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Antioxidants
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Redox Biology of Glyoxalases
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Redox Biology of Glyoxalases

A special issue of Antioxidants (ISSN 2076-3921).

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 67132

Special Issue Editor

Prof. Cinzia Antognelli

E-Mail Website
Guest Editor
Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy
Interests: glyoxalases; methylglyoxal; advanced glycation end products; oxidative stress; antioxidants; oncology; toxicology; apoptosis; epithelial-to-mesenchymal transition; epigenetics; epidemiology

Special Issue Information

Dear Colleagues,

Glyoxalases, comprising glyoxalase 1 and 2, are enzymes that play a critical role in limiting intracellular accumulation of methylglyoxal (MG), a highly reactive dicarbonyl compound formed as a by-product of different metabolic pathways. MG readily reacts with lipids, nucleic acids, and proteins to form a heterogeneous family of advanced glycation end-products (AGEs). AGEs are able to exert complex pleiotropic effects on normal and pathologic processes in cells, including generation of reactive oxygen species (ROS) and oxidative stress or inflammation, events often culminating in distinct biological outcomes, frequently associated with aging, diabetes, cancer, neurodegenerative, and cardio- and cerebrovascular diseases. However, there is also evidence that some MG-derived AGEs are endowed with antioxidant properties. These apparently divergent functions imply that MG-derived AGEs, and consequently glyoxalases, may exert different or even opposite biological effects within cells, frequently in a context-dependent manner. On the other hand, novel redox-dependent mechanisms are emerging in the complex network of regulation of glyoxalases and MG-derived AGEs.

In this Special Issue, I invite investigators to contribute with original research, perspectives, or review articles that describe the relationship between glyoxalases, MG-derived AGEs, and redox biology as it relates to diverse aspects of applied biology research, such as human biology, health sciences, plant sciences, toxicology, and microbiology. Studies with implications for the development of safe, effective, and innovative preventive and therapeutic strategies, including nutraceutical approaches, to modulate redox-dependent regulation of glyoxalases and/or MG-derived AGEs, and, consequently, cell and tissue dysfunctions, are also welcome.

I hope that this Special issue will provide an instrument for communication and dissemination of the most recent findings about the fascinating and rapidly developing topic, the redox biology of glyoxalases.

I look forward to your contribution.

Prof. Cinzia Antognelli
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Glyoxalases
  • Reactive oxygen/ species
  • Methylglyoxal
  • Advanced glycation end products
  • Redox biology
  • Antioxidants
  • Redox-dependent cell signaling
  • Epigenetic
  • Nutraceuticals

Published Papers (21 papers)

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11 pages, 2009 KiB  
Communication
The Glyoxalase System Is a Novel Cargo of Amniotic Fluid Stem-Cell-Derived Extracellular Vesicles
by Rita Romani, Vincenzo Nicola Talesa and Cinzia Antognelli
Antioxidants 2022, 11(8), 1524; https://doi.org/10.3390/antiox11081524 - 05 Aug 2022
Cited by 1 | Viewed by 1583
Abstract
The glyoxalase system is a ubiquitous cellular metabolic pathway whose main physiological role is the removal of methylglyoxal (MG). MG, a glycolysis byproduct formed by the spontaneous degradation of triosephosphates glyceraldehyde-3-phosphate (GA3P) and dihydroxyacetonephosphate (DHAP), is an arginine-directed glycating agent and precursor of [...] Read more.
The glyoxalase system is a ubiquitous cellular metabolic pathway whose main physiological role is the removal of methylglyoxal (MG). MG, a glycolysis byproduct formed by the spontaneous degradation of triosephosphates glyceraldehyde-3-phosphate (GA3P) and dihydroxyacetonephosphate (DHAP), is an arginine-directed glycating agent and precursor of the major advanced glycation end product arginine-derived, hydroimidazolone (MG-H1). Extracellular vesicles (EVs) are a heterogeneous family of lipid-bilayer-vesicular structures released by virtually all living cells, involved in cell-to-cell communication, specifically by transporting biomolecules to recipient cells, driving distinct biological responses. Emerging evidence suggests that included in the EVs cargo there are different metabolic enzymes. Specifically, recent research has pointed out that EVs derived from human amniotic fluid stem cell (HASC-EVs) contain glycolytic pay-off phase enzymes, such as glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Since GAPDH catalyzes the sixth step of glycolysis using as a substrate GA3P, from which MG spontaneously origins, we wanted to investigate whether MG-derived MG-H1, as well as glyoxalases, could be novel molecule cargo in these EVs. By using immunoassays and spectrophotometric methods, we found, for the first time ever, that HASC-EVs contain functional glyoxalases and MG-H1, pioneering research to novel and exciting roles of these eclectic proteins, bringing them to the limelight once more. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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22 pages, 3932 KiB  
Article
Antioxidant Properties of Cerium Oxide Nanoparticles Prevent Retinal Neovascular Alterations In Vitro and In Vivo
by Annamaria Tisi, Fanny Pulcini, Giulia Carozza, Vincenzo Mattei, Vincenzo Flati, Maurizio Passacantando, Cinzia Antognelli, Rita Maccarone and Simona Delle Monache
Antioxidants 2022, 11(6), 1133; https://doi.org/10.3390/antiox11061133 - 09 Jun 2022
Cited by 10 | Viewed by 2204
Abstract
In this study, we investigated whether cerium oxide nanoparticles (CeO2-NPs), a promising antioxidant nanomaterial, may contrast retinal vascular alterations induced by oxidative damage in vitro and in vivo. For the in vivo experiments, the light damage (LD) animal model of Age-Related [...] Read more.
In this study, we investigated whether cerium oxide nanoparticles (CeO2-NPs), a promising antioxidant nanomaterial, may contrast retinal vascular alterations induced by oxidative damage in vitro and in vivo. For the in vivo experiments, the light damage (LD) animal model of Age-Related Macular Degeneration (AMD) was used and the CeO2-NPs were intravitreally injected. CeO2-NPs significantly decreased vascular endothelial growth factor (VEGF) protein levels, reduced neovascularization in the deep retinal plexus, and inhibited choroidal sprouting into the photoreceptor layer. The in vitro experiments were performed on human retinal pigment epithelial (ARPE-19) cells challenged with H2O2; we demonstrated that CeO2-NPs reverted H2O2-induced oxidative stress-dependent effects on this cell model. We further investigated the RPE–endothelial cells interaction under oxidative stress conditions in the presence or absence of CeO2-NPs through two experimental paradigms: (i) treatment of human umbilical vein endothelial cells (HUVECs) with conditioned media from ARPE-19 cells, and (ii) coculture of ARPE-19 and HUVECs. In both experimental conditions, CeO2-NPs were able to revert the detrimental effect of H2O2 on angiogenesis in vitro by realigning the level of tubule formation to that of the control. Altogether, our results indicate, for the first time, that CeO2-NPs can counteract retinal neovascularization and may be a new therapeutic strategy for the treatment of wet AMD. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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15 pages, 3875 KiB  
Article
Effect of Pholiota nameko Polysaccharides Inhibiting Methylglyoxal-Induced Glycation Damage In Vitro
by His Lin, Ting-Yun Lin, Jer-An Lin, Kuan-Chen Cheng, Shella Permatasari Santoso, Chun-Hsu Chou and Chang-Wei Hsieh
Antioxidants 2021, 10(10), 1589; https://doi.org/10.3390/antiox10101589 - 10 Oct 2021
Cited by 5 | Viewed by 2574
Abstract
Advanced glycation end products (AGEs) can induce oxidative stress and inflammation. AGEs are major risk factors for the development of many aging-related diseases, such as cancer and diabetes. In this study, Pholiota nameko polysaccharides (PNPs) were prepared from water extract of P. nameko [...] Read more.
Advanced glycation end products (AGEs) can induce oxidative stress and inflammation. AGEs are major risk factors for the development of many aging-related diseases, such as cancer and diabetes. In this study, Pholiota nameko polysaccharides (PNPs) were prepared from water extract of P. nameko via graded alcohol precipitation (40%, 60%, and 80% v/v). We explored the in vitro antiglycation ability of the PNPs and inhibition of methylglyoxal (MG)-induced Hs68 cell damage. In a bovine serum albumin (BSA) glycation system, PNPs significantly inhibited the formation of Amadori products. Fluorescence spectrophotometry revealed that the PNPs trapped MG and reduced MG-induced changes in functional groups (carbonyl and ε-NH2) in the BSA. Pretreating Hs68 cells with PNPs enhanced the cell survival rate and protected against MG-induced cell damage. This was due to decreased intracellular ROS content. PNPs thus mitigate skin cell damage and oxidative stress resulting from glycation stress, making them a potential raw material for antiaging-related skincare products. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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18 pages, 2660 KiB  
Article
Glyoxalase-I Is Upregulated in Acute Cerulein-Induced Pancreatitis: A New Mechanism in Pancreatic Inflammation?
by Marcus Hollenbach, Sebastian Sonnenberg, Ines Sommerer, Jana Lorenz and Albrecht Hoffmeister
Antioxidants 2021, 10(10), 1574; https://doi.org/10.3390/antiox10101574 - 05 Oct 2021
Viewed by 1639
Abstract
Inflammation caused by oxidative stress (ROS) demonstrates an essential mechanism in the pathogenesis of acute pancreatitis (AP). Important sources for ROS comprise the reactive compound methylglyoxal (MGO) itself and the MGO-derived formation of advanced glycation end-products (AGEs). AGEs bind to the transmembrane receptor [...] Read more.
Inflammation caused by oxidative stress (ROS) demonstrates an essential mechanism in the pathogenesis of acute pancreatitis (AP). Important sources for ROS comprise the reactive compound methylglyoxal (MGO) itself and the MGO-derived formation of advanced glycation end-products (AGEs). AGEs bind to the transmembrane receptor RAGE and activate NF-κB, and lead to the production of pro-inflammatory cytokines. MGO is detoxified by glyoxalase-I (Glo-I). The importance of Glo-I was shown in different models of inflammation and carcinogenesis. Nevertheless, the role of Glo-I and MGO in AP has not been evaluated so far. This study analyzed Glo-I in cerulein-(CN)-induced AP and determined the effects of Glo-I knockdown, overexpression and pharmacological modulation. Methods: AP was induced in C57BL6/J mice by i.p. injection of CN. Glo-I was analyzed in explanted pancreata by Western Blot, qRT-PCR and immunohistochemistry. AR42J cells were differentiated by dexamethasone and stimulated with 100 nM of CN. Cells were simultaneously treated with ethyl pyruvate (EP) or S-p-bromobenzylglutathione-cyclopentyl-diester (BrBz), two Glo-I modulators. Knockdown and overexpression of Glo-I was achieved by transient transfection with Glo-I siRNA and pEGFP-N1-Glo-I-Vector. Amylase secretion, TNF-α production (ELISA) and expression of Glo-I, RAGE and NF-κB were measured. Results: Glo-I was significantly upregulated on protein and mRNA levels in CN-treated mice and AR42J cells. Dexamethasone-induced differentiation of AR42J cells increased the expression of Glo-I and RAGE. Treatment of AR42J cells with CN and EP or BrBz resulted in a significant reduction of CN-induced amylase secretion, NF-κB, RAGE and TNF-α. Overexpression of Glo-I led to a significant reduction of CN-induced amylase levels, NF-κB expression and TNF-α, whereas Glo-I knockdown revealed only slight alterations. Measurements of specific Glo-I activity and MGO levels indicated a complex regulation in the model of CN-induced AP. Conclusion: Glo-I is overexpressed in a model of CN-induced AP. Pharmacological modulation and overexpression of Glo-I reduced amylase secretion and the release of pro-inflammatory cytokines in AP in vitro. Targeting Glo-I in AP seems to be an interesting approach for future in vivo studies of AP. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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19 pages, 5265 KiB  
Article
Glyoxal-Lysine Dimer, an Advanced Glycation End Product, Induces Oxidative Damage and Inflammatory Response by Interacting with RAGE
by Hee-Weon Lee, Min Ji Gu, Yoonsook Kim, Jee-Young Lee, Seungju Lee, In-Wook Choi and Sang Keun Ha
Antioxidants 2021, 10(9), 1486; https://doi.org/10.3390/antiox10091486 - 17 Sep 2021
Cited by 9 | Viewed by 2745
Abstract
The glyoxal-lysine dimer (GOLD), which is a glyoxal (GO)-derived advanced glycation end product (AGE), is produced by the glycation reaction. In this study, we evaluated the effect of GOLD on the oxidative damage and inflammatory response in SV40 MES 13 mesangial cells. GOLD [...] Read more.
The glyoxal-lysine dimer (GOLD), which is a glyoxal (GO)-derived advanced glycation end product (AGE), is produced by the glycation reaction. In this study, we evaluated the effect of GOLD on the oxidative damage and inflammatory response in SV40 MES 13 mesangial cells. GOLD significantly increased the linkage with the V-type immunoglobulin domain of RAGE, a specific receptor of AGE. We found that GOLD treatment increased RAGE expression and reactive oxygen species (ROS) production in mesangial cells. GOLD remarkably regulated the protein and mRNA expression of nuclear factor erythroid 2-related factor 2 (NRF2) and glyoxalase 1 (GLO1). In addition, mitochondrial deterioration and inflammation occurred via GOLD-induced oxidative stress in mesangial cells. GOLD regulated the mitogen-activated protein kinase (MAPK) and the release of proinflammatory cytokines associated with the inflammatory mechanism of mesangial cells. Furthermore, oxidative stress and inflammatory responses triggered by GOLD were suppressed through RAGE inhibition using RAGE siRNA. These results demonstrate that the interaction of GOLD and RAGE plays an important role in the function of mesangial cells. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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19 pages, 4250 KiB  
Article
Methylglyoxal-Dependent Glycative Stress Is Prevented by the Natural Antioxidant Oleuropein in Human Dental Pulp Stem Cells through Nrf2/Glo1 Pathway
by Simona Delle Monache, Fanny Pulcini, Roberta Frosini, Vincenzo Mattei, Vincenzo Nicola Talesa and Cinzia Antognelli
Antioxidants 2021, 10(5), 716; https://doi.org/10.3390/antiox10050716 - 01 May 2021
Cited by 30 | Viewed by 2749
Abstract
Methylglyoxal (MG) is a potent precursor of glycative stress (abnormal accumulation of advanced glycation end products, AGEs), a relevant condition underpinning the etiology of several diseases, including those of the oral cave. At present, synthetic agents able to trap MG are known; however, [...] Read more.
Methylglyoxal (MG) is a potent precursor of glycative stress (abnormal accumulation of advanced glycation end products, AGEs), a relevant condition underpinning the etiology of several diseases, including those of the oral cave. At present, synthetic agents able to trap MG are known; however, they have never been approved for clinical use because of their severe side effects. Hence, the search of bioactive natural scavengers remains a sector of strong research interest. Here, we investigated whether and how oleuropein (OP), the major bioactive component of olive leaf, was able to prevent MG-dependent glycative stress in human dental pulp stem cells (DPSCs). The cells were exposed to OP at 50 µM for 24 h prior to the administration of MG at 300 µM for additional 24 h. We found that OP prevented MG-induced glycative stress and DPSCs impairment by restoring the activity of Glyoxalase 1 (Glo1), the major detoxifying enzyme of MG, in a mechanism involving the redox-sensitive transcription factor Nrf2. Our results suggest that OP holds great promise for the development of preventive strategies for MG-derived AGEs-associated oral diseases and open new paths in research concerning additional studies on the protective potential of this secoiridoid. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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19 pages, 6745 KiB  
Article
Tracing the Evolution of Plant Glyoxalase III Enzymes for Structural and Functional Divergence
by Brijesh Kumar, Charanpreet Kaur, Ashwani Pareek, Sudhir K. Sopory and Sneh L. Singla-Pareek
Antioxidants 2021, 10(5), 648; https://doi.org/10.3390/antiox10050648 - 23 Apr 2021
Cited by 10 | Viewed by 2478
Abstract
Glyoxalase pathway is the primary route for metabolism of methylglyoxal (MG), a toxic ubiquitous metabolite that affects redox homeostasis. It neutralizes MG using Glyoxalase I and Glyoxalase II (GLYI and GLYII) enzymes in the presence of reduced glutathione. In addition, there also exists [...] Read more.
Glyoxalase pathway is the primary route for metabolism of methylglyoxal (MG), a toxic ubiquitous metabolite that affects redox homeostasis. It neutralizes MG using Glyoxalase I and Glyoxalase II (GLYI and GLYII) enzymes in the presence of reduced glutathione. In addition, there also exists a shorter route for the MG detoxification in the form of Glyoxalase III (GLYIII) enzymes, which can convert MG into D-lactate in a single-step without involving glutathione. GLYIII proteins in different systems demonstrate diverse functional capacities and play a vital role in oxidative stress response. To gain insight into their evolutionary patterns, here we studied the evolution of GLYIII enzymes across prokaryotes and eukaryotes, with special emphasis on plants. GLYIII proteins are characterized by the presence of DJ-1_PfpI domains thereby, belonging to the DJ-1_PfpI protein superfamily. Our analysis delineated evolution of double DJ-1_PfpI domains in plant GLYIII. Based on sequence and structural characteristics, plant GLYIII enzymes could be categorized into three different clusters, which followed different evolutionary trajectories. Importantly, GLYIII proteins from monocots and dicots group separately in each cluster and the each of the two domains of these proteins also cluster differentially. Overall, our findings suggested that GLYIII proteins have undergone significant evolutionary changes in plants, which is likely to confer diversity and flexibility in their functions. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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15 pages, 5108 KiB  
Article
Biochemical Regulation of the Glyoxalase System in Response to Insulin Signaling
by Der-Yen Lee, Yu-Chin Lin and Geen-Dong Chang
Antioxidants 2021, 10(2), 326; https://doi.org/10.3390/antiox10020326 - 22 Feb 2021
Cited by 5 | Viewed by 1961
Abstract
Methylglyoxal (MG) is a reactive glycation metabolite and potentially induces dicarbonyl stress. The production of MG in cells is increased along with an increase in carbohydrate metabolism. The efficiency of the glyoxalase system, consisting of glyoxalase 1 (GlxI) and glyoxalase 2 (GlxII), is [...] Read more.
Methylglyoxal (MG) is a reactive glycation metabolite and potentially induces dicarbonyl stress. The production of MG in cells is increased along with an increase in carbohydrate metabolism. The efficiency of the glyoxalase system, consisting of glyoxalase 1 (GlxI) and glyoxalase 2 (GlxII), is crucial for turning the accumulated MG into nontoxic metabolites. Converting MG-glutathione hemithioacetal to S-d-lactoylglutathione by GlxI is the rate-determining step of the enzyme system. In this study, we found lactic acid accumulated during insulin stimulation in cells, however, cellular MG and S-d-lactoylglutathione also increased due to the massive flux of glycolytic intermediates. The insulin-induced accumulation of MG and S-d-lactoylglutathione were efficiently removed by the treatment of metformin, possibly via affecting the glyoxalase system. With the application of isotopic 13C3-MG, the flux of MG from extracellular and intracellular origins was dissected. While insulin induced an influx of extracellular MG, metformin inhibited the trafficking of MG across the plasma membrane. Therefore, metformin could maintain the extracellular MG by means of reducing the secretion of MG rather than facilitating the scavenging. In addition, metformin may affect the glyoxalase system by controlling the cellular redox state through replenishing reduced glutathione. Overall, alternative biochemical regulation of the glyoxalase system mediated by insulin signaling or molecules like biguanides may control cellular MG homeostasis. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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12 pages, 1265 KiB  
Article
Polymorphisms in Glyoxalase I Gene Are Not Associated with Glyoxalase I Expression in Whole Blood or Markers of Methylglyoxal Stress: The CODAM Study
by Kim Maasen, Nordin M. J. Hanssen, Carla J. H. van der Kallen, Coen D. A. Stehouwer, Marleen M. J. van Greevenbroek and Casper G. Schalkwijk
Antioxidants 2021, 10(2), 219; https://doi.org/10.3390/antiox10020219 - 02 Feb 2021
Cited by 2 | Viewed by 2160
Abstract
Glyoxalase 1 (Glo1) is the rate-limiting enzyme in the detoxification of methylglyoxal (MGO) into D-lactate. MGO is a major precursor of advanced glycation endproducts (AGEs), and both are associated with development of age-related diseases. Since genetic variation in GLO1 may alter the expression [...] Read more.
Glyoxalase 1 (Glo1) is the rate-limiting enzyme in the detoxification of methylglyoxal (MGO) into D-lactate. MGO is a major precursor of advanced glycation endproducts (AGEs), and both are associated with development of age-related diseases. Since genetic variation in GLO1 may alter the expression and/or the activity of Glo1, we examined the association of nine SNPs in GLO1 with Glo1 expression and markers of MGO stress (MGO in fasting plasma and after an oral glucose tolerance test, D-lactate in fasting plasma and urine, and MGO-derived AGEs CEL and MG-H1 in fasting plasma and urine). We used data of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM, n = 546, 60 ± 7 y, 25% type 2 diabetes). Outcomes were compared across genotypes using linear regression, adjusted for age, sex, and glucose metabolism status. We found that SNP4 (rs13199033) was associated with Glo1 expression (AA as reference, standardized beta AT = −0.29, p = 0.02 and TT = −0.39, p = 0.3). Similarly, SNP13 (rs3799703) was associated with Glo1 expression (GG as reference, standardized beta AG = 0.17, p = 0.14 and AA = 0.36, p = 0.005). After correction for multiple testing these associations were not significant. For the other SNPs, we observed no consistent associations over the different genotypes. Thus, polymorphisms of GLO1 were not associated with Glo1 expression or markers of MGO stress, suggesting that these SNPs are not functional, although activity/expression might be altered in other tissues. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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15 pages, 1285 KiB  
Article
Protection of Polyphenols against Glyco-Oxidative Stress: Involvement of Glyoxalase Pathway
by Laura Cianfruglia, Camilla Morresi, Tiziana Bacchetti, Tatiana Armeni and Gianna Ferretti
Antioxidants 2020, 9(10), 1006; https://doi.org/10.3390/antiox9101006 - 16 Oct 2020
Cited by 13 | Viewed by 3973
Abstract
Chronic high glucose (HG) exposure increases methylglyoxal (MGO)-derived advanced glycation end-products (AGEs) and is involved in the onset of pathological conditions, such as diabetes, atherosclerosis and chronic-degenerative diseases. Under physiologic conditions the harmful effects of MGO are contrasted by glyoxalase system that is [...] Read more.
Chronic high glucose (HG) exposure increases methylglyoxal (MGO)-derived advanced glycation end-products (AGEs) and is involved in the onset of pathological conditions, such as diabetes, atherosclerosis and chronic-degenerative diseases. Under physiologic conditions the harmful effects of MGO are contrasted by glyoxalase system that is implicated in the detoxification of Reactive Carbonyl Species (RCS) and maintain the homeostasis of the redox environment of the cell. Polyphenols are the most abundant antioxidants in the diet and present various health benefits. Aims of the study were to investigate the effects of HG-chronic exposure on glyco-oxidation and glyoxalase system in intestinal cells, using CaCo-2 cells. Moreover, we studied the effect of apple polyphenols on glyco-oxidative stress. Our data demonstrated that HG-treatment triggers glyco-oxidation stress with a significant increase in intracellular Reactive Oxygen Species (ROS), lipid peroxidation, AGEs, and increase of Glyoxalase I (GlxI) activity. On the contrary, Glyoxalase II (GlxII) activity was lower in HG-treated cells. We demonstrate that apple polyphenols exert a protective effect against oxidative stress and dicarbonyl stress. The increase of total antioxidant capacity and glutathione (GSH) levels in HG-treated cells in the presence of apple polyphenols was associated with a decrease of GlxI activity. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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17 pages, 2873 KiB  
Article
Methylglyoxal-Induced Dysfunction in Brain Endothelial Cells via the Suppression of Akt/HIF-1α Pathway and Activation of Mitophagy Associated with Increased Reactive Oxygen Species
by Donghyun Kim, Kyeong-A Kim, Jeong-Hyeon Kim, Eun-Hye Kim and Ok-Nam Bae
Antioxidants 2020, 9(9), 820; https://doi.org/10.3390/antiox9090820 - 03 Sep 2020
Cited by 20 | Viewed by 4734
Abstract
Methylglyoxal (MG) is a dicarbonyl compound, the level of which is increased in the blood of diabetes patients. MG is reported to be involved in the development of cerebrovascular complications in diabetes, but the exact mechanisms need to be elucidated. Here, we investigated [...] Read more.
Methylglyoxal (MG) is a dicarbonyl compound, the level of which is increased in the blood of diabetes patients. MG is reported to be involved in the development of cerebrovascular complications in diabetes, but the exact mechanisms need to be elucidated. Here, we investigated the possible roles of oxidative stress and mitophagy in MG-induced functional damage in brain endothelial cells (ECs). Treatment of MG significantly altered metabolic stress as observed by the oxygen-consumption rate and barrier-integrity as found in impaired trans-endothelial electrical resistance in brain ECs. The accumulation of MG adducts and the disturbance of the glyoxalase system, which are major detoxification enzymes of MG, occurred concurrently. Reactive oxygen species (ROS)-triggered oxidative damage was observed with increased mitochondrial ROS production and the suppressed Akt/hypoxia-inducible factor 1 alpha (HIF-1α) pathway. Along with the disturbance of mitochondrial bioenergetic function, parkin-1-mediated mitophagy was increased by MG. Treatment of N-acetyl cysteine significantly reversed mitochondrial damage and mitophagy. Notably, MG induced dysregulation of tight junction proteins including occludin, claudin-5, and zonula occluden-1 in brain ECs. Here, we propose that diabetic metabolite MG-associated oxidative stress may contribute to mitochondrial damage and autophagy in brain ECs, resulting in the dysregulation of tight junction proteins and the impairment of permeability. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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16 pages, 2204 KiB  
Article
Chebulic Acid Prevents Methylglyoxal-Induced Mitochondrial Dysfunction in INS-1 Pancreatic β-Cells
by Hyun-jung Yoo, Chung-Oui Hong, Sang Keun Ha and Kwang-Won Lee
Antioxidants 2020, 9(9), 771; https://doi.org/10.3390/antiox9090771 - 20 Aug 2020
Cited by 6 | Viewed by 4047
Abstract
To investigate the anti-diabetic properties of chebulic acid (CA) associated with the prevention of methyl glyoxal (MG)-induced mitochondrial dysfunction in INS-1 pancreatic β-cells, INS-1 cells were pre-treated with CA (0.5, 1.0, and 2.0 μM) for 48 h and then treated with 2 mM [...] Read more.
To investigate the anti-diabetic properties of chebulic acid (CA) associated with the prevention of methyl glyoxal (MG)-induced mitochondrial dysfunction in INS-1 pancreatic β-cells, INS-1 cells were pre-treated with CA (0.5, 1.0, and 2.0 μM) for 48 h and then treated with 2 mM MG for 8 h. The effects of CA and MG on INS-1 cells were evaluated using the following: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; glyoxalase 1 (Glo-1) expression via Western blot and enzyme activity assays; Nrf-2, nuclear factor erythroid 2-related factor 2 protein expression via Western blot assay; reactive oxygen species (ROS) production assay; mRNA expression of mitochondrial dysfunction related components (UCP2, uncoupling protein 2; VDAC1, voltage-dependent anion-selective channel-1; cyt c, cytochrome c via quantitative reverse transcriptase-PCR; mitochondrial membrane potential (MMP); adenosine triphosphate (ATP) synthesis; glucose-stimulated insulin secretion (GSIS) assay. The viability of INS-1 cells was maintained upon pre-treating with CA before exposure to MG. CA upregulated Glo-1 protein expression and enzyme activity in INS-1 cells and prevented MG-induced ROS production. Mitochondrial dysfunction was alleviated by CA pretreatment; this occurred via the downregulation of UCP2, VDAC1, and cyt c mRNA expression and the increase of MMP and ATP synthesis. Further, CA pre-treatment promoted the recovery from MG-induced decrease in GSIS. These results indicated that CA could be employed as a therapeutic agent in diabetes due to its ability to prevent MG-induced development of insulin sensitivity and oxidative stress-induced dysfunction of β-cells. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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19 pages, 4380 KiB  
Article
Redox-Sensitive Glyoxalase 1 Up-Regulation Is Crucial for Protecting Human Lung Cells from Gold Nanoparticles Toxicity
by Angela Gambelunghe, Stefano Giovagnoli, Alessandro Di Michele, Simona Boncompagni, Marco Dell’Omo, Kerstin Leopold, Ivo Iavicoli, Vincenzo Nicola Talesa and Cinzia Antognelli
Antioxidants 2020, 9(8), 697; https://doi.org/10.3390/antiox9080697 - 03 Aug 2020
Cited by 10 | Viewed by 2273
Abstract
Gold nanoparticles (AuNPs) are considered nontoxic upon acute exposure, at least when they are equal or above 5 nm size. However, the safeguard mechanisms contributing to maintain cell viability are scarcely explored so far. Here, we investigated the cyto-protective role of Glyoxalase 1 [...] Read more.
Gold nanoparticles (AuNPs) are considered nontoxic upon acute exposure, at least when they are equal or above 5 nm size. However, the safeguard mechanisms contributing to maintain cell viability are scarcely explored so far. Here, we investigated the cyto-protective role of Glyoxalase 1 (Glo1), a key enzyme involved in the control of deleterious dicarbonyl stress, in two human cell types of the respiratory tract, after an acute exposure to AuNPs with a main size of 5 nm. We found that the redox sensitive Nrf-2-mediated up-regulation of Glo1 was crucial to protect cells from AuNPs-induced toxicity. However, cells challenged with a pro-inflammatory/pro-oxidative insult become susceptible to the pro-apoptotic effect of AuNPs. Notably, the surviving cells undergo epigenetic changes associated with the onset of a partial epithelial to mesenchymal transition (EMT) process (metastable phenotype), driven by the increase in dicarbonyl stress, consequent to Glo1 inactivation. As a physiological respiratory epithelium is required for the normal respiratory function, the knowledge of the protective mechanisms avoiding or (when challenged) promoting its modification/damage might provide insight into the genesis, and, most importantly, prevention of potential health effects that might occur in subjects exposed to AuNPs, through targeted surveillance programs, at least under specific influencing factors. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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22 pages, 10644 KiB  
Article
Adeno-Associated Viral Transfer of Glyoxalase-1 Blunts Carbonyl and Oxidative Stresses in Hearts of Type 1 Diabetic Rats
by Fadhel A. Alomar, Abdullah Al-Rubaish, Fahad Al-Muhanna, Amein K. Al-Ali, JoEllyn McMillan, Jaipaul Singh and Keshore R. Bidasee
Antioxidants 2020, 9(7), 592; https://doi.org/10.3390/antiox9070592 - 06 Jul 2020
Cited by 7 | Viewed by 2737
Abstract
Accumulation of methylglyoxal (MG) arising from downregulation of its primary degrading enzyme glyoxalase-1 (Glo1) is an underlying cause of diabetic cardiomyopathy (DC). This study investigated if expressing Glo1 in rat hearts shortly after the onset of Type 1 diabetes mellitus (T1DM) would blunt [...] Read more.
Accumulation of methylglyoxal (MG) arising from downregulation of its primary degrading enzyme glyoxalase-1 (Glo1) is an underlying cause of diabetic cardiomyopathy (DC). This study investigated if expressing Glo1 in rat hearts shortly after the onset of Type 1 diabetes mellitus (T1DM) would blunt the development of DC employing the streptozotocin-induced T1DM rat model, an adeno-associated virus containing Glo1 driven by the endothelin-1 promoter (AAV2/9-Endo-Glo1), echocardiography, video edge, confocal imaging, and biochemical/histopathological assays. After eight weeks of T1DM, rats developed DC characterized by a decreased E:A ratio, fractional shortening, and ejection fraction, and increased isovolumetric relaxation time, E: e’ ratio, and circumferential and longitudinal strains. Evoked Ca2+ transients and contractile kinetics were also impaired in ventricular myocytes. Hearts from eight weeks T1DM rats had lower Glo1 and GSH levels, elevated carbonyl/oxidative stress, microvascular leakage, inflammation, and fibrosis. A single injection of AAV2/9 Endo-Glo1 (1.7 × 1012 viron particles/kg) one week after onset of T1DM, potentiated GSH, and blunted MG accumulation, carbonyl/oxidative stress, microvascular leakage, inflammation, fibrosis, and impairments in cardiac and myocyte functions that develop after eight weeks of T1DM. These new data indicate that preventing Glo1 downregulation by administering AAV2/9-Endo-Glo1 to rats one week after the onset of T1DM, blunted the DC that develops after eight weeks of diabetes by attenuating carbonyl/oxidative stresses, microvascular leakage, inflammation, and fibrosis. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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18 pages, 1352 KiB  
Article
Discovery of GLO1 New Related Genes and Pathways by RNA-Seq on A2E-Stressed Retinal Epithelial Cells Could Improve Knowledge on Retinitis Pigmentosa
by Luigi Donato, Concetta Scimone, Simona Alibrandi, Giacomo Nicocia, Carmela Rinaldi, Antonina Sidoti and Rosalia D’Angelo
Antioxidants 2020, 9(5), 416; https://doi.org/10.3390/antiox9050416 - 13 May 2020
Cited by 29 | Viewed by 3681
Abstract
Endogenous antioxidants protect cells from reactive oxygen species (ROS)-related deleterious effects, and an imbalance in the oxidant/antioxidant systems generates oxidative stress. Glyoxalase 1 (GLO1) is a ubiquitous cellular enzyme involved in detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis whose excess can [...] Read more.
Endogenous antioxidants protect cells from reactive oxygen species (ROS)-related deleterious effects, and an imbalance in the oxidant/antioxidant systems generates oxidative stress. Glyoxalase 1 (GLO1) is a ubiquitous cellular enzyme involved in detoxification of methylglyoxal (MG), a cytotoxic byproduct of glycolysis whose excess can produce oxidative stress. In retinitis pigmentosa, one of the most diffuse cause of blindness, oxidative damage leads to photoreceptor death. To clarify the role of GLO1 in retinitis pigmentosa onset and progression, we treated human retinal pigment epithelium cells by the oxidant agent A2E. Transcriptome profiles between treated and untreated cells were performed by RNA-Seq, considering two time points (3 and 6 h), after the basal one. The exposure to A2E highlighted significant expression differences and splicing events in 370 GLO1 first-neighbor genes, and 23 of them emerged from pathway clustered analysis as main candidates to be associated with retinitis pigmentosa. Such a hypothesis was corroborated by the involvement of previously analyzed genes in specific cellular activities related to oxidative stress, such as glyoxylate and dicarboxylate metabolism, glycolysis, axo-dendritic transport, lipoprotein activity and metabolism, SUMOylation and retrograde transport at the trans-Golgi network. Our findings could be the starting point to explore unclear molecular mechanisms involved in retinitis pigmentosa etiopathogenesis. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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19 pages, 6498 KiB  
Article
Iron and Advanced Glycation End Products: Emerging Role of Iron in Androgen Deficiency in Obesity
by Seu-Hwa Chen, Kuo-Ching Yuan, Yu-Chieh Lee, Chun-Kuang Shih, Sung-Hui Tseng, Alexey A. Tinkov, Anatoly V. Skalny and Jung-Su Chang
Antioxidants 2020, 9(3), 261; https://doi.org/10.3390/antiox9030261 - 22 Mar 2020
Cited by 11 | Viewed by 3412
Abstract
The literature suggests a bidirectional relationship between testosterone (T) and iron, but mechanisms underlying this relationship remain unclear. We investigated effects of iron on advanced glycation end products (AGEs) in obesity-related androgen deficiency. In total, 111 men were recruited, and iron biomarkers and [...] Read more.
The literature suggests a bidirectional relationship between testosterone (T) and iron, but mechanisms underlying this relationship remain unclear. We investigated effects of iron on advanced glycation end products (AGEs) in obesity-related androgen deficiency. In total, 111 men were recruited, and iron biomarkers and N(ɛ)-(carboxymethyl)lysine (CML) were measured. In an animal study, rats were fed a 50% high-fat diet (HFD) with (0.25, 1, and 2 g ferric iron/kg diet) or without ferric citrate for 12 weeks. Obese rats supplemented with >1 g iron/kg diet had decreased testicular total T compared to HFD alone. Immunohistochemical staining showed that >1 g of ferric iron increased iron and AGE retention in testicular interstitial tissues, which is associated with increased expression of the receptor for AGEs (RAGE), tumor necrosis factor-α, and nitric oxide. Compared with normal weight, overweight/obese men had lower T levels and higher rates of hypogonadism (19% vs. 11.3%) and iron overload (29.8% vs.15.9%). A correlation analysis showed serum total T was positively correlated with transferrin saturation (r = 0.242, p = 0.007) and cathepsin D (r = 0.330, p = 0.001), but negatively correlated with red blood cell aggregation (r = −0.419, p<0.0001) and CML (r = −0.209, p < 0.05). In conclusion, AGEs may partially explain the underlying relationship between dysregulated iron and T deficiency. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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Review

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24 pages, 2849 KiB  
Review
Glyoxalase 2: Towards a Broader View of the Second Player of the Glyoxalase System
by Andrea Scirè, Laura Cianfruglia, Cristina Minnelli, Brenda Romaldi, Emiliano Laudadio, Roberta Galeazzi, Cinzia Antognelli and Tatiana Armeni
Antioxidants 2022, 11(11), 2131; https://doi.org/10.3390/antiox11112131 - 28 Oct 2022
Cited by 7 | Viewed by 1966
Abstract
Glyoxalase 2 is a mitochondrial and cytoplasmic protein belonging to the metallo-β-lactamase family encoded by the hydroxyacylglutathione hydrolase (HAGH) gene. This enzyme is the second enzyme of the glyoxalase system that is responsible for detoxification of the α-ketothaldehyde methylglyoxal in cells. The two [...] Read more.
Glyoxalase 2 is a mitochondrial and cytoplasmic protein belonging to the metallo-β-lactamase family encoded by the hydroxyacylglutathione hydrolase (HAGH) gene. This enzyme is the second enzyme of the glyoxalase system that is responsible for detoxification of the α-ketothaldehyde methylglyoxal in cells. The two enzymes glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2) form the complete glyoxalase pathway, which utilizes glutathione as cofactor in eukaryotic cells. The importance of Glo2 is highlighted by its ubiquitous distribution in prokaryotic and eukaryotic organisms. Its function in the system has been well defined, but in recent years, additional roles are emerging, especially those related to oxidative stress. This review focuses on Glo2 by considering its genetics, molecular and structural properties, its involvement in post-translational modifications and its interaction with specific metabolic pathways. The purpose of this review is to focus attention on an enzyme that, from the most recent studies, appears to play a role in multiple regulatory pathways that may be important in certain diseases such as cancer or oxidative stress-related diseases. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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34 pages, 2789 KiB  
Review
Metabolic Shades of S-D-Lactoylglutathione
by Miklós Péter Kalapos, Cinzia Antognelli and Lidia de Bari
Antioxidants 2022, 11(5), 1005; https://doi.org/10.3390/antiox11051005 - 20 May 2022
Cited by 4 | Viewed by 2932
Abstract
S-D-lactoylglutathione (SDL) is an intermediate of the glutathione-dependent metabolism of methylglyoxal (MGO) by glyoxalases. MGO is an electrophilic compound that is inevitably produced in conjunction with glucose breakdown and is essentially metabolized via the glyoxalase route. In the last decades, MGO metabolism and [...] Read more.
S-D-lactoylglutathione (SDL) is an intermediate of the glutathione-dependent metabolism of methylglyoxal (MGO) by glyoxalases. MGO is an electrophilic compound that is inevitably produced in conjunction with glucose breakdown and is essentially metabolized via the glyoxalase route. In the last decades, MGO metabolism and its cytotoxic effects have been under active investigation, while almost nothing is known about SDL. This article seeks to fill the gap by presenting an overview of the chemistry, biochemistry, physiological role and clinical importance of SDL. The effects of intracellular SDL are investigated in three main directions: as a substrate for post-translational protein modifications, as a reservoir for mitochondrial reduced glutathione and as an energy currency. In essence, all three approaches point to one direction, namely, a metabolism-related regulatory role, enhancing the cellular defense against insults. It is also suggested that an increased plasma concentration of SDL or its metabolites may possibly serve as marker molecules in hemolytic states, particularly when the cause of hemolysis is a disturbance of the pay-off phase of the glycolytic chain. Finally, SDL could also represent a useful marker in such metabolic disorders as diabetes mellitus or ketotic states, in which its formation is expected to be enhanced. Despite the lack of clear-cut evidence underlying the clinical and experimental findings, the investigation of SDL metabolism is a promising field of research. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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23 pages, 1138 KiB  
Review
Carbonyl Stress in Red Blood Cells and Hemoglobin
by Olga V. Kosmachevskaya, Natalia N. Novikova and Alexey F. Topunov
Antioxidants 2021, 10(2), 253; https://doi.org/10.3390/antiox10020253 - 07 Feb 2021
Cited by 16 | Viewed by 6199
Abstract
The paper overviews the peculiarities of carbonyl stress in nucleus-free mammal red blood cells (RBCs). Some functional features of RBCs make them exceptionally susceptible to reactive carbonyl compounds (RCC) from both blood plasma and the intracellular environment. In the first case, these compounds [...] Read more.
The paper overviews the peculiarities of carbonyl stress in nucleus-free mammal red blood cells (RBCs). Some functional features of RBCs make them exceptionally susceptible to reactive carbonyl compounds (RCC) from both blood plasma and the intracellular environment. In the first case, these compounds arise from the increased concentrations of glucose or ketone bodies in blood plasma, and in the second—from a misbalance in the glycolysis regulation. RBCs are normally exposed to RCC—methylglyoxal (MG), triglycerides—in blood plasma of diabetes patients. MG modifies lipoproteins and membrane proteins of RBCs and endothelial cells both on its own and with reactive oxygen species (ROS). Together, these phenomena may lead to arterial hypertension, atherosclerosis, hemolytic anemia, vascular occlusion, local ischemia, and hypercoagulation phenotype formation. ROS, reactive nitrogen species (RNS), and RCC might also damage hemoglobin (Hb), the most common protein in the RBC cytoplasm. It was Hb with which non-enzymatic glycation was first shown in living systems under physiological conditions. Glycated HbA1c is used as a very reliable and useful diagnostic marker. Studying the impacts of MG, ROS, and RNS on the physiological state of RBCs and Hb is of undisputed importance for basic and applied science. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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17 pages, 3019 KiB  
Review
Interplay among Oxidative Stress, Methylglyoxal Pathway and S-Glutathionylation
by Lidia de Bari, Andrea Scirè, Cristina Minnelli, Laura Cianfruglia, Miklos Peter Kalapos and Tatiana Armeni
Antioxidants 2021, 10(1), 19; https://doi.org/10.3390/antiox10010019 - 28 Dec 2020
Cited by 29 | Viewed by 5399
Abstract
Reactive oxygen species (ROS) are produced constantly inside the cells as a consequence of nutrient catabolism. The balance between ROS production and elimination allows to maintain cell redox homeostasis and biological functions, avoiding the occurrence of oxidative distress causing irreversible oxidative damages. A [...] Read more.
Reactive oxygen species (ROS) are produced constantly inside the cells as a consequence of nutrient catabolism. The balance between ROS production and elimination allows to maintain cell redox homeostasis and biological functions, avoiding the occurrence of oxidative distress causing irreversible oxidative damages. A fundamental player in this fine balance is reduced glutathione (GSH), required for the scavenging of ROS as well as of the reactive 2-oxoaldehydes methylglyoxal (MGO). MGO is a cytotoxic compound formed constitutively as byproduct of nutrient catabolism, and in particular of glycolysis, detoxified in a GSH-dependent manner by the glyoxalase pathway consisting in glyoxalase I and glyoxalase II reactions. A physiological increase in ROS production (oxidative eustress, OxeS) is promptly signaled by the decrease of cellular GSH/GSSG ratio which can induce the reversible S-glutathionylation of key proteins aimed at restoring the redox balance. An increase in MGO level also occurs under oxidative stress (OxS) conditions probably due to several events among which the decrease in GSH level and/or the bottleneck of glycolysis caused by the reversible S-glutathionylation and inhibition of glyceraldehyde-3-phosphate dehydrogenase. In the present review, it is shown how MGO can play a role as a stress signaling molecule in response to OxeS, contributing to the coordination of cell metabolism with gene expression by the glycation of specific proteins. Moreover, it is highlighted how the products of MGO metabolism, S-D-lactoylglutathione (SLG) and D-lactate, which can be taken up and metabolized by mitochondria, could play important roles in cell response to OxS, contributing to cytosol-mitochondria crosstalk, cytosolic and mitochondrial GSH pools, energy production, and the restoration of the GSH/GSSG ratio. The role for SLG and glyoxalase II in the regulation of protein function through S-glutathionylation under OxS conditions is also discussed. Overall, the data reported here stress the need for further studies aimed at understanding what role the evolutionary-conserved MGO formation and metabolism can play in cell signaling and response to OxS conditions, the aberration of which may importantly contribute to the pathogenesis of diseases associated to elevated OxS. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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15 pages, 893 KiB  
Review
The Glyoxalase System—New Insights into an Ancient Metabolism
by Jakob Morgenstern, Marta Campos Campos, Peter Nawroth and Thomas Fleming
Antioxidants 2020, 9(10), 939; https://doi.org/10.3390/antiox9100939 - 01 Oct 2020
Cited by 26 | Viewed by 4130
Abstract
The glyoxalase system was discovered over a hundred years ago and since then it has been claimed to provide the role of an indispensable enzyme system in order to protect cells from a toxic byproduct of glycolysis. This review gives a broad overview [...] Read more.
The glyoxalase system was discovered over a hundred years ago and since then it has been claimed to provide the role of an indispensable enzyme system in order to protect cells from a toxic byproduct of glycolysis. This review gives a broad overview of what has been postulated in the last 30 years of glyoxalase research, but within this context it also challenges the concept that the glyoxalase system is an exclusive tool of detoxification and that its substrate, methylglyoxal, is solely a detrimental burden for every living cell due to its toxicity. An overview of consequences of a complete loss of the glyoxalase system in various model organisms is presented with an emphasis on the role of alternative detoxification pathways of methylglyoxal. Furthermore, this review focuses on the overlooked posttranslational modification of Glyoxalase 1 and its possible implications for cellular maintenance under various (patho-)physiological conditions. As a final note, an intriguing point of view for the substrate methylglyoxal is offered, the concept of methylglyoxal (MG)-mediated hormesis. Full article
(This article belongs to the Special Issue Redox Biology of Glyoxalases)
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