via distinct pathways during differentiation, mitosis, stress, and degeneration,” Molecular Biology of the Cell, vol. 18, no. 10, pp. 3835–3844, 2007. View at: Publisher Site | Google Scholar
163. X. Fan, R. Subramaniam, M. F. Weiss, and V. M. Monnier, “Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor κB and intracellular reactive oxygen species formation,” Archives of Biochemistry and Biophysics, vol. 409, no. 2, pp. 274–286, 2003. View at: Publisher Site | Google Scholar
164. A. Pal, I. Bhattacharya, K. Bhattacharya, C. Mandal, and M. Ray, “Methylglyoxal induced activation of murine peritoneal macrophages and surface markers of T lymphocytes in Sarcoma-180 bearing mice: Involvement of MAP kinase, NF-κβ signal transduction pathway,” Molecular Immunology, vol. 46, no. 10, pp. 2039–2044, 2009. View at: Publisher Site | Google Scholar
165. S.-M. Huang, C.-L. Hsu, H.-C. Chuang, P.-H. Shih, C.-H. Wu, and G.-C. Yen, “Inhibitory effect of vanillic acid on methylglyoxal-mediated glycation in apoptotic Neuro-2A cells,” NeuroToxicology, vol. 29, no. 6, pp. 1016–1022, 2008. View at: Publisher Site | Google Scholar
166. L. Heimfarth, S. O. Loureiro, P. Pierozan et al., “Methylglyoxal-induced cytotoxicity in neonatal rat brain: a role for oxidative stress and MAP kinases,” Metabolic Brain Disease, vol. 28, no. 3, pp. 429–438, 2013. View at: Publisher Site | Google Scholar
167. P. Matafome, C. Sena, and R. Seica, “Methylglyoxal, obesity, and diabetes,” Endocrine, vol. 43, no. 3, pp. 472–484, 2013. View at: Publisher Site | Google Scholar

Copyright

Copyright © 2014 Cristina Angeloni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.