Showing papers on "Methylglyoxal published in 2018"

Methylglyoxal-derived posttranslational arginine modifications are abundant histone marks

Abstract: Histone posttranslational modifications (PTMs) regulate chromatin dynamics, DNA accessibility, and transcription to expand the genetic code Many of these PTMs are produced through cellular metabolism to offer both feedback and feedforward regulation Herein we describe the existence of Lys and Arg modifications on histones by a glycolytic by-product, methylglyoxal (MGO) Our data demonstrate that adduction of histones by MGO is an abundant modification, present at the same order of magnitude as Arg methylation These modifications were detected on all four core histones at critical residues involved in both nucleosome stability and reader domain binding In addition, MGO treatment of cells lacking the major detoxifying enzyme, glyoxalase 1, results in marked disruption of H2B acetylation and ubiquitylation without affecting H2A, H3, and H4 modifications Using RNA sequencing, we show that MGO is capable of altering gene transcription, most notably in cells lacking GLO1 Finally, we show that the deglycase DJ-1 protects histones from adduction by MGO Collectively, our findings demonstrate the existence of a previously undetected histone modification derived from glycolysis, which may have far-reaching implications for the control of gene expression and protein transcription linked to metabolism

Neuroprotection through flavonoid: Enhancement of the glyoxalase pathway.

Abstract: The glyoxalase pathway functions to detoxify reactive dicarbonyl compounds, most importantly methylglyoxal. The glyoxalase pathway is an antioxidant defense mechanism that is essential for neuroprotection. Excessive concentrations of methylglyoxal have deleterious effects on cells, leading to increased levels of inflammation and oxidative stress. Neurodegenerative diseases - including Alzheimer's, Parkinson's, Aging and Autism Spectrum Disorder - are often induced or exacerbated by accumulation of methylglyoxal. Antioxidant compounds possess several distinct mechanisms that enhance the glyoxalase pathway and function as neuroprotectants. Flavonoids are well-researched secondary plant metabolites that appear to be effective in reducing levels of oxidative stress and inflammation in neural cells. Novel flavonoids could be designed, synthesized and tested to protect against neurodegenerative diseases through regulating the glyoxalase pathway.

Methylglyoxal in Manuka Honey - Correlation with Antibacterial Properties

Abstract: A perfect linear correlation was found for methylglyoxal levels in 61 samples of Manuka honey, ranging from 189 to 835 mg/kg, and the corresponding antibacterial activities of the samples, which were between 12.4% and 30.9% equivalent phenol concentration. This clearly underlines that methylglyoxal is the dominant bioactive com - pound in Manuka honey and above concentrations of around 150 mg/kg directly responsible for the characteristic antibacterial properties of Manuka honey. Methylglyoxal can be a suitable tool for labelling the unique bioactivity of Manuka honey.

Exogenous nitric oxide donor and arginine provide protection against short-term drought stress in wheat seedlings

Abstract: Nitric oxide (NO) is an important plant signaling molecule that has a vital role in abiotic stress tolerance. In the present study, we assessed drought-induced (15 and 30% PEG, polyethylene glycol) damage in wheat (Triticum aestivum L. cv. Prodip) seedlings and mitigation by the synergistic effect of exogenous Arg (0.5 mM l-Arginine) and an NO donor (0.5 mM sodium nitroprusside, SNP). Drought stress sharply decreased the leaf relative water content (RWC) but markedly increased the proline (Pro) content in wheat seedlings. Drought stress caused overproduction of reactive oxygen species (ROS) and methylglyoxal (MG) due to the inefficiency of antioxidant enzymes, the glyoxalase system, and the ascorbate-glutathione pool. However, supplementation with the NO donor and Arg enhanced the antioxidant defense system (both non-enzymatic and enzymatic components) in drought-stressed seedlings. Application of the NO donor and Arg also enhanced the glyoxalase system and reduced the MG content by increasing the activities of the glyoxalase system enzymes (Gly I and Gly II), which restored the leaf RWC and further increased the Pro content under drought stress conditions. Exogenous NO donor and Arg application enhanced the endogenous NO content, which positively regulated the antioxidant system and reduced ROS production. Thus, the present study reveals the crucial roles of Arg and NO in enhancing drought stress tolerance in wheat seedlings by upgrading their water status and reducing oxidative stress and MG toxicity.

Exogenous Silicon Protects Brassica napus Plants from Salinity-Induced Oxidative Stress Through the Modulation of AsA-GSH Pathway, Thiol-Dependent Antioxidant Enzymes and Glyoxalase Systems

Abstract: Although silicon (Si) has showed its potential role in mitigating abiotic stress-induced damages in many plant species its role in coordinated induction of antioxidant defense is yet to be elucidated. Therefore, we studied rapeseed (Brassica napus) seedlings applied with exogenous Si for changes occurring in antioxidant defense and glyoxalase systems. Seedlings (12-day-old) grown semi-hydroponically were exposed to Si (silicon dioxide, SiO2; 1 mM) solely and in combination with NaCl (100 and 200 mM) for 48 h. Salinity created oxidative damage by increasing H2O2 and malondialdehyde (MDA) contents resulting in disruption of antioxidant defense system and in arousing methylglyoxal (MG) toxicity by the down-regulation of glyoxalase enzyme activities. Exogenous Si treatment showed reduction of both H2O2 and MDA contents and up-regulation of antioxidant components including the activities of related enzymes (APX, MDHAR, DHAR, GR, GST, GPX and CAT) and the contents of AsA and GSH. Enhanced activities of glyoxalase I (Gly I) and glyoxalase II (Gly II) detoxified the toxic MG. Thus, this study clearly indicates that Si improved plant tolerance to salinity stress through enhancement of both antioxidant defense and glyoxalase systems that led to reduced oxidative damage and MG toxicity.

Visualization of methylglyoxal in living cells and diabetic mice model with a 1,8-naphthalimide-based two-photon fluorescent probe

Abstract: Methylglyoxal (MGO), a dicarbonyl metabolite, is the most studied precursor of advanced glycation end-products (AGEs) and its elevated levels have also been associated with various pathologies. Hence, the development of effective methods for monitoring MGO in live cells and in vivo is of great importance for ascertaining the onset and progress of related diseases. Herein, we designed and synthesized an endoplasmic reticulum-targeting two-photon fluorescent probe called NI-OPD for the detection of MGO with high selectivity, sensitivity, and hypotoxicity. The probe was successfully applied for monitoring MGO in living cells and a diabetic mice model. The two-photon fluorescence images confirmed that the endogenous MGO in the liver and kidney tissues of diabetic mice is higher than that of normal mice. Furthermore, it revealed that after treatment with metformin, a widely used hypoglycemia drug, the diabetic mice showed a decreased concentration of MGO in liver and kidney tissues. Thus, NI-OPD may serve as a useful tool for the detection of MGO and for studying the relationships between MGO and pathological and biological processes in biosystems.

Nitrogen-Containing, Light-Absorbing Oligomers Produced in Aerosol Particles Exposed to Methylglyoxal, Photolysis, and Cloud Cycling.

Abstract: Aqueous methylglyoxal chemistry has often been implicated as an important source of oligomers in atmospheric aerosol. Here we report on chemical analysis of brown carbon aerosol particles collected from cloud cycling/photolysis chamber experiments, where gaseous methylglyoxal and methylamine interacted with glycine, ammonium, or methylammonium sulfate seed particles. Eighteen N-containing oligomers were identified in the particulate phase by liquid chromatography/diode array detection/electrospray ionization high-resolution quadrupole time-of-flight mass spectrometry. Chemical formulas were determined and, for 6 major oligomer products, MS2 fragmentation spectra were used to propose tentative structures and mechanisms. Electronic absorption spectra were calculated for six tentative product structures by an ab initio second order algebraic-diagrammatic-construction/density functional theory approach. For five structures, matching calculated and measured absorption spectra suggest that they are dominant lig...

Jasmonic Acid Improves Growth Performance of Soybean Under Nickel Toxicity By Regulating Nickel Uptake, Redox Balance, and Oxidative Stress Metabolism

Abstract: Soil contamination with nickel (Ni) is a persistent threat to crop production worldwide. The present study examined the putative roles of jasmonic acid (JA) in improving Ni tolerance in soybean. Our findings showed that priming of soybean seeds with JA significantly improved the growth performance of soybean when grown under excessive Ni. The enhanced Ni tolerance of soybean prompted by JA could be ascribed to its ability to regulate Ni uptake and accumulation, and to decrease Ni-induced membrane damage as evidenced by reduced levels of reactive oxygen species (ROS), malondialdehyde, lipoxygenase activity, and electrolyte leakage in Ni-stressed plants. JA also boosted redox states and antioxidant capacity in Ni-stressed plants by maintaining increased levels of ascorbate and glutathione, and enhanced activities of ROS-detoxifying enzymes compared with Ni-stressed alone plants. Additionally, methylglyoxal detoxification system was significantly upregulated in JA-primed and “JA-primed + Ni-stressed” plants, indicating an alleviating effect of JA on Ni-induced methylglyoxal toxicity. Our results conclude that JA-mediated regulation of Ni uptake and accumulation, and enhanced ROS metabolism by activating antioxidant defense and glyoxalase systems contributed to improved performance of soybean under excessive Ni, thereby suggesting JA as an effective stress regulator in mitigating Ni toxicity in economically important soybean, and perhaps in other crops.

Compensatory mechanisms for methylglyoxal detoxification in experimental & clinical diabetes

Abstract: Objectives The deficit of Glyoxalase I (Glo1) and the subsequent increase in methylglyoxal (MG) has been reported to be one the five mechanisms by which hyperglycemia causes diabetic late complications. Aldo-keto reductases (AKR) have been shown to metabolize MG; however, the relative contribution of this superfamily to the detoxification of MG in vivo, particularly within the diabetic state, remains unknown. Methods CRISPR/Cas9-mediated genome editing was used to generate a Glo1 knock-out (Glo1−/−) mouse line. Streptozotocin was then applied to investigate metabolic changes under hyperglycemic conditions. Results Glo1−/− mice were viable and showed no elevated MG or MG-H1 levels under hyperglycemic conditions. It was subsequently found that the enzymatic efficiency of various oxidoreductases in the liver and kidney towards MG were increased in the Glo1−/− mice. The functional relevance of this was supported by the altered distribution of alternative detoxification products. Furthermore, it was shown that MG-dependent AKR activity is a potentially clinical relevant pathway in human patients suffering from diabetes. Conclusions These data suggest that in the absence of GLO1, AKR can effectively compensate to prevent the accumulation of MG. The combination of metabolic, enzymatic, and genetic factors, therefore, may provide a better means of identifying patients who are at risk for the development of late complications caused by elevated levels of MG.

Diphlorethohydroxycarmalol Attenuates Methylglyoxal-Induced Oxidative Stress and Advanced Glycation End Product Formation in Human Kidney Cells.

Abstract: Diabetic nephropathy is the leading cause of end-stage renal disease in patients with diabetes mellitus. Oxidative stress has been shown to play an important role in pathogeneses of renal damage in diabetic patients. Here, we investigated the protective effect of diphlorethohydroxycarmalol (DPHC), which is a polyphenol isolated from an edible seaweed, Ishige okamurae, on methylglyoxal-induced oxidative stress in HEK cells, a human embryonic kidney cell line. DPHC treatment inhibited methylglyoxal- (MGO-) induced cytotoxicity and ROS production. DPHC activated the Nrf2 transcription factor and increased the mRNA expression of antioxidant and detoxification enzymes, consequently reducing MGO-induced advanced glycation end product formation. In addition, DPHC increased glyoxalase-1 mRNA expression and attenuated MGO-induced advanced glycation end product formation in HEK cells. These results suggest that DPHC possesses a protective activity against MGO-induced cytotoxicity in human kidney cells by preventing oxidative stress and advanced glycation end product formation. Therefore, it could be used as a potential therapeutic agent for the prevention of diabetic nephropathy.

GLYI and D-LDH play key role in methylglyoxal detoxification and abiotic stress tolerance.

Abstract: Methylglyoxal(MG) is a potent cytotoxin that is produced as a byproduct of various metabolic reactions in the cell. The major enzymes for MG detoxification are Glyoxalase I(GLYI), Glyoxalase II(GLYII) and D-lactate dehydrogenase(D-LDH). These three enzymes work together and convert MG into D-pyruvate, which directly goes to TCA cycle. Here, a comparative study of the ability of MG detoxification of these three enzymes has been done in both E. coli and yeast. Ectopic expression of these three genes from Arabidopsis in E. coli in presence of different abiotic stress revealed the contribution of each of these genes in detoxifying MG. Yeast mutants of MG detoxification enzymes were also grown in different stress conditions to record the effect of each gene. These mutants were also used for complementation assays using the respective MG detoxifying genes from Arabidopsis in presence of various stress conditions. The MG content and the corresponding growth of cells was measured in all the bacterial as well as yeast strains. This study reveals differential contribution of MG detoxification enzymes in mitigating MG levels and alleviating stress in both prokaryotes as well as eukaryotes. GLYI and D-LDH were found to be key enzymes in MG detoxification under various abiotic stresses.

Eucommia ulmoides Ameliorates Glucotoxicity by Suppressing Advanced Glycation End-Products in Diabetic Mice Kidney.

Abstract: Eucommia ulmoides Oliv. (EU), also known as Du-Zhong, is a medicinal herb commonly used in Asia to treat hypertension and diabetes. Despite evidence of the protective effects of EU against diabetes, its precise effects and mechanisms of action against advanced glycation end-products (AGEs) are unclear. In this study, we evaluated the effects of EU on AGEs-induced renal disease and explored the possible underlying mechanisms using streptozotocin (STZ)-induced diabetic mice. STZ-induced diabetic mice received EU extract (200 mg/kg) orally for 6 weeks. EU treatment did not change blood glucose and glycated hemoglobin (HbA1c) levels in diabetic mice. However, the EU-treated group showed a significant increase in the protein expression and activity of glyoxalase 1 (Glo1), which detoxifies the AGE precursor, methylglyoxal (MGO). EU significantly upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression but downregulated that of receptor for AGE (RAGE). Furthermore, histological and immunohistochemical analyses of kidney tissue showed that EU reduced periodic acid–Schiff (PAS)-positive staining, AGEs, and MGO accumulation in diabetic mice. Based on these findings, we concluded that EU ameliorated the renal damage in diabetic mice by inhibiting AGEs formation and RAGE expression and reducing oxidative stress, through the Glo1 and Nrf2 pathways.

Investigating the Glycating Effects of Glucose, Glyoxal and Methylglyoxal on Human Sperm

Abstract: Glycation is the non-enzymatic reaction between reducing sugars, such as glucose, and proteins, lipids or nucleic acids, producing Advanced Glycation End (AGE) products. AGEs, produced during natural senescence as well as through lifestyle factors such as diet and smoking, are key pathogenic compounds in the initiation and progression of diabetes. Importantly, many of these factors and conditions also have influence on male fertility, affecting sperm count and semen quality, contributing to the decreasing trend in male fertility. This study investigated the impact of AGEs on sperm damage. In vitro sperm glycation assays were used to determine the levels and localization of the potent AGE compound, carboxymethyl-lysine (CML) in response to treatment with the glycating compounds glucose, glyoxal and methylglyoxal. Sperm function assays were then used to assess the effects of glycation on motility and hyaluronan binding, and levels of oxidative DNA damage were analyzed through measurement of the marker, 8-oxoguanine. Results showed that glyoxal, but not glucose or methylglyoxal, induced significant increases in CML levels on sperm and this correlated with an increase in 8-oxoguanine. Immunocytochemistry revealed that AGEs were located on all parts of the sperm cell and most prominently on the head region. Sperm motility and hyaluronidase activity were not adversely affected by glycation. Together, the observed detrimental effects of the increased levels of AGE on DNA integrity, without an effect on motility and hyaluronidase activity, suggest that sperm may retain some fertilizing capacity under these adverse conditions.

Digestibility of Bovine Serum Albumin and Peptidomics of the Digests: Effect of Glycation Derived from α-Dicarbonyl Compounds.

Abstract: α-Dicarbonyl compounds, which are widely generated during sugar fragmentation and oil oxidation, are important precursors of advanced glycation end products (AGEs). In this study, the effect of glycation derived from glyoxal (GO), methylglyoxal (MGO) and diacetyl (DA) on the in vitro digestibility of bovine serum albumin (BSA) was investigated. Glycation from α-dicarbonyl compounds reduced digestibility of BSA in both gastric and intestinal stage of digestion according to measurement of degree of hydrolysis. Changes in peptide composition of digests induced by glycation were displayed, showing absence of peptides, occurrence of new peptides and formation of peptide-AGEs, based on the results obtained using liquid chromatography electron-spray-ionization tandem mass spectrometry (LC-ESI-MS/MS). Crosslinked glycation structures derived from DA largely reduced the sensitivity of glycated BSA towards digestive proteases based on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) results. Network structures were found to remain in the digests of glycated samples by transmission electron microscope (TEM), thus the impact of AGEs in unabsorbed digests on the gut flora should be an interest for further studies.

TRPC proteins contribute to development of diabetic retinopathy and regulate glyoxalase 1 activity and methylglyoxal accumulation.

Abstract: Objective Diabetic retinopathy (DR) is induced by an accumulation of reactive metabolites such as ROS, RNS, and RCS species, which were reported to modulate the activity of cation channels of the TRPC family. In this study, we use Trpc1/4/5/6−/− compound knockout mice to analyze the contribution of these TRPC proteins to diabetic retinopathy. Methods We used Nanostring- and qPCR-based analysis to determine mRNA levels of TRPC channels in control and diabetic retinae and retinal cell types. Chronic hyperglycemia was induced by Streptozotocin (STZ) treatment. To assess the development of diabetic retinopathy, vasoregression, pericyte loss, and thickness of individual retinal layers were analyzed. Plasma and cellular methylglyoxal (MG) levels, as well as Glyoxalase 1 (GLO1) enzyme activity and protein expression, were measured in WT and Trpc1/4/5/6−/− cells or tissues. MG-evoked toxicity in cells of both genotypes was compared by MTT assay. Results We find that Trpc1/4/5/6−/− mice are protected from hyperglycemia-evoked vasoregression determined by the formation of acellular capillaries and pericyte drop-out. In addition, Trpc1/4/5/6−/− mice are resistant to the STZ-induced reduction in retinal layer thickness. The RCS metabolite methylglyoxal, which represents a key mediator for the development of diabetic retinopathy, was significantly reduced in plasma and red blood cells (RBCs) of STZ-treated Trpc1/4/5/6−/− mice compared to controls. GLO1 is the major MG detoxifying enzyme, and its activity and protein expression were significantly elevated in Trpc1/4/5/6-deficient cells, which led to significantly increased resistance to MG toxicity. GLO1 activity was also increased in retinal extracts from Trpc1/4/5/6−/− mice. The TRPCs investigated here are expressed at different levels in endothelial and glial cells of the retina. Conclusion The protective phenotype in diabetic retinopathy observed in Trpc1/4/5/6−/− mice is suggestive of a predominant action of TRPCs in Muller cells and microglia because of their central position in the retention of a proper homoeostasis of the neurovascular unit.