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Journal articles on the topic 'Dicarbonyl stress'

Author: Grafiati
Published: 25 May 2024

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1

Csongová, Melinda, Jean L. J. M. Scheijen, Marjo P. H. van de Waarenburg, Radana Gurecká, Ivana Koborová, Tamás Tábi, Éva Szökö, Casper G. Schalkwijk, and Katarína Šebeková. "Association of α-Dicarbonyls and Advanced Glycation End Products with Insulin Resistance in Non-Diabetic Young Subjects: A Case-Control Study." Nutrients 14, no. 22 (November 21, 2022): 4929. http://dx.doi.org/10.3390/nu14224929.

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α-Dicarbonyls and advanced glycation end products (AGEs) may contribute to the pathogenesis of insulin resistance by a variety of mechanisms. To investigate whether young insulin-resistant subjects present markers of increased dicarbonyl stress, we determined serum α-dicarbonyls-methylglyoxal, glyoxal, 3-deoxyglucosone; their derived free- and protein-bound, and urinary AGEs using the UPLC/MS-MS method; soluble receptors for AGEs (sRAGE), and cardiometabolic risk markers in 142 (49% females) insulin resistant (Quantitative Insulin Sensitivity Check Index (QUICKI) ≤ 0.319) and 167 (47% females) age-, and waist-to-height ratio-matched insulin-sensitive controls aged 16-to-22 years. The between-group comparison was performed using the two-factor (sex, presence/absence of insulin resistance) analysis of variance; multiple regression via the orthogonal projection to latent structures model. In comparison with their insulin-sensitive peers, young healthy insulin-resistant individuals without diabetes manifest alterations throughout the α-dicarbonyls-AGEs-sRAGE axis, dominated by higher 3-deoxyglucosone levels. Variables of α-dicarbonyls-AGEs-sRAGE axis were associated with insulin sensitivity independently from cardiometabolic risk markers, and sex-specifically. Cleaved RAGE associates with QUICKI only in males; while multiple α-dicarbonyls and AGEs independently associate with QUICKI particularly in females, who displayed a more advantageous cardiometabolic profile compared with males. Further studies are needed to elucidate whether interventions alleviating dicarbonyl stress ameliorate insulin resistance.
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2

Nigro, Cecilia, Alessia Leone, Francesca Fiory, Immacolata Prevenzano, Antonella Nicolò, Paola Mirra, Francesco Beguinot, and Claudia Miele. "Dicarbonyl Stress at the Crossroads of Healthy and Unhealthy Aging." Cells 8, no. 7 (July 19, 2019): 749. http://dx.doi.org/10.3390/cells8070749.

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Dicarbonyl stress occurs when dicarbonyl metabolites (i.e., methylglyoxal, glyoxal and 3-deoxyglucosone) accumulate as a consequence of their increased production and/or decreased detoxification. This toxic condition has been associated with metabolic and age-related diseases, both of which are characterized by a pro-inflammatory and pro-oxidant state. Methylglyoxal (MGO) is the most reactive dicarbonyl and the one with the highest endogenous flux. It is the precursor of the major quantitative advanced glycated products (AGEs) in physiological systems, arginine-derived hydroimidazolones, which accumulate in aging and dysfunctional tissues. The aging process is characterized by a decline in the functional properties of cells, tissues and whole organs, starting from the perturbation of crucial cellular processes, including mitochondrial function, proteostasis and stress-scavenging systems. Increasing studies are corroborating the causal relationship between MGO-derived AGEs and age-related tissue dysfunction, unveiling a previously underestimated role of dicarbonyl stress in determining healthy or unhealthy aging. This review summarizes the latest evidence supporting a causal role of dicarbonyl stress in age-related diseases, including diabetes mellitus, cardiovascular disease and neurodegeneration.
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Ahmad, Khurshid, Sibhghatulla Shaikh, Eun Ju Lee, Yong-Ho Lee, and Inho Choi. "Consequences of Dicarbonyl Stress on Skeletal Muscle Proteins in Type 2 Diabetes." Current Protein & Peptide Science 21, no. 9 (December 11, 2020): 878–89. http://dx.doi.org/10.2174/1389203720666191119100759.

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Skeletal muscle is the largest organ in the body and constitutes almost 40% of body mass. It is also the primary site of insulin-mediated glucose uptake, and skeletal muscle insulin resistance, that is, diminished response to insulin, is characteristic of Type 2 diabetes (T2DM). One of the foremost reasons posited to explain the etiology of T2DM involves the modification of proteins by dicarbonyl stress due to an unbalanced metabolism and accumulations of dicarbonyl metabolites. The elevated concentration of dicarbonyl metabolites (i.e., glyoxal, methylglyoxal, 3-deoxyglucosone) leads to DNA and protein modifications, causing cell/tissue dysfunctions in several metabolic diseases such as T2DM and other age-associated diseases. In this review, we recapitulated reported effects of dicarbonyl stress on skeletal muscle and associated extracellular proteins with emphasis on the impact of T2DM on skeletal muscle and provided a brief introduction to the prevention/inhibition of dicarbonyl stress.
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Rabbani, Naila, Mingzhan Xue, and Paul J. Thornalley. "Methylglyoxal-induced dicarbonyl stress in aging and disease: first steps towards glyoxalase 1-based treatments." Clinical Science 130, no. 19 (August 23, 2016): 1677–96. http://dx.doi.org/10.1042/cs20160025.

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Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in aging and disease. It is produced by increased formation and/or decreased metabolism of dicarbonyl metabolites. MG (methylglyoxal) is a dicarbonyl metabolite of relatively high flux of formation and precursor of the most quantitatively and functionally important spontaneous modifications of protein and DNA clinically. Major MG-derived adducts are arginine-derived hydroimidazolones of protein and deoxyguanosine-derived imidazopurinones of DNA. These are formed non-oxidatively. The glyoxalase system provides an efficient and essential basal and stress-response-inducible enzymatic defence against dicarbonyl stress by the reduced glutathione-dependent metabolism of methylglyoxal by glyoxalase 1. The GLO1 gene encoding glyoxalase 1 has low prevalence duplication and high prevalence amplification in some tumours. Dicarbonyl stress contributes to aging, disease and activity of cytotoxic chemotherapeutic agents. It is found at a low, moderate and severe level in obesity, diabetes and renal failure respectively, where it contributes to the development of metabolic and vascular complications. Increased glyoxalase 1 expression confers multidrug resistance to cancer chemotherapy and has relatively high prevalence in liver, lung and breast cancers. Studies of dicarbonyl stress are providing improved understanding of aging and disease and the basis for rational design of novel pharmaceuticals: glyoxalase 1 inducers for obesity, diabetes and cardiovascular disease and glyoxalase 1 inhibitors for multidrug-resistant tumours. The first clinical trial of a glyoxalase 1 inducer in overweight and obese subjects showed improved glycaemic control, insulin resistance and vascular function.
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5

Tatone, Carla, Ursula Eichenlaub-Ritter, and Fernanda Amicarelli. "Dicarbonyl stress and glyoxalases in ovarian function." Biochemical Society Transactions 42, no. 2 (March 20, 2014): 433–38. http://dx.doi.org/10.1042/bst20140023.

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The ovary is the main regulator of female fertility. Changes in maternal health and physiology can disrupt intraovarian homoeostasis thereby compromising oocyte competence and fertility. Research has only recently devoted attention to the involvement of dicarbonyl stress in ovarian function. On this basis, the present review focuses on clinical and experimental research supporting the role of dicarbonyl overload and AGEs (advanced glycation end-products) as key contributors to perturbations of the ovarian microenvironment leading to lower fertility. Particular emphasis has been given to oocyte susceptibility to methylglyoxal, a powerful glycating agent, whose levels are known to increase during aging and metabolic disorders. According to the literature, the ovary and the oocyte itself can rely on the glyoxalase system to counteract the possible dicarbonyl overload such as that which may occur in reproductive-age women and patients with PCOS (polycystic ovarian syndrome) or diabetes. Overall, although biochemical methods for proper evaluation of dicarbonyl stress in oocytes and the ovarian microenvironment need to be established, AGEs can be proposed as predictive markers and/or therapeutic targets in new strategies for improving reproductive counselling and infertility therapies.
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6

Masania, Jinit, Malgorzata Malczewska-Malec, Urszula Razny, Joanna Goralska, Anna Zdzienicka, Beata Kiec-Wilk, Anna Gruca, et al. "Dicarbonyl stress in clinical obesity." Glycoconjugate Journal 33, no. 4 (June 24, 2016): 581–89. http://dx.doi.org/10.1007/s10719-016-9692-0.

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7

Alouffi, Sultan, and Mohd Wajid Ali Khan. "Dicarbonyls Generation, Toxicities, Detoxifications and Potential Roles in Diabetes Complications." Current Protein & Peptide Science 21, no. 9 (December 11, 2020): 890–98. http://dx.doi.org/10.2174/1389203720666191010155145.

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It has been well established that advanced glycation end-products (AGEs) have a strong correlation with diabetes and its secondary complications. Moreover, dicarbonyls, especially, methylglyoxal (MG) and glyoxal, accelerate AGEs formation and hence, have potential roles in the pathogenesis of diabetes. They can also induce oxidative stress and concomitantly decrease the efficiency of antioxidant enzymes. Increased proinflammatory cytokines (tumor necrosis factor-α and interleukin- 1β) are secreted by monocytes due to the dicarbonyl-modified proteins. High levels of blood dicarbonyls have been identified in diabetes and its associated complications (retinopathy, nephropathy and neuropathy). This review aims to provide a better understanding by including in-depth information about the formation of MG and glyoxal through multiple pathways with a focus on their biological functions and detoxifications. The potential role of these dicarbonyls in secondary diabetic complications is also discussed.
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8

Rabbani, Naila, and Paul J. Thornalley. "Dicarbonyls linked to damage in the powerhouse: glycation of mitochondrial proteins and oxidative stress." Biochemical Society Transactions 36, no. 5 (September 19, 2008): 1045–50. http://dx.doi.org/10.1042/bst0361045.

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Protection of mitochondrial proteins from glycation by endogenous dicarbonyl compounds, methylglyoxal and glyoxal, was found recently to prevent increased formation of reactive oxygen species and oxidative and nitrosative damage to the proteome during aging and produce life extension in the nematode Caenorhabditis elegans. This suggests that dicarbonyl glycation damage to the mitochondrial proteome may be a preceding event to mitochondrial dysfunction leading to oxidative stress. Future research will address the functional charges in mitochondrial proteins that are the targets for dicarbonyl glycation.
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9

Mey, Jacob T., Brian K. Blackburn, Edwin R. Miranda, Alec B. Chaves, Joan Briller, Marcelo G. Bonini, and Jacob M. Haus. "Dicarbonyl stress and glyoxalase enzyme system regulation in human skeletal muscle." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 314, no. 2 (February 1, 2018): R181—R190. http://dx.doi.org/10.1152/ajpregu.00159.2017.

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Skeletal muscle insulin resistance is a hallmark of Type 2 diabetes (T2DM) and may be exacerbated by protein modifications by methylglyoxal (MG), known as dicarbonyl stress. The glyoxalase enzyme system composed of glyoxalase 1/2 (GLO1/GLO2) is the natural defense against dicarbonyl stress, yet its protein expression, activity, and regulation remain largely unexplored in skeletal muscle. Therefore, this study investigated dicarbonyl stress and the glyoxalase enzyme system in the skeletal muscle of subjects with T2DM (age: 56 ± 5 yr.; BMI: 32 ± 2 kg/m2) compared with lean healthy control subjects (LHC; age: 27 ± 1 yr.; BMI: 22 ± 1 kg/m2). Skeletal muscle biopsies obtained from the vastus lateralis at basal and insulin-stimulated states of the hyperinsulinemic (40 mU·m−2·min−1)–euglycemic (5 mM) clamp were analyzed for proteins related to dicarbonyl stress and glyoxalase biology. At baseline, T2DM had increased carbonyl stress and lower GLO1 protein expression (−78.8%), which inversely correlated with BMI, percent body fat, and HOMA-IR, while positively correlating with clamp-derived glucose disposal rates. T2DM also had lower NRF2 protein expression (−31.6%), which is a positive regulator of GLO1, while Keap1 protein expression, a negative regulator of GLO1, was elevated (207%). Additionally, insulin stimulation during the clamp had a differential effect on NRF2, Keap1, and MG-modified protein expression. These data suggest that dicarbonyl stress and the glyoxalase enzyme system are dysregulated in T2DM skeletal muscle and may underlie skeletal muscle insulin resistance. Whether these phenotypic differences contribute to the development of T2DM warrants further investigation.
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10

Antognelli, Cinzia, Andrea Perrelli, Tatiana Armeni, Vincenzo Nicola Talesa, and Saverio Francesco Retta. "Dicarbonyl Stress and S-Glutathionylation in Cerebrovascular Diseases: A Focus on Cerebral Cavernous Malformations." Antioxidants 9, no. 2 (February 1, 2020): 124. http://dx.doi.org/10.3390/antiox9020124.

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Dicarbonyl stress is a dysfunctional state consisting in the abnormal accumulation of reactive α-oxaldehydes leading to increased protein modification. In cells, post-translational changes can also occur through S-glutathionylation, a highly conserved oxidative post-translational modification consisting of the formation of a mixed disulfide between glutathione and a protein cysteine residue. This review recapitulates the main findings supporting a role for dicarbonyl stress and S-glutathionylation in the pathogenesis of cerebrovascular diseases, with specific emphasis on cerebral cavernous malformations (CCM), a vascular disease of proven genetic origin that may give rise to various clinical signs and symptoms at any age, including recurrent headaches, seizures, focal neurological deficits, and intracerebral hemorrhage. A possible interplay between dicarbonyl stress and S-glutathionylation in CCM is also discussed.
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11

Shafie, Alaa, Mingzhan Xue, Guy Barker, Daniel Zehnder, Paul J. Thornalley, and Naila Rabbani. "Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cells in vitro." Biochemical Journal 473, no. 22 (November 10, 2016): 4255–70. http://dx.doi.org/10.1042/bcj20160691.

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Glyoxalase 1 (Glo1) is a cytoplasmic enzyme with a cytoprotective function linked to metabolism of the cytotoxic side product of glycolysis, methylglyoxal (MG). It prevents dicarbonyl stress — the abnormal accumulation of reactive dicarbonyl metabolites, increasing protein and DNA damage. Increased Glo1 expression delays ageing and suppresses carcinogenesis, insulin resistance, cardiovascular disease and vascular complications of diabetes and renal failure. Surprisingly, gene trapping by the International Mouse Knockout Consortium (IMKC) to generate putative Glo1 knockout mice produced a mouse line with the phenotype characterised as normal and healthy. Here, we show that gene trapping mutation was successful, but the presence of Glo1 gene duplication, probably in the embryonic stem cells (ESCs) before gene trapping, maintained wild-type levels of Glo1 expression and activity and sustained the healthy phenotype. In further investigation of the consequences of dicarbonyl stress in ESCs, we found that prolonged exposure of mouse ESCs in culture to high concentrations of MG and/or hypoxia led to low-level increase in Glo1 copy number. In clinical translation, we found a high prevalence of low-level GLO1 copy number increase in renal failure where there is severe dicarbonyl stress. In conclusion, the IMKC Glo1 mutant mouse is not deficient in Glo1 expression through duplication of the Glo1 wild-type allele. Dicarbonyl stress and/or hypoxia induces low-level copy number alternation in ESCs. Similar processes may drive rare GLO1 duplication in health and disease.
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12

Laus, Maura Nicoletta, Federica Blando, and Mario Soccio. "Glyoxalase I Assay as a Possible Tool for Evaluation of Biological Activity of Antioxidant-Rich Plant Extracts." Plants 12, no. 5 (March 3, 2023): 1150. http://dx.doi.org/10.3390/plants12051150.

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The health-promoting properties of natural plant bioactive compounds are mainly attributable to their ability to counteract oxidative stress. This is considered a major causative factor in aging and aging-related human diseases, in which a causal role is also ascribed to dicarbonyl stress. This is due to accumulation of methylglyoxal (MG) and other reactive dicarbonyl species, leading to macromolecule glycation and cell/tissue dysfunction. The glyoxalase (GLYI) enzyme, catalyzing the rate-limiting step of the GSH-dependent MG detoxification pathway, plays a key role in cell defense against dicarbonyl stress. Therefore, the study of GLYI regulation is of relevant interest. In particular, GLYI inducers are important for pharmacological interventions to sustain healthy aging and to improve dicarbonyl-related diseases; GLYI inhibitors, allowing increased MG levels to act as proapoptotic agents in tumor cells, are of special interest in cancer treatment. In this study, we performed a new in vitro exploration of biological activity of plant bioactive compounds by associating the measurement of their antioxidant capacity (AC) with the evaluation of their potential impact on dicarbonyl stress measured as capability to modulate GLYI activity. AC was evaluated using TEAC, ORAC, and LOX-FL methods. The GLYI assay was performed using a human recombinant isoform, in comparison with the recently characterized GLYI activity of durum wheat mitochondria. Different plant extracts were tested, obtained from plant sources with very high phytochemical content (‘Sun Black’ and wildtype tomatoes, black and ‘Polignano’ carrots, and durum wheat grain). Results showed high antioxidant properties of the tested extracts, associated with different modes (no effect, activation, and inhibition) and effectiveness in modulating both GLYI activity sources. Overall, results indicate the GLYI assay as an advisable and promising tool for researching plant foods as a source of natural antioxidant compounds acting as GLYI enzymatic regulators to be used for dietary management associated the treatment of oxidative/dicarbonyl-promoted diseases.
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13

Stratmann, Bernd. "Dicarbonyl Stress in Diabetic Vascular Disease." International Journal of Molecular Sciences 23, no. 11 (May 31, 2022): 6186. http://dx.doi.org/10.3390/ijms23116186.

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Late vascular complications play a prominent role in the diabetes-induced increase in morbidity and mortality. Diabetes mellitus is recognised as a risk factor driving atherosclerosis and cardiovascular mortality; even after the normalisation of blood glucose concentration, the event risk is amplified—an effect called “glycolytic memory”. The hallmark of this glycolytic memory and diabetic pathology are advanced glycation end products (AGEs) and reactive glucose metabolites such as methylglyoxal (MGO), a highly reactive dicarbonyl compound derived mainly from glycolysis. MGO and AGEs have an impact on vascular and organ structure and function, contributing to organ damage. As MGO is not only associated with hyperglycaemia in diabetes but also with other risk factors for diabetic vascular complications such as obesity, dyslipidaemia and hypertension, MGO is identified as a major player in the development of vascular complications in diabetes both on micro- as well as macrovascular level. In diabetes mellitus, the detoxifying system for MGO, the glyoxalase system, is diminished, accounting for the increased MGO concentration and glycotoxic load. This overview will summarise current knowledge on the effect of MGO and AGEs on vascular function.
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14

Park, Min, Takanori Nishimura, Carlos D. Baeza-Garza, Stuart T. Caldwell, Pamela Boon Li Pun, Hiran A. Prag, Tim Young, et al. "Confirmation of the Cardioprotective Effect of MitoGamide in the Diabetic Heart." Cardiovascular Drugs and Therapy 34, no. 6 (September 26, 2020): 823–34. http://dx.doi.org/10.1007/s10557-020-07086-7.

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Abstract Purpose HFpEF (heart failure with preserved ejection fraction) is a major consequence of diabetic cardiomyopathy with no effective treatments. Here, we have characterized Akita mice as a preclinical model of HFpEF and used it to confirm the therapeutic efficacy of the mitochondria-targeted dicarbonyl scavenger, MitoGamide. Methods and Results A longitudinal echocardiographic analysis confirmed that Akita mice develop diastolic dysfunction with reduced E peak velocity, E/A ratio and extended isovolumetric relaxation time (IVRT), while the systolic function remains comparable with wild-type mice. The myocardium of Akita mice had a decreased ATP/ADP ratio, elevated mitochondrial oxidative stress and increased organelle density, compared with that of wild-type mice. MitoGamide, a mitochondria-targeted 1,2-dicarbonyl scavenger, exhibited good stability in vivo, uptake into cells and mitochondria and reactivity with dicarbonyls. Treatment of Akita mice with MitoGamide for 12 weeks significantly improved the E/A ratio compared with the vehicle-treated group. Conclusion Our work confirms that the Akita mouse model of diabetes replicates key clinical features of diabetic HFpEF, including cardiac and mitochondrial dysfunction. Furthermore, in this independent study, MitoGamide treatment improved diastolic function in Akita mice.
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15

Peter, Andreas, Erwin Schleicher, Elisabeth Kliemank, Julia Szendroedi, Alfred Königsrainer, Hans-Ulrich Häring, Peter P. Nawroth, and Thomas Fleming. "Accumulation of Non-Pathological Liver Fat Is Associated with the Loss of Glyoxalase I Activity in Humans." Metabolites 14, no. 4 (April 7, 2024): 209. http://dx.doi.org/10.3390/metabo14040209.

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The underlying molecular mechanisms for the development of non-alcoholic fatty liver (NAFL) and its progression to advanced liver diseases remain elusive. Glyoxalase 1 (Glo1) loss, leading to elevated methylglyoxal (MG) and dicarbonyl stress, has been implicated in various diseases, including obesity-related conditions. This study aimed to investigate changes in the glyoxalase system in individuals with non-pathological liver fat. Liver biopsies were obtained from 30 individuals with a narrow range of BMI (24.6–29.8 kg/m2). Whole-body insulin sensitivity was assessed using HOMA-IR. Liver biopsies were analyzed for total triglyceride content, Glo1 and Glo2 mRNA, protein expression, and activity. Liquid chromatography–tandem mass spectrometry determined liver dicarbonyl content and oxidation and glycation biomarkers. Liver Glo1 activity showed an inverse correlation with HOMA-IR and liver triglyceride content, but not BMI. Despite reduced Glo1 activity, no associations were found with elevated liver dicarbonyls or glycation markers. A sex dimorphism was observed in Glo1, with females exhibiting significantly lower liver Glo1 protein expression and activity, and higher liver MG-H1 content compared to males. This study demonstrates that increasing liver fat, even within a non-pathological range, is associated with reduced Glo1 activity.
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Liccardo, Maria, Luigi Sapio, Shana Perrella, Ivana Sirangelo, and Clara Iannuzzi. "Genistein Prevents Apoptosis and Oxidative Stress Induced by Methylglyoxal in Endothelial Cells." Molecules 29, no. 8 (April 10, 2024): 1712. http://dx.doi.org/10.3390/molecules29081712.

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Glycolytic overload promotes accumulation of the highly reactive dicarbonyl compounds, resulting in harmful conditions called dicarbonyl stress. Methylglyoxal (MG) is a highly reactive dicarbonyl species and its accumulation plays a crucial pathophysiological role in diabetes and its vascular complications. MG cytotoxicity is mediated by reactive oxygen species (ROS) generation, a key event underlying the intracellular signaling pathways leading to inflammation and apoptosis. The identification of compounds able to inhibit ROS signaling pathways and counteract the MG-induced toxicity is a crucial step for developing new therapeutic strategies in the treatment of diabetic vascular complications. In this study, the effect of genistein, a natural soybean isoflavone, has been evaluated on MG-induced cytotoxicity in human endothelial cells. Our results show that genistein is able to counteract the MG-induced apoptosis by restraining ROS production, thus inhibiting the MAPK signaling pathways and caspase-3 activation. These findings identify a beneficial role for genistein, providing new insights for its potential clinical applications in preserving endothelial function in diabetic vascular complications.
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Syed, Nida Ali, Attya Bhatti, and Peter John. "Molecular Link between Glo-1 Expression and Markers of Hyperglycemia and Oxidative Stress in Vascular Complications of Type 2 Diabetes Mellitus." Antioxidants 12, no. 9 (August 23, 2023): 1663. http://dx.doi.org/10.3390/antiox12091663.

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Chronic hyperglycemia and oxidative stress in Type 2 Diabetes Mellitus trigger cellular dysfunction via the formation of Advanced Glycation End Products (AGEs), resulting in dicarbonyl stress. Glyoxalase-1 (Glo-1) is the main defense against dicarbonyl stress. The aim of this study was to explore any cross-talk between Glo-1 and markers of hyperglycemia and oxidative stress. The siRNA-mediated downregulation of Glo-1 was performed in human microvascular endothelial cell line (HMEC-1). A Glo-1 transgenic rat model was developed. Glo-1 activity, as determined spectrophotometrically, and methylglyoxal were quantified using UPLC-MS/MS and the expression of representative markers of hyperglycemia and oxidative stress was performed using quantitative real-time PCR. A significant increase in the expression of Vascular Cell Adhesion Molecule-1 (VCAM-1) was observed in the case of the siRNA-mediated downregulation of Glo-1 in the microvasculature model under hyperglycemic conditions (p-value < 0.001), as well the as overexpression of Glo-1 in the macrovasculature (p-value = 0.0125). The expression of thioredoxin interacting protein (TXNIP) was found to be significantly upregulated in wildtype diabetic conditions vs. Glo-1 transgenic control conditions (p-value = 0.008), whereas the downregulation of Glo-1 had no impact on TXNIP expression. These findings substantiate the role of VCAM as an important marker of dicarbonyl stress (represented by Glo-1 downregulation), as well as of hyperglycemia, in diabetic vascular complications. Our findings also suggest a potential feedback loop that may exist between Glo-1 and TXNIP, as the highest expression of TXNIP is observed in cases of wildtype diabetic conditions, and the lowest expression of TXNIP is observed when Glo-1 transgene is being expressed in absence of dicarbonyl stress.
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18

Yumnam, Silvia, Lalita Subedi, and Sun Yeou Kim. "Glyoxalase System in the Progression of Skin Aging and Skin Malignancies." International Journal of Molecular Sciences 22, no. 1 (December 30, 2020): 310. http://dx.doi.org/10.3390/ijms22010310.

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Dicarbonyl compounds, including methylglyoxal (MGO) and glyoxal (GO), are mainly formed as byproducts of glucose metabolism. The main glyoxalase system consists of glyoxalase I and II (Glo1 and Glo2) and is the main enzyme involved in the detoxification of dicarbonyl stress, which occurs as an accumulation of MGO or GO due to decreased activity or expression of Glo1. Dicarbonyl stress is a major cause of cellular and tissue dysfunction that causes various health issues, including diabetes, aging, and cancer. The skin is the largest organ in the body. In this review, we discuss the role of the glyoxalase system in the progression of skin aging, and more importantly, skin malignancies. We also discuss the future prospects of the glyoxalase system in other skin abnormalities such as psoriasis and vitiligo, including hyperpigmentation. Finally, in the present review, we suggest the role of glyoxalase in the progression of skin aging and glyoxalase system as a potential target for anticancer drug development for skin cancer.
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19

Xue, Mingzhan, Naila Rabbani, Hiroshi Momiji, Precious Imbasi, M. Maqsud Anwar, Neil Kitteringham, B. Kevin Park, et al. "Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation." Biochemical Journal 443, no. 1 (March 14, 2012): 213–22. http://dx.doi.org/10.1042/bj20111648.

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Abnormal cellular accumulation of the dicarbonyl metabolite MG (methylglyoxal) occurs on exposure to high glucose concentrations, inflammation, cell aging and senescence. It is associated with increased MG-adduct content of protein and DNA linked to increased DNA strand breaks and mutagenesis, mitochondrial dysfunction and ROS (reactive oxygen species) formation and cell detachment from the extracellular matrix. MG-mediated damage is countered by glutathione-dependent metabolism by Glo1 (glyoxalase 1). It is not known, however, whether Glo1 has stress-responsive up-regulation to counter periods of high MG concentration or dicarbonyl stress. We identified a functional ARE (antioxidant-response element) in the 5′-untranslated region of exon 1 of the mammalian Glo1 gene. Transcription factor Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) binds to this ARE, increasing basal and inducible expression of Glo1. Activators of Nrf2 induced increased Glo1 mRNA, protein and activity. Increased expression of Glo1 decreased cellular and extracellular concentrations of MG, MG-derived protein adducts, mutagenesis and cell detachment. Hepatic, brain, heart, kidney and lung Glo1 mRNA and protein were decreased in Nrf2−/− mice, and urinary excretion of MG protein and nucleotide adducts were increased approximately 2-fold. We conclude that dicarbonyl stress is countered by up-regulation of Glo1 in the Nrf2 stress-responsive system, protecting protein and DNA from increased damage and preserving cell function.
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Muniyappa, Ranganath, and Pothur R. Srinivas. "Dicarbonyl Stress and Atherosclerosis: Is It All RAGE?" Diabetes 63, no. 11 (October 23, 2014): 3587–89. http://dx.doi.org/10.2337/db14-0953.

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21

Cruz, Nadia, Marcos Flores, Inés Urquiaga, and Felipe Ávila. "Modulation of 1,2-Dicarbonyl Compounds in Postprandial Responses Mediated by Food Bioactive Components and Mediterranean Diet." Antioxidants 11, no. 8 (August 3, 2022): 1513. http://dx.doi.org/10.3390/antiox11081513.

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Glycoxidative stress with the consequent generation of advanced glycation end products has been implied in the etiology of numerous non-communicable chronic diseases. During the postprandial state, the levels of 1,2-dicarbonyl compounds can increase, depending on numerous factors, including characteristics of the subjects mainly related to glucose metabolism disorders and nutritional status, as well as properties related to the chemical composition of meals, including macronutrient composition and the presence of dietary bioactive molecules and macromolecules. In this review, we examine the chemical, biochemical, and physiological pathways that contribute to postprandial generation of 1,2-dicarbonyl compounds. The modulation of postprandial 1,2-dicarbonyl compounds is discussed in terms of biochemical pathways regulating the levels of these compounds, as well as the effect of phenolic compounds, dietary fiber, and dietary patterns, such as Mediterranean and Western diets.
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22

Rabbani, Naila. "Methylglyoxal and glyoxalase 1—a metabolic stress pathway-linking hyperglycemia to the unfolded protein response and vascular complications of diabetes." Clinical Science 136, no. 11 (May 30, 2022): 819–24. http://dx.doi.org/10.1042/cs20220099.

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Abstract The study of the glyoxalase system by Thornalley and co-workers in clinical diabetes mellitus and correlation with diabetic complications revealed increased exposure of patients with diabetes to the reactive, dicarbonyl metabolite methylglyoxal (MG). Twenty-eight years later, extended and built on by Thornalley and co-workers and others, the glyoxalase system is an important pathway contributing to the development of insulin resistance and vascular complications of diabetes. Other related advances have been: characterization of a new kind of metabolic stress—‘dicarbonyl stress’; identification of the major physiological advanced glycation endproduct (AGE), MG-H1; physiological substrates of the unfolded protein response (UPR); new therapeutic agents—‘glyoxalase 1 (Glo1) inducers’; and a refined mechanism underlying the link of dysglycemia to the development of insulin resistance and vascular complications of diabetes.
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Rabbani, Naila, Maryam Al-Motawa, and Paul J. Thornalley. "Protein Glycation in Plants—An Under-Researched Field with Much Still to Discover." International Journal of Molecular Sciences 21, no. 11 (May 30, 2020): 3942. http://dx.doi.org/10.3390/ijms21113942.

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Recent research has identified glycation as a non-enzymatic post-translational modification of proteins in plants with a potential contributory role to the functional impairment of the plant proteome. Reducing sugars with a free aldehyde or ketone group such as glucose, fructose and galactose react with the N-terminal and lysine side chain amino groups of proteins. A common early-stage glycation adduct formed from glucose is Nε-fructosyl-lysine (FL). Saccharide-derived reactive dicarbonyls are arginine residue-directed glycating agents, forming advanced glycation endproducts (AGEs). A dominant dicarbonyl is methylglyoxal—formed mainly by the trace-level degradation of triosephosphates, including through the Calvin cycle of photosynthesis. Methylglyoxal forms the major quantitative AGE, hydroimidazolone MG-H1. Glucose and methylglyoxal concentrations in plants change with the developmental stage, senescence, light and dark cycles and also likely biotic and abiotic stresses. Proteomics analysis indicates that there is an enrichment of the amino acid residue targets of glycation, arginine and lysine residues, in predicted functional sites of the plant proteome, suggesting the susceptibility of proteins to functional inactivation by glycation. In this review, we give a brief introduction to glycation, glycating agents and glycation adducts in plants. We consider dicarbonyl stress, the functional vulnerability of the plant proteome to arginine-directed glycation and the likely role of methylglyoxal-mediated glycation in the activation of the unfolded protein response in plants. The latter is linked to the recent suggestion of protein glycation in sugar signaling in plant metabolism. The overexpression of glyoxalase 1, which suppresses glycation by methylglyoxal and glyoxal, produced plants resistant to high salinity, drought, extreme temperature and other stresses. Further research to decrease protein glycation in plants may lead to improved plant growth and assist the breeding of plant varieties resistant to environmental stress and senescence—including plants of commercial ornamental and crop cultivation value.
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Subati, Tuerdi, Zhenjiang Yang, Matthew B. Murphy, Joshua M. Stark, David Z. Trykall, Sean S. Davies, Joey V. Barnett, and Katherine T. Murray. "Isolevuglandins Promote Mitochondrial Dysfunction and Electrophysiologic Abnormalities in Atrial Cardiomyocytes." Cells 13, no. 6 (March 9, 2024): 483. http://dx.doi.org/10.3390/cells13060483.

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Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, yet the cellular and molecular mechanisms underlying the AF substrate remain unclear. Isolevuglandins (IsoLGs) are highly reactive lipid dicarbonyl products that mediate oxidative stress-related injury. In murine hypertension, the lipid dicarbonyl scavenger 2-hydroxybenzylamine (2-HOBA) reduced IsoLGs and AF susceptibility. We hypothesized that IsoLGs mediate detrimental pathophysiologic effects in atrial cardiomyocytes that promote the AF substrate. Using Seahorse XFp extracellular flux analysis and a luminescence assay, IsoLG exposure suppressed intracellular ATP production in atrial HL-1 cardiomyocytes. IsoLGs caused mitochondrial dysfunction, with reduced mitochondrial membrane potential, increased mitochondrial reactive oxygen species (ROS) with protein carbonylation, and mitochondrial DNA damage. Moreover, they generated cytosolic preamyloid oligomers previously shown to cause similar detrimental effects in atrial cells. In mouse atrial and HL-1 cells, patch clamp experiments demonstrated that IsoLGs rapidly altered action potentials (AP), implying a direct effect independent of oligomer formation by reducing the maximum Phase 0 upstroke slope and shortening AP duration due to ionic current modifications. IsoLG-mediated mitochondrial and electrophysiologic abnormalities were blunted or totally prevented by 2-HOBA. These findings identify IsoLGs as novel mediators of oxidative stress-dependent atrial pathophysiology and support the investigation of dicarbonyl scavengers as a novel therapeutic approach to prevent AF.
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Kolibabka, M., P. Friedrichs, N. Dietrich, T. Fleming, A. Schlotterer, and H. P. Hammes. "Dicarbonyl Stress Mimics Diabetic Neurovascular Damage in the Retina." Experimental and Clinical Endocrinology & Diabetes 124, no. 07 (May 24, 2016): 437–39. http://dx.doi.org/10.1055/s-0042-106081.

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26

Sabrina, Radjei, Leblanc Emmanuelle, Schnebert Sylvianne, Nizard Carine, Friguet Bertrand, and Petropoulos Isabelle. "Skin protection against dicarbonyl stress by the glyoxalase system." Free Radical Biology and Medicine 75 (October 2014): S19—S20. http://dx.doi.org/10.1016/j.freeradbiomed.2014.10.635.

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27

Cepas, Vanesa, Friederike Manig, Juan C. Mayo, Michael Hellwig, Debora Collotta, Valentina Sanmartino, Rebeca Carrocera-Pumarino, Massimo Collino, Thomas Henle, and Rosa M. Sainz. "In Vitro Evaluation of the Toxicological Profile and Oxidative Stress of Relevant Diet-Related Advanced Glycation End Products and Related 1,2-Dicarbonyls." Oxidative Medicine and Cellular Longevity 2021 (August 8, 2021): 1–20. http://dx.doi.org/10.1155/2021/9912240.

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During food processing and storage, and in tissues and fluids under physiological conditions, the Maillard reaction occurs. During this reaction, reactive 1,2-dicarbonyl compounds arise as intermediates that undergo further reactions to form advanced glycation end products (AGEs). Diet is the primary source of exogenous AGEs. Endogenously formed AGEs have been proposed as a risk factor in the pathogenesis of diet-related diseases such as diabetes, insulin resistance, cardiovascular diseases, or chronic disease. AGEs may differently contribute to the diet-related exacerbation of oxidative stress, inflammation, and protein modifications. Here, to understand the contribution of each compound, we tested individually, for the first time, the effect of five 1,2-dicarbonyl compounds 3-deoxyglucosone (3-DG), 3-deoxygalactosone (3-DGal), 3,4-dideoxyglucosone-3-ene (3,4-DGE), glyoxal (GO), and methylglyoxal (MGO) and four different glycated amino acids N-ε-(carboxyethyl)lysine (CEL), N- ε -(carboxymethyl)lysine (CML), methylglyoxal-derived hydroimidazolone-1 (MG-H1), and pyrraline (Pyrr) in a cell line of human keratinocytes (HaCaT). We found that most of the glycated amino acids, i.e., CEL, CML, and MG-H1, did not show any cytotoxicity. At the same time, 1,2-dicarbonyl compounds 3-DGal, 3,4-DGE, GO, and MGO increased the production of reactive oxygen species and induced cell death. MGO induced cell death by apoptosis, whereas 3-DGal and 3,4-DGE induced nuclear translocation of the proinflammatory NF-κB transcription pathway, and the activation of the pyroptosis-related NLRP3 inflammasome cascade. Overall, these results demonstrate the higher toxic impact of 1,2-dicarbonyl compounds on mucosal epithelial cells when compared to glycated amino acids and the selective activation of intracellular signaling pathways involved in the crosstalk mechanisms linking oxidative stress to excessive inflammation.
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Rabbani, Naila, and Paul J. Thornalley. "Emerging Glycation-Based Therapeutics—Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors." International Journal of Molecular Sciences 23, no. 5 (February 23, 2022): 2453. http://dx.doi.org/10.3390/ijms23052453.

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The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)—a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer—particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.
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McCarty, Mark F., James J. DiNicolantonio, and James H. O’Keefe. "Nutraceutical Prevention of Diabetic Complications—Focus on Dicarbonyl and Oxidative Stress." Current Issues in Molecular Biology 44, no. 9 (September 18, 2022): 4314–38. http://dx.doi.org/10.3390/cimb44090297.

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Oxidative and dicarbonyl stress, driven by excess accumulation of glycolytic intermediates in cells that are highly permeable to glucose in the absence of effective insulin activity, appear to be the chief mediators of the complications of diabetes. The most pathogenically significant dicarbonyl stress reflects spontaneous dephosphorylation of glycolytic triose phosphates, giving rise to highly reactive methylglyoxal. This compound can be converted to harmless lactate by the sequential activity of glyoxalase I and II, employing glutathione as a catalyst. The transcription of glyoxalase I, rate-limiting for this process, is promoted by Nrf2, which can be activated by nutraceutical phase 2 inducers such as lipoic acid and sulforaphane. In cells exposed to hyperglycemia, glycine somehow up-regulates Nrf2 activity. Zinc can likewise promote glyoxalase I transcription, via activation of the metal-responsive transcription factor (MTF) that binds to the glyoxalase promoter. Induction of glyoxalase I and metallothionein may explain the protective impact of zinc in rodent models of diabetic complications. With respect to the contribution of oxidative stress to diabetic complications, promoters of mitophagy and mitochondrial biogenesis, UCP2 inducers, inhibitors of NAPDH oxidase, recouplers of eNOS, glutathione precursors, membrane oxidant scavengers, Nrf2 activators, and correction of diabetic thiamine deficiency should help to quell this.
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30

Cordone, Valeria, Alessandra Pecorelli, Mascia Benedusi, Silvano Santini, Stefano Falone, Joussef Hayek, Fernanda Amicarelli, and Giuseppe Valacchi. "Antiglycative Activity and RAGE Expression in Rett Syndrome." Cells 8, no. 2 (February 15, 2019): 161. http://dx.doi.org/10.3390/cells8020161.

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Rett syndrome (RTT) is a human neurodevelopmental disorder, whose pathogenesis has been linked to both oxidative stress and subclinical inflammatory status (OxInflammation). Methylglyoxal (MG), a glycolytic by-product with cytotoxic and pro-oxidant power, is the major precursor in vivo of advanced glycation end products (AGEs), which are known to exert their detrimental effect via receptor- (e.g., RAGE) or non-receptor-mediated mechanisms in several neurological diseases. On this basis, we aimed to compare fibroblasts from healthy subjects (CTR) with fibroblasts from RTT patients (N = 6 per group), by evaluating gene/protein expression patterns, and enzymatic activities of glyoxalases (GLOs), along with the levels of MG-dependent damage in both basal and MG-challenged conditions. Our results revealed that RTT is linked to an alteration of the GLOs system (specifically, increased GLO2 activity), that ensures unchanged MG-dependent damage levels. However, RTT cells underwent more pronounced cell death upon exogenous MG-treatment, as compared to CTR, and displayed lower RAGE levels than CTR, with no alterations following MG-treatment, thus suggesting that an adaptive response to dicarbonyl stress may occur. In conclusion, besides OxInflammation, RTT is associated with reshaping of the major defense systems against dicarbonyl stress, along with an altered cellular stress response towards pro-glycating insults.
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Santini, S. J., G. Tarantino, A. Alisi, and C. Balsano. "OC-01Oleuropein prevents copper-catalyzed dicarbonyl stress in NAFLD mice." Digestive and Liver Disease 53 (October 2021): S1. http://dx.doi.org/10.1016/j.dld.2021.07.021.

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32

Xin, Ying, Elisabeth Hertle, Carla J. H. van der Kallen, Casper G. Schalkwijk, Coen D. A. Stehouwer, and Marleen M. J. van Greevenbroek. "Associations of dicarbonyl stress with complement activation: the CODAM study." Diabetologia 63, no. 5 (January 28, 2020): 1032–42. http://dx.doi.org/10.1007/s00125-020-05098-4.

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33

Shumaev, Konstantin B., Olga V. Kosmachevskaya, Elvira I. Nasybullina, Enno K. Ruuge, and Alexey F. Topunov. "Role of Nitric Oxide-Derived Metabolites in Reactions of Methylglyoxal with Lysine and Lysine-Rich Protein Leghemoglobin." International Journal of Molecular Sciences 24, no. 1 (December 22, 2022): 168. http://dx.doi.org/10.3390/ijms24010168.

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Carbonyl stress occurs when reactive carbonyl compounds (RCC), such as reducing sugars, dicarbonyls etc., accumulate in the organism. The interaction of RCC carbonyl groups with amino groups of molecules is called the Maillard reaction. One of the most active RCCs is α-dicarbonyl methylglyoxal (MG) that modifies biomolecules forming non-enzymatic glycation products. Organic free radicals are formed in the reaction between MG and lysine or Nα-acetyllysine. S-nitrosothiols and nitric oxide (•NO) donor PAPA NONOate increased the yield of organic free radical intermediates, while other •NO-derived metabolites, namely, nitroxyl anion and dinitrosyl iron complexes (DNICs) decreased it. At the late stages of the Maillard reaction, S-nitrosoglutathione (GSNO) also inhibited the formation of glycation end products (AGEs). The formation of a new type of DNICs, bound with Maillard reaction products, was found. The results obtained were used to explain the glycation features of legume hemoglobin—leghemoglobin (Lb), which is a lysine-rich protein. In Lb, lysine residues can form fluorescent cross-linked AGEs, and •NO-derived metabolites slow down their formation. The knowledge of these processes can be used to increase the stability of Lb. It can help in better understanding the impact of stress factors on legume plants and contribute to the production of recombinant Lb for biotechnology.
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34

Jarisarapurin, Wattanased, Khwandow Kunchana, Linda Chularojmontri, and Suvara K. Wattanapitayakul. "Unripe Carica papaya Protects Methylglyoxal-Invoked Endothelial Cell Inflammation and Apoptosis via the Suppression of Oxidative Stress and Akt/MAPK/NF-κB Signals." Antioxidants 10, no. 8 (July 21, 2021): 1158. http://dx.doi.org/10.3390/antiox10081158.

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Methylglyoxal (MGO), a highly reactive dicarbonyl compound, causes endothelial oxidative stress and vascular complications in diabetes. Excessive MGO-induced ROS production triggers eNOS uncoupling, inflammatory responses, and cell death signaling cascades. Our previous study reported that unripe Carica papaya (UCP) had antioxidant activities that prevented H2O2-induced endothelial cell death. Therefore, this study investigated the preventive effect of UCP on MGO-induced endothelial cell damage, inflammation, and apoptosis. The human endothelial cell line (EA.hy926) was pretreated with UCP for 24 h, followed by MGO-induced dicarbonyl stress. Treated cells were evaluated for intracellular ROS/O2•− formation, cell viability, apoptosis, NO releases, and cell signaling through eNOS, iNOS, COX-2, NF-κB, Akt, MAPK (JNK and p38), and AMPK/SIRT1 autophagy pathways. UCP reduced oxidative stress and diminished phosphorylation of Akt, stress-activated MAPK, leading to the decreases in NF-kB-activated iNOS and COX-2 expression. However, UCP had no impact on the autophagy pathway (AMPK and SIRT1). Although UCP pretreatment decreased eNOS phosphorylation, the amount of NO production was not altered. The signaling of eNOS and NO production were decreased after MGO incubation, but these effects were unaffected by UCP pretreatment. In summary, UCP protected endothelial cells against carbonyl stress by the mechanisms related to ROS/O2•− scavenging activities, suppression of inflammatory signaling, and inhibition of JNK/p38/apoptosis pathway. Thus, UCP shows considerable promise for developing novel functional food and nutraceutical products to reduce risks of endothelial inflammation and vascular complications in diabetes.
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35

Beisswenger, P. J., K. S. Drummond, R. G. Nelson, S. K. Howell, B. S. Szwergold, and M. Mauer. "Susceptibility to Diabetic Nephropathy Is Related to Dicarbonyl and Oxidative Stress." Diabetes 54, no. 11 (October 25, 2005): 3274–81. http://dx.doi.org/10.2337/diabetes.54.11.3274.

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36

NAGARAJ, RAM H., TOMOKO OYA-ITO, MANJUNATHA BHAT, and BINGFEN LIU. "Dicarbonyl Stress and Apoptosis of Vascular Cells: Prevention by αB-Crystallin." Annals of the New York Academy of Sciences 1043, no. 1 (June 2005): 158–65. http://dx.doi.org/10.1196/annals.1333.020.

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37

Wondrak, Georg T., Daniel Cervantes-Laurean, Michael J. Roberts, Jaber G. Qasem, Moonsun Kim, Elaine L. Jacobson, and Myron K. Jacobson. "Identification of α-dicarbonyl scavengers for cellular protection against carbonyl stress." Biochemical Pharmacology 63, no. 3 (February 2002): 361–73. http://dx.doi.org/10.1016/s0006-2952(01)00915-7.

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38

Gambelunghe, Angela, Stefano Giovagnoli, Alessandro Di Michele, Simona Boncompagni, Marco Dell’Omo, Kerstin Leopold, Ivo Iavicoli, Vincenzo Nicola Talesa, and Cinzia Antognelli. "Redox-Sensitive Glyoxalase 1 Up-Regulation Is Crucial for Protecting Human Lung Cells from Gold Nanoparticles Toxicity." Antioxidants 9, no. 8 (August 3, 2020): 697. http://dx.doi.org/10.3390/antiox9080697.

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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.
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39

Rabbani, Naila, and Paul J. Thornalley. "Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease." Biochemical and Biophysical Research Communications 458, no. 2 (March 2015): 221–26. http://dx.doi.org/10.1016/j.bbrc.2015.01.140.

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40

Santini, S. J., I. Settepanella, and C. Balsano. "Oleuropein prevents liver damage in NAFL mice by modulating copper-catalyzed dicarbonyl stress." Digestive and Liver Disease 53 (March 2021): S31. http://dx.doi.org/10.1016/j.dld.2020.12.077.

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41

Donnellan, Leigh, Clifford Young, Bradley S. Simpson, Mitchell Acland, Varinderpal S. Dhillon, Maurizio Costabile, Michael Fenech, Peter Hoffmann, and Permal Deo. "Proteomic Analysis of Methylglyoxal Modifications Reveals Susceptibility of Glycolytic Enzymes to Dicarbonyl Stress." International Journal of Molecular Sciences 23, no. 7 (March 28, 2022): 3689. http://dx.doi.org/10.3390/ijms23073689.

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Methylglyoxal (MGO) is a highly reactive cellular metabolite that glycates lysine and arginine residues to form post-translational modifications known as advanced glycation end products. Because of their low abundance and low stoichiometry, few studies have reported their occurrence and site-specific locations in proteins. Proteomic analysis of WIL2-NS B lymphoblastoid cells in the absence and presence of exogenous MGO was conducted to investigate the extent of MGO modifications. We found over 500 MGO modified proteins, revealing an over-representation of these modifications on many glycolytic enzymes, as well as ribosomal and spliceosome proteins. Moreover, MGO modifications were observed on the active site residues of glycolytic enzymes that could alter their activity. We similarly observed modification of glycolytic enzymes across several epithelial cell lines and peripheral blood lymphocytes, with modification of fructose bisphosphate aldolase being observed in all samples. These results indicate that glycolytic proteins could be particularly prone to the formation of MGO adducts.
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Santini, S. J., A. Iezzi, G. Tarantino, A. Alisi, and C. Balsano. "Oleuropein prevents liver damage in NAFL mice by modulating copper-catalyzed dicarbonyl stress." Digestive and Liver Disease 54 (March 2022): S22—S23. http://dx.doi.org/10.1016/j.dld.2022.01.042.

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43

Yurevich, V. R., and I. N. Mikheytseva. "Dicarbonyl Stress in Eye Tissue of Rabbits with Ocular Hypertension in Experimental Diabetes." Ukraïnsʹkij žurnal medicini, bìologìï ta sportu 4, no. 2 (April 8, 2019): 100–106. http://dx.doi.org/10.26693/jmbs04.02.100.

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44

Cho, Chi-Heung, Chang-Jun Lee, Min-Gyeong Kim, Bomi Ryu, Jun-Geon Je, Yoonsook Kim, and Sang-Hoon Lee. "Therapeutic Potential of Phlorotannin-Rich Ecklonia cava Extract on Methylglyoxal-Induced Diabetic Nephropathy in In Vitro Model." Marine Drugs 20, no. 6 (May 27, 2022): 355. http://dx.doi.org/10.3390/md20060355.

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Advanced glycation end-products (AGEs) play a vital role in the pathogenesis of diabetic complications. Methylglyoxal (MGO), one of the major precursors of AGEs, is a highly reactive dicarbonyl compound that plays an important role in the pathogenesis of diabetic nephropathy. This study was designed to evaluate the therapeutic potential of phlorotannin-rich Ecklonia cava extract (ECE) on MGO-induced diabetic nephropathy in in vitro models using mouse glomerular mesangial cells. ECE showed anti-glycation activity via breaking of AGEs-collagen cross-links and inhibition of AGEs formation and AGE-collagen cross-linking formation. The renoprotective effects were determined by assessing intracellular reactive oxygen species (ROS) and MGO accumulation, cell apoptosis, and the Nrf-2/ARE signaling pathway. MGO-induced renal damage, intracellular ROS production level, and MGO-protein adduct accumulation were significantly decreased by pretreating ECE. Moreover, ECE pretreatment exhibited preventive properties against MGO-induced dicarbonyl stress via activation of the Nrf2/ARE signaling pathway and reduction of RAGE protein expression in mouse glomerular mesangial cells. Collectively, these results indicated potential anti-glycation properties and prominent preventive effects of ECE against MGO-induced renal damage. Additionally, ECE may be utilized for the management of AGE-related diabetic nephropathy.
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Morgenstern, Jakob, Thomas Fleming, Dagmar Schumacher, Volker Eckstein, Marc Freichel, Stephan Herzig, and Peter Nawroth. "Loss of Glyoxalase 1 Induces Compensatory Mechanism to Achieve Dicarbonyl Detoxification in Mammalian Schwann Cells." Journal of Biological Chemistry 292, no. 8 (December 12, 2016): 3224–38. http://dx.doi.org/10.1074/jbc.m116.760132.

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The glyoxalase system is a highly specific enzyme system existing in all mammalian cells that is responsible for the detoxification of dicarbonyl species, primarily methylglyoxal (MG). It has been implicated to play an essential role in preventing the increased formation of advanced glycation end products under certain pathological conditions. We have established the first glyoxalase 1 knock-out model (GLO1−/−) in mammalian Schwann cells using the CRISPR/Cas9 technique to investigate compensatory mechanisms. Neither elevated concentrations of MG nor associated protein modifications were observed in GLO1−/− cells. Alternative detoxification of MG in GLO1−/− is achieved by increased catalytic efficiency of aldose reductase toward hemithioacetal (product of glutathione and MG), which is most likely caused by S-nitrosylation of aldose reductase. The hemithioacetal is mainly converted into lactaldehyde, which is paralleled by a loss of reduced glutathione. Inhibition of aldose reductase in GLO1−/− cells is associated with an increased sensitivity against MG, elevated intracellular MG levels, associated modifications, as well as increased oxidative stress. Our data suggest that aldose reductase can compensate for the loss of GLO1. This might be of clinical importance within the context of neuronal diseases caused by an impaired glyoxalase system and elevated levels of dicarbonyl species, such as MG.
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van Bussel, Bas, Marcel van de Poll, Casper Schalkwijk, and Dennis Bergmans. "Increased Dicarbonyl Stress as a Novel Mechanism of Multi-Organ Failure in Critical Illness." International Journal of Molecular Sciences 18, no. 2 (February 7, 2017): 346. http://dx.doi.org/10.3390/ijms18020346.

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47

Sabrina, Radjei, Bertrand Figuet, Isabelle Petropoulos, and Carine Nizard. "Role of glyoxalases system in skin aging and in response to dicarbonyl mediated stress." Free Radical Biology and Medicine 65 (September 2013): S45. http://dx.doi.org/10.1016/j.freeradbiomed.2013.08.070.

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48

Skop, V., H. Malinska, J. Trnovska, and L. Kazdova. "The protective effect of metformin on hypertriglyceridemia-induced dicarbonyl stress in serum and tissues." Atherosclerosis 241, no. 1 (July 2015): e58. http://dx.doi.org/10.1016/j.atherosclerosis.2015.04.204.

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49

Rabbani, Naila. "AGEomics Biomarkers and Machine Learning—Realizing the Potential of Protein Glycation in Clinical Diagnostics." International Journal of Molecular Sciences 23, no. 9 (April 21, 2022): 4584. http://dx.doi.org/10.3390/ijms23094584.

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Protein damage by glycation, oxidation and nitration is a continuous process in the physiological system caused by reactive metabolites associated with dicarbonyl stress, oxidative stress and nitrative stress, respectively. The term AGEomics is defined as multiplexed quantitation of spontaneous modification of proteins damage and other usually low-level modifications associated with a change of structure and function—for example, citrullination and transglutamination. The method of quantitation is stable isotopic dilution analysis liquid chromatography—tandem mass spectrometry (LC-MS/MS). This provides robust quantitation of normal and damaged or modified amino acids concurrently. AGEomics biomarkers have been used in diagnostic algorithms using machine learning methods. In this review, I describe the utility of AGEomics biomarkers and provide evidence why these are close to the phenotype of a condition or disease compared to other metabolites and metabolomic approaches and how to train and test algorithms for clinical diagnostic and screening applications with high accuracy, sensitivity and specificity using machine learning approaches.
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Ashour, Amal, Mingzhan Xue, Maryam Al-Motawa, Paul J. Thornalley, and Naila Rabbani. "Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer." BMJ Open Diabetes Research & Care 8, no. 2 (October 2020): e001458. http://dx.doi.org/10.1136/bmjdrc-2020-001458.

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IntroductionPatients with diabetes have increased risk of periodontal disease, with increased risk of weakening of periodontal ligament and tooth loss. Periodontal ligament is produced and maintained by periodontal ligament fibroblasts (PDLFs). We hypothesized that metabolic dysfunction of PDLFs in hyperglycemia produces an accumulation of the reactive glycating agent, methylglyoxal (MG), leading to increased formation of the major advanced glycation endproduct, MG-H1 and PDLF dysfunction. The aim of this study was to assess if there is dicarbonyl stress and functional impairment of human PDLFs in primary culture in high glucose concentration—a model of hyperglycemia, to characterize the metabolic drivers of it and explore remedial intervention by the glyoxalase 1 inducer dietary supplement, trans-resveratrol and hesperetin combination (tRES-HESP).Research design and methodsHuman PDLFs were incubated in low and high glucose concentration in vitro. Metabolic and enzymatic markers of MG and glucose control were quantified and related changes in the cytoplasmic proteome and cell function—binding to collagen-I, assessed. Reversal of PDLF dysfunction by tRES-HESP was explored.ResultsIn high glucose concentration cultures, there was a ca. twofold increase in cellular MG, cellular protein MG-H1 content and decreased attachment of PDLFs to collagen-I. This was driven by increased hexokinase-2 linked glucose metabolism and related increased MG formation. Proteomics analysis revealed increased abundance of chaperonins, heat shock proteins (HSPs), Golgi-to-endoplasmic reticulum transport and ubiquitin E3 ligases involved in misfolded protein degradation in high glucose concentration, consistent with activation of the unfolded protein response by increased misfolded MG-modified proteins. PDLF dysfunction was corrected by tRES-HESP.ConclusionsIncreased hexokinase-2 linked glucose metabolism produces dicarbonyl stress, increased MG-modified protein, activation of the unfolded protein response and functional impairment of PDLFs in high glucose concentration. tRES-HESP resolves this at source by correcting increased glucose metabolism and may be of benefit in prevention of diabetic periodontal disease.
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