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Glyoxalase System in Health and Disease 2017

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2017) | Viewed by 79080

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Prof. Dr. Casper G. Schalkwijk

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Department of Internal Medicine, CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Universiteitssingel 50, 6200MD Maastricht, The Netherlands
Interests: endothelial cell biology; obesity; insulin resistance; vascular complications; endothelial function
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Dear Colleagues,

Endogenous methylglyoxal is formed from metabolic intermediates of carbohydrates and fatty acids. Methylglyoxal is the major precursor in the formation of advanced glycation endproducts. The glyoxalase system is the main system involved in the detoxification of methylglyoxal. Despite the detoxification of methylglyoxal, some diseases still lead to elevated levels of cellular methylglyoxal. Increased levels of methylglyoxal and/or dysfunction of the glyoxalase system have frequently been found in relation to ageing and age-related diseases, such as vascular diseases and diabetes. In this Special Issue, I invite investigators to contribute original research articles or review articles that will stimulate the continuing efforts to understand the role of the glyoxalase system, as well as the mechanism underlying methylglyoxal-induced cell/organ under normal and diseased conditions. Our aim is to provide a comprehensive update of the glyoxalase system and methylglyoxal in age-related diseases and therapeutic options.

Prof. Dr. Casper G. Schalkwijk
Guest Editor

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Keywords

Glyoxalase
Methylglyoxal
Ageing
Age-related disease
Translational medicine
Molecular mechanism
Biomarkers
Drug discovery

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Published Papers (10 papers)

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Research

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9 pages, 1337 KiB

Open AccessArticle

Deleterious Effect of Advanced CKD on Glyoxalase System Activity not Limited to Diabetes Aetiology

by Lukáš Pácal, Katarína Chalásová, Anna Pleskačová, Jitka Řehořová, Josef Tomandl and Kateřina Kaňková

Int. J. Mol. Sci. 2018, 19(5), 1517; https://doi.org/10.3390/ijms19051517 - 18 May 2018

Cited by 3 | Viewed by 4335

Abstract

Methylglyoxal production is increased in diabetes. Methylglyoxal is efficiently detoxified by enzyme glyoxalase 1 (GLO1). The aim was to study the effect of diabetic and CKD milieu on (a) GLO1 gene expression in peripheral blood mononuclear cells; (b) GLO1 protein levels in whole blood; and (c) GLO1 activity in RBCs in vivo in diabetic vs. non-diabetic subjects with normal or slightly reduced vs. considerably reduced renal function (CKD1-2 vs. CKD3-4). A total of 83 subjects were included in the study. Gene expression was measured using real-time PCR, and protein levels were quantified using Western blotting. Erythrocyte GLO1 activity was measured spectrophotometrically. GLO1 gene expression was significantly higher in subjects with CKD1-2 compared to CKD3-4. GLO1 protein level was lower in diabetics than in non-diabetics. GLO1 activity in RBCs differed between the four groups being significantly higher in diabetics with CKD1-2 vs. healthy subjects and vs. nondiabeticsfig with CKD3-4. GLO1 activity was significantly higher in diabetics compared to nondiabetics. In conclusion, both diabetes and CKD affects the glyoxalase system. It appears that CKD in advanced stages has prevailing and suppressive effects compared to hyperglycaemia. CKD decreases GLO1 gene expression and protein levels (together with diabetes) without concomitant changes of GLO1 activity. Full article

(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)

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12 pages, 1407 KiB

Open AccessArticle

Advanced Glycation Endproducts Are Increased in the Animal Model of Multiple Sclerosis but Cannot Be Reduced by Pyridoxamine Treatment or Glyoxalase 1 Overexpression

by Suzan Wetzels, Kristiaan Wouters, Toshio Miyata, Jean L. J. M. Scheijen, Jerome J. A. Hendriks, Casper G. Schalkwijk and Tim Vanmierlo

Int. J. Mol. Sci. 2018, 19(5), 1311; https://doi.org/10.3390/ijms19051311 - 27 Apr 2018

Cited by 15 | Viewed by 5285

Abstract

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS). The immune response in MS patients leads to the infiltration of immune cells in the CNS and their subsequent activation. Immune cell activation induces a switch towards glycolysis. During glycolysis, the dicarbonyl product methylglyoxal (MGO) is produced. MGO is a glycating agent that can rapidly form advanced glycation endproducts (AGEs). In turn, AGEs are able to induce inflammatory responses. The glyoxalase system is the endogenous defense system of the body to reduce the burden of MGO thereby reducing AGE formation. This system consists of glyoxalase-1 and glyoxalase-2 which are able to detoxify MGO to D-lactate. We investigated whether AGE levels are induced in experimental autoimmune encephalitis (EAE), an inflammatory animal model of MS. Twenty seven days post EAE induction, MGO and AGE (N^ε-(carboxymethyl)lysine (CML), N^ε-(carboxyethyl)lysine (CEL), 5-hydro-5-methylimidazolone (MG-H1)) levels were significantly increased in the spinal cord of mice subjected to EAE. Yet, pyridoxamine treatment and glyoxalase-1 overexpression were unable to counteract AGE production during EAE and did not influence the clinical course of EAE. In conclusion, AGEs levels increase during EAE in the spinal cord, but AGE-modifying treatments do not inhibit EAE-induced AGE production and do not affect disease progression. Full article

(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)

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15 pages, 1974 KiB

Open AccessArticle

miR-214-Dependent Increase of PHLPP2 Levels Mediates the Impairment of Insulin-Stimulated Akt Activation in Mouse Aortic Endothelial Cells Exposed to Methylglyoxal

by Cecilia Nigro, Paola Mirra, Immacolata Prevenzano, Alessia Leone, Francesca Fiory, Michele Longo, Serena Cabaro, Francesco Oriente, Francesco Beguinot and Claudia Miele

Int. J. Mol. Sci. 2018, 19(2), 522; https://doi.org/10.3390/ijms19020522 - 9 Feb 2018

Cited by 18 | Viewed by 5783

Abstract

Evidence has been provided linking microRNAs (miRNAs) and diabetic complications, by the regulation of molecular pathways, including insulin-signaling, involved in the pathophysiology of vascular dysfunction. Methylglyoxal (MGO) accumulates in diabetes and is associated with cardiovascular complications. This study aims to analyze the contribution of miRNAs in the MGO-induced damaging effect on insulin responsiveness in mouse aortic endothelial cells (MAECs). miRNA modulation was performed by transfection of specific miRNA mimics and inhibitors in MAECs, treated or not with MGO. miRNA-target protein levels were evaluated by Western blot. PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) regulation by miR-214 was tested by luciferase assays and by the use of a target protector specific for miR-214 on PHLPP2-3′UTR. This study reveals a 4-fold increase of PHLPP2 in MGO-treated MAECs. PHLPP2 levels inversely correlate with miR-214 modulation. Moreover, miR-214 overexpression is able to reduce PHLPP2 levels in MGO-treated MAECs. Interestingly, a direct regulation of PHLPP2 is proved to be dependent by miR-214. Finally, the inhibition of miR-214 impairs the insulin-dependent Akt activation, while its overexpression rescues the insulin effect on Akt activation in MGO-treated MAECs. In conclusion, this study shows that PHLPP2 is a target of miR-214 in MAECs, and identifies miR-214 downregulation as a contributing factor to MGO-induced endothelial insulin-resistance. Full article

(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)

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21 pages, 3617 KiB

Open AccessArticle

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

by Rahul Jandial, Josh Neman, Punnajit P. Lim, Daniel Tamae, Claudia M. Kowolik, Gerald E. Wuenschell, Sarah C. Shuck, Alexandra K. Ciminera, Luis R. De Jesus, Ching Ouyang, Mike Y. Chen and John Termini

Int. J. Mol. Sci. 2018, 19(2), 406; https://doi.org/10.3390/ijms19020406 - 30 Jan 2018

Cited by 27 | Viewed by 6402

Abstract

Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S-(p-bromobenzyl) glutathione dicyclopentyl ester (p-BrBzGSH(Cp)₂) increased levels of the DNA-AGE N²-1-(carboxyethyl)-2′-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp)₂ exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors. Full article

(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)

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Review

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17 pages, 2121 KiB

Open AccessReview

Glyoxalases in Urological Malignancies

by Cinzia Antognelli and Vincenzo Nicola Talesa

Int. J. Mol. Sci. 2018, 19(2), 415; https://doi.org/10.3390/ijms19020415 - 31 Jan 2018

Cited by 50 | Viewed by 4500

Abstract

Urological cancers include a spectrum of malignancies affecting organs of the reproductive and/or urinary systems, such as prostate, kidney, bladder, and testis. Despite improved primary prevention, detection and treatment, urological cancers are still characterized by an increasing incidence and mortality worldwide. While advances have been made towards understanding the molecular bases of these diseases, a complete understanding of the pathological mechanisms remains an unmet research goal that is essential for defining safer pharmacological therapies and prognostic factors, especially for the metastatic stage of these malignancies for which no effective therapies are currently being used. Glyoxalases, consisting of glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2), are enzymes that catalyze the glutathione-dependent metabolism of cytotoxic methylglyoxal (MG), thus protecting against cellular damage and apoptosis. They are generally overexpressed in numerous cancers as a survival strategy by providing a safeguard through enhancement of MG detoxification. Increasing evidence suggests that glyoxalases, especially Glo1, play an important role in the initiation and progression of urological malignancies. In this review, we highlight the critical role of glyoxalases as regulators of tumorigenesis in the prostate through modulation of various critical signaling pathways, and provide an overview of the current knowledge on glyoxalases in bladder, kidney and testis cancers. We also discuss the promise and challenges for Glo1 inhibitors as future anti-prostate cancer (PCa) therapeutics and the potential of glyoxalases as biomarkers for PCa diagnosis. Full article

(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)

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32 pages, 2378 KiB

Open AccessReview

Probing Protein Glycation by Chromatography and Mass Spectrometry: Analysis of Glycation Adducts

by Alena Soboleva, Maria Vikhnina, Tatiana Grishina and Andrej Frolov

Int. J. Mol. Sci. 2017, 18(12), 2557; https://doi.org/10.3390/ijms18122557 - 28 Nov 2017

Cited by 56 | Viewed by 9543

Abstract

Glycation is a non-enzymatic post-translational modification of proteins, formed by the reaction of reducing sugars and α-dicarbonyl products of their degradation with amino and guanidino groups of proteins. Resulted early glycation products are readily involved in further transformation, yielding a heterogeneous group of advanced glycation end products (AGEs). Their formation is associated with ageing, metabolic diseases, and thermal processing of foods. Therefore, individual glycation adducts are often considered as the markers of related pathologies and food quality. In this context, their quantification in biological and food matrices is required for diagnostics and establishment of food preparation technologies. For this, exhaustive protein hydrolysis with subsequent amino acid analysis is the strategy of choice. Thereby, multi-step enzymatic digestion procedures ensure good recoveries for the most of AGEs, whereas tandem mass spectrometry (MS/MS) in the multiple reaction monitoring (MRM) mode with stable isotope dilution or standard addition represents “a gold standard” for their quantification. Although the spectrum of quantitatively assessed AGE structures is continuously increases, application of untargeted profiling techniques for identification of new products is desired, especially for in vivo characterization of anti-glycative systems. Thereby, due to a high glycative potential of plant metabolites, more attention needs to be paid on plant-derived AGEs. Full article

(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)

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19 pages, 2894 KiB

Open AccessReview

The Role of Glyoxalase-I (Glo-I), Advanced Glycation Endproducts (AGEs), and Their Receptor (RAGE) in Chronic Liver Disease and Hepatocellular Carcinoma (HCC)

by Marcus Hollenbach

Int. J. Mol. Sci. 2017, 18(11), 2466; https://doi.org/10.3390/ijms18112466 - 20 Nov 2017

Cited by 48 | Viewed by 8031

Abstract

Glyoxalase-I (Glo-I) and glyoxalase-II (Glo-II) comprise the glyoxalase system and are responsible for the detoxification of methylglyoxal (MGO). MGO is formed non-enzymatically as a by-product, mainly in glycolysis, and leads to the formation of advanced glycation endproducts (AGEs). AGEs bind to their receptor, RAGE, and activate intracellular transcription factors, resulting in the production of pro-inflammatory cytokines, oxidative stress, and inflammation. This review will focus on the implication of the Glo-I/AGE/RAGE system in liver injury and hepatocellular carcinoma (HCC). AGEs and RAGE are upregulated in liver fibrosis, and the silencing of RAGE reduced collagen deposition and the tumor growth of HCC. Nevertheless, data relating to Glo-I in fibrosis and cirrhosis are preliminary. Glo-I expression was found to be reduced in early and advanced cirrhosis with a subsequent increase of MGO-levels. On the other hand, pharmacological modulation of Glo-I resulted in the reduced activation of hepatic stellate cells and therefore reduced fibrosis in the CCl₄-model of cirrhosis. Thus, current research highlighted the Glo-I/AGE/RAGE system as an interesting therapeutic target in chronic liver diseases. These findings need further elucidation in preclinical and clinical studies. Full article

(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)

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9 pages, 197 KiB

Open AccessReview

Zebrafish as a Model for the Study of Microvascular Complications of Diabetes and Their Mechanisms

by Karl Heckler and Jens Kroll

Int. J. Mol. Sci. 2017, 18(9), 2002; https://doi.org/10.3390/ijms18092002 - 19 Sep 2017

Cited by 56 | Viewed by 11529

Abstract

Diabetes mellitus (DM) is a crucial metabolic disease that leads to severe disorders. These include macrovascular complications such as myocardial infarction, stroke, and peripheral artery disease and microvascular complications including diabetic nephropathy, neuropathy, and retinopathy. Diabetes mellitus, along with its associated organ pathologies, is one of the key problems in today’s medicine. Zebrafish is an upcoming disease model organism in diabetes research. Its glucose metabolism and the pathways of reactive metabolite formation are very similar to those of humans. Moreover, several physiological and pathophysiological pathways that also exist in humans and other mammals have been identified in this species or are currently under intense investigation. Zebrafish offer sophisticated imaging techniques and allow simple and fast genetic and pharmacological approaches with a high throughput. In this review, we highlight achievements and mechanisms concerning microvascular complications discovered in zebrafish, and we discuss the advantages and disadvantages of zebrafish as a model for studying diabetic complications. Full article

(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)

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24 pages, 1127 KiB

Open AccessReview

Dicarbonyls and Advanced Glycation End-Products in the Development of Diabetic Complications and Targets for Intervention

by Sebastian Brings, Thomas Fleming, Marc Freichel, Martina U. Muckenthaler, Stephan Herzig and Peter P. Nawroth

Int. J. Mol. Sci. 2017, 18(5), 984; https://doi.org/10.3390/ijms18050984 - 5 May 2017

Cited by 167 | Viewed by 13103

Abstract

Advanced glycation end-products (AGEs) are non-enzymatic protein and amino acid adducts as well as DNA adducts which form from dicarbonyls and glucose. AGE formation is enhanced in diabetes and is associated with the development of diabetic complications. In the current review, we discuss mechanisms that lead to enhanced AGE levels in the context of diabetes and diabetic complications. The methylglyoxal-detoxifying glyoxalase system as well as alternative pathways of AGE detoxification are summarized. Therapeutic approaches to interfere with different pathways of AGE formation are presented. Full article

(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)

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19 pages, 1462 KiB

Open AccessReview

The Glyoxalase System and Methylglyoxal-Derived Carbonyl Stress in Sepsis: Glycotoxic Aspects of Sepsis Pathophysiology

by Thomas Schmoch, Florian Uhle, Benedikt H. Siegler, Thomas Fleming, Jakob Morgenstern, Peter P. Nawroth, Markus A. Weigand and Thorsten Brenner

Int. J. Mol. Sci. 2017, 18(3), 657; https://doi.org/10.3390/ijms18030657 - 17 Mar 2017

Cited by 32 | Viewed by 9430

Abstract

Sepsis remains one of the leading causes of death in intensive care units. Although sepsis is caused by a viral, fungal or bacterial infection, it is the dysregulated generalized host response that ultimately leads to severe dysfunction of multiple organs and death. The concomitant profound metabolic changes are characterized by hyperglycemia, insulin resistance, and profound transformations of the intracellular energy supply in both peripheral and immune cells. A further hallmark of the early phases of sepsis is a massive formation of reactive oxygen (ROS; e.g., superoxide) as well as nitrogen (RNS; e.g., nitric oxide) species. Reactive carbonyl species (RCS) form a third crucial group of highly reactive metabolites, which until today have been not the focus of interest in sepsis. However, we previously showed in a prospective observational clinical trial that patients suffering from septic shock are characterized by significant methylglyoxal (MG)-derived carbonyl stress, with the glyoxalase system being downregulated in peripheral blood mononuclear cells. In this review, we give a detailed insight into the current state of research regarding the metabolic changes that entail an increased MG-production in septicemia. Thus, we point out the special role of the glyoxalase system in the context of sepsis. Full article

(This article belongs to the Special Issue Glyoxalase System in Health and Disease 2017)

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