The formation and accumulation of advanced glycation endproducts (AGEs) are related to diabetes and other age-related diseases. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is the major precursor in the formation of AGEs. MGO is mainly formed as a byproduct of glycolysis. Under physiological circumstances, MGO is detoxified by the glyoxalase system into D-lactate, with glyoxalase I (GLO1) as the key enzyme in the anti-glycation defence. New insights indicate that increased levels of MGO and the major MGO-derived AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1), and dysfunctioning of the glyoxalase system are linked to several age-related health problems, such as diabetes, cardiovascular disease, cancer and disorders of the central nervous system. The present review summarizes the mechanisms through which MGO is formed, its detoxification by the glyoxalase system and its effect on biochemical pathways in relation to the development of age-related diseases. Although several scavengers of MGO have been developed over the years, therapies to treat MGO-associated complications are not yet available for application in clinical practice. Small bioactive inducers of GLO1 can potentially form the basis for new treatment strategies for age-related disorders in which MGO plays a pivotal role.

INTRODUCTION

The Maillard reaction is a process in which reducing sugars react spontaneously with amino residues in proteins, lipids and nucleic acids, to form advanced glycation endproducts (AGEs). Although elevated levels of glucose have been thought to play a primary role in the Maillard reaction, glucose is among the least reactive sugars in biological systems [1]. The formation of AGEs is now believed to result mainly from the action of various reactive metabolites other than glucose, such as methylglyoxal (MGO) [2]. It has become increasingly clear that the highly reactive glucose-derived metabolite MGO is the most potent glycating agent in the very fast generation of glycation adducts on cellular and short-lived extracellular proteins, lipids and DNA [3]. In the glycation reaction, MGO is up to 20 000-fold more reactive than glucose. MGO is mainly formed in cells by the non-enzymatic degradation of the triose phosphates glyceraldehyde 3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP), derived from glycolysis [4]. MGO reacts primarily with arginine residues of proteins, forming the AGE methylglyoxal-derived hydroimidazolone 1 (MG-H1) [5]. Arginine residues are thus hotspots for MGO modifications. As arginine residues are often present in the functional domains of proteins, such modifications by MGO contribute to alterations in cellular proteins and dysfunctioning of cells, and can subsequently lead to health problems.

Emerging evidence indicates that MGO not only is important for diabetic complications, but also plays a role in the development of other age-related diseases such as obesity [6], atherosclerosis [7], cancer [8] and neurodegenerative disorders [9]. The awareness that MGO can initiate potentially deleterious changes, leading to protein dysfunction, has raised concern in relation to healthy living. The harmful effects of MGO are counteracted in organisms by means of an enzymatic glyoxalase defence system, which converts MGO to D-lactate. In this process, glyoxalase I (GLO1) is the most crucial enzyme [10]. GLO1 is a key regulator of MGO levels, which means that alterations in GLO1 levels influence MGO production, and hence have an effect on the development of health problems. To further highlight the potential importance of MGO and GLO1 for human health, we focus below on the glycation reaction, paying special attention to the role that MGO and GLO1 play in the development of disease. In the present review, we give an overview of the biochemical mechanisms and the significant extent to which MGO and GLO1 contribute to protein glycation and age-related diseases.

METABOLISM OF MGO

MGO can be formed in several ways. It modifies proteins and nucleic acids, and is detoxified by several enzymatic pathways (Figure 1).

Biology of MGO

Figure 1
Biology of MGO

MGO is mainly formed as a byproduct of glycolysis and autoxidation of glucose. Other sources of MGO are catabolism of threonine and acetone, lipid peroxidation and degradation of glycated proteins. Increased levels of MGO are predominantly detoxified by the glyoxalase system, which converts MGO into its endproduct D-lactate, via the formation of the intermediate S-D-lactoylglutathione. In addition, ALDH and AR comprise minor pathways of MGO detoxification. If MGO production exceeds the detoxification capacity, MGO can modify arginine residues to form MG-H1, -H2 and -H3, AP and THP. When MGO reacts with lysine, it forms CEL and MOLD, whereas it forms MODIC when it forms a dimer cross-link with arginine and lysine.

Figure 1
Biology of MGO

MGO is mainly formed as a byproduct of glycolysis and autoxidation of glucose. Other sources of MGO are catabolism of threonine and acetone, lipid peroxidation and degradation of glycated proteins. Increased levels of MGO are predominantly detoxified by the glyoxalase system, which converts MGO into its endproduct D-lactate, via the formation of the intermediate S-D-lactoylglutathione. In addition, ALDH and AR comprise minor pathways of MGO detoxification. If MGO production exceeds the detoxification capacity, MGO can modify arginine residues to form MG-H1, -H2 and -H3, AP and THP. When MGO reacts with lysine, it forms CEL and MOLD, whereas it forms MODIC when it forms a dimer cross-link with arginine and lysine.

Formation of MGO

Endogenous MGO is derived from metabolic intermediates of carbohydrates, proteins and fatty acids [11]. Most of the MGO is formed as a byproduct of glycolysis by the non-enzymatic degradation of G3P and DHAP [4,10]. This pathway results in the formation of MGO in all cells and organisms, with a formation rate of about 120 μM/day under normoglycaemic conditions [4,12]. Although this production constitutes only 0.1% of the glucotriose flux, its biological effect is important because of the high reactivity of MGO with proteins and nucleic acids. Minor sources of MGO are autoxidation of glucose and degradation of glycated proteins [13], and also oxidation of acetone in the catabolism of ketone bodies during diabetic ketoacidosis [14], catabolism of threonine [15] and lipid peroxidation [16] (Figure 1).

Although concentrations of MGO have frequently been measured in tissues and plasma of various species, providing a reliable estimate of MGO levels is a challenging task. Published estimates of MGO concentrations in plasma and tissues vary by more than a factor of 1000 [17]. As recently reviewed by Kalapos [18], plasma MGO can originate from various sources, including in situ formation from glycated proteins, formation and release or outflow from cells and exogenous sources. Under physiological circumstances, an important source of plasma MGO seems to be in situ formation, whereas under pathophysiological circumstances, such as diabetes, increased intracellular formation of MGO and leakage from cells also contribute significantly to plasma MGO levels. Although MGO is also present in several daily consumed products [19], exogenous sources of MGO are not likely to be significant for plasma MGO levels. In the literature, plasma concentrations of MGO have been measured ranging from circa 100 nM to 400 μM [2022]. These variations most probably reflect the different analytical methods used, however. In particular, the formation of MGO during pre-analytical processing can lead to an over-estimation of its concentration [17]. During sample processing, MGO may be formed by degradation of monosaccharides, glycated proteins and glycolytic intermediates, conditions of high temperature or pH, oxidizing conditions and peroxidase activity [17]. To minimize the formation of MGO during sample processing, such conditions should therefore be avoided. The current state-of-the art technique for the measurement of MGO is ultra-performance liquid chromatography–tandem MS (UPLC-MS/MS), as recently described in detail [17,22]. By taking such precautionary measures and applying UPLC-MS/MS, plasma levels of MGO in healthy individuals have been estimated at about 132 nM [17]. In individuals with type 2 diabetes, plasma MGO concentrations are about 1.3-fold higher than in healthy individuals [22]. Importantly, plasma MGO levels increase during the postprandial period in patients with type 1 diabetes and reflect the degree of hyperglycaemia [23]. In patients with renal disease, up to 3.7-fold higher plasma levels of MGO have been reported; these levels increase with the stage of the disease [24,25]. Cellular MGO levels have been estimated at 1–5 μM MGO [26,27].

Detoxification of MGO

To prevent accumulation of MGO, it can be detoxified by various pathways (see Figure 1). The most important enzymatic detoxification system is the glyoxalase system (Figure 2). This system, which is active in the cytoplasm of all mammalian cells, converts MGO to D-lactate via the intermediate product S-D-lactoylglutathione. In mammals, the glyoxalase system involves two major enzymes, namely GLO1 (lactoylglutathione methylglyoxal lyase) and GLO2 (hydroxyacylglutathione hydrolase). It also requires a catalytic amount of reduced glutathione (GSH) [28]. Under normal conditions, >99% of MGO is metabolized via the glyoxalase system [29]. Minor pathways of MGO detoxification include aldehyde dehydrogenase (ALDH) and aldose reductase (AR) [3032]. ALDH catalyses the oxidation of MGO to pyruvate [30], whereas AR metabolizes MGO mainly by means of the formation of hydroxyacetone [31,32].

The glyoxalase system

Figure 2
The glyoxalase system

MGO forms a hemithioacetal with GSH, serving as a substrate for GLO1. GLO1 catalyses the conversion of the MGO–GSH hemithioacetal to the thioester S-D-lactoylglutathione. The GLO2 enzyme catalyses the hydrolysis of S-D-lactoylglutathione to form the endproduct D-lactate. During this reaction, GSH is recycled.

Figure 2
The glyoxalase system

MGO forms a hemithioacetal with GSH, serving as a substrate for GLO1. GLO1 catalyses the conversion of the MGO–GSH hemithioacetal to the thioester S-D-lactoylglutathione. The GLO2 enzyme catalyses the hydrolysis of S-D-lactoylglutathione to form the endproduct D-lactate. During this reaction, GSH is recycled.

MGO and disease

Figure 3
MGO and disease

MGO plays an important role in the process of ageing, but also in the pathogenesis of several age-related diseases, such as diabetes, obesity, cancer, disorders of the central nervous system, hypertension and atherosclerosis. MGO is also involved in epigenetics.

Figure 3
MGO and disease

MGO plays an important role in the process of ageing, but also in the pathogenesis of several age-related diseases, such as diabetes, obesity, cancer, disorders of the central nervous system, hypertension and atherosclerosis. MGO is also involved in epigenetics.

TARGETS OF MGO

The two most important targets of MGO are protein residues and nucleic acids. Modification of these targets results in the formation of MGO-derived AGEs and DNA adducts, respectively.

Modification of proteins by MGO and its functional consequences

MGO is believed to be the most important precursor of AGEs. Via modification of protein residues, MGO leads to the formation of MGO-derived AGEs (see Figure 1), which result from modification of the amino acids arginine and, to a much lesser extent, lysine [33]. In an irreversible reaction with arginine, MGO mainly leads to the formation of MGO-derived hydroimidazolones (MG-Hs). These cyclic hydroimidazolones are formed as three structural isoforms: MG-H1, MG-H2 and MG-H3. MG-H1 is the most important MGO-derived AGE, because it accounts for >90% of all MGO adducts, equivalent to MG-H1 residues in 1–5% of all proteins [5,31,34]. Peptide mapping by MS has identified protein-specific MG-H1 hotspots, e.g. Arg410 has been identified as the major MG-H1 hotspot on human serum albumin. Minor hotspots are Arg114, Arg186, Arg218 and Arg428. These modifications of albumin lead to the inhibition of antioxidant capacity, esterase activity and decreased drug-binding affinity [3537]. MGO-modified albumin also increases the synthesis and secretion of proinflammatory markers such as tumour necrosis factor α (TNF-α) and interleukin-1β in monocytes, and stimulates receptor-mediated endocytosis and degradation of proteins [3842]. Other important MG-H1-modified proteins are collagen [27,43], haemoglobin [44] and lens proteins [5].

It has been estimated that MG-H1 modifications have the greatest physiological consequences when they increase by a factor of 2 to 3 on, for instance, vascular type IV collagen [27]. This modification of type IV collagen leads to decreased integrin binding, detachment of endothelial cells from the vascular wall and inhibition of angiogenesis [27]. Similar increases of MG-H1 modifications of mitochondrial proteins have been linked to a 2- to 3-fold increase in oxidative stress, most probably as a result of electron leakage from the electron transport chain [45]. MG-H1 modification of 20S proteasomal subunit proteins decreases proteasome activity [46]. Moreover, heat shock protein 27 (HSP27) is an important MG-H1-modified protein, with its hydroimidazolone modification resulting in the enhancement of chaperone function, a factor that may play an important role in the reduction of protein aggregation in the lens during ageing and cataract formation [47]. Recently, it has been described that MG-H1 also serves as a ligand for the receptor of AGEs (RAGE), resulting in signal transduction, which could play a role in the development of various health problems [48].

In addition to the hydroimidazolones, modification of arginine by MGO results in the formation of Nδ-(5-hydroxy-4,6-dimethylpyramidine-2-yl)-L-ornithine (argpyrimidine–AP) [49], and Nδ-(4-carboxy-4,6-dimethyl-5,6-dihydroxy-1,4,5,6-tetrahydropyrimidine-2-yl)-L-ornithine (tetrahydropyrimidine–THP) [50]. Modification of HSP27 by AP also leads to heightened chaperone activity and lower apoptotic activity in lens epithelial cells, probably because it inhibits reactive oxygen species (ROS) generation and caspase activity [51,52]. AP-modified HSP27 in lens epithelial cells may therefore cope better with stress conditions that induce apoptosis during ageing and cataract conditions. AP modifications of HSP27 have also been detected in endothelial [53] and cardiac [54] cells. Furthermore, van Eupen et al. [55] have recently described THP modifications in atherosclerotic lesions and increased plasma levels of THP in patients with type 1 diabetes, which is associated with the endothelial dysfunction marker soluble vascular cell adhesion molecule 1 (sVCAM1) [55], strengthening the evidence that THP may be involved in the development of vascular disease. Finally, MGO can react irreversibly with lysine residues to form Nε-(1-carboxyethyl)lysine (CEL) [56] and the lysine dimer 1,3-di(Nε-lysino)-4-methyl-imidazolium (MOLD) [57]. MGO can also cross-link arginine and lysine residues to form the adduct 2-ammonio-6-{(2-[(4-ammonio-5-oxido-5-oxopentyl)amino]-4-methyl-4,5-dihydro-1H-imidazol-5-ylidene)amino}hexanoate (MODIC) [58].

Modification of DNA by MGO and its functional consequences

DNA is also susceptible to glycation by MGO. Under physiological conditions, deoxyguanosine (dG) is the most reactive nucleotide to link to MGO. In vivo, DNA glycation products were described for the first time by Schneider et al. [59], who identified N2-carboxyethyl-2′-deoxyguanosine (CEdG) in human urine samples with an antibody. More sensitive methods, such as quantitative LC electrospray ionization tandem MS, are now being developed, which allow screening for DNA glycation products in vivo [60]. These methods have helped to identify the imidazopurinone 3-(2′-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purin-9(8)one (MGdG) as the major nucleotide AGE [61]. Up to 1 in 100 000 nucleotides in DNA is an MGdG adduct [61]. Modification of DNA by MGO results in higher numbers of DNA strand breaks [61], nucleotide transversions [62], DNA–DNA cross-links [63], DNA–protein cross-links [64] and glycation of the nucleosomal protein histone H2A [65]. Although the biological consequences of MGO-derived DNA adducts have not yet been fully established, the non-enzymatic glycation of DNA by MGO may have severe implications for various pathological conditions, such as age-related complications.

THE GLYOXALASE SYSTEM

The glyoxalase system, as discovered in 1913, is the main system involved in the detoxification of MGO. It involves the rate-limiting enzyme GLO1 and GLO2. Moreover, glyoxalase III (GLO3) has been identified in Escherichia coli (E. coli).

Glyoxalase I

GLO1 catalyses the conversion of the MGO–GSH hemithioacetal to the thioester S-D-lactoylglutathione [10]. Under physiological conditions, the fragmentation of the hemithioacetal to MGO and GSH is about 1 000 times faster than the isomerization rate of the hemithioacetal catalysed by GLO1 [31]. Other substrates of GLO1 include GSH-derived hemithioacetals, which are formed from different α-dicarbonyls, such as glyoxal, hydroxypyruvaldehyde and phenylglyoxal [66,67].

The GLO1 gene is ubiquitously expressed in all tissues of prokaryotic and eukaryotic organisms, with about 0.2 μg GLO1/g of protein [68]. The human GLO1 enzyme is a homodimeric Zn2+-dependent isomerase, of which the two monomers are formed by means of non-covalent bonds. Based on gel filtration, the dimer has a molecular mass of 46 kDa (based on sequence analysis, the molecular mass of GLO1 is 42 kDa) and exists as three alloenzymes: GLO1-1, GLO1-2 and GLO2-2 [68]. These phenotypes represent the homozygous and heterozygous expression of a diallelic gene on an autosomal locus–GLO1 and GLO2, respectively. The GLO1 locus is located on chromosome 6 and the gene promoter of GLO1 contains an insulin and metal response element [69].

The mechanisms regulating GLO1 activity may be complex, comprising both regulation of gene expression and post-translational modifications of the enzyme. Although N-acetylation and oxidation do not affect GLO1 activity, S-glutathionylation strongly inhibits it [70]. In addition, GLO1 has been described as a nitric oxide (NO)-responsive protein [71]. GLO1 is also modified by phosphorylation of Thr107 and nitrosylation of Cys139 [70,72]. TNF-α-induced modulation of GLO1 activity through phosphorylation by protein kinase A (PKA) results in caspase-independent cell death, accompanied by increased production of ROS [73]. As the TNF-α-induced phosphorylation of GLO1 is not involved in the detoxification pathway of MGO, the real biological function of phosphorylated GLO1 remains to be determined.

In quiescent cells, the activity of GLO1 lies in the range 0.06–1.10 units/mg of protein, increasing in proliferating cells to 1.12–2.69 units/mg of protein [74]. In fetal tissues, GLO1 activity is about three times higher than in the corresponding adult tissues [68]. In cases of obesity or diabetes, contrary findings have been reported on the activity of GLO1: both increased and decreased GLO1 activities have been found in various tissues. In the red blood cells of leptin-deficient obese ob/ob mice, GLO1 activity increases to a level that is 50–60% higher than in lean controls. However, the whole blood concentration of MGO also increases, by a factor of 14 [75]. Moreover, in leptin receptor-mutated obese db/db mice, GLO1 protein has been shown to increase by about 50% in the glomeruli, whereas the enzyme activity of GLO1 decreases [76]. Hanssen et al. [77] have established that incubation of monocytes with TNF-α or hypoxia results in a decrease in enzymatic GLO1 activity. In addition, during the process of ageing, the activity of GLO1 has been shown to decrease [45].

Genetically, the GLO1 gene is a hotspot for copy number variation [78]. Approximately 2% of the human population has copy number increases of the GLO1 gene. These copy numbers are often linked to an increased risk of obesity and diabetes, and to ageing [78]. The additional copies are mostly functional, resulting in a 2- to 4-fold increase in the expression and activity of GLO1 [78]. In addition, various single nucleotide polymorphisms (SNPs) of GLO1 have been identified. Previous results show a significant link between the minor alleles rs1130534 (Gly124Gly) and rs1049346 (5′-UTR) and decreased enzyme activity [79]. A large epidemiological study demonstrated that nine tag SNPs that cover the common GLO1 gene variations are not associated with the prevalence of hypertension, markers of atherosclerosis or renal function [80]. However, another SNP in GLO1, Ala111Glu, has been identified as a susceptibility marker for the development of autism, most probably because it influences the accumulation of MGO, which in turn forms AGEs that induce the expression of the AGE receptor during neuronal development [8183]. As a result of this pathway, it is believed that GLO1 has crucial influence in the pathology of autism. It has been suggested that the same SNP is also associated with panic disorder, although this has been demonstrated only in patients with no agoraphobia [84].

Glyoxalase II and III

GLO2 is the second enzyme in the glyoxalase system. It catalyses the hydrolysis of S-D-lactoylglutathione, to form GSH and D-lactate [74]. Similar to GLO1, GLO2 is present in almost all living organisms, although it has been reported as absent in certain mammals [85,86]. The human GLO2 enzyme is a monomer with a molecular mass of 23 kDa [74], and is encoded by the hydroxyacylglutathione hydrolase (HAGH) gene. Genetic polymorphisms of GLO2 are extremely rare. The GSH moiety of the hemithioacetal is a highly specific target for the GLO2 enzyme, although it can also react with other thioesters [10].

In E. coli, GLO3 has been identified as an enzyme catalysing the conversion of MGO to D-lactate, without the need for GSH or any other co-factors [87]. In this reaction, the intermediate S-D-lactoylglutathione is not formed. Although GLO3 has so far been identified only in bacteria, results from a human study describe the activity of a DJ-1 homologue that is able to convert MGO into lactic acid without the need for GSH [88]. However, further research is necessary for the identification of a human GLO3 enzyme.

MGO AND GLYOXALASE IN DISEASE

Increased levels of MGO and/or dysfunction of the glyoxalase system has frequently been found in relation to ageing and age-related diseases. Here, we summarize the role of MGO and the glyoxalase system in diabetes and its related vascular complications, cardiovascular disease (CVD), cancer, disorders of the central nervous system, ageing and epigenetics.

Diabetes and its vascular complications

Diabetes has become a major twenty-first century epidemic, and is currently one of the largest health problems in the world, affecting almost 10% of the adult population in 2011 [89]. After the discovery that high glucose concentrations in vitro result in the formation of MGO and cellular dysfunction [12,53,90], subsequent studies have reinforced the importance of MGO in diabetes and diabetes-associated complications. Indeed, patients with either type 1 or type 2 diabetes have higher plasma levels of MGO and MGO-derived AGEs [20,55]. Dysfunctioning of the vascular endothelium is regarded as an important factor in the pathogenesis of diabetic micro- and macro-angiopathy. In this section, we describe the role of MGO in diabetes-related endothelial dysfunction and in micro- and macro-vascular complications. In addition, the role of MGO is discussed in obesity and insulin resistance, i.e. the major risk factors for diabetes.

Endothelial dysfunction in diabetes

The endothelium, a single layer of endothelial cells, is essential for the control of vascular functions. Dysfunctioning of the vascular endothelium in diabetes is regarded as an important initial factor in the pathogenesis of diabetic micro- and macro- angiopathy [91]. Diabetes-related endothelial dysfunction is characterized by changes in vasoregulation, increased levels of oxidative stress, inflammation and altered barrier function of the endothelium [92]. Metabolic alterations in endothelial cells are not harmless, but mediate dysfunction. In this respect, it is important to note that endothelial cells rely primarily on glycolysis for ATP production, with GLUT-1 (glucose transporter 1) as the main route for glucose uptake [93]. In contrast to, for instance, smooth muscle cells, glucose transport into endothelial cells takes place by means of facilitated diffusion, independent of insulin. An increase in blood glucose concentrations will thus lead to a rise in the intracellular accumulation of glucose and its metabolites, including MGO [94].

The importance of MGO for endothelial dysfunction in diabetes has recently been investigated in a rat study, which showed that GLO1 overexpression improved diabetes-induced impairment of NO-mediated relaxation [95]. In vivo, exogenous administration of MGO to rats induces diabetes-like microvascular changes [96] and impairment of endothelial function [97]. Over-expression of GLO1 prevents impairment of angiogenesis in human endothelial cells [98] and endothelial dysfunction in diabetic rats [99]. Moreover, overexpression of GLO1 completely prevents hyperglycaemia-induced AGE formation [90], indicating that MGO is indeed the most important AGE precursor in endothelial cells.

Several mechanisms that explain the effect of MGO on endothelial function have been investigated. In human aortic endothelial cells, it has been established that MGO induces mitochondrial oxidative stress by stimulating superoxide production and NO synthase (NOS) [100]. Likewise, overexpression of GLO1 in Caenorhabditis elegans (C. elegans) decreases the modification of mitochondrial proteins by MGO, thereby reducing mitochondrial ROS production [45].

Multiple in vitro studies have investigated the effect of MGO on cellular damage [6]. MGO causes induction of oxidative stress [101,102], genotoxicity [103,104] and apoptosis [105107]. More specifically for endothelial cells, MGO modulates endothelial NOS (eNOS)-associated functions and NADPH oxidase activity [108,109]. In addition, exposure of vascular smooth muscle cells (VSMCs) to MGO also causes oxidative stress [110,111] and decreased hydrogen sulfide levels [112]. Hydrogen sulfide levels are usually responsible for ATP-sensitive K+ (KATP) channel activation, and disruption of the KATP channels results in abnormalities of contractility and dysfunctioning of responses to local vasoactive regulators [113]. Thus, the direct effects of MGO on endothelial cells and VSMCs mainly involve dysregulation of vasorelaxation. It should be emphasized, however, that in some of these studies high and non-physiological concentrations of MGO were used from commercial stock solutions, which are often contaminated with formaldehyde and other substances [17]. For this reason, studies with high concentrations of commercial batches of MGO, which do not include the preparation of high-purity MGO, should be interpreted with care.

Nevertheless, there is sufficient evidence that MGO plays an important role in the pathogenesis of endothelial dysfunction in diabetes.

Microvascular complications in diabetes

Results from both experimental and clinical studies of diabetes have demonstrated that hyperglycaemia-induced MGO plays an important role in the pathogenesis of microvascular complications.

Diabetic nephropathy

Diabetic nephropathy is the major cause of end-stage renal disease in western societies, and it affects about 30% of all people with diabetes. Clinically, this condition is characterized by the development of proteinuria and a decline in the glomerular filtration rate [114]. Diabetic nephropathy progresses over a long period of time, and is a major risk factor for the development of macrovascular complications in diabetes [114].

Multiple studies demonstrated that high plasma levels of MGO are associated with the prevalence of diabetic nephropathy [115117]. Moreover, the MGO-derived AGEs, MG-H1 and CEL, are shown to be early indicators of progression of important diabetic nephropathy lesions, with MG-H1 as a significant independent predictor of glomerular basement membrane increase [118]. Experimental studies in cultured cells and kidneys from diabetic mice have demonstrated that high glucose levels induced MGO modification of the co-repressor mSin3A, resulting in enhanced angiopoietin-2 expression, sensitizing microvascular endothelial cells to the proinflammatory effects of TNF-α [119]. Moreover, it has been reported that MGO inhibits the electron respiratory chain in renal cells, leading to mitochondrial dysfunction, which may play an important role in renal cellular toxicity and the development of diabetic nephropathy [120].

In line with this, it has been demonstrated that overexpression of GLO1 in streptozotocin-induced diabetic rats improves renal function and protects against albuminuria [99,121,122]. The importance of GLO1 for normal kidney functioning has also been confirmed by a recent study in non-diabetic mice, in which a reduction in GLO1 by siRNA was found to increase MG-H1 residues in proteins of renal glomeruli and tubules, accompanied by the development of albuminuria and mesangial expansion [123]. Moreover, a study in rats has shown that overexpression of GLO1 ameliorates renal ischaemia–reperfusion injury via reduction of MGO accumulation in tubular cells [124].

Taken together, these data demonstrate that MGO plays an important role in the pathogenesis of diabetic nephropathy. Loss of podocytes in the glomerulus may be a mechanism that potentially explains the contribution of MGO to the development of such complications [99].

Diabetic retinopathy

Retinopathy is a second common microvascular complication of diabetes and is characterized by a spectrum of lesions within the retina, leading to increased vascular permeability, capillary microaneurysms, capillary degeneration and neovascularization [114]. In 2010, 40% of all cases of blindness in Europe were caused by diabetic retinopathy [125], which is associated in its turn with increased risk of life-threatening systemic vascular complications, such as stroke, coronary heart disease and heart failure [126].

Results from clinical studies have demonstrated that, in both type 1 [127] and type 2 [128] diabetes, increased serum levels of MG-H1 are associated with the development of diabetic retinopathy. Moreover, it has been shown that serum MG-H1 levels are higher in patients with proliferative retinopathy than in those with non-proliferative retinopathy. In rats, retinal levels of MG-H1 increased by 279% within 24 weeks of diabetes [129].

To understand the involvement of MGO in diabetic retinopathy, several studies focused on pathways via which MGO contributes to retinal damage. Two experimental studies have demonstrated that culturing retinal endothelial cells under high glucose concentrations results in higher MGO levels [130,131], which subsequently leads to an imbalance in the ratio of vascular endothelial growth factor (VEGF) and angiopoietin-2. Consequently, capillary permeability and apoptosis increase and proliferation of retinal endothelial cells reduces [131]. In line with this, seeding retinal pericytes on MGO-modified fibronectin triggers apoptosis through a combination of increased oxidative stress and a reduction of αB-crystallin [132].

Overexpression of the GLO1 enzyme has been shown to protect against premature death of pericytes and endothelial cells under conditions of high glucose concentrations [133], supporting the hypothesis that increased MGO levels are involved in the pathogenesis of diabetic retinopathy. In addition, it has been found that GLO1 overexpression in diabetic rats prevents hyperglycaemia-induced formation of MGO-derived AGEs in the neural retina, and protects against retinal capillary degeneration over 6 months of diabetes [46,134]. It also prevents the dysfunctioning of Müller's glia in the retina and the degeneration of retinal capillaries. Recently, it has been demonstrated that MGO increases the expression of CD74 in the retina, which is a marker of microglia activation [135], and that it induces mitochondrial dysfunction and oxidative DNA damage in human epithelial lens cells in vitro [136,137]. MGO has also been shown to induce cell death via nuclear factor κB (NFκB) activation in the diabetic lens [138].

Together, these findings support the hypothesis that increased levels of MGO are involved in the pathogenesis of diabetic retinopathy, probably via activation of proapoptotic triggers such as the NFκB pathway, oxidative stress and mitochondrial dysfunction.

Diabetic neuropathy

Diabetic neuropathy is a syndrome that involves both somatic and autonomic divisions of the peripheral nervous system. The prevalence of neuropathy is about 50% in all individuals with diabetes, which is accompanied by a 15% risk of amputation of one or more of the lower extremities [114]. Numerous studies have confirmed the role played by glycation in diabetic neuropathy [139], although until now only a few studies have focused specifically on the importance of MGO and glyoxalase.

Previously, it has been shown that elevated plasma levels of MGO can discriminate between type 2 diabetes patients with and those without neurological pain [140], and that skin MG-H1 is strongly associated with the progression of neuropathy in type 1 diabetes [141]. In line with this, results from an experimental study have demonstrated that sciatic nerves have high levels of MGO; these levels are even higher in streptozotocin-induced diabetes [34].

MGO causes depolarization of the sensory neurons, and induces post-translational modifications of the voltage-gated sodium channel Na(v)1.8 [140]. As a result of this, treatment with MGO evokes mechanical hyperalgesia, leading to increased blood flow to the brain regions involved in processing pain [140].

In vitro, MGO has been identified to activate p38 mitogen-activated protein kinase (MAPK) in Schwann cells, leading to the induction of apoptosis [142]. Moreover, MGO affects neuronal cell viability by deleterious effects on signal transducer and activator of transcription 3 (STAT3) signalling, resulting in down-regulation of the antiapoptotic protein Bcl-2 [143].

MGO has also been described as a modifier of cysteine residues of the transient receptor potential channel subfamily A, member 1 (TPRA1) [144146]. This modification results in slower conduction velocity in unmyelinated peripheral nerve fibres and stimulation of proinflammatory neuropeptide release [147].

Few studies have investigated the effect of GLO1 on diabetic neuropathy. Diabetic mice with reduced GLO1 levels have been shown to have increased mechanical thresholds, indicative of the development of neuropathy, loss of epidermal fibres and reduced activity of mitochondrial oxidative phosphorylation proteins [148].

All in all, suggestive and divergent evidence of mechanistic links between MGO and diabetic neuropathy has been provided by several studies. Although extensive future research is required to confirm these results, data so far indicate that MGO contributes in a major way to the pathogenesis of diabetic neuropathy.

Macrovascular complications in diabetes

CVD is a major cause of mortality in people with diabetes [149]. In most cases, the underlying process is atherosclerosis, a pathological condition characterized by the formation of atheromatous plaques in the intima of the arterial wall [150]. Advanced atherosclerotic plaques consist of a necrotic core containing cholesterol and dead macrophages, which are covered by a fibrous cap consisting of smooth muscle cells and collagen. Ruptured plaques are defined as a disruption of the fibrous cap and a thrombus that is constantly present in the necrotic core, which may occlude an artery, creating a significant risk of CVD that can result in myocardial infarction or stroke [151]. Previous studies have proposed that high metabolic activity in atherosclerotic plaques can contribute to the development of plaque rupture [152]. One aspect of increased metabolic activity is the formation of AGEs [153]. Several studies have shown that the AGE Nε-(carboxymethyl)lysine (CML) indeed accumulates in human atherosclerotic plaques [154,155]. There is increasing evidence to suggest that MGO, in particular, could play a major role in the development of atherosclerosis. Administering MGO directly via drinking water has been shown to increase atherosclerosis [156]. MGO has also been described as a predictor of intimal thickening in type 2 diabetes [157].

Low-density lipoprotein (LDL) plays a significant role in the enhancement, development and progression of atherosclerosis, through a pathway that involves endothelial cell dysfunction, lipid oxidation and accumulation, foam cell formation and inflammatory responses. Research has demonstrated that LDL can be modified by MGO, resulting in a change in both its physiochemical and its biological properties [158161]. More specifically, MGO modifies arginine residues of the protein component of LDL, mainly apolipoprotein B100 (apoB100), which results in the formation of MG-H1 [159,162]. These modifications lead to the formation of a more atherogenic LDL particle, thus stimulating the development of atherosclerosis. In addition to LDL, high-density lipoprotein (HDL) can also be modified by MGO. The main HDL functions are esterification of cholesterol and reverse cholesterol transport; however, HDL has several other antiatherogenic effects, such as antioxidative, vasodilatory and anti-inflammatory functions [163]. In type 2 diabetes, 4.5% of all HDL is modified by MGO or related dicarbonyl compounds [164], resulting in a decrease in antioxidant and anti-inflammatory activities of the HDL enzyme paraoxonase-1 [165]. Moreover, due to restructuring of the HDL protein, its stability and plasma half-life in vivo are decreased after modification by MGO [164]. Whether these MGO-modified lipoprotein particles are indeed more atherogenic in vivo is not yet known.

Next to the crucial lipoproteins in atherosclerosis, the platelet-derived growth factor receptor β (PDGFRβ) is also known to be a target of MGO modification. PDGFRβ is involved in the proliferation of smooth muscle cells, and MGO modification of this protein may lead to a fragile thin cap at the atherosclerotic lesion, creating a rupture-vulnerable plaque [166].

Surprisingly, overexpression of GLO1 does not lead to decreased atherosclerotic lesion size in streptozotocin-induced diabetic ApoE−/− mice [167]. Comparable results have been obtained by Geoffrion et al. [121], who found no effects on diabetic atherosclerosis of either GLO1 overexpression or GLO1 knockdown. In contrast, exposure to MGO, either from an exogeneous source or generated after inhibition of GLO1, is able to augment atherogenesis in ApoE−/− mice, with a similar magnitude to that observed in diabetic mice [156]. Although further studies are needed to explain the seemingly contrasting results, it is likely that GLO1 overexpression may not protect against AGE formation in hyperlipidaemic conditions, such as in ApoE−/− mice, because GLO1 does not come into sufficient contact with the AGE precursors derived from lipid oxidation. This seems a serious possibility, because GLO1 is present in the cytosol where glycolysis takes place, but not in the cellular membranes and lipid particles where lipid oxidation mainly occurs.

In addition to atherosclerosis, both experimental and human studies have shown that diabetes is also associated with the impairment of ischaemia-driven neovascularization, increasing rates of lower limb amputations, heart failure and mortality after ischaemic events. The direct modification of hypoxia-inducible factor 1α (HIF1α), or its co-activator p300, by MGO, and the reduced binding to relevant promoters of genes required for neovascularization have been described as one of the mechanisms involved in defective, ischaemia-induced, new vessel formation in diabetes [168,169]. Another mechanism by which MGO induces macrovascular damage, is via reduction of sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2a), which normally translocates Ca2+ from the cytoplasm to the lumen of the sarco(endo)plasmic reticulum during cardiac relaxation. In a rat model of type 1 diabetes, it has been shown that MGO reduces the ability of SERCA2a to perform this translocation, resulting in diastolic dysfunction of the heart [170]. It is interesting that the over-expression of GLO1 does attenuate mild oxidative damage in the diabetic rat heart, by reducing MGO levels [171].

Thus, although GLO1 overexpression is obviously not capable of reducing the pathogenesis of atherosclerosis, findings so far provide strong evidence that higher levels of MGO are associated with the development of macrovascular complications in diabetes.

Obesity

The incidence of obesity has reached epidemic proportions, and contributes to the increasing prevalence of type 2 diabetes and CVD [172]. Excessive food consumption, low-energy expenditure, hyperglycaemia and hyperlipidaemia can all augment the formation of MGO in obese individuals. It has been observed that, in obese Zucker rats, an accumulation of MGO in adipose tissue takes place, accompanied by an increase in serum levels of MGO [173]. Cell proliferation experiments have shown that direct incubation of adipocytes with MGO results in an increased proliferation of these cells, suggesting that MGO may be involved in the expansion of the adipose tissue in obesity [173]. In vivo, it has recently been demonstrated that long-term MGO administration (14 weeks) to normal rats leads to structural changes in the adipose tissue microvasculature, hypoadiponectinaemia and lipolysis. These effects are associated with increased tissue glycation and impaired expression of apoptotic and angiogenic markers, but not with insulin resistance [174,175]. In contrast, short-term MGO administration (8 weeks) causes much less severe effects, despite the fact that tissue accumulation of CEL takes place [176,177].

In db/db mice, an animal model of obesity, decreased activity of GLO1 has been found in the renal cortex [76]. However, in red blood cells of obese mice, GLO1 activity was increased by 50–60% compared with that of lean controls, and GLO2 activity rose by 20–30% [75]. A proteomics study has demonstrated that GLO1 protein levels increase in the skeletal muscle of rats on a high-fat diet [178]. Furthermore, increased mRNA expression and activity of the GLO1 enzyme have been linked to mice that prefer high-carbohydrate diets [28]. These contradictory results show that further study is needed to clarify the role of GLO1 in obesity.

Despite these contradictory results from multiple studies, these data have shown the importance of MGO and GLO1 during the development of obesity and adipose tissue dysfunction, suggesting their potential influence on the onset of type 2 diabetes. The underlying mechanism and the activity of GLO1 in obesity still have to be further elucidated.

Insulin resistance

Insulin resistance is characterized by a reduced responsiveness to the action of insulin on glucose uptake, metabolism or storage, and other targets of insulin signalling [179]. Several studies have demonstrated that direct or indirect administration of MGO to Sprague–Dawley rats results in insulin resistance [180183]. There is increasing evidence from experimental studies that MGO may contribute to the pathogenesis of insulin resistance by means of direct functional modifications of the insulin molecule and interference in the complex molecular pathways of insulin signalling. Moreover, we recently demonstrated in a large cohort study that plasma D-lactate levels, as a reflection of plasma MGO concentrations, are independently associated with insulin resistance [184].

In vitro incubation of human insulin with MGO has been shown to yield attachment of MGO to an arginine residue of the insulin β-chain adducts, which is accompanied by functional changes [185]. In comparison with the effect of native insulin in the same concentrations, a significant decrease of glucose uptake induced by MGO-modified insulin adducts has been observed in 3T3-L1 adipocytes and L8 skeletal muscle cells. Unlike native insulin, MGO-modified insulin adducts diminishes the feedback inhibition of insulin release from pancreatic β-cells. The degradation of MGO-modified insulin through liver cells decreases as well [185]. In this way, the formation of the MGO–insulin adduct reduces insulin-mediated glucose uptake, impairs autocrine control of insulin secretion and decreases insulin clearance. Although these structural and functional abnormalities of the insulin molecule may contribute to the pathogenesis of insulin resistance, no data are available yet about the presence of MGO–insulin adducts in vivo.

In addition, MGO has been shown to modify activity of the insulin signalling pathway. A short exposure of L6 muscle cells to MGO induces an inhibition of insulin-stimulated phosphorylation of protein kinase B (PKB) and extracellular signal-regulated protein kinase 1/2 (ERK1/2), without affecting insulin receptor tyrosine phosphorylation [186]. Importantly, these harmful effects of MGO are independent of ROS, but appear to be a direct consequence of MGO-induced impairment of insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation. Also, in 3T3-L1 adipocytes, MGO impairs insulin signalling, as indicated by decreased insulin-induced IRS-1 tyrosine phosphorylation [181]. Incubation of the pancreatic INS-1E β-cells with MGO results in glycogen synthase kinase-3 (GSK-3)-mediated impairment of insulin secretion and action [187]. As this shows, MGO can directly and significantly interrupt the insulin signalling pathway. In an animal model of insulin resistance, a close correlation has been established between the development of insulin resistance and elevated MGO levels in serum and adipose tissue [181]. Both the insulin resistant state and elevated MGO levels are reversed by the major GSH precursor N-acetylcysteine (NAC). The ability of NAC to block MGO impairment of phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) activity and IRS-1 phosphorylation has further confirmed the role that MGO plays in the development of insulin resistance. In addition to the effect of insulin on glucose metabolism, it also exerts a direct effect on endothelial cells. MGO has recently been identified as an inducer of endothelial insulin resistance [188]. It impairs the action of insulin on the endothelium both in vitro and in vivo, at least partly, through an ERK1/2-mediated mechanism.

In conclusion, the increase in endogenous MGO has been shown to impair the insulin signalling pathway and to decrease insulin-stimulated glucose uptake in several tissues, both of which can contribute to the development of insulin resistance. These findings may be instrumental in further elucidating the role of MGO in the development of insulin resistance, and developing new strategies for controlling insulin resistance.

Cardiovascular disease

Next to diabetes-related cardiovascular complications, MGO is also associated with non-diabetes-related CVD. The two most described cardiovascular complications in relation to MGO and GLO1 are atherosclerosis and hypertension.

Atherosclerosis

As described above, MGO is an important factor that influences the pathogenesis of diabetes-associated atherosclerosis. However, it is also involved in the development of non-diabetes-associated atherosclerosis [2,97].

We have recently demonstrated that the MGO-derived AGEs MG-H1 and THP can be found in atherosclerotic plaques, and that MG-H1 is associated with rupture-prone phenotypes of the plaque [55,77]. It is interesting that no differences were found between diabetic and non-diabetic individuals, indicating that the metabolic dysfunction in atherosclerotic plaques has a greater influence on the accumulation of AGEs, including MG-H1, than the hyperglycaemic environment. Immunohistochemical staining has shown that the macrophage is the predominant cell type in the atherosclerotic plaque for MG-H1 accumulation [77]. Macrophages are characterized by high activity of the glycolytic pathway, and the atherosclerotic environment of inflammation and hypoxia stimulates glucose uptake by macrophages, the latter probably resulting in enhanced MGO production [77,152,189]. However, in addition to formation of MGO by glycolysis, MGO can also result from lipid oxidation. Indeed, higher lipid contents of the plaque are associated with higher MG-H1 levels [77].

LDL is an important target for MGO modification in atherosclerosis. Glycation of LDL by MGO results in decreased LDL particle size, increased atherogenicity and reduced affinity for the LDL receptor [159,190]. As a result of this, less LDL can be cleared from the circulation, which means that higher amounts will become trapped in the vessel wall. As macrophages take up oxidized LDL in atherosclerotic lesions, MGO formation in macrophages is likely to play an important role in the process of atherosclerosis [77]. Moreover, in the atherosclerotic plaque, MG-H1 levels co-localize with markers of inflammation, hypoxia, apoptosis and oxidative stress [77], suggesting that an increase of MG-H1 in the plaque and consequent macrophage death can contribute to the transition of stable plaques to rupture-prone plaques.

Apart from increased prevalence in plaque macrophages, the detoxification of MGO by the glyoxalase system can also be impaired in atherosclerotic lesions. Indeed, mRNA, protein and activity levels of GLO1 are lower in ruptured plaques compared with stable plaques [77], which confirms the finding of increased MGO levels in atherosclerosis. All in all, it can be said that MGO has been proven to have an influence on the development of atherosclerosis, by either increased formation of or impaired detoxification by GLO1. As increased levels of MGO modifications in the plaque are associated with a rupture-prone phenotype, inhibition of MGO would prevent not only the development, but also the progression, of atherosclerosis. Therefore, further insights into the molecular mechanisms at hand may help to improve the management of atherosclerotic lesions.

Hypertension

According to the World Health Organization, hypertension is responsible for almost 13% of all deaths worldwide, which makes it a major threat to public health. A link between MGO accumulation and hypertension has been demonstrated in rats with increased MGO levels in aortic and renal tissues [183,191193]. Administering MGO to rats leads to a significant rise in systolic blood pressure [194,195] and higher plasma levels of aldosterone, renin, angiotensin and catecholamines [195]. Similarly, a diet high in fructose–a precursor of MGO–induces hypertension and renal injury in rats [196,197]. Although a dose of 1% MGO in drinking water did not induce hypertension in Sprague–Dawley rats [183], surprisingly enough the same dose in combination with a high-salt diet induced hypertension and enhanced renal oxidative stress [183], suggesting that MGO causes hypertension only in rats with enhanced renal oxidative stress. Previous findings from a mouse study indicate that MGO-induced hypertension partially takes place via the angiotensin II type-1 receptor-mediated pathway [198]. In addition, an increase in cytosolic [Ca2+] through MGO, resulting in vascular retention, has been suggested as an underlying mechanism to link MGO to hypertension [194]. An improvement in blood pressure has been observed in rats after treatment with aminoguanidine, which is an MGO scavenger [199,200].

To conclude, MGO has been demonstrated to have an important influence on the development of hypertension. This suggests that it may be clinically useful as a biomarker or potential therapeutic target for combating hypertension. Indeed, in humans, multiple regression analysis has revealed that MGO is an independent risk factor for increased systolic blood pressure over a 5-year period [157].

Cancer

Cancer is the leading cause of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer-related deaths in 2012 [201]. Cancer is a disease characterized by uncontrolled growth and proliferation of abnormal cells. As mentioned above, MGO plays an important role in the process of cell death [105107]. Due to lack of oxygen, tumours primarily rely on anaerobic metabolism of glucose. To compensate for this inefficient energy supply, tumours show a higher rate of glucose uptake and glycolysis. An important consequence is intracellular formation of MGO. To survive, cancer cells with such a high glycolytic rate require a high rate of detoxification of MGO. The increased expression and activity of the GLO1 enzyme found in many tumours therefore stimulate growth and avoid MGO-induced apoptosis. The survival-promoting effects of GLO1 over-expression have been attributed to NFκB and activator protein-1, which results in activation of the PI3K/PKB pathway [202,203]. In addition, GLO1 reduces intracellular MGO levels. As a consequence, activation of p38 MAPK is decreased and the NFκB pathway is induced, which leads to inhibition of the proapoptotic Bax and p53 proteins, and enhanced expression of the antiapoptotic Bcl-2 protein [204,205]. Moreover, it was indicated that AP modification of HSP27 in human lung squamous cell carcinomas could play a role in the inhibition of caspase activation, and thereby prevent apoptosis [206]. Thus, these findings suggest that GLO1 plays a crucial role in the survival and proliferation of tumour cells by enhancing MGO detoxification.

Overexpression of GLO1, commonly caused by GLO1 gene amplification, has been associated with multidrug resistance in chemotherapy [8]. This was demonstrated for the first time in fibroblasts with an induced overexpression of GLO1, which protected the cells against the toxic effects of the anti-tumour agents mitomycin C and doxorubicin [207]. Moreover, it was shown that inhibition of GLO1 in tumour cells with high GLO1 expression levels prevented multidrug resistance and increased sensitivity to anti-cancer therapies. One of the first developed GLO1-inhibiting agents in tumour cells is S-p-bromobenzylglutathione cyclopentyl diester (BBGD) [208]. This agent directly induces the activation of the stress-activated protein kinases, cJun N-terminal kinase 1 (JNK1) and p38 MAPK, resulting in activation of the caspases. Eventually, this leads to apoptosis in GLO1-over-expressing tumour cells. Moreover, inhibition of GLO1 promotes apoptosis indirectly via increasing intracellular MGO levels, leading to the release of cytochrome c from mitochondria, thereby inducing apoptosis by modifying the mitochondrial permeability transition pore [209]. However, it has been demonstrated that BBGD does not directly inhibit the activity of GLO1, but requires hydrolysis by a tumour non-specific esterase to exhibit GLO1 inhibitor activity [208]. Nowadays, more potent GLO1 inhibitors have been described, such as methotrexate [210] and the polyphenol curcumin [211,212].

In conclusion, overexpression of GLO1 in tumour cells promotes cell survival and proliferation through reduction of intracellular MGO levels. In addition, high levels of GLO1 are associated with multidrug resistance. Therefore, GLO1 is a potential molecular target to increase the efficacy of anti-cancer therapy.

Disorders of the central nervous system

With respect to brain functioning, various studies have linked glycation to disorders of the central nervous system. In this section, we describe the role of MGO and GLO1 in Alzheimer's disease, Parkinson's disease, schizophrenia and anxiety disorders.

Alzheimer's disease

Impaired activity of GLO1 and increased serum levels of MGO have been described as being associated with impaired cognitive function, in particular Alzheimer's disease [213216]. In the cerebrospinal fluid (CSF) of patients with Alzheimer's disease, higher levels of MG-H1 and other glycation-free adducts have been found compared with the CSF of healthy controls [217]. Multiple studies have investigated the molecular mechanisms that might explain the role of MGO in Alzheimer's disease. In vitro incubation of neuroblastoma cells with MGO increased the activity of the proapoptotic protein Bax and caused a decrease in the antiapoptotic protein Bcl-2. In combination, these processes resulted in more apoptotic cells, which are known to play a key role in the development of Alzheimer's disease [218]. High levels of MGO also caused impairment of the oxidative status of brain mitochondria [219], which possibly contributes further to the pathogenesis of Alzheimer's disease [220]. Moreover, depletion of GSH and subsequent inadequate functioning of the glyoxalase system may have a major effect [221,222]. In line with this, an increased GSSG:GSH ratio in patients with Alzheimer's disease is associated with disease severity [221].

Parkinson's disease

Besides Alzheimer's disease, there is also evidence that MGO plays a role in the development of Parkinson's disease. Parkinson's disease is accompanied by increased protein glycation [223,224], and it has been found that a mutation of the DJ-1 gene is a risk factor for Parkinson's disease. DJ-1 normally controls the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor, which regulates the cellular response to oxidative stress, including the expression of GLO1 [225]. These data suggest that a change in the activity of GLO1 could play a role in Parkinson's disease, possibly via elevation of MGO levels.

Schizophrenia

A few studies also report on the role of MGO and GLO1 in the pathogenesis of schizophrenia. Heterozygous frameshift mutations and the homozygous Ala111 phenotype in GLO1 have been described in association with low GLO1 activity, and a concomitant increase in carbonyl stress in a subset of schizophrenia patients [226,227]. However, sample sizes are very small, so additional human or mouse genetic studies are needed to confirm the role of MGO and GLO1 in schizophrenia.

Anxiety disorders

In contrast, increased expression levels of GLO1 and, consequently, lower MGO concentrations in the brain have been reported in relation to anxiety [228231]. Direct MGO infusions into the brains of mice caused an anxiolytic effect [232], which was mediated by a decrease in the GABAA-receptor activation–GABA (γ-aminobutyric acid) being a major known mediator of anxiety [233]. This finding suggests that MGO and low levels of GLO1 enable the brain to put things and events into perspective, although additional studies are needed to confirm this hypothesis.

Ageing and epigenetics

In addition to specific complications, MGO and GLO1 are also extensively described in relation to the ageing process and epigenetics, which could both give rise to a wide variety of diseases.

Ageing

During the ageing process, an increase in protein damage takes place as a result of non-enzymatic glycation [234]. The physiological consequences of this non-enzymatic glycation and the aetiology of a range of important age-related diseases have been described in a number of excellent reviews [6,7,28,74,179,235].

Several studies have demonstrated the effects of GLO1 during ageing, as described in the review by Xue et al. [235]. In 1960, a study on humans reported for the first time that GLO1 activity in human arterial tissue decreases with age, which suggests a potential link between a decline in glyoxalase activity and an increased risk of age-related CVD [236]. Later, McLellan and Thornalley [237] described a decline in both GLO1 and GLO2 activity in old red blood cells during the ageing process. In older people's brains, smaller numbers of GLO1-expressing neurons are found than in the brains of younger individuals [238], which links GLO1 to age-related cognitive impairment, as described above. Thus, GLO1 seems to be directly involved in the ageing process. In addition, GLO1 has been described as an important player in lifespan regulation. It was shown that, during ageing, the activity of GLO1 declines in the nematode C. elegans [45]. The downstream consequences of GLO1 reduction have been demonstrated by overexpression of the GLO1 homologue in C. elegans, resulting in an increase of the mean and maximum lifespan by about 30%; silencing the GLO1 homologue decreased the lifespan by about 50% [45,239]. Similar findings have been described in the ageing model of Podospora anserina [240]. Moreover, elderly rats with an overexpression of GLO1 showed an amelioration of senescence, which was associated with protection against the age-dependent decline of renal functions [241]. Together, these findings suggest that GLO1 belongs to the network of genes that influence longevity.

Multiple studies have also demonstrated a decreased activity of the glyoxalase system and subsequently accumulation of MGO-derived AGEs in the ageing human lens, which can potentially contribute to the development of age-dependent cataracts [5,56,57,242245]. Age-related endothelial dysfunction is ameliorated by an overexpression of the GLO1 enzyme, because it leads to the inhibition of MGO and subsequent inhibition of eNOS phosphorylation [246]. Moreover, Fleming et al. [247] have shown that ageing-associated impairment of wound healing is related to decreased GLO1 transcription, expression and activity. Treatment with the MGO scavenger aminoguanidine restores wound healing in elderly mice, suggesting a causative influence of MGO on the impairment of wound healing.

In conclusion, the balance between the production of MGO and its detoxification by GLO1 can significantly contribute to the ageing process; managing this balance is important for the prevention of age-related health problems.

Epigenetics

Epigenetics is the study of modifications in gene expression that concentrate on changes in gene expression not involving changes in DNA nucleotide sequences [248]. Although epigenetics is not a disease in itself, it plays an important role in several age-related diseases. Modification in gene expression through DNA methylation and chromatin remodelling via histone modifications are believed to be the most important epigenetic changes [248]. Although not much research has been done on MGO in epigenetics, a study from El-Osta et al. [249] has described MGO having an important role in epigenetic changes. Transient hyperglycaemia leads to increased p65 gene expression and subsequent increased NFκB activation, resulting in inflammatory gene expression. This phenomenon can be attributed to the activation of histone methylation associated with the p65 promoter, in particular monomethylation of the Lys4 of histone 3 (H3K4), which is mediated by histone methyltransferase (HMT). The mammalian HMT SET7 is known to methylate H3K4. GLO1 prevents the hyperglycaemia-induced increase in p65 expression, which points towards a significant influence of MGO on epigenetic DNA methylation. The same study has shown that, in a non-diabetic GLO1 knockdown mouse model, H3K4 SET7-mediated monomethylation and subsequent p65 expression tend to increase. It has also been demonstrated that MGO can induce substantial modifications in secondary and tertiary structures of nucleosomal protein histone H2A [65]. Thus, as epigenetic changes form the basis of many diseases, management of MGO levels could be a major factor in the prevention of multiple complications.

SCAVENGERS OF MGO

Below, we discuss the scavengers of MGO that have been studied most extensively in human studies, namely aminoguanidine, alagebrium, metformin and pyridoxamine. In addition, we briefly discuss the function of benfotiamine.

Aminoguanidine

The AGE-lowering effects of aminoguanidine were first described by Brownlee et al. in 1986 [250]. Aminoguanidine is a scavenging agent of MGO and other α-dicarbonyls; it consists of a nucleophilic hydrazine group and a dicarbonyl-directing guanidine group [251]. In experimental diabetes, aminoguanidine has been proven to be very effective in lowering AGE formation and preventing diabetic complications such as nephropathy [252,253], retinopathy [254] and neuropathy [255]. However, the use of aminoguanidine in clinical trials has shown disappointing results. Two large double-blind randomized controlled trials (RCTs) have studied the effects of aminoguanidine in patients with type 1 [256] and type 2 [257] diabetes. In both studies, the primary end-point was the doubling time of serum creatinine. In individuals with type 1 diabetes, 2–4 years of treatment with aminoguanidine did not significantly decrease this primary endpoint. The study in patients with type 2 diabetes was initially planned to continue for 2 years, but was terminated prematurely because of a lack of efficacy and safety concerns about gastrointestinal disturbance, lupus-like illness, abnormal liver function, flu-like symptoms and vasculitis. For these reasons, aminoguanidine is at present not considered to be an effective treatment of diabetic complications.

Alagebrium

Although alagebrium (also known as ALT-711) has often been described as an AGE cross-link breaker [258], there is now overwhelming evidence that it is, rather, an inhibitor of AGE formation [259], with inhibition of MGO as the probable underlying mechanism. In experimental studies, pharmacological intervention with alagebrium has proved effective for the reduction of large artery stiffness, left ventricular mass, diastolic stiffness of the heart, atherosclerosis and diabetic nephropathy [260]. Clinical trials with alagebrium have shown mixed results. Whereas one RCT found beneficial effects on cardiovascular variables in hypertensive individuals [261], another yielded no beneficial results [262]. Furthermore, two uncontrolled studies in hypertensive individuals have reported improved aortic augmentation index and flow-mediated dilatation after 8 weeks of alagebrium treatment, as well as improvements in the left ventricular mass and diastolic cardiac function after 16 weeks of treatment [263,264]. No improvements were seen in other vascular parameters. Although the results from experimental studies have been promising, the efficacy of alagebrium in clinical trials has not met expectations.

Metformin

Due to its beneficial effects on CVD, metformin has become one of the most widely prescribed oral glucose-lowering agents for type 2 diabetes. The main blood glucose-lowering activity of metformin is believed to be that of suppression of hepatic gluconeogenesis and increasing cellular uptake of glucose [265,266], most probably via inhibition of mitochondrial glycerophosphate dehydrogenase [267]. It has been demonstrated that metformin can also trap MGO [268], which might explain the beneficial effect of metformin on cardiovascular complications in patients with type 2 diabetes [269]. Indeed, it has been shown that metformin treatment is able to reduce systemic plasma MGO levels [20]. The effect of metformin on MGO has recently been confirmed in a prospective, non-randomized, 24-week trial in patients with type 2 diabetes [270]. However, the reduction in MGO is accompanied by a significant increase in the activity of GLO1 in circulating cells, indicating that the reduction of MGO is most probably due not to the scavenging properties of metformin, but to the restoration of GLO1 activity. Other trials have also reported that metformin is effective in reducing glycation, but it has no additional effects compared with other anti-hyperglycaemic treatments. These data suggest that the AGE-inhibiting effects of metformin result from an improvement in glycaemic control or increased levels of GLO1, rather than from direct inhibition of MGO [260]. The very low rate constant of metformin and MGO also indicates that quenching of MGO is not the primary effect by which metformin reduces systemic MGO concentrations [271].

Pyridoxamine

The natural vitamin B6 analogue, pyridoxamine, has been described as an anti-glycating agent, which operates via the quenching of reactive α-dicarbonyl compounds such as MGO [272]. Preclinical studies in animal models of diabetic nephropathy have reported the efficacy of oral pyridoxamine supplementation for preserving renal function [273277]. In a phase II clinical trial, pyridoxamine not only inhibited the formation of CML and CEL, but also improved kidney function in patients with type 2 diabetes and overt nephropathy [278]. However, a second, placebo-controlled clinical trial found no beneficial effect of pyridoxamine on the reduction of creatinine levels, although it has been suggested that individuals with less advanced renal impairment might benefit [279]. In a third clinical trial, treatment with pyridoxamine significantly decreased the formation of AGEs, inflammation and pain in patients with osteoarthritis. No adverse effects of pyridoxamine were found after 6 months of treatment [280]. As pyridoxamine has a demonstrated beneficial effect on the treatment of diabetes-associated complications, and as it has a favourable safety profile with no adverse effects, it is currently being studied as a potential treatment for type 2 diabetes.

Benfotiamine

Benfotiamine is commonly used as a treatment for diabetic neuropathy; it activates transketolase, which directs glucose substrates to the pentose phosphate pathway [281]. Therefore, benfotiamine blocks several hyperglycaemia-induced pathways, including formation of MGO. Although benfotiamine is thus not a direct scavenger of MGO, it can potentially decrease MGO levels by reducing the level of its substrate.

GLO1-INDUCING COMPOUNDS

Previous studies have shown that there are potentially several classes of compounds that can promote GLO1 expression and activity. It is not only synthetic drugs such as candesartan [282] that possess GLO1-stimulating properties; more naturally occurring compounds have a similar effect. Nagaraj et al. [283] have shown that pyridoxamine not only quenches MGO, but can also increase GLO1 activity, an effect that they have demonstrated in the retina of diabetic rats. Furthermore, polyphenols such as resveratrol and fisetine are known to up-regulate GLO1 expression [284,285]. A class of interesting, naturally occurring compounds is the isothiocyanates, which include phenethyl isothiocyanate and sulforaphane [286]. These compounds, which can be found in cruciferous vegetables, are known to activate Nrf2 [287]. Nrf2 is a master switch in the protection against oxidative damage and mediates antioxidant-responsive element (ARE)-dependent induction of antioxidant enzymes, such as haem oxygenase, catalase and superoxide dismutase [288]. GLO1 has an ARE in its promoter, and it has been shown that activators of Nrf2 increase the levels of GLO1 mRNA, protein and activity [286], thereby decreasing MGO levels [289]. Increased expression of GLO1 reduces cellular and extracellular concentrations of MGO, MGO-derived protein adducts, mutagenesis and cell detachment [286]. In agreement with this, GLO1 mRNA and protein levels have been shown to decrease in the liver, brain, heart, kidney and lung in Nrf2−/− mice; urinary excretion of MGO and nucleotide adducts increase by some 100% [286]. These findings underline the importance of the regulatory increase of cell defences against MGO via the Nrf2–ARE–GLO1 pathway. Another Nrf2-inducing compound is bardoxolone methyl, which has mainly been described as a potential treatment of chronic kidney disease. Although bardoxolone methyl has not so far been described in relation to GLO1 activation, its potential to induce Nrf2 may result in GLO1 induction [290293].

Based on these findings, bioactive inducers of GLO1 could thus be used for patients with age-related disorders in which MGO play a pivotal role.

CONCLUSIONS AND FUTURE STUDY

There is much scientific evidence to suggest that the very reactive glycolytic intermediate MGO engenders the development of multiple health problems and complications. Although MGO can be detoxified endogenously by the glyoxalase system, increased levels of MGO under pathophysiological conditions result in the formation of ROS and AGEs. Accumulation of MGO, ROS and AGEs in various tissues can subsequently contribute to age-related health problems such as diabetes, CVD, cancer and disorders of the central nervous system. Despite the progress made in recent years, further research is needed to pinpoint the underlying mechanisms of how MGO contributes to the development of these diseases. Several pharmacological interventions have been developed to inhibit the accumulation of MGO, of which pyridoxamine is currently regarded as the most important MGO scavenger. From a clinical point of view, the reduction in the accumulation of MGO and enhancement of GLO1 activity could provide new therapeutic opportunities aimed at reducing the pathophysiological modifications associated with increased levels of MGO.

Abbreviations

     
  • AGE

    advanced glycation endproduct

  •  
  • ALDH

    aldehyde dehydrogenase

  •  
  • AP

    argpyrimidine or Nδ-(5-hydroxy-4,6-dimethylpyramidine-2-yl)-L-ornithine

  •  
  • AR

    aldose reductase

  •  
  • ARE

    antioxidant-responsive element

  •  
  • BBGD

    S-p-bromobenzylglutathione cyclopentyl diester

  •  
  • CEL

    Nε-(1-carboxyethyl)lysine

  •  
  • CML

    Nε-(carboxymethyl)lysine

  •  
  • CSF

    cerebrospinal fluid

  •  
  • CVD

    cardiovascular disease

  •  
  • DHAP

    dihydroxyacetone phosphate

  •  
  • eNOS

    endothelial nitric oxide synthase

  •  
  • ERK

    extracellular signal-regulated protein kinase

  •  
  • G3P

    glyceraldehyde 3-phosphate

  •  
  • GLO1

    glyoxalase I

  •  
  • HDL

    high-density lipoprotein

  •  
  • HMT

    histone methyltransferase

  •  
  • HSP

    heat shock protein

  •  
  • IRS-1

    insulin receptor substrate 1

  •  
  • LDL

    low-density lipoprotein

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MG-H1

    methylglyoxal-derived hydroimidazolone 1

  •  
  • MGO

    methylglyoxal

  •  
  • MODIC

    2-ammonio-6-{(2-[(4-ammonio-5-oxido-5-oxopentyl)amino]-4-methyl-4,5-dihydro-1H-imidazol-5-ylidene)amino}hexanoate

  •  
  • MOLD

    1,3-di(Nε-lysino)-4-methyl-imidazolium

  •  
  • NFκB

    nuclear factor κB

  •  
  • NAC

    N-acetylcysteine

  •  
  • Nrf2

    nuclear factor (erythroid-derived 2)-like 2

  •  
  • NO

    nitric oxide

  •  
  • PDGFRβ

    platelet-derived growth factor receptor β

  •  
  • PI3K

    phosphatidylinositol 4,5-bisphosphate 3-kinase

  •  
  • PKB

    protein kinase B

  •  
  • RCT

    randomized controlled trial

  •  
  • ROS

    reactive oxygen species

  •  
  • SERCA2a

    sarco(endo)plasmic reticulum Ca2+ ATPase

  •  
  • SNP

    single nucleotide polymorphism

  •  
  • THP

    tetrahydropyrimidine or Nδ-(4-carboxy-4,6-dimethyl-5,6-dihydroxy-1,4,5,6-tetrahydropyrimidine-2-yl)-L-ornithine

  •  
  • TNF-α

    tumour necrosis factor α

  •  
  • UPLC

    ultra-performance liquid chromatography

  •  
  • VSMC

    vascular smooth muscle cell

References

References
1
Singh
R.
Barden
A.
Mori
T.
Beilin
L.
Advanced glycation end-products: a review
Diabetologia
2001
, vol. 
44
 (pg. 
129
-
146
)
[PubMed]
2
Brownlee
M.
Biochemistry and molecular cell biology of diabetic complications
Nature
2001
, vol. 
414
 (pg. 
813
-
820
)
[PubMed]
3
Westwood
M.E.
Thornalley
P.J.
Molecular characteristics of methylglyoxal-modified bovine and human serum albumins. Comparison with glucose-derived advanced glycation endproduct-modified serum albumins
J. Protein Chem.
1995
, vol. 
14
 (pg. 
359
-
372
)
[PubMed]
4
Phillips
S.A.
Thornalley
P.J.
The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal
Eur. J. Biochem.
1993
, vol. 
212
 (pg. 
101
-
105
)
[PubMed]
5
Ahmed
N.
Thornalley
P.J.
Dawczynski
J.
Franke
S.
Strobel
J.
Stein
G.
Haik
G.M.
Methylglyoxal-derived hydroimidazolone advanced glycation end-products of human lens proteins
Invest. Ophthalmol. Vis. Sci.
2003
, vol. 
44
 (pg. 
5287
-
5292
)
[PubMed]
6
Matafome
P.
Sena
C.
Seica
R.
Methylglyoxal, obesity, and diabetes
Endocrine
2013
, vol. 
43
 (pg. 
472
-
484
)
[PubMed]
7
Hanssen
N.M.
Stehouwer
C.D.
Schalkwijk
C.G.
Methylglyoxal and glyoxalase I in atherosclerosis
Biochem. Soc. Trans.
2014
, vol. 
42
 (pg. 
443
-
449
)
[PubMed]
8
Thornalley
P.J.
Rabbani
N.
Glyoxalase in tumourigenesis and multidrug resistance
Semin. Cell Dev. Biol.
2011
, vol. 
22
 (pg. 
318
-
325
)
[PubMed]
9
Srikanth
V.
Westcott
B.
Forbes
J.
Phan
T.G.
Beare
R.
Venn
A.
Pearson
S.
Greenaway
T.
Parameswaran
V.
Münch
G.
Methylglyoxal, cognitive function and cerebral atrophy in older people
J. Gerontol. A Biol. Sci. Med. Sci.
2013
, vol. 
68
 (pg. 
68
-
73
)
[PubMed]
10
Sousa Silva
M.
Gomes
R.A.
Ferreira
A.E.
Ponces, Freire
A.
Cordeiro
C.
The glyoxalase pathway: the first hundred years … and beyond
Biochem. J.
2013
, vol. 
453
 (pg. 
1
-
15
)
[PubMed]
11
Kalapos
M.P.
Methylglyoxal in living organisms: chemistry, biochemistry, toxicology and biological implications
Toxicol. Lett.
1999
, vol. 
110
 (pg. 
145
-
175
)
[PubMed]
12
Thornalley
P.J.
Modification of the glyoxalase system in human red blood cells by glucose in vitro
Biochem. J.
1988
, vol. 
254
 (pg. 
751
-
755
)
[PubMed]
13
Thornalley
P.J.
Langborg
A.
Minhas
H.S.
Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose
Biochem. J.
1999
, vol. 
344
 
Pt 1
(pg. 
109
-
116
)
[PubMed]
14
Reichard
G.A.
Jr
Skutches
C.L.
Hoeldtke
R.D.
Owen
O.E.
Acetone metabolism in humans during diabetic ketoacidosis
Diabetes
1986
, vol. 
35
 (pg. 
668
-
674
)
[PubMed]
15
Lyles
G.A.
Chalmers
J.
The metabolism of aminoacetone to methylglyoxal by semicarbazide-sensitive amine oxidase in human umbilical artery
Biochem. Pharmacol.
1992
, vol. 
43
 (pg. 
1409
-
1414
)
[PubMed]
16
Baynes
J.W.
Thorpe
S.R.
Glycoxidation and lipoxidation in atherogenesis
Free Radic. Biol. Med.
2000
, vol. 
28
 (pg. 
1708
-
1716
)
[PubMed]
17
Rabbani
N.
Thornalley
P.J.
Measurement of methylglyoxal by stable isotopic dilution analysis LC-MS/MS with corroborative prediction in physiological samples
Nat. Protoc.
2014
, vol. 
9
 (pg. 
1969
-
1979
)
[PubMed]
18
Kalapos
M.P.
Where does plasma methylglyoxal originate from?
Diabetes Res. Clin. Pract.
2013
, vol. 
99
 (pg. 
260
-
271
)
19
Degen
J.
Hellwig
M.
Henle
T.
1,2-dicarbonyl compounds in commonly consumed foods
J. Agric. Food Chem.
2012
, vol. 
60
 (pg. 
7071
-
7079
)
[PubMed]
20
Beisswenger
P.J.
Howell
S.K.
Touchette
A.D.
Lal
S.
Szwergold
B.S.
Metformin reduces systemic methylglyoxal levels in type 2 diabetes
Diabetes
1999
, vol. 
48
 (pg. 
198
-
202
)
[PubMed]
21
Lapolla
A.
Flamini
R.
Lupo
A.
Arico
N.C.
Rugiu
C.
Reitano
R.
Tubaro
M.
Ragazzi
E.
Seraglia
R.
Traldi
P.
Evaluation of glyoxal and methylglyoxal levels in uremic patients under peritoneal dialysis
Ann. N. Y. Acad. Sci.
2005
, vol. 
1043
 (pg. 
217
-
224
)
[PubMed]
22
Scheijen
J.L.
Schalkwijk
C.G.
Quantification of glyoxal, methylglyoxal and 3-deoxyglucosone in blood and plasma by ultra performance liquid chromatography tandem mass spectrometry: evaluation of blood specimen
Clin. Chem. Lab. Med.
2014
, vol. 
52
 (pg. 
85
-
91
)
[PubMed]
23
Beisswenger
P.
Heine
R.J.
Leiter
L.A.
Moses
A.
Tuomilehto
J.
Prandial glucose regulation in the glucose triad: emerging evidence and insights
Endocrine
2004
, vol. 
25
 (pg. 
195
-
202
)
[PubMed]
24
Nakayama
K.
Nakayama
M.
Iwabuchi
M.
Terawaki
H.
Sato
T.
Kohno
M.
Ito
S.
Plasma alpha-oxoaldehyde levels in diabetic and nondiabetic chronic kidney disease patients
Am. J. Nephrol.
2008
, vol. 
28
 (pg. 
871
-
878
)
[PubMed]
25
Lu
J.
Randell
E.
Han
Y.
Adeli
K.
Krahn
J.
Meng
Q.H.
Increased plasma methylglyoxal level, inflammation, and vascular endothelial dysfunction in diabetic nephropathy
Clin. Biochem.
2011
, vol. 
44
 (pg. 
307
-
311
)
[PubMed]
26
Phillips
S.A.
Mirrlees
D.
Thornalley
P.J.
Modification of the glyoxalase system in streptozotocin-induced diabetic rats. Effect of the aldose reductase inhibitor Statil
Biochem. Pharmacol.
1993
, vol. 
46
 (pg. 
805
-
811
)
[PubMed]
27
Dobler
D.
Ahmed
N.
Song
L.
Eboigbodin
K.E.
Thornalley
P.J.
Increased dicarbonyl metabolism in endothelial cells in hyperglycemia induces anoikis and impairs angiogenesis by RGD and GFOGER motif modification
Diabetes
2006
, vol. 
55
 (pg. 
1961
-
1969
)
[PubMed]
28
Rabbani
N.
Thornalley
P.J.
Glyoxalase in diabetes, obesity and related disorders
Semin. Cell Dev. Biol.
2011
, vol. 
22
 (pg. 
309
-
317
)
[PubMed]
29
Rabbani
N.
Thornalley
P.J.
Dicarbonyl proteome and genome damage in metabolic and vascular disease
Biochem. Soc. Trans.
2014
, vol. 
42
 (pg. 
425
-
432
)
[PubMed]
30
Izaguirre
G.
Kikonyogo
A.
Pietruszko
R.
Methylglyoxal as substrate and inhibitor of human aldehyde dehydrogenase: comparison of kinetic properties among the three isozymes
Comp. Biochem. Physiol. B Biochem. Mol. Biol.
1998
, vol. 
119
 (pg. 
747
-
754
)
[PubMed]
31
Rabbani
N.
Thornalley
P.J.
Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome
Amino Acids
2012
, vol. 
42
 (pg. 
1133
-
1142
)
[PubMed]
32
Baba
S.P.
Barski
O.A.
Ahmed
Y.
O’Toole
T.E.
Conklin
D.J.
Bhatnagar
A.
Srivastava
S.
Reductive metabolism of AGE precursors: a metabolic route for preventing AGE accumulation in cardiovascular tissue
Diabetes
2009
, vol. 
58
 (pg. 
2486
-
2497
)
[PubMed]
33
Lo
T.W.
Westwood
M.E.
McLellan
A.C.
Selwood
T.
Thornalley
P.J.
Binding and modification of proteins by methylglyoxal under physiological conditions. A kinetic and mechanistic study with N-alpha-acetylarginine, N-alpha-acetylcysteine, and N-alpha-acetyllysine, and bovine serum albumin
J. Biol. Chem.
1994
, vol. 
269
 (pg. 
32299
-
32305
)
[PubMed]
34
Thornalley
P.J.
Battah
S.
Ahmed
N.
Karachalias
N.
Agalou
S.
Babaei-Jadidi
R.
Dawnay
A.
Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry
Biochem. J.
2003
, vol. 
375
 (pg. 
581
-
592
)
[PubMed]
35
Ahmed
N.
Thornalley
P.J.
Peptide mapping of human serum albumin modified minimally by methylglyoxal in vitro and in vivo
Ann. N. Y. Acad. Sci.
2005
, vol. 
1043
 (pg. 
260
-
266
)
[PubMed]
36
Watanabe
H.
Tanase
S.
Nakajou
K.
Maruyama
T.
Kragh-Hansen
U.
Otagiri
M.
Role of arg-410 and tyr-411 in human serum albumin for ligand binding and esterase-like activity
Biochem. J.
2000
, vol. 
349
 
Pt 3
(pg. 
813
-
819
)
[PubMed]
37
Faure
P.
Troncy
L.
Lecomte
M.
Wiernsperger
N.
Lagarde
M.
Ruggiero
D.
Halimi
S.
Albumin antioxidant capacity is modified by methylglyoxal
Diabetes Metab.
2005
, vol. 
31
 (pg. 
169
-
177
)
[PubMed]
38
Abordo
E.A.
Thornalley
P.J.
Synthesis and secretion of tumour necrosis factor-alpha by human monocytic THP-1 cells and chemotaxis induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts
Immunol. Lett.
1997
, vol. 
58
 (pg. 
139
-
147
)
[PubMed]
39
Westwood
M.E.
McLellan
A.C.
Thornalley
P.J.
Receptor-mediated endocytic uptake of methylglyoxal-modified serum albumin. Competition with advanced glycation end product-modified serum albumin at the advanced glycation end product receptor
J. Biol. Chem.
1994
, vol. 
269
 (pg. 
32293
-
32298
)
[PubMed]
40
Fan
X.
Subramaniam
R.
Weiss
M.F.
Monnier
V.M.
Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor kappaB and intracellular reactive oxygen species formation
Arch. Biochem. Biophys.
2003
, vol. 
409
 (pg. 
274
-
286
)
[PubMed]
41
Westwood
M.E.
Thornalley
P.J.
Induction of synthesis and secretion of interleukin 1 beta in the human monocytic THP-1 cells by human serum albumins modified with methylglyoxal and advanced glycation endproducts
Immunol. Lett.
1996
, vol. 
50
 (pg. 
17
-
21
)
[PubMed]
42
Westwood
M.E.
Argirov
O.K.
Abordo
E.A.
Thornalley
P.J.
Methylglyoxal-modified arginine residues–a signal for receptor-mediated endocytosis and degradation of proteins by monocytic THP-1 cells
Biochim. Biophys. Acta
1997
, vol. 
1356
 (pg. 
84
-
94
)
[PubMed]
43
Monnier
V.M.
Sell
D.R.
Strauch
C.
Sun
W.
Lachin
J.M.
Cleary
P.A.
Genuth
S.
The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes
J. Diabetes Complications
2013
, vol. 
27
 (pg. 
141
-
149
)
[PubMed]
44
Bose
T.
Bhattacherjee
A.
Banerjee
S.
Chakraborti
A.S.
Methylglyoxal-induced modifications of hemoglobin: structural and functional characteristics
Arch. Biochem. Biophys.
2013
, vol. 
529
 (pg. 
99
-
104
)
[PubMed]
45
Morcos
M.
Du
X.
Pfisterer
F.
Hutter
H.
Sayed
A.A.
Thornalley
P.
Ahmed
N.
Baynes
J.
Thorpe
S.
Kukudov
G.
, et al. 
Glyoxalase-1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans
Aging Cell
2008
, vol. 
7
 (pg. 
260
-
269
)
[PubMed]
46
Queisser
M.A.
Yao
D.
Geisler
S.
Hammes
H.P.
Lochnit
G.
Schleicher
E.D.
Brownlee
M.
Preissner
K.T.
Hyperglycemia impairs proteasome function by methylglyoxal
Diabetes
2010
, vol. 
59
 (pg. 
670
-
678
)
[PubMed]
47
Nagaraj
R.H.
Panda
A.K.
Shanthakumar
S.
Santhoshkumar
P.
Pasupuleti
N.
Wang
B.
Biswas
A.
Hydroimidazolone modification of the conserved Arg12 in small heat shock proteins: studies on the structure and chaperone function using mutant mimics
PloS ONE
2012
, vol. 
7
 pg. 
e30257
 
[PubMed]
48
Xue
J.
Ray
R.
Singer
D.
Bohme
D.
Burz
D.S.
Rai
V.
Hoffmann
R.
Shekhtman
A.
The receptor for advanced glycation end products (RAGE) specifically recognizes methylglyoxal-derived AGEs
Biochemistry
2014
, vol. 
53
 (pg. 
3327
-
3335
)
[PubMed]
49
Shipanova
I.N.
Glomb
M.A.
Nagaraj
R.H.
Protein modification by methylglyoxal: chemical nature and synthetic mechanism of a major fluorescent adduct
Arch. Biochem. Biophys.
1997
, vol. 
344
 (pg. 
29
-
36
)
[PubMed]
50
Oya
T.
Hattori
N.
Mizuno
Y.
Miyata
S.
Maeda
S.
Osawa
T.
Uchida
K.
Methylglyoxal modification of protein. Chemical and immunochemical characterization of methylglyoxal-arginine adducts
J. Biol. Chem.
1999
, vol. 
274
 (pg. 
18492
-
18502
)
[PubMed]
51
Oya-Ito
T.
Liu
B.F.
Nagaraj
R.H.
Effect of methylglyoxal modification and phosphorylation on the chaperone and anti-apoptotic properties of heat shock protein 27
J. Cell Biochem.
2006
, vol. 
99
 (pg. 
279
-
291
)
[PubMed]
52
Nagaraj
R.H.
Oya-Ito
T.
Padayatti
P.S.
Kumar
R.
Mehta
S.
West
K.
Levison
B.
Sun
J.
Crabb
J.W.
Padival
A.K.
Enhancement of chaperone function of alpha-crystallin by methylglyoxal modification
Biochemistry
2003
, vol. 
42
 (pg. 
10746
-
10755
)
[PubMed]
53
Schalkwijk
C.G.
van Bezu
J.
van der Schors
R.C.
Uchida
K.
Stehouwer
C.D.
van Hinsbergh
V.W.
Heat-shock protein 27 is a major methylglyoxal-modified protein in endothelial cells
FEBS Lett.
2006
, vol. 
580
 (pg. 
1565
-
1570
)
[PubMed]
54
Gawlowski
T.
Stratmann
B.
Stork
I.
Engelbrecht
B.
Brodehl
A.
Niehaus
K.
Korfer
R.
Tschoepe
D.
Milting
H.
Heat shock protein 27 modification is increased in the human diabetic failing heart
Horm. Metab. Res.
2009
, vol. 
41
 (pg. 
594
-
599
)
[PubMed]
55
van Eupen
M.G.
Schram
M.T.
Colhoun
H.M.
Hanssen
N.M.
Niessen
H.W.
Tarnow
L.
Parving
H.H.
Rossing
P.
Stehouwer
C.D.
Schalkwijk
C.G.
The methylglyoxal-derived AGE tetrahydropyrimidine is increased in plasma of individuals with type 1 diabetes mellitus and in atherosclerotic lesions and is associated with sVCAM-1
Diabetologia
2013
, vol. 
56
 (pg. 
1845
-
1855
)
[PubMed]
56
Ahmed
M.U.
Brinkmann Frye
E.
Degenhardt
T.P.
Thorpe
S.R.
Baynes
J.W.
N-epsilon-(carboxyethyl)lysine, a product of the chemical modification of proteins by methylglyoxal, increases with age in human lens proteins
Biochem. J.
1997
, vol. 
324
 
Pt 2
(pg. 
565
-
570
)
[PubMed]
57
Frye
E.B.
Degenhardt
T.P.
Thorpe
S.R.
Baynes
J.W.
Role of the Maillard reaction in aging of tissue proteins. Advanced glycation end product-dependent increase in imidazolium cross-links in human lens proteins
J. Biol. Chem.
1998
, vol. 
273
 (pg. 
18714
-
18719
)
[PubMed]
58
Lederer
M.O.
Klaiber
R.G.
Cross-linking of proteins by Maillard processes: characterization and detection of lysine-arginine cross-links derived from glyoxal and methylglyoxal
Bioorg. Med. Chem.
1999
, vol. 
7
 (pg. 
2499
-
2507
)
[PubMed]
59
Schneider
M.
Thoss
G.
Hubner-Parajsz
C.
Kientsch-Engel
R.
Stahl
P.
Pischetsrieder
M.
Determination of glycated nucleobases in human urine by a new monoclonal antibody specific for N2-carboxyethyl-2′-deoxyguanosine
Chem. Res. Toxicol.
2004
, vol. 
17
 (pg. 
1385
-
1390
)
[PubMed]
60
Synold
T.
Xi
B.
Wuenschell
G.E.
Tamae
D.
Figarola
J.L.
Rahbar
S.
Termini
J.
Advanced glycation end products of DNA: quantification of N2-(1-Carboxyethyl)-2′-deoxyguanosine in biological samples by liquid chromatography electrospray ionization tandem mass spectrometry
Chem. Res. Toxicol.
2008
, vol. 
21
 (pg. 
2148
-
2155
)
[PubMed]
61
Thornalley
P.J.
Waris
S.
Fleming
T.
Santarius
T.
Larkin
S.J.
Winklhofer-Roob
B.M.
Stratton
M.R.
Rabbani
N.
Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance
Nucleic Acids Res.
2010
, vol. 
38
 (pg. 
5432
-
5442
)
[PubMed]
62
Murata-Kamiya
N.
Kamiya
H.
Kaji
H.
Kasai
H.
Methylglyoxal induces G:C to C:G and G:C to T:A transversions in the supF gene on a shuttle vector plasmid replicated in mammalian cells
Mutat. Res.
2000
, vol. 
468
 (pg. 
173
-
182
)
[PubMed]
63
Tu
C.Y.
Chen
Y.F.
Lii
C.K.
Wang
T.S.
Methylglyoxal induces DNA crosslinks in ECV304 cells via a reactive oxygen species-independent protein carbonylation pathway
Toxicol. in Vitro
2013
, vol. 
27
 (pg. 
1211
-
1219
)
[PubMed]
64
Petrova
K.V.
Millsap
A.D.
Stec
D.F.
Rizzo
C.J.
Characterization of the deoxyguanosine-lysine cross-link of methylglyoxal
Chem. Res. Toxicol.
2014
, vol. 
27
 (pg. 
1019
-
1029
)
[PubMed]
65
Mir
A.R.
Uddin
M.
Alam
K.
Ali
A.
Methylglyoxal mediated conformational changes in histone H2A-generation of carboxyethylated advanced glycation end products
Int. J. Biol. Macromol.
2014
, vol. 
69
 (pg. 
260
-
266
)
[PubMed]
66
Vander Jagt
D.L.
Daub
E.
Krohn
J.A.
Han
L.P.
Effects of pH and thiols on the kinetics of yeast glyoxalase I
An evaluation of the random pathway mechanism. Biochemistry
1975
, vol. 
14
 (pg. 
3669
-
3675
)
67
Vander Jagt
D.L.
Han
L.P.
Lehman
C.H.
Kinetic evaluation of substrate specificity in the glyoxalase-I-catalyzed disproportionation of ketoaldehydes
Biochemistry
1972
, vol. 
11
 (pg. 
3735
-
3740
)
[PubMed]
68
Thornalley
P.J.
Glyoxalase I–structure, function and a critical role in the enzymatic defence against glycation
Biochem. Soc. Trans.
2003
, vol. 
31
 (pg. 
1343
-
1348
)
[PubMed]
69
Ranganathan
S.
Ciaccio
P.J.
Walsh
E.S.
Tew
K.D.
Genomic sequence of human glyoxalase-I: analysis of promoter activity and its regulation
Gene
1999
, vol. 
240
 (pg. 
149
-
155
)
[PubMed]
70
Birkenmeier
G.
Stegemann
C.
Hoffmann
R.
Gunther
R.
Huse
K.
Birkemeyer
C.
Posttranslational modification of human glyoxalase 1 indicates redox-dependent regulation
PloS ONE
2010
, vol. 
5
 pg. 
e10399
 
[PubMed]
71
Mitsumoto
A.
Kim
K.R.
Oshima
G.
Kunimoto
M.
Okawa
K.
Iwamatsu
A.
Nakagawa
Y.
Glyoxalase I is a novel nitric-oxide-responsive protein
Biochem. J.
1999
, vol. 
344
 
Pt 3
(pg. 
837
-
844
)
[PubMed]
72
de Hemptinne
V.
Rondas
D.
Toepoel
M.
Vancompernolle
K.
Phosphorylation on Thr-106 and NO-modification of glyoxalase I suppress the TNF-induced transcriptional activity of NF-kappaB
Mol. Cell Biochem.
2009
, vol. 
325
 (pg. 
169
-
178
)
[PubMed]
73
Van Herreweghe
F.
Mao
J.
Chaplen
F.W.
Grooten
J.
Gevaert
K.
Vandekerckhove
J.
Vancompernolle
K.
Tumor necrosis factor-induced modulation of glyoxalase I activities through phosphorylation by PKA results in cell death and is accompanied by the formation of a specific methylglyoxal-derived AGE
Proc. Natl. Acad. Sci. U.S.A.
2002
, vol. 
99
 (pg. 
949
-
954
)
[PubMed]
74
Thornalley
P.J.
The glyoxalase system in health and disease
Mol. Aspects Med.
1993
, vol. 
14
 (pg. 
287
-
371
)
[PubMed]
75
Atkins
T.W.
Thornally
P.J.
Erythrocyte glyoxalase activity in genetically obese (ob/ob) and streptozotocin diabetic mice
Diabetes Res.
1989
, vol. 
11
 (pg. 
125
-
129
)
[PubMed]
76
Barati
M.T.
Merchant
M.L.
Kain
A.B.
Jevans
A.W.
McLeish
K.R.
Klein
J.B.
Proteomic analysis defines altered cellular redox pathways and advanced glycation end-product metabolism in glomeruli of db/db diabetic mice
Am. J. Physiol. Renal Physiol.
2007
, vol. 
293
 (pg. 
F1157
-
1165
)
[PubMed]
77
Hanssen
N.M.
Wouters
K.
Huijberts
M.S.
Gijbels
M.J.
Sluimer
J.C.
Scheijen
J.L.
Heeneman
S.
Biessen
E.A.
Daemen
M.J.
Brownlee
M.
, et al. 
Higher levels of advanced glycation endproducts in human carotid atherosclerotic plaques are associated with a rupture-prone phenotype
Eur. Heart J.
2014
, vol. 
35
 (pg. 
1137
-
1146
)
[PubMed]
78
Shafie
A.
Xue
M.
Thornalley
P.J.
Rabbani
N.
Copy number variation of glyoxalase I
Biochem. Soc. Trans.
2014
, vol. 
42
 (pg. 
500
-
503
)
[PubMed]
79
Peculis
R.
Konrade
I.
Skapare
E.
Fridmanis
D.
Nikitina-Zake
L.
Lejnieks
A.
Pirags
V.
Dambrova
M.
Klovins
J.
Identification of glyoxalase 1 polymorphisms associated with enzyme activity
Gene
2013
, vol. 
515
 (pg. 
140
-
143
)
[PubMed]
80
Engelen
L.
Ferreira
I.
Brouwers
O.
Henry
R.M.
Dekker
J.M.
Nijpels
G.
Heine
R.J.
van Greevenbroek
M.M.
van der Kallen
C.J.
Blaak
E.E.
, et al. 
Polymorphisms in glyoxalase 1 gene are not associated with vascular complications: the Hoorn and CoDAM studies
J. Hypertens.
2009
, vol. 
27
 (pg. 
1399
-
1403
)
[PubMed]
81
Barua
M.
Jenkins
E.C.
Chen
W.
Kuizon
S.
Pullarkat
R.K.
Junaid
M.A.
Glyoxalase I polymorphism rs2736654 causing the Ala111Glu substitution modulates enzyme activity–implications for autism
Autism Res.
2011
, vol. 
4
 (pg. 
262
-
270
)
[PubMed]
82
Junaid
M.A.
Kowal
D.
Barua
M.
Pullarkat
P.S.
Sklower Brooks
S.
Pullarkat
R.K.
Proteomic studies identified a single nucleotide polymorphism in glyoxalase I as autism susceptibility factor
Am. J. Med. Genet. A
2004
, vol. 
131
 (pg. 
11
-
17
)
[PubMed]
83
Gabriele
S.
Lombardi
F.
Sacco
R.
Napolioni
V.
Altieri
L.
Tirindelli
M.C.
Gregorj
C.
Bravaccio
C.
Rousseau
F.
Persico
A.M.
The GLO1 C332 (Ala111) allele confers autism vulnerability: Family-based genetic association and functional correlates
J. Psychiatr. Res.
2014
, vol. 
59
 (pg. 
108
-
116
)
[PubMed]
84
Politi
P.
Minoretti
P.
Falcone
C.
Martinelli
V.
Emanuele
E.
Association analysis of the functional Ala111Glu polymorphism of the glyoxalase I gene in panic disorder
Neurosci. Lett.
2006
, vol. 
396
 (pg. 
163
-
166
)
[PubMed]
85
Agar
N.S.
Board
P.G.
Bell
K.
Studies of erythrocyte glyoxalase II in various domestic species: discovery of glyoxalase II deficiency in the horse
Animal Blood Groups Biochem. Genet.
1984
, vol. 
15
 (pg. 
67
-
70
)
86
Valentine
W.N.
Paglia
D.E.
Neerhout
R.C.
Konrad
P.N.
Erythrocyte glyoxalase II deficiency with coincidental hereditary elliptocytosis
Blood
1970
, vol. 
36
 (pg. 
797
-
808
)
[PubMed]
87
Misra
K.
Banerjee
A.B.
Ray
S.
Ray
M.
Glyoxalase III from Escherichia coli: a single novel enzyme for the conversion of methylglyoxal into D-lactate without reduced glutathione
Biochem. J.
1995
, vol. 
305
 
Pt 3
(pg. 
999
-
1003
)
[PubMed]
88
Lee
J.Y.
Song
J.
Kwon
K.
Jang
S.
Kim
C.
Baek
K.
Kim
J.
Park
C.
Human DJ-1 and its homologs are novel glyoxalases
Human Mol. Genet.
2012
, vol. 
21
 (pg. 
3215
-
3225
)
89
Danaei
G.
Finucane
M.M.
Lu
Y.
Singh
G.M.
Cowan
M.J.
Paciorek
C.J.
Lin
J.K.
Farzadfar
F.
Khang
Y.H.
Stevens
G.A.
, et al. 
National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants
Lancet
2011
, vol. 
378
 (pg. 
31
-
40
)
[PubMed]
90
Shinohara
M.
Thornalley
P.J.
Giardino
I.
Beisswenger
P.
Thorpe
S.R.
Onorato
J.
Brownlee
M.
Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis
J. Clin. Invest.
1998
, vol. 
101
 (pg. 
1142
-
1147
)
[PubMed]
91
Schalkwijk
C.G.
Stehouwer
C.D.
Vascular complications in diabetes mellitus: the role of endothelial dysfunction
Clin. Sci. (Lond.)
2005
, vol. 
109
 (pg. 
143
-
159
)
[PubMed]
92
Eringa
E.C.
Serne
E.H.
Meijer
R.I.
Schalkwijk
C.G.
Houben
A.J.
Stehouwer
C.D.
Smulders
Y.M.
van Hinsbergh
V.W.
Endothelial dysfunction in (pre)diabetes: characteristics, causative mechanisms and pathogenic role in type 2 diabetes
Rev. Endocr. Metab. Disord.
2013
, vol. 
14
 (pg. 
39
-
48
)
[PubMed]
93
De Bock
K.
Georgiadou
M.
Carmeliet
P.
Role of endothelial cell metabolism in vessel sprouting
Cell Metab.
2013
, vol. 
18
 (pg. 
634
-
647
)
[PubMed]
94
Abebe
W.
Mozaffari
M.
Endothelial dysfunction in diabetes: potential application of circulating markers as advanced diagnostic and prognostic tools
EPMA J.
2010
, vol. 
1
 (pg. 
32
-
45
)
[PubMed]
95
Brouwers
O.
Niessen
P.M.
Haenen
G.
Miyata
T.
Brownlee
M.
Stehouwer
C.D.
De Mey
J.G.
Schalkwijk
C.G.
Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stress
Diabetologia
2010
, vol. 
53
 (pg. 
989
-
1000
)
[PubMed]
96
Berlanga
J.
Cibrian
D.
Guillen
I.
Freyre
F.
Alba
J.S.
Lopez-Saura
P.
Merino
N.
Aldama
A.
Quintela
A.M.
Triana
M.E.
, et al. 
Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds
Clin. Sci. (Lond.)
2005
, vol. 
109
 (pg. 
83
-
95
)
[PubMed]
97
Sena
C.M.
Matafome
P.
Crisostomo
J.
Rodrigues
L.
Fernandes
R.
Pereira
P.
Seica
R.M.
Methylglyoxal promotes oxidative stress and endothelial dysfunction
Pharmacol. Res.
2012
, vol. 
65
 (pg. 
497
-
506
)
[PubMed]
98
Ahmed
U.
Dobler
D.
Larkin
S.J.
Rabbani
N.
Thornalley
P.J.
Reversal of hyperglycemia-induced angiogenesis deficit of human endothelial cells by overexpression of glyoxalase 1 in vitro
Ann. N. Y. Acad. Sci.
2008
, vol. 
1126
 (pg. 
262
-
264
)
[PubMed]
99
Brouwers
O.
Niessen
P.M.
Miyata
T.
Ostergaard
J.A.
Flyvbjerg
A.
Peutz-Kootstra
C.J.
Sieber
J.
Mundel
P.H.
Brownlee
M.
Janssen
B.J.
, et al. 
Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes
Diabetologia
2014
, vol. 
57
 (pg. 
224
-
235
)
[PubMed]
100
Miyazawa
N.
Abe
M.
Souma
T.
Tanemoto
M.
Abe
T.
Nakayama
M.
Ito
S.
Methylglyoxal augments intracellular oxidative stress in human aortic endothelial cells
Free Radic. Res.
2010
, vol. 
44
 (pg. 
101
-
107
)
[PubMed]
101
Nagaraj
R.H.
Oya-Ito
T.
Bhat
M.
Liu
B.
Dicarbonyl stress and apoptosis of vascular cells: prevention by alphaB-crystallin
Ann. N. Y. Acad. Sci.
2005
, vol. 
1043
 (pg. 
158
-
165
)
[PubMed]
102
Chan
W.H.
Wu
H.J.
Methylglyoxal and high glucose co-treatment induces apoptosis or necrosis in human umbilical vein endothelial cells
J. Cell Biochem.
2008
, vol. 
103
 (pg. 
1144
-
1157
)
[PubMed]
103
Hou
S.M.
Nori
P.
Fang
J.L.
Vaca
C.E.
Methylglyoxal induces hprt mutation and DNA adducts in human T-lymphocytes in vitro
Environ. Mol. Mutagen
1995
, vol. 
26
 (pg. 
286
-
291
)
[PubMed]
104
Kang
Y.
Edwards
L.G.
Thornalley
P.J.
Effect of methylglyoxal on human leukaemia 60 cell growth: modification of DNA G1 growth arrest and induction of apoptosis
Leuk. Res.
1996
, vol. 
20
 (pg. 
397
-
405
)
[PubMed]
105
Chan
W.H.
Wu
H.J.
Shiao
N.H.
Apoptotic signaling in methylglyoxal-treated human osteoblasts involves oxidative stress, c-Jun N-terminal kinase, caspase-3, and p21-activated kinase 2
J. Cell Biochem.
2007
, vol. 
100
 (pg. 
1056
-
1069
)
[PubMed]
106
Du
J.
Suzuki
H.
Nagase
F.
Akhand
A.A.
Ma
X.Y.
Yokoyama
T.
Miyata
T.
Nakashima
I.
Superoxide-mediated early oxidation and activation of ASK1 are important for initiating methylglyoxal-induced apoptosis process
Free Radic. Biol. Med.
2001
, vol. 
31
 (pg. 
469
-
478
)
[PubMed]
107
Okado
A.
Kawasaki
Y.
Hasuike
Y.
Takahashi
M.
Teshima
T.
Fujii
J.
Taniguchi
N.
Induction of apoptotic cell death by methylglyoxal and 3-deoxyglucosone in macrophage-derived cell lines
Biochem. Biophys. Res. Commun.
1996
, vol. 
225
 (pg. 
219
-
224
)
[PubMed]
108
Su
Y.
Qadri
S.M.
Wu
L.
Liu
L.
Methylglyoxal modulates endothelial nitric oxide synthase-associated functions in EA.hy926 endothelial cells
Cardiovasc. Diabetol.
2013
, vol. 
12
 pg. 
134
 
[PubMed]
109
Phalitakul
S.
Okada
M.
Hara
Y.
Yamawaki
H.
Vaspin prevents methylglyoxal-induced apoptosis in human vascular endothelial cells by inhibiting reactive oxygen species generation
Acta. Physiol. (Oxf.)
2013
, vol. 
209
 (pg. 
212
-
219
)
[PubMed]
110
Chang
T.
Wang
R.
Wu
L.
Methylglyoxal-induced nitric oxide and peroxynitrite production in vascular smooth muscle cells
Free Radic. Biol. Med.
2005
, vol. 
38
 (pg. 
286
-
293
)
[PubMed]
111
Wang
H.
Meng
Q.H.
Chang
T.
Wu
L.
Fructose-induced peroxynitrite production is mediated by methylglyoxal in vascular smooth muscle cells
Life Sci.
2006
, vol. 
79
 (pg. 
2448
-
2454
)
[PubMed]
112
Chang
T.
Untereiner
A.
Liu
J.
Wu
L.
Interaction of methylglyoxal and hydrogen sulfide in rat vascular smooth muscle cells
Antioxid. Redox Signal.
2010
, vol. 
12
 (pg. 
1093
-
1100
)
[PubMed]
113
Yang
Y.
Li
S.
Konduru
A.S.
Zhang
S.
Trower
T.C.
Shi
W.
Cui
N.
Yu
L.
Wang
Y.
Zhu
D.
, et al. 
Prolonged exposure to methylglyoxal causes disruption of vascular KATP channel by mRNA instability
Am. J. Physiol. Cell Physiol.
2012
, vol. 
303
 (pg. 
C1045
-
1054
)
[PubMed]
114
Forbes
J.M.
Cooper
M.E.
Mechanisms of diabetic complications
Physiol. Rev.
2013
, vol. 
93
 (pg. 
137
-
188
)
[PubMed]
115
Lu
J.
Randell
E.
Han
Y.
Adeli
K.
Krahn
J.
Meng
Q.H.
Increased plasma methylglyoxal level, inflammation, and vascular endothelial dysfunction in diabetic nephropathy
Clin. Biochem.
2011
, vol. 
44
 (pg. 
307
-
311
)
[PubMed]
116
Nakayama
K.
Nakayama
M.
Iwabuchi
M.
Terawaki
H.
Sato
T.
Kohno
M.
Ito
S.
Plasma alpha-oxoaldehyde levels in diabetic and nondiabetic chronic kidney disease patients
Am. J. Nephrol.
2008
, vol. 
28
 (pg. 
871
-
878
)
[PubMed]
117
Beisswenger
P.J.
Drummond
K.S.
Nelson
R.G.
Howell
S.K.
Szwergold
B.S.
Mauer
M.
Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress
Diabetes
2005
, vol. 
54
 (pg. 
3274
-
3281
)
[PubMed]
118
Beisswenger
P.J.
Howell
S.K.
Russell
G.B.
Miller
M.E.
Rich
S.S.
Mauer
M.
Early progression of diabetic nephropathy correlates with methylglyoxal-derived advanced glycation end products
Diabetes Care
2013
, vol. 
36
 (pg. 
3234
-
3239
)
[PubMed]
119
Yao
D.
Taguchi
T.
Matsumura
T.
Pestell
R.
Edelstein
D.
Giardino
I.
Suske
G.
Rabbani
N.
Thornalley
P.J.
Sarthy
V.P.
, et al. 
High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A
J. Biol. Chem.
2007
, vol. 
282
 (pg. 
31038
-
31045
)
[PubMed]
120
Rosca
M.G.
Monnier
V.M.
Szweda
L.I.
Weiss
M.F.
Alterations in renal mitochondrial respiration in response to the reactive oxoaldehyde methylglyoxal
Am. J. Physiol. Renal Physiol.
2002
, vol. 
283
 (pg. 
F52
-
F59
)
[PubMed]
121
Geoffrion
M.
Du
X.
Irshad
Z.
Vanderhyden
B.C.
Courville
K.
Sui
G.
D'Agati
V.D.
Ott-Braschi
S.
Rabbani
N.
Thornalley
P.J.
, et al. 
Differential effects of glyoxalase 1 overexpression on diabetic atherosclerosis and renal dysfunction in streptozotocin-treated, apolipoprotein E-deficient mice
Physiol. Rep.
2014
, vol. 
2
 pg. 
e12043
  
doi: 10.14814/phy2.12043
122
Liu
Y.-W. W.
Zhu
X.
Zhang
L.
Lu
Q.
Wang
J.-Y. Y.
Zhang
F.
Guo
H.
Yin
J.-L. L.
Yin
X.-X. X.
Up-regulation of glyoxalase 1 by mangiferin prevents diabetic nephropathy progression in streptozotocin-induced diabetic rats
Eur. J. Pharmacol.
2013
, vol. 
721
 (pg. 
355
-
364
)
[PubMed]
123
Giacco
F.
Du
X.
D’Agati
V.D.
Milne
R.
Sui
G.
Geoffrion
M.
Brownlee
M.
Knockdown of glyoxalase 1 mimics diabetic nephropathy in nondiabetic mice
Diabetes
2014
, vol. 
63
 (pg. 
291
-
299
)
[PubMed]
124
Kumagai
T.
Nangaku
M.
Kojima
I.
Nagai
R.
Ingelfinger
J.R.
Miyata
T.
Fujita
T.
Inagi
R.
Glyoxalase I overexpression ameliorates renal ischemia-reperfusion injury in rats
Am. J. Physiol. Renal Physiol.
2009
, vol. 
296
 (pg. 
F912
-
F921
)
[PubMed]
125
Bourne
R.R.
Jonas
J.B.
Flaxman
S.R.
Keeffe
J.
Leasher
J.
Naidoo
K.
Parodi
M.B.
Pesudovs
K.
Price
H.
White
R.A.
, et al. 
Prevalence and causes of vision loss in high-income countries and in Eastern and Central Europe: 1990–2010
Br. J. Ophthalmol.
2014
, vol. 
98
 (pg. 
629
-
638
)
[PubMed]
126
Cheung
N.
Mitchell
P.
Wong
T.Y.
Diabetic retinopathy
Lancet
2010
, vol. 
376
 (pg. 
124
-
136
)
[PubMed]
127
Fosmark
D.S.
Berg
J.P.
Jensen
A.-B. B.
Sandvik
L.
Agardh
E.
Agardh
C.-D. D.
Hanssen
K.F.
Increased retinopathy occurrence in type 1 diabetes patients with increased serum levels of the advanced glycation endproduct hydroimidazolone
Acta Ophthalmol.
2009
, vol. 
87
 (pg. 
498
-
500
)
[PubMed]
128
Fosmark
D.S.
Torjesen
P.A.
Kilhovd
B.K.
Berg
T.J.
Sandvik
L.
Hanssen
K.F.
Agardh
C.-D. D.
Agardh
E.
Increased serum levels of the specific advanced glycation end product methylglyoxal-derived hydroimidazolone are associated with retinopathy in patients with type 2 diabetes mellitus
Metabolism: Clin. Exp.
2006
, vol. 
55
 (pg. 
232
-
236
)
129
Karachalias
N.
Babaei-Jadidi
R.
Ahmed
N.
Thornalley
P.J.
Accumulation of fructosyl-lysine and advanced glycation end products in the kidney, retina and peripheral nerve of streptozotocin-induced diabetic rats
Biochem. Soc. Trans.
2003
, vol. 
31
 (pg. 
1423
-
1425
)
[PubMed]
130
Padayatti
P.S.
Jiang
C.
Glomb
M.A.
Uchida
K.
Nagaraj
R.H.
High concentrations of glucose induce synthesis of argpyrimidine in retinal endothelial cells
Curr. Eye Res.
2001
, vol. 
23
 (pg. 
106
-
115
)
[PubMed]
131
Bento
C.F.
Fernandes
R.
Matafome
P.
Sena
C.
Seiça
R.
Pereira
P.
Methylglyoxal-induced imbalance in the ratio of vascular endothelial growth factor to angiopoietin 2 secreted by retinal pigment epithelial cells leads to endothelial dysfunction
Exp. Physiol.
2010
, vol. 
95
 (pg. 
955
-
970
)
[PubMed]
132
Liu
B.
Bhat
M.
Padival
A.K.
Smith
D.G.
Nagaraj
R.H.
Effect of dicarbonyl modification of fibronectin on retinal capillary pericytes
Invest. Ophthalmol. Vis. Sci.
2004
, vol. 
45
 (pg. 
1983
-
1995
)
[PubMed]
133
Miller
A.G.
Smith
D.G.
Bhat
M.
Nagaraj
R.H.
Glyoxalase I is critical for human retinal capillary pericyte survival under hyperglycemic conditions
J. Biol. Chem.
2006
, vol. 
281
 (pg. 
11864
-
11871
)
[PubMed]
134
Berner
A.K.
Brouwers
O.
Pringle
R.
Klaassen
I.
Colhoun
L.
McVicar
C.
Brockbank
S.
Curry
J.W.
Miyata
T.
Brownlee
M.
, et al. 
Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology
Diabetologia
2012
, vol. 
55
 (pg. 
845
-
854
)
[PubMed]
135
Wang
J.
Lin
J.
Schlotterer
A.
Wu
L.
Fleming
T.
Busch
S.
Dietrich
N.
Hammes
H.P.
CD74 indicates microglial activation in experimental diabetic retinopathy and exogenous methylglyoxal mimics the response in normoglycemic retina
Acta Diabetol.
2014
, vol. 
51
 (pg. 
813
-
821
)
[PubMed]
136
Wang
Y.H.
Han
Y.P.
Yu
H.T.
Pu
X.P.
Du
G.H.
Protocatechualdehyde prevents methylglyoxal-induced mitochondrial dysfunction and AGEs-RAGE axis activation in human lens epithelial cells
Eur. J. Pharmacol.
2014
, vol. 
738
 (pg. 
374
-
383
)
[PubMed]
137
Kim
J.
Kim
N.H.
Sohn
E.
Kim
C.S.
Kim
J.S.
Methylglyoxal induces cellular damage by increasing argpyrimidine accumulation and oxidative DNA damage in human lens epithelial cells
Biochem. Biophys. Res. Commun.
2010
, vol. 
391
 (pg. 
346
-
351
)
[PubMed]
138
Kim
J.
Kim
O.S.
Kim
C.S.
Sohn
E.
Jo
K.
Kim
J.S.
Accumulation of argpyrimidine, a methylglyoxal-derived advanced glycation end product, increases apoptosis of lens epithelial cells both in vitro and in vivo
Exp. Mol. Med.
2012
, vol. 
44
 (pg. 
167
-
175
)
[PubMed]
139
Sugimoto
K.
Yasujima
M.
Yagihashi
S.
Role of advanced glycation end products in diabetic neuropathy
Curr. Pharm. Des.
2008
, vol. 
14
 (pg. 
953
-
961
)
[PubMed]
140
Bierhaus
A.
Fleming
T.
Stoyanov
S.
Leffler
A.
Babes
A.
Neacsu
C.
Sauer
S.K.
Eberhardt
M.
Schnölzer
M.
Lasitschka
F.
, et al. 
Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy
Nat. Med.
2012
, vol. 
18
 (pg. 
926
-
933
)
[PubMed]
141
Genuth
S.
Sun
W.
Cleary
P.
Gao
X.
Sell
D.R.
Lachin
J.
Monnier
V.M.
Skin advanced glycation endproducts (AGEs) glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes
Diabetes
2015
, vol. 
64
 (pg. 
266
-
278
)
[PubMed]
142
Fukunaga
M.
Miyata
S.
Liu
B.F.
Miyazaki
H.
Hirota
Y.
Higo
S.
Hamada
Y.
Ueyama
S.
Kasuga
M.
Methylglyoxal induces apoptosis through activation of p38 MAPK in rat Schwann cells
Biochem. Biophys. Res. Commun.
2004
, vol. 
320
 (pg. 
689
-
695
)
[PubMed]
143
Lee
H.K.
Seo
I.A.
Suh
D.J.
Lee
H.J.
Park
H.T.
A novel mechanism of methylglyoxal cytotoxicity in neuroglial cells
J. Neurochem.
2009
, vol. 
108
 (pg. 
273
-
284
)
[PubMed]
144
Ohkawara
S.
Tanaka-Kagawa
T.
Furukawa
Y.
Jinno
H.
Methylglyoxal activates the human transient receptor potential ankyrin 1 channel
J. Toxicol. Sci.
2012
, vol. 
37
 (pg. 
831
-
835
)
[PubMed]
145
Andersson
D.A.
Gentry
C.
Light
E.
Vastani
N.
Vallortigara
J.
Bierhaus
A.
Fleming
T.
Bevan
S.
Methylglyoxal evokes pain by stimulating TRPA1
PloS ONE
2013
, vol. 
8
 pg. 
e77986
 
[PubMed]
146
Koivisto
A.
Hukkanen
M.
Saarnilehto
M.
Chapman
H.
Kuokkanen
K.
Wei
H.
Viisanen
H.
Akerman
K.E.
Lindstedt
K.
Pertovaara
A.
Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy
Pharmacol. Res.
2012
, vol. 
65
 (pg. 
149
-
158
)
[PubMed]
147
Eberhardt
M.J.
Filipovic
M.R.
Leffler
A.
de la Roche
J.
Kistner
K.
Fischer
M.J.
Fleming
T.
Zimmermann
K.
Ivanovic-Burmazovic
I.
Nawroth
P.P.
, et al. 
Methylglyoxal activates nociceptors through transient receptor potential channel A1 (TRPA1): a possible mechanism of metabolic neuropathies
J. Biol. Chem.
2012
, vol. 
287
 (pg. 
28291
-
28306
)
[PubMed]
148
Jack
M.
Wright
D.
Role of advanced glycation endproducts and glyoxalase I in diabetic peripheral sensory neuropathy
Transl. Res.
2012
, vol. 
159
 (pg. 
355
-
365
)
[PubMed]
149
Grundy
S.M.
Benjamin
I.J.
Burke
G.L.
Chait
A.
Eckel
R.H.
Howard
B.V.
Mitch
W.
Jr, Smith
S.C.
Sowers
J.R.
Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association
Circulation
1999
, vol. 
100
 (pg. 
1134
-
1146
)
[PubMed]
150
Ross
R.
Atherosclerosis–an inflammatory disease
N. Engl. J. Med.
1999
, vol. 
340
 (pg. 
115
-
126
)
[PubMed]
151
Virmani
R.
Burke
A.P.
Farb
A.
Kolodgie
F.D.
Pathology of the vulnerable plaque
J. Am. Coll. Cardiol.
2006
, vol. 
47
 (pg. 
C13
-
C18
)
[PubMed]
152
Rudd
J.H.
Warburton
E.A.
Fryer
T.D.
Jones
H.A.
Clark
J.C.
Antoun
N.
Johnstrom
P.
Davenport
A.P.
Kirkpatrick
P.J.
Arch
B.N.
, et al. 
Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography
Circulation
2002
, vol. 
105
 (pg. 
2708
-
2711
)
[PubMed]
153
Basta
G.
Schmidt
A.M.
De Caterina
R.
Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes
Cardiovasc. Res.
2004
, vol. 
63
 (pg. 
582
-
592
)
[PubMed]
154
Kume
S.
Takeya
M.
Mori
T.
Araki
N.
Suzuki
H.
Horiuchi
S.
Kodama
T.
Miyauchi
Y.
Takahashi
K.
Immunohistochemical and ultrastructural detection of advanced glycation end products in atherosclerotic lesions of human aorta with a novel specific monoclonal antibody
Am. J. Pathol.
1995
, vol. 
147
 (pg. 
654
-
667
)
[PubMed]
155
Baidoshvili
A.
Niessen
H.W.
Stooker
W.
Huybregts
R.A.
Hack
C.E.
Rauwerda
J.A.
Meijer
C.J.
Eijsman
L.
van Hinsbergh
V.W.
Schalkwijk
C.G.
N(omega)-(carboxymethyl)lysine depositions in human aortic heart valves: similarities with atherosclerotic blood vessels
Atherosclerosis
2004
, vol. 
174
 (pg. 
287
-
292
)
[PubMed]
156
Tikellis
C.
Pickering
R.J.
Tsorotes
D.
Huet
O.
Cooper
M.E.
Jandeleit-Dahm
K.
Thomas
M.C.
Dicarbonyl stress in the absence of hyperglycemia increases endothelial inflammation and atherogenesis similar to that observed in diabetes
Diabetes
2014
, vol. 
63
 (pg. 
3915
-
3925
)
[PubMed]
157
Ogawa
S.
Nakayama
K.
Nakayama
M.
Mori
T.
Matsushima
M.
Okamura
M.
Senda
M.
Nako
K.
Miyata
T.
Ito
S.
Methylglyoxal is a predictor in type 2 diabetic patients of intima-media thickening and elevation of blood pressure
Hypertension
2010
, vol. 
56
 (pg. 
471
-
476
)
[PubMed]
158
Schalkwijk
C.G.
Vermeer
M.A.
Stehouwer
C.D.
te Koppele
J.
Princen
H.M.
van Hinsbergh
V.W.
Effect of methylglyoxal on the physico-chemical and biological properties of low-density lipoprotein
Biochim. Biophys. Acta
1998
, vol. 
1394
 (pg. 
187
-
198
)
[PubMed]
159
Rabbani
N.
Godfrey
L.
Xue
M.
Shaheen
F.
Geoffrion
M.
Milne
R.
Thornalley
P.J.
Glycation of LDL by methylglyoxal increases arterial atherogenicity: a possible contributor to increased risk of cardiovascular disease in diabetes
Diabetes
2011
, vol. 
60
 (pg. 
1973
-
1980
)
[PubMed]
160
Turk
Z.
Cavlovic-Naglic
M.
Turk
N.
Relationship of methylglyoxal-adduct biogenesis to LDL and triglyceride levels in diabetics
Life Sci.
2011
, vol. 
89
 (pg. 
485
-
490
)
[PubMed]
161
Brown
B.E.
Dean
R.T.
Davies
M.J.
Glycation of low-density lipoproteins by methylglyoxal and glycolaldehyde gives rise to the in vitro formation of lipid-laden cells
Diabetologia
2005
, vol. 
48
 (pg. 
361
-
369
)
[PubMed]
162
Rabbani
N.
Chittari
M.V.
Bodmer
C.W.
Zehnder
D.
Ceriello
A.
Thornalley
P.J.
Increased glycation and oxidative damage to apolipoprotein B100 of LDL cholesterol in patients with type 2 diabetes and effect of metformin
Diabetes
2010
, vol. 
59
 (pg. 
1038
-
1045
)
[PubMed]
163
Rye
K.A.
Bursill
C.A.
Lambert
G.
Tabet
F.
Barter
P.J.
The metabolism and anti-atherogenic properties of HDL
J. Lipid Res.
2009
, vol. 
50
 
Suppl
(pg. 
S195
-
S200
)
[PubMed]
164
Godfrey
L.
Yamada-Fowler
N.
Smith
J.
Thornalley
P.J.
Rabbani
N.
Arginine-directed glycation and decreased HDL plasma concentration and functionality
Nutr. Diabetes
2014
, vol. 
4
 pg. 
e134
 
[PubMed]
165
Bacchetti
T.
Masciangelo
S.
Armeni
T.
Bicchiega
V.
Ferretti
G.
Glycation of human high density lipoprotein by methylglyoxal: effect on HDL-paraoxonase activity
Metabolism: Clin. Exp.
2014
, vol. 
63
 (pg. 
307
-
311
)
166
Cantero
A.V.
Portero-Otin
M.
Ayala
V.
Auge
N.
Sanson
M.
Elbaz
M.
Thiers
J.C.
Pamplona
R.
Salvayre
R.
Negre-Salvayre
A.
Methylglyoxal induces advanced glycation end product (AGEs) formation and dysfunction of PDGF receptor-beta: implications for diabetic atherosclerosis
FASEB J.
2007
, vol. 
21
 (pg. 
3096
-
3106
)
[PubMed]
167
Hanssen
N.M.
Brouwers
O.
Gijbels
M.J.
Wouters
K.
Wijnands
E.
Cleutjens
J.P.
De Mey
J.G.
Miyata
T.
Biessen
E.A.
Stehouwer
C.D.
, et al. 
Glyoxalase 1 overexpression does not affect atherosclerotic lesion size and severity in ApoE−/− mice with or without diabetes
Cardiovasc. Res.
2014
, vol. 
104
 (pg. 
160
-
170
)
[PubMed]
168
Thangarajah
H.
Yao
D.
Chang
E.I.
Shi
Y.
Jazayeri
L.
Vial
I.N.
Galiano
R.D.
Du
X.L.
Grogan
R.
Galvez
M.G.
, et al. 
The molecular basis for impaired hypoxia-induced VEGF expression in diabetic tissues
Proc. Natl. Acad. Sci. U.S.A.
2009
, vol. 
106
 (pg. 
13505
-
13510
)
[PubMed]
169
Ceradini
D.J.
Yao
D.
Grogan
R.H.
Callaghan
M.J.
Edelstein
D.
Brownlee
M.
Gurtner
G.C.
Decreasing intracellular superoxide corrects defective ischemia-induced new vessel formation in diabetic mice
J. Biol. Chem.
2008
, vol. 
283
 (pg. 
10930
-
10938
)
[PubMed]
170
Shao
C.H.
Capek
H.L.
Patel
K.P.
Wang
M.
Tang
K.
DeSouza
C.
Nagai
R.
Mayhan
W.
Periasamy
M.
Bidasee
K.R.
Carbonylation contributes to SERCA2a activity loss and diastolic dysfunction in a rat model of type 1 diabetes
Diabetes
2011
, vol. 
60
 (pg. 
947
-
959
)
[PubMed]
171
Brouwers
O.
de Vos-Houben
J.M.
Niessen
P.M.
Miyata
T.
van Nieuwenhoven
F.
Janssen
B.J.
Hageman
G.
Stehouwer
C.D.
Schalkwijk
C.G.
Mild oxidative damage in the diabetic rat heart is attenuated by glyoxalase-1 overexpression
Int. J. Mol. Sci.
2013
, vol. 
14
 (pg. 
15724
-
15739
)
[PubMed]
172
Haslam
D.W.
James
W.P.
Obesity
Lancet
2005
, vol. 
366
 (pg. 
1197
-
1209
)
[PubMed]
173
Jia
X.
Chang
T.
Wilson
T.W.
Wu
L.
Methylglyoxal mediates adipocyte proliferation by increasing phosphorylation of Akt1
PLoS ONE
2012
, vol. 
7
 pg. 
e36610
 
[PubMed]
174
Rodrigues
L.
Matafome
P.
Crisostomo
J.
Santos-Silva
D.
Sena
C.
Pereira
P.
Seica
R.
Advanced glycation end products and diabetic nephropathy: a comparative study using diabetic and normal rats with methylglyoxal-induced glycation
J. Physiol. Biochem.
2014
, vol. 
70
 (pg. 
173
-
184
)
[PubMed]
175
Crisostomo
J.
Matafome
P.
Santos-Silva
D.
Rodrigues
L.
Sena
C.M.
Pereira
P.
Seica
R.
Methylglyoxal chronic administration promotes diabetes-like cardiac ischaemia disease in Wistar normal rats
Nutr. Metab. Cardiovasc. Dis.
2013
, vol. 
23
 (pg. 
1223
-
1230
)
[PubMed]
176
Rodrigues
T.
Matafome
P.
Santos-Silva
D.
Sena
C.
Seica
R.
Reduction of methylglyoxal-induced glycation by pyridoxamine improves adipose tissue microvascular lesions
J. Diabetes Res.
2013
, vol. 
2013
 pg. 
690650
 
[PubMed]
177
Rodrigues
T.
Matafome
P.
Seica
R.
Methylglyoxal further impairs adipose tissue metabolism after partial decrease of blood supply
Arch. Physiol. Biochem.
2013
, vol. 
119
 (pg. 
209
-
218
)
[PubMed]
178
Kim
D.H.
Joo
J.I.
Choi
J.W.
Yun
J.W.
Differential expression of skeletal muscle proteins in high-fat diet-fed rats in response to capsaicin feeding
Proteomics
2010
, vol. 
10
 (pg. 
2870
-
2881
)
[PubMed]
179
Schalkwijk
C.G.
Brouwers
O.
Stehouwer
C.D.
Modulation of insulin action by advanced glycation endproducts: a new player in the field
Horm. Metab. Res.
2008
, vol. 
40
 (pg. 
614
-
619
)
[PubMed]
180
Dhar
A.
Dhar
I.
Desai
K.M.
Wu
L.
Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose
Br. J. Pharmacol.
2010
, vol. 
161
 (pg. 
1843
-
1856
)
[PubMed]
181
Jia
X.
Wu
L.
Accumulation of endogenous methylglyoxal impaired insulin signaling in adipose tissue of fructose-fed rats
Mol. Cell Biochem.
2007
, vol. 
306
 (pg. 
133
-
139
)
[PubMed]
182
Dhar
A.
Dhar
I.
Jiang
B.
Desai
K.M.
Wu
L.
Chronic methylglyoxal infusion by minipump causes pancreatic beta-cell dysfunction and induces type 2 diabetes in Sprague–Dawley rats
Diabetes
2011
, vol. 
60
 (pg. 
899
-
908
)
[PubMed]
183
Guo
Q.
Mori
T.
Jiang
Y.
Hu
C.
Osaki
Y.
Yoneki
Y.
Sun
Y.
Hosoya
T.
Kawamata
A.
Ogawa
S.
, et al. 
Methylglyoxal contributes to the development of insulin resistance and salt sensitivity in Sprague–Dawley rats
J. Hypertens.
2009
, vol. 
27
 (pg. 
1664
-
1671
)
[PubMed]
184
Maessen
D.E.M.
Scheijen
J.L.J.M.
Gaens
K.H.
Van Greevenbroek
M.M.J.
Van der Kallen
C.J.
Stehouwer
C.D.
Schalkwijk
C.G.
Higher plasma concentrations of the methylglyoxal metabolite D-lactate are independently associated with insulin resistance: the CODAM study
J. Diabetes Metab.
2014
, vol. 
5
 pg. 
457
  
doi: 10.4172/2155-6156.1000457
185
Jia
X.
Olson
D.J.
Ross
A.R.
Wu
L.
Structural and functional changes in human insulin induced by methylglyoxal
FASEB J.
2006
, vol. 
20
 (pg. 
1555
-
1557
)
[PubMed]
186
Riboulet-Chavey
A.
Pierron
A.
Durand
I.
Murdaca
J.
Giudicelli
J.
Van Obberghen
E.
Methylglyoxal impairs the insulin signaling pathways independently of the formation of intracellular reactive oxygen species
Diabetes
2006
, vol. 
55
 (pg. 
1289
-
1299
)
[PubMed]
187
Fiory
F.
Lombardi
A.
Miele
C.
Giudicelli
J.
Beguinot
F.
Van Obberghen
E.
Methylglyoxal impairs insulin signalling and insulin action on glucose-induced insulin secretion in the pancreatic beta cell line INS-1E
Diabetologia
2011
, vol. 
54
 (pg. 
2941
-
2952
)
[PubMed]
188
Nigro
C.
Raciti
G.A.
Leone
A.
Fleming
T.H.
Longo
M.
Prevenzano
I.
Fiory
F.
Mirra
P.
D’Esposito
V.
Ulianich
L.
, et al. 
Methylglyoxal impairs endothelial insulin sensitivity both in vitro and in vivo
Diabetologia
2014
, vol. 
57
 (pg. 
1485
-
1494
)
[PubMed]
189
Deichen
J.T.
Prante
O.
Gack
M.
Schmiedehausen
K.
Kuwert
T.
Uptake of [18F]fluorodeoxyglucose in human monocyte–macrophages in vitro
Eur. J. Nucl. Med. Mol. Imaging
2003
, vol. 
30
 (pg. 
267
-
273
)
[PubMed]
190
Schalkwijk
C.G.
Vermeer
M.A.
Stehouwer
C.D.
te Koppele
J.
Princen
H.M.
van Hinsbergh
V.W.
Effect of methylglyoxal on the physico-chemical and biological properties of low-density lipoprotein
Biochim. Biophys. Acta
1998
, vol. 
1394
 (pg. 
187
-
198
)
[PubMed]
191
Wu
L.
Juurlink
B.H.
Increased methylglyoxal and oxidative stress in hypertensive rat vascular smooth muscle cells
Hypertension
2002
, vol. 
39
 (pg. 
809
-
814
)
[PubMed]
192
Wang
X.
Desai
K.
Clausen
J.T.
Wu
L.
Increased methylglyoxal and advanced glycation end products in kidney from spontaneously hypertensive rats
Kidney Int.
2004
, vol. 
66
 (pg. 
2315
-
2321
)
[PubMed]
193
Wang
X.
Desai
K.
Chang
T.
Wu
L.
Vascular methylglyoxal metabolism and the development of hypertension
J. Hypertens.
2005
, vol. 
23
 (pg. 
1565
-
1573
)
[PubMed]
194
Vasdev
S.
Ford
C.A.
Longerich
L.
Parai
S.
Gadag
V.
Wadhawan
S.
Aldehyde induced hypertension in rats: prevention by N-acetyl cysteine
Artery
1998
, vol. 
23
 (pg. 
10
-
36
)
[PubMed]
195
Dhar
I.
Dhar
A.
Wu
L.
Desai
K.M.
Methylglyoxal, a reactive glucose metabolite, increases renin angiotensin aldosterone and blood pressure in male Sprague–Dawley rats
Am. J. Hypertens.
2014
, vol. 
27
 (pg. 
308
-
316
)
[PubMed]
196
Guo
Q.
Mori
T.
Jiang
Y.
Hu
C.
Ohsaki
Y.
Yoneki
Y.
Nakamichi
T.
Ogawa
S.
Sato
H.
Ito
S.
Losartan modulates muscular capillary density and reverses thiazide diuretic-exacerbated insulin resistance in fructose-fed rats
Hypertens. Res.
2012
, vol. 
35
 (pg. 
48
-
54
)
[PubMed]
197
Sanchez-Lozada
L.G.
Tapia
E.
Jimenez
A.
Bautista
P.
Cristobal
M.
Nepomuceno
T.
Soto
V.
Avila-Casado
C.
Nakagawa
T.
Johnson
R.J.
, et al. 
Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats
Am. J. Physiol. Renal Physiol.
2007
, vol. 
292
 (pg. 
F423
-
F429
)
[PubMed]
198
Chen
X.
Mori
T.
Guo
Q.
Hu
C.
Ohsaki
Y.
Yoneki
Y.
Zhu
W.
Jiang
Y.
Endo
S.
Nakayama
K.
, et al. 
Carbonyl stress induces hypertension and cardio-renal vascular injury in Dahl salt-sensitive rats
Hypertens. Res.
2013
, vol. 
36
 (pg. 
361
-
367
)
[PubMed]
199
Wang
X.
Chang
T.
Jiang
B.
Desai
K.
Wu
L.
Attenuation of hypertension development by aminoguanidine in spontaneously hypertensive rats: role of methylglyoxal
Am. J. Hypertens.
2007
, vol. 
20
 (pg. 
629
-
636
)
[PubMed]
200
Wang
X.
Jia
X.
Chang
T.
Desai
K.
Wu
L.
Attenuation of hypertension development by scavenging methylglyoxal in fructose-treated rats
J. Hypertens.
2008
, vol. 
26
 (pg. 
765
-
772
)
[PubMed]
201
International Agency for Research on Cancer
World Cancer Report 2014
2014
Geneva
World Health Organization
202
Hosoda
F.
Arai
Y.
Okada
N.
Shimizu
H.
Miyamoto
M.
Kitagawa
N.
Katai
H.
Taniguchi
H.
Yanagihara
K.
Imoto
I.
, et al. 
Integrated genomic and functional analyses reveal glyoxalase I as a novel metabolic oncogene in human gastric cancer
Oncogene
2014
(pg. 
1
-
11
doi: 10.1038/onc.2014.57
203
Antognelli
C.
Mezzasoma
L.
Fettucciari
K.
Mearini
E.
Talesa
V.N.
Role of glyoxalase I in the proliferation and apoptosis control of human LNCaP and PC3 prostate cancer cells
Prostate
2013
, vol. 
73
 (pg. 
121
-
132
)
[PubMed]
204
Loarca
L.
Sassi-Gaha
S.
Artlett
C.M.
Two alpha-dicarbonyls down-regulate migration, invasion, and adhesion of liver cancer cells in a p53-dependent manner
Dig. Liver Dis.
2013
, vol. 
45
 (pg. 
938
-
946
)
[PubMed]
205
Antognelli
C.
Mezzasoma
L.
Fettucciari
K.
Talesa
V.N.
A novel mechanism of methylglyoxal cytotoxicity in prostate cancer cells
Int. J. Biochem. Cell Biol.
2013
, vol. 
45
 (pg. 
836
-
844
)
[PubMed]
206
van Heijst
J.W.
Niessen
H.W.
Musters
R.J.
van Hinsbergh
V.W.
Hoekman
K.
Schalkwijk
C.G.
Argpyrimidine-modified Heat shock protein 27 in human non-small cell lung cancer: a possible mechanism for evasion of apoptosis
Cancer Lett.
2006
, vol. 
241
 (pg. 
309
-
319
)
[PubMed]
207
Ranganathan
S.
Walsh
E.S.
Tew
K.D.
Glyoxalase I in detoxification: studies using a glyoxalase I transfectant cell line
Biochem. J.
1995
, vol. 
309
 
Pt 1
(pg. 
127
-
131
)
[PubMed]
208
Thornalley
P.J.
Edwards
L.G.
Kang
Y.
Wyatt
C.
Davies
N.
Ladan
M.J.
Double
J.
Antitumour activity of S-p-bromobenzylglutathione cyclopentyl diester in vitro and in vivo. Inhibition of glyoxalase I and induction of apoptosis
Biochem. Pharmacol.
1996
, vol. 
51
 (pg. 
1365
-
1372
)
[PubMed]
209
Speer
O.
Morkunaite-Haimi
S.
Liobikas
J.
Franck
M.
Hensbo
L.
Linder
M.D.
Kinnunen
P.K.
Wallimann
T.
Eriksson
O.
Rapid suppression of mitochondrial permeability transition by methylglyoxal. Role of reversible arginine modification
J. Biol. Chem.
2003
, vol. 
278
 (pg. 
34757
-
34763
)
210
Bartyik
K.
Turi
S.
Orosz
F.
Karg
E.
Methotrexate inhibits the glyoxalase system in vivo in children with acute lymphoid leukaemia
Eur. J. Cancer
2004
, vol. 
40
 (pg. 
2287
-
2292
)
[PubMed]
211
Santel
T.
Pflug
G.
Hemdan
N.Y.
Schafer
A.
Hollenbach
M.
Buchold
M.
Hintersdorf
A.
Lindner
I.
Otto
A.
Bigl
M.
, et al. 
Curcumin inhibits glyoxalase 1: a possible link to its anti-inflammatory and anti-tumor activity
PloS ONE
2008
, vol. 
3
 pg. 
e3508
 
[PubMed]
212
Yuan
M.
Luo
M.
Song
Y.
Xu
Q.
Wang
X.
Cao
Y.
Bu
X.
Ren
Y.
Hu
X.
Identification of curcumin derivatives as human glyoxalase I inhibitors: A combination of biological evaluation, molecular docking, 3D-QSAR and molecular dynamics simulation studies
Bioorg. Med. Chem.
2011
, vol. 
19
 (pg. 
1189
-
1196
)
[PubMed]
213
Chen
F.
Wollmer
M.A.
Hoerndli
F.
Munch
G.
Kuhla
B.
Rogaev
E.I.
Tsolaki
M.
Papassotiropoulos
A.
Gotz
J.
Role for glyoxalase I in Alzheimer's disease
Proc. Natl. Acad. Sci. U.S.A.
2004
, vol. 
101
 (pg. 
7687
-
7692
)
[PubMed]
214
Beeri
M.S.
Moshier
E.
Schmeidler
J.
Godbold
J.
Uribarri
J.
Reddy
S.
Sano
M.
Grossman
H.T.
Cai
W.
Vlassara
H.
, et al. 
Serum concentration of an inflammatory glycotoxin, methylglyoxal, is associated with increased cognitive decline in elderly individuals
Mech. Ageing Dev.
2011
, vol. 
132
 (pg. 
583
-
587
)
[PubMed]
215
Srikanth
V.
Westcott
B.
Forbes
J.
Phan
T.G.
Beare
R.
Venn
A.
Pearson
S.
Greenaway
T.
Parameswaran
V.
Munch
G.
Methylglyoxal, cognitive function and cerebral atrophy in older people
J. Gerontol. A Biol. Sci. Med. Sci.
2013
, vol. 
68
 (pg. 
68
-
73
)
[PubMed]
216
Angeloni
C.
Zambonin
L.
Hrelia
S.
Role of methylglyoxal in Alzheimer's disease
Biomed. Res. Int.
2014
, vol. 
2014
 pg. 
238485
 
[PubMed]
217
Ahmed
N.
Ahmed
U.
Thornalley
P.J.
Hager
K.
Fleischer
G.
Munch
G.
Protein glycation, oxidation and nitration adduct residues and free adducts of cerebrospinal fluid in Alzheimer's disease and link to cognitive impairment
J. Neurochem.
2005
, vol. 
92
 (pg. 
255
-
263
)
[PubMed]
218
Tajes
M.
Eraso-Pichot
A.
Rubio-Moscardo
F.
Guivernau
B.
Bosch-Morato
M.
Valls-Comamala
V.
Munoz
F.J.
Methylglyoxal reduces mitochondrial potential and activates Bax and caspase-3 in neurons: Implications for Alzheimer's disease
Neurosc. Lett.
2014
, vol. 
580
 (pg. 
78
-
82
)
219
Cardoso
S.
Carvalho
C.
Marinho
R.
Simoes
A.
Sena
C.M.
Matafome
P.
Santos
M.S.
Seica
R.M.
Moreira
P.I.
Effects of methylglyoxal and pyridoxamine in rat brain mitochondria bioenergetics and oxidative status
J. Bioenerg. Biomembr.
2014
, vol. 
46
 (pg. 
347
-
355
)
[PubMed]
220
Markesbery
W.R.
Oxidative stress hypothesis in Alzheimer's disease
Free Radic. Biol. Med.
1997
, vol. 
23
 (pg. 
134
-
147
)
[PubMed]
221
Lloret
A.
Badia
M.C.
Mora
N.J.
Pallardo
F.V.
Alonso
M.D.
Vina
J.
Vitamin E paradox in Alzheimer's disease: it does not prevent loss of cognition and may even be detrimental
J. Alzheimers Dis.
2009
, vol. 
17
 (pg. 
143
-
149
)
[PubMed]
222
Kuhla
B.
Boeck
K.
Schmidt
A.
Ogunlade
V.
Arendt
T.
Munch
G.
Luth
H.J.
Age- and stage-dependent glyoxalase I expression and its activity in normal and Alzheimer's disease brains
Neurobiol. Aging
2007
, vol. 
28
 (pg. 
29
-
41
)
[PubMed]
223
Auburger
G.
Kurz
A.
The role of glyoxalases for sugar stress and aging, with relevance for dyskinesia, anxiety, dementia and Parkinson's disease
Aging (Albany, NY)
2011
, vol. 
3
 (pg. 
5
-
9
)
224
Kurz
A.
Rabbani
N.
Walter
M.
Bonin
M.
Thornalley
P.
Auburger
G.
Gispert
S.
Alpha-synuclein deficiency leads to increased glyoxalase I expression and glycation stress
Cell. Mol. Life Sci.
2011
, vol. 
68
 (pg. 
721
-
733
)
[PubMed]
225
Hipkiss
A.R.
Aging risk factors and Parkinson's disease: contrasting roles of common dietary constituents
Neurobiol. Aging
2014
, vol. 
35
 (pg. 
1469
-
1472
)
[PubMed]
226
Arai
M.
Yuzawa
H.
Nohara
I.
Ohnishi
T.
Obata
N.
Iwayama
Y.
Haga
S.
Toyota
T.
Ujike
H.
Ichikawa
T.
, et al. 
Enhanced carbonyl stress in a subpopulation of schizophrenia
Arch. Gen. Psychiatry
2010
, vol. 
67
 (pg. 
589
-
597
)
[PubMed]
227
Toyosima
M.
Maekawa
M.
Toyota
T.
Iwayama
Y.
Arai
M.
Ichikawa
T.
Miyashita
M.
Arinami
T.
Itokawa
M.
Yoshikawa
T.
Schizophrenia with the 22q11.2 deletion and additional genetic defects: case history
Br. J. Psychiatry
2011
, vol. 
199
 (pg. 
245
-
246
)
[PubMed]
228
Kromer
S.A.
Kessler
M.S.
Milfay
D.
Birg
I.N.
Bunck
M.
Czibere
L.
Panhuysen
M.
Putz
B.
Deussing
J.M.
Holsboer
F.
, et al. 
Identification of glyoxalase-I as a protein marker in a mouse model of extremes in trait anxiety
J. Neurosci.
2005
, vol. 
25
 (pg. 
4375
-
4384
)
[PubMed]
229
Hovatta
I.
Tennant
R.S.
Helton
R.
Marr
R.A.
Singer
O.
Redwine
J.M.
Ellison
J.A.
Schadt
E.E.
Verma
I.M.
Lockhart
D.J.
, et al. 
Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice
Nature
2005
, vol. 
438
 (pg. 
662
-
666
)
[PubMed]
230
Ditzen
C.
Jastorff
A.M.
Kessler
M.S.
Bunck
M.
Teplytska
L.
Erhardt
A.
Kromer
S.A.
Varadarajulu
J.
Targosz
B.S.
Sayan-Ayata
E.F.
, et al. 
Protein biomarkers in a mouse model of extremes in trait anxiety
Mol. Cell Proteomics
2006
, vol. 
5
 (pg. 
1914
-
1920
)
[PubMed]
231
Williams
R.T.
Lim
J.E.
Harr
B.
Wing
C.
Walters
R.
Distler
M.G.
Teschke
M.
Wu
C.
Wiltshire
T.
Su
A.I.
, et al. 
A common and unstable copy number variant is associated with differences in Glo1 expression and anxiety-like behavior
PloS ONE
2009
, vol. 
4
 pg. 
e4649
 
[PubMed]
232
Hambsch
B.
Chen
B.G.
Brenndorfer
J.
Meyer
M.
Avrabos
C.
Maccarrone
G.
Liu
R.H.
Eder
M.
Turck
C.W.
Landgraf
R.
Methylglyoxal-mediated anxiolysis involves increased protein modification and elevated expression of glyoxalase 1 in the brain
J. Neurochem.
2010
, vol. 
113
 (pg. 
1240
-
1251
)
[PubMed]
233
Distler
M.G.
Plant
L.D.
Sokoloff
G.
Hawk
A.J.
Aneas
I.
Wuenschell
G.E.
Termini
J.
Meredith
S.C.
Nobrega
M.A.
Palmer
A.A.
Glyoxalase 1 increases anxiety by reducing GABAA receptor agonist methylglyoxal
J. Clin. Invest.
2012
, vol. 
122
 (pg. 
2306
-
2315
)
[PubMed]
234
Poggioli
S.
Bakala
H.
Friguet
B.
Age-related increase of protein glycation in peripheral blood lymphocytes is restricted to preferential target proteins
Exp. Gerontol.
2002
, vol. 
37
 (pg. 
1207
-
1215
)
[PubMed]
235
Xue
M.
Rabbani
N.
Thornalley
P.J.
Glyoxalase in ageing
Semin. Cell Dev. Biol.
2011
, vol. 
22
 (pg. 
293
-
301
)
[PubMed]
236
Kirk
J.E.
The glyoxalase I activity of arterial tissue in individuals of various ages
J. Gerontol.
1960
, vol. 
15
 (pg. 
139
-
141
)
[PubMed]
237
McLellan
A.C.
Thornalley
P.J.
Glyoxalase activity in human red blood cells fractioned by age
Mech. Ageing Dev.
1989
, vol. 
48
 (pg. 
63
-
71
)
[PubMed]
238
Kuhla
B.
Boeck
K.
Luth
H.J.
Schmidt
A.
Weigle
B.
Schmitz
M.
Ogunlade
V.
Munch
G.
Arendt
T.
Age-dependent changes of glyoxalase I expression in human brain
Neurobiol. Aging
2006
, vol. 
27
 (pg. 
815
-
822
)
[PubMed]
239
Schlotterer
A.
Kukudov
G.
Bozorgmehr
F.
Hutter
H.
Du
X.
Oikonomou
D.
Ibrahim
Y.
Pfisterer
F.
Rabbani
N.
Thornalley
P.
, et al. 
C. elegans as model for the study of high glucose- mediated life span reduction
Diabetes
2009
, vol. 
58
 (pg. 
2450
-
2456
)
[PubMed]
240
Scheckhuber
C.Q.
Mack
S.J.
Strobel
I.
Ricciardi
F.
Gispert
S.
Osiewacz
H.D.
Modulation of the glyoxalase system in the aging model Podospora anserina: effects on growth and lifespan
Aging (Albany NY)
2010
, vol. 
2
 (pg. 
969
-
980
)
[PubMed]
241
Ikeda
Y.
Inagi
R.
Miyata
T.
Nagai
R.
Arai
M.
Miyashita
M.
Itokawa
M.
Fujita
T.
Nangaku
M.
Glyoxalase I retards renal senescence
Am. J. Pathol.
2011
, vol. 
179
 (pg. 
2810
-
2821
)
[PubMed]
242
Haik
G.M.
Jr
Lo
T.W.
Thornalley
P.J.
Methylglyoxal concentration and glyoxalase activities in the human lens
Exp. Eye Res.
1994
, vol. 
59
 (pg. 
497
-
500
)
[PubMed]
243
Shamsi
F.A.
Lin
K.
Sady
C.
Nagaraj
R.H.
Methylglyoxal-derived modifications in lens aging and cataract formation
Invest. Ophthalmol. Vis. Sci.
1998
, vol. 
39
 (pg. 
2355
-
2364
)
[PubMed]
244
Mailankot
M.
Padmanabha
S.
Pasupuleti
N.
Major
D.
Howell
S.
Nagaraj
R.H.
Glyoxalase I activity and immunoreactivity in the aging human lens
Biogerontology
2009
, vol. 
10
 (pg. 
711
-
720
)
[PubMed]
245
Fan
X.
Sell
D.R.
Zhang
J.
Nemet
I.
Theves
M.
Lu
J.
Strauch
C.
Halushka
M.K.
Monnier
V.M.
Anaerobic vs aerobic pathways of carbonyl and oxidant stress in human lens and skin during aging and in diabetes: A comparative analysis
Free Radic. Biol. Med.
2010
, vol. 
49
 (pg. 
847
-
856
)
[PubMed]
246
Jo-Watanabe
A.
Ohse
T.
Nishimatsu
H.
Takahashi
M.
Ikeda
Y.
Wada
T.
Shirakawa
J.
Nagai
R.
Miyata
T.
Nagano
T.
, et al. 
Glyoxalase I reduces glycative and oxidative stress and prevents age-related endothelial dysfunction through modulation of endothelial nitric oxide synthase phosphorylation
Aging Cell
2014
, vol. 
13
 (pg. 
519
-
528
)
[PubMed]
247
Fleming
T.H.
Theilen
T.M.
Masania
J.
Wunderle
M.
Karimi
J.
Vittas
S.
Bernauer
R.
Bierhaus
A.
Rabbani
N.
Thornalley
P.J.
, et al. 
Aging-dependent reduction in glyoxalase 1 delays wound healing
Gerontology
2013
, vol. 
59
 (pg. 
427
-
437
)
[PubMed]
248
Verma
M.
Srivastava
S.
Epigenetics in cancer: implications for early detection and prevention
Lancet Oncol.
2002
, vol. 
3
 (pg. 
755
-
763
)
[PubMed]
249
El-Osta
A.
Brasacchio
D.
Yao
D.
Pocai
A.
Jones
P.L.
Roeder
R.G.
Cooper
M.E.
Brownlee
M.
Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia
J. Exp. Med.
2008
, vol. 
205
 (pg. 
2409
-
2417
)
[PubMed]
250
Brownlee
M.
Vlassara
H.
Kooney
A.
Ulrich
P.
Cerami
A.
Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking
Science
1986
, vol. 
232
 (pg. 
1629
-
1632
)
[PubMed]
251
Lo
T.W.
Selwood
T.
Thornalley
P.J.
The reaction of methylglyoxal with aminoguanidine under physiological conditions and prevention of methylglyoxal binding to plasma proteins
Biochem. Pharmacol.
1994
, vol. 
48
 (pg. 
1865
-
1870
)
[PubMed]
252
Soulis-Liparota
T.
Cooper
M.
Papazoglou
D.
Clarke
B.
Jerums
G.
Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat
Diabetes
1991
, vol. 
40
 (pg. 
1328
-
1334
)
[PubMed]
253
Soulis
T.
Cooper
M.E.
Vranes
D.
Bucala
R.
Jerums
G.
Effects of aminoguanidine in preventing experimental diabetic nephropathy are related to the duration of treatment
Kidney Int.
1996
, vol. 
50
 (pg. 
627
-
634
)
[PubMed]
254
Hammes
H.P.
Martin
S.
Federlin
K.
Geisen
K.
Brownlee
M.
Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy
Proc. Natl. Acad. Sci. U.S.A.
1991
, vol. 
88
 (pg. 
11555
-
11558
)
[PubMed]
255
Kihara
M.
Schmelzer
J.D.
Poduslo
J.F.
Curran
G.L.
Nickander
K.K.
Low
P.A.
Aminoguanidine effects on nerve blood flow, vascular permeability, electrophysiology, and oxygen free radicals
Proc. Natl. Acad. Sci. U.S.A.
1991
, vol. 
88
 (pg. 
6107
-
6111
)
[PubMed]
256
Bolton
W.K.
Cattran
D.C.
Williams
M.E.
Adler
S.G.
Appel
G.B.
Cartwright
K.
Foiles
P.G.
Freedman
B.I.
Raskin
P.
Ratner
R.E.
, et al. 
Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy
Am. J. Nephrol.
2004
, vol. 
24
 (pg. 
32
-
40
)
[PubMed]
257
Freedman
B.I.
Wuerth
J.P.
Cartwright
K.
Bain
R.P.
Dippe
S.
Hershon
K.
Mooradian
A.D.
Spinowitz
B.S.
Design and baseline characteristics for the aminoguanidine Clinical Trial in Overt Type 2 Diabetic Nephropathy (ACTION II)
Control Clin. Trials
1999
, vol. 
20
 (pg. 
493
-
510
)
[PubMed]
258
Vasan
S.
Foiles
P.
Founds
H.
Therapeutic potential of breakers of advanced glycation end product-protein crosslinks
Arch. Biochem. Biophys.
2003
, vol. 
419
 (pg. 
89
-
96
)
[PubMed]
259
Sell
D.R.
Monnier
V.M.
Molecular basis of arterial stiffening: role of glycation–a mini-review
Gerontology
2012
, vol. 
58
 (pg. 
227
-
237
)
[PubMed]
260
Engelen
L.
Stehouwer
C.D.
Schalkwijk
C.G.
Current therapeutic interventions in the glycation pathway: evidence from clinical studies
Diabetes Obes. Metab.
2013
, vol. 
15
 (pg. 
677
-
689
)
[PubMed]
261
Kass
D.A.
Shapiro
E.P.
Kawaguchi
M.
Capriotti
A.R.
Scuteri
A.
deGroof
R.C.
Lakatta
E.G.
Improved arterial compliance by a novel advanced glycation end-product crosslink breaker
Circulation
2001
, vol. 
104
 (pg. 
1464
-
1470
)
[PubMed]
262
Hartog
J.W.
Willemsen
S.
van Veldhuisen
D.J.
Posma
J.L.
van Wijk
L.M.
Hummel
Y.M.
Hillege
H.L.
Voors
A.A.
Effects of alagebrium, an advanced glycation endproduct breaker, on exercise tolerance and cardiac function in patients with chronic heart failure
Eur. J. Heart Fail.
2011
, vol. 
13
 (pg. 
899
-
908
)
[PubMed]
263
Zieman
S.J.
Melenovsky
V.
Clattenburg
L.
Corretti
M.C.
Capriotti
A.
Gerstenblith
G.
Kass
D.A.
Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension
J. Hypertens.
2007
, vol. 
25
 (pg. 
577
-
583
)
[PubMed]
264
Little
W.C.
Zile
M.R.
Kitzman
D.W.
Hundley
W.G.
O’Brien
T.X.
Degroof
R.C.
The effect of alagebrium chloride (ALT-711), a novel glucose cross-link breaker, in the treatment of elderly patients with diastolic heart failure
J. Card. Fail.
2005
, vol. 
11
 (pg. 
191
-
195
)
[PubMed]
265
Viollet
B.
Guigas
B.
Sanz Garcia
N.
Leclerc
J.
Foretz
M.
Andreelli
F.
Cellular and molecular mechanisms of metformin: an overview
Clin. Sci. (Lond.)
2012
, vol. 
122
 (pg. 
253
-
270
)
[PubMed]
266
Giannarelli
R.
Aragona
M.
Coppelli
A.
Del Prato
S.
Reducing insulin resistance with metformin: the evidence today
Diabetes Metab.
2003
, vol. 
29
 (pg. 
6S28
-
35
)
267
Madiraju
A.K.
Erion
D.M.
Rahimi
Y.
Zhang
X.M.
Braddock
D.T.
Albright
R.A.
Prigaro
B.J.
Wood
J.L.
Bhanot
S.
MacDonald
M.J.
, et al. 
Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase
Nature
2014
, vol. 
510
 (pg. 
542
-
546
)
[PubMed]
268
Ruggiero-Lopez
D.
Lecomte
M.
Moinet
G.
Patereau
G.
Lagarde
M.
Wiernsperger
N.
Reaction of metformin with dicarbonyl compounds. Possible implication in the inhibition of advanced glycation end product formation
Biochem. Pharmacol.
1999
, vol. 
58
 (pg. 
1765
-
1773
)
[PubMed]
269
UK Prospective Diabetes Study (UKPDS) Group
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34)
Lancet
1998
, vol. 
352
 (pg. 
854
-
865
)
[PubMed]
270
Kender
Z.
Fleming
T.
Kopf
S.
Torzsa
P.
Grolmusz
V.
Herzig
S.
Schleicher
E.
Racz
K.
Reismann
P.
Nawroth
P.P.
Effect of metformin on methylglyoxal metabolism in patients with type 2 diabetes
Exp. Clin. Endocrinol. Diabetes
2014
, vol. 
122
 (pg. 
316
-
319
)
[PubMed]
271
Battah
S.A.N.
Thornalley
PJ.
Kinetics and mechanism of the reaction of metformin with methylglyoxal
Int. Congress Series
2002
, vol. 
1245
 (pg. 
355
-
356
)
272
Voziyan
P.A.
Hudson
B.G.
Pyridoxamine as a multifunctional pharmaceutical: targeting pathogenic glycation and oxidative damage
Cell. Mol. Life Sci.
2005
, vol. 
62
 (pg. 
1671
-
1681
)
[PubMed]
273
Degenhardt
T.P.
Alderson
N.L.
Arrington
D.D.
Beattie
R.J.
Basgen
J.M.
Steffes
M.W.
Thorpe
S.R.
Baynes
J.W.
Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat
Kidney Int.
2002
, vol. 
61
 (pg. 
939
-
950
)
[PubMed]
274
Zhu
P.
Lin
H.
Sun
C.
Lin
F.
Yu
H.
Zhuo
X.
Zhou
C.
Deng
Z.
Synergistic effects of telmisartan and pyridoxamine on early renal damage in spontaneously hypertensive rats
Mol. Med. Rep.
2012
, vol. 
5
 (pg. 
655
-
662
)
[PubMed]
275
Waanders
F.
van den Berg
E.
Nagai
R.
van Veen
I.
Navis
G.
van Goor
H.
Renoprotective effects of the AGE-inhibitor pyridoxamine in experimental chronic allograft nephropathy in rats
Nephrol. Dia.l Transplant.
2008
, vol. 
23
 (pg. 
518
-
524
)
276
Alderson
N.L.
Chachich
M.E.
Youssef
N.N.
Beattie
R.J.
Nachtigal
M.
Thorpe
S.R.
Baynes
J.W.
The AGE inhibitor pyridoxamine inhibits lipemia and development of renal and vascular disease in Zucker obese rats
Kidney Int.
2003
, vol. 
63
 (pg. 
2123
-
2133
)
[PubMed]
277
Tanimoto
M.
Gohda
T.
Kaneko
S.
Hagiwara
S.
Murakoshi
M.
Aoki
T.
Yamada
K.
Ito
T.
Matsumoto
M.
Horikoshi
S.
, et al. 
Effect of pyridoxamine (K-163), an inhibitor of advanced glycation end products, on type 2 diabetic nephropathy in KK-A(y)/Ta mice
Metabolism: Clin. Exp.
2007
, vol. 
56
 (pg. 
160
-
167
)
278
Williams
M.E.
Bolton
W.K.
Khalifah
R.G.
Degenhardt
T.P.
Schotzinger
R.J.
McGill
J.B.
Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy
Am. J. Nephrol.
2007
, vol. 
27
 (pg. 
605
-
614
)
[PubMed]
279
Lewis
E.J.
Greene
T.
Spitalewiz
S.
Blumenthal
S.
Berl
T.
Hunsicker
L.G.
Pohl
M.A.
Rohde
R.D.
Raz
I.
Yerushalmy
Y.
, et al. 
Pyridorin in type 2 diabetic nephropathy
J. Am. Soc. Nephrol.
2012
, vol. 
23
 (pg. 
131
-
136
)
[PubMed]
280
Garg
S.
Syngle
A.
Vohra
K.
Efficacy and tolerability of advanced glycation end-products inhibitor in osteoarthritis: a randomized, double-blind, placebo-controlled study
Clin. J. Pain.
2013
, vol. 
29
 (pg. 
717
-
724
)
[PubMed]
281
Hammes
H.P.
Du
X.
Edelstein
D.
Taguchi
T.
Matsumura
T.
Ju
Q.
Lin
J.
Bierhaus
A.
Nawroth
P.
Hannak
D.
, et al. 
Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy
Nat. Med.
2003
, vol. 
9
 (pg. 
294
-
299
)
[PubMed]
282
Miller
A.G.
Tan
G.
Binger
K.J.
Pickering
R.J.
Thomas
M.C.
Nagaraj
R.H.
Cooper
M.E.
Wilkinson-Berka
J.L.
Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-I function
Diabetes
2010
, vol. 
59
 (pg. 
3208
-
3215
)
[PubMed]
283
Nagaraj
R.H.
Sarkar
P.
Mally
A.
Biemel
K.M.
Lederer
M.O.
Padayatti
P.S.
Effect of pyridoxamine on chemical modification of proteins by carbonyls in diabetic rats: characterization of a major product from the reaction of pyridoxamine and methylglyoxal
Arch. Biochem. Biophys.
2002
, vol. 
402
 (pg. 
110
-
119
)
[PubMed]
284
Cheng
A.S.
Cheng
Y.H.
Chiou
C.H.
Chang
T.L.
Resveratrol upregulates Nrf2 expression to attenuate methylglyoxal-induced insulin resistance in Hep G2 cells
J. Agric. Food Chem.
2012
, vol. 
60
 (pg. 
9180
-
9187
)
[PubMed]
285
Maher
P.
Dargusch
R.
Ehren
J.L.
Okada
S.
Sharma
K.
Schubert
D.
Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes
PloS ONE
2011
, vol. 
6
 pg. 
e21226
 
[PubMed]
286
Xue
M.
Rabbani
N.
Momiji
H.
Imbasi
P.
Anwar
M.M.
Kitteringham
N.
Park
B.K.
Souma
T.
Moriguchi
T.
Yamamoto
M.
, et al. 
Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation
Biochem. J.
2012
, vol. 
443
 (pg. 
213
-
222
)
[PubMed]
287
Das
B.N.
Kim
Y.W.
Keum
Y.S.
Mechanisms of Nrf2/Keap1-dependent phase II cytoprotective and detoxifying gene expression and potential cellular targets of chemopreventive isothiocyanates
Oxid. Med. Cell Longev.
2013
, vol. 
2013
 pg. 
839409
 
[PubMed]
288
Mann
G.E.
Niehueser-Saran
J.
Watson
A.
Gao
L.
Ishii
T.
de Winter
P.
Siow
R.C.
Nrf2/ARE regulated antioxidant gene expression in endothelial and smooth muscle cells in oxidative stress: implications for atherosclerosis and preeclampsia
Sheng Li Xue Bao
2007
, vol. 
59
 (pg. 
117
-
127
)
[PubMed]
289
Hsu
W.H.
Lee
B.H.
Chang
Y.Y.
Hsu
Y.W.
Pan
T.M.
A novel natural Nrf2 activator with PPARgamma-agonist (monascin) attenuates the toxicity of methylglyoxal and hyperglycemia
Toxicol. Appl. Pharmacol.
2013
, vol. 
272
 (pg. 
842
-
851
)
[PubMed]
290
Impellizzeri
D.
Esposito
E.
Attley
J.
Cuzzocrea
S.
Targeting inflammation: new therapeutic approaches in chronic kidney disease (CKD)
Pharmacol. Res.
2014
, vol. 
81
 (pg. 
91
-
102
)
[PubMed]
291
McCullough
P.A.
Ali
S.
Cardiac and renal function in patients with type 2 diabetes who have chronic kidney disease: potential effects of bardoxolone methyl
Drug Des. Devel. Ther.
2012
, vol. 
6
 (pg. 
141
-
149
)
[PubMed]
292
Thomas
M.
A preliminary evaluation of bardoxolone methyl for the treatment of diabetic nephropathy
Expert Opin. Drug Metab. Toxicol.
2012
, vol. 
8
 (pg. 
1015
-
1022
)
[PubMed]
293
Thomas
M.C.
Bardoxolone: augmenting the Yin in chronic kidney disease
Diab. Vasc. Dis. Res.
2011
, vol. 
8
 (pg. 
303
-
304
)
[PubMed]