Showing papers on "Methylglyoxal published in 2013"
TL;DR: The evidence of the biological actions of honey can be ascribed to its polyphenolic contents which, in turn, are usually associated to its antioxidant and anti-inflammatory actions, as well as to its cardiovascular, antiproliferative and antimicrobial benefits.
Abstract: In the long human tradition honey has been used not only as a nutrient but also as a medicine. Its composition is rather variable and depends on the floral source and on external factors, such as seasonal, environmental conditions and processing. In this review, specific attention is focused on absorption, metabolism, and beneficial biological activities of honey compounds in human. Honey is a supersaturated solution of sugars, mainly composed of fructose (38%) and glucose (31%), containing also minerals, proteins, free amino acids, enzymes, vitamins and polyphenols. Among polyphenols, flavonoids are the most abundant and are closely related to its biological functions. Honey positively affects risk factors for cardiovascular diseases by inhibiting inflammation, improving endothelial function, as well as the plasma lipid profile, and increasing low-density lipoprotein resistance to oxidation. Honey also displays an important antitumoral capacity, where polyphenols again are considered responsible for its complementary and overlapping mechanisms of chemopreventive activity in multistage carcinogenesis, by inhibiting mutagenesis or inducing apoptosis. Moreover, honey positively modulates the glycemic response by reducing blood glucose, serum fructosamine or glycosylated hemoglobin concentrations and exerts antibacterial properties caused by its consistent amount of hydrogen peroxide and non-peroxide factors as flavonoids, methylglyoxal and defensin-1 peptide. In conclusion, the evidence of the biological actions of honey can be ascribed to its polyphenolic contents which, in turn, are usually associated to its antioxidant and anti-inflammatory actions, as well as to its cardiovascular, antiproliferative and antimicrobial benefits.
233 citations
TL;DR: The aim of the present review is to show the evolution of thought regarding the glyoxalase pathway since its discovery 100 years ago, the current knowledge on the glyxalase enzymes and their recognized role in the control of glycation processes.
Abstract: The discovery of the enzymatic formation of lactic acid from methylglyoxal dates back to 1913 and was believed to be associated with one enzyme termed ketonaldehydemutase or glyoxalase, the latter designation prevailed. However, in 1951 it was shown that two enzymes were needed and that glutathione was the required catalytic co-factor. The concept of a metabolic pathway defined by two enzymes emerged at this time. Its association to detoxification and anti-glycation defence are its presently accepted roles, since methylglyoxal exerts irreversible effects on protein structure and function, associated with misfolding. This functional defence role has been the rationale behind the possible use of the glyoxalase pathway as a therapeutic target, since its inhibition might lead to an increased methylglyoxal concentration and cellular damage. However, metabolic pathway analysis showed that glyoxalase effects on methylglyoxal concentration are likely to be negligible and several organisms, from mammals to yeast and protozoan parasites, show no phenotype in the absence of one or both glyoxalase enzymes. The aim of the present review is to show the evolution of thought regarding the glyoxalase pathway since its discovery 100 years ago, the current knowledge on the glyoxalase enzymes and their recognized role in the control of glycation processes.
214 citations
TL;DR: This review summarizes the mechanisms of MG formation, detoxification, and action and reviews the current knowledge about its implication on the pathophysiology and complications of obesity and diabetes.
Abstract: Methylglyoxal (MG) is a highly reactive compound derived mainly from glucose and fructose metabolism. This metabolite has been implicated in diabetic complications as it is a strong AGE precursor. Furthermore, recent studies suggested a role for MG in insulin resistance and beta-cell dysfunction. Although several drugs have been developed in the recent years to scavenge MG and inhibit AGE formation, we are still far from having an effective strategy to prevent MG-induced mechanisms. This review summarizes the mechanisms of MG formation, detoxification, and action. Furthermore, we review the current knowledge about its implication on the pathophysiology and complications of obesity and diabetes.
144 citations
TL;DR: Tan et al. as discussed by the authors provided chemical insights into aqueous phase OH-radical-initiated reactions leading to secondary organic aerosol (SOA) formation from methylglyoxal and used this and a previously published glyoxal mechanism to provide SOA yields for use in chemical transport models.
Abstract: . Atmospherically abundant, volatile water-soluble organic compounds formed through gas-phase chemistry (e.g., glyoxal (C 2 ), methylglyoxal (C 3 ), and acetic acid) have great potential to form secondary organic aerosol (SOA) via aqueous chemistry in clouds, fogs, and wet aerosols. This paper (1) provides chemical insights into aqueous-phase OH-radical-initiated reactions leading to SOA formation from methylglyoxal and (2) uses this and a previously published glyoxal mechanism (Lim et al., 2010) to provide SOA yields for use in chemical transport models. Detailed reaction mechanisms including peroxy radical chemistry and a full kinetic model for aqueous photochemistry of acetic acid and methylglyoxal are developed and validated by comparing simulations with the experimental results from previous studies (Tan et al., 2010, 2012). This new methylglyoxal model is then combined with the previous glyoxal model (Lim et al., 2010), and is used to simulate the profiles of products and to estimate SOA yields. At cloud-relevant concentrations (~ 10 −6 − ~ 10 −3 M; Munger et al., 1995) of glyoxal and methylglyoxal, the major photooxidation products are oxalic acid and pyruvic acid, and simulated SOA yields (by mass) are ~ 120% for glyoxal and ~ 80% for methylglyoxal. During droplet evaporation oligomerization of unreacted methylglyoxal/glyoxal that did not undergo aqueous photooxidation could enhance yields. In wet aerosols, where total dissolved organics are present at much higher concentrations (~ 10 M), the major oxidation products are oligomers formed via organic radical–radical reactions, and simulated SOA yields (by mass) are ~ 90% for both glyoxal and methylglyoxal. Non-radical reactions (e.g., with ammonium) could enhance yields.
126 citations
TL;DR: Although there is a close association between methylglyoxal and carbohydrate metabolism, the presence of this 1,2-dicarbonyl in the plasma is mainly due to other mechanisms, and protein glycation and aminoacetone degradation are proposed to be the major and the minor sources of plasma methyl glyoxal under normal conditions.
108 citations
TL;DR: It is demonstrated that TRPA1 is required both for the acute pain response evoked by topical MG and for the long-lasting pronociceptive effects associated with elevated MG in vivo, suggesting that results obtained with this compound should be interpreted with caution.
Abstract: Diabetic neuropathy is a severe complication of long-standing diabetes and one of the major etiologies of neuropathic pain. Diabetes is associated with an increased formation of reactive oxygen species and the electrophilic dicarbonyl compound methylglyoxal (MG). Here we show that MG stimulates heterologously expressed TRPA1 in CHO cells and natively expressed TRPA1 in MDCK cells and DRG neurons. MG evokes [Ca(2+)]i-responses in TRPA1 expressing DRG neurons but is without effect in neurons cultured from Trpa1(-/-) mice. Consistent with a direct, intracellular action, we show that methylglyoxal is significantly more potent as a TRPA1 agonist when applied to the intracellular face of excised membrane patches than to intact cells. Local intraplantar administration of MG evokes a pain response in Trpa1(+/+) but not in Trpa1(-/-) mice. Furthermore, persistently increased MG levels achieved by two weeks pharmacological inhibition of glyoxalase-1 (GLO-1), the rate-limiting enzyme responsible for detoxification of MG, evokes a progressive and marked thermal (cold and heat) and mechanical hypersensitivity in wildtype but not in Trpa1(-/-) mice. Our results thus demonstrate that TRPA1 is required both for the acute pain response evoked by topical MG and for the long-lasting pronociceptive effects associated with elevated MG in vivo. In contrast to our observations in DRG neurons, MG evokes indistinguishable [Ca(2+)]i-responses in pancreatic β-cells cultured from Trpa1(+/+) and Trpa1(-/-) mice. In vivo, the TRPA1 antagonist HC030031 impairs glucose clearance in the glucose tolerance test both in Trpa1(+/+) and Trpa1(-/-) mice, indicating a non-TRPA1 mediated effect and suggesting that results obtained with this compound should be interpreted with caution. Our results show that TRPA1 is the principal target for MG in sensory neurons but not in pancreatic β-cells and that activation of TRPA1 by MG produces a painful neuropathy with the behavioral hallmarks of diabetic neuropathy.
105 citations
TL;DR: Dietary MGO is rapidly degraded during the digestion process in the intestine and, therefore, exerts no influence on the MGO level in vivo.
Abstract: Methylglyoxal (MGO) is responsible for the pronounced antibacterial activity of manuka honey, in which it may reach concentrations up to 800 mg/kg. As MGO formed in vivo is discussed to play a role in diabetic complications, the metabolic transit of dietary MGO was studied within a 3 day dietary recall with four healthy volunteers. Determination of MGO in 24 h urine was performed with GC-MS after derivatization with O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine, and D-lactate was quantified enzymatically. Following a diet virtually free from MGO and other glycation compounds, a defined amount of MGO (500 μmol in manuka honey) was administered in the morning of day 2. Renal excretion was between 0.1 and 0.4 μmol/day for MGO and between 50 and 220 μmol/day for D-lactate. No influence on excretion of both compounds was observed following administration of MGO. To investigate the stability of MGO under physiological conditions, a simulated in vitro gastrointestinal digestion was performed with MGO-containing honey. After 8 h of in vitro digestion, only 5-20% of the initial methylglyoxal was recovered. This indicates that dietary MGO is rapidly degraded during the digestion process in the intestine and, therefore, exerts no influence on the MGO level in vivo.
75 citations
TL;DR: Cell culture parameters also affected the extent of modifications by methylglyoxal, a highly reactive metabolite that can be generated from glucose or lipids or other metabolic pathways, which highlights the impact that cell culture conditions can have on the product quality of recombinant protein pharmaceuticals.
Abstract: Heterogeneity is common among protein therapeutics. For example, the so-called acidic species (charge variants) are typically observed when recombinant monoclonal antibodies (mAbs) are analyzed by weak-cation exchange chromatography (WCX). Several protein post-translational modifications have been established as contributors but still cannot completely account for all heterogeneity. As reported herein, an unexpected modification by methylglyoxal (MGO) was identified, for the first time, in a recombinant monoclonal antibody expressed in Chinese hamster ovary (CHO) cells. Modifications of arginine residues by methylglyoxal lead to two adducts (dihydroxyimidazolidine and hydroimidazolone) with increases of molecular weights of 72 and 54 Da, respectively. In addition, the modification by methylglyoxal causes the antibody to elute earlier in the weak cation exchange chromatogram. Consequently, the extent to which an antibody was modified at multiple sites corresponds to the degree of shift in elution time. Fur...
74 citations
TL;DR: It is shown that resveratrol, a kind of phytoalexin found in the skin of grapes, red wine and other botanical extracts, can alleviate the adverse effects caused by methylglyoxal, such as inhibition of oocyte maturation and disruption of spindle assembly.
Abstract: Methylglyoxal, a reactive dicarbonyl compound, is mainly formed from glycolysis. Methylglyoxal can lead to the dysfunction of mitochondria, the depletion of cellular anti-oxidation enzymes and the formation of advanced glycation ends. Previous studies showed that the accumulation of methylglyoxal and advanced glycation ends can impair the oocyte maturation and reduce the oocyte quality in aged and diabetic females. In this study, we showed that resveratrol, a kind of phytoalexin found in the skin of grapes, red wine and other botanical extracts, can alleviate the adverse effects caused by methylglyoxal, such as inhibition of oocyte maturation and disruption of spindle assembly. Besides, methylglyoxal-treated oocytes displayed more DNA double strands breaks and this can also be decreased by treatment of resveratrol. Further investigation of these processes revealed that methylglyoxal may affect the oocyte quality by resulting in excessive reactive oxygen species production, aberrant mitochondrial distribution and high level lipid peroxidation, and resveratrol can block these cytotoxic changes. Collectively, our results showed that resveratrol can protect the oocytes from methylglyoxal-induced cytotoxicity and this was mainly through the correction of the abnormity of cellular reactive oxygen species metabolism.
73 citations
TL;DR: The effects of vaspin on MGO‐induced apoptosis of human umbilical vein ECs (HUVECs) are investigated and shown to have anti‐inflammatory and antimigratory effects in vascular smooth muscle cells.
Abstract: Aim: Vaspin (visceral adipose tissue-derived serine protease inhibitor) is anovel adipocytokine found in visceral white adipose tissues of obese type 2diabetic rats. We have previously shown that vaspin has anti-inflammatoryand antimigratory effects in vascular smooth muscle cells. Methylglyoxal(MGO) is an active metabolite of glucose and mediates diabetic vascularcomplications including endothelial cell (EC) apoptosis. Nonetheless,effects of vaspin on MGO-induced apoptosis of vascular EC remain to bedetermined. We investigated the effects of vaspin on MGO-induced apop-tosis of human umbilical vein ECs (HUVECs).Methods: Human umbilical vein ECs were treated with MGO (560 l M ,12 h) in the absence or presence of vaspin (1 ng mL 1 , pre-treatment for2 h). Cell death was evaluated by a cell counting assay. Apoptosis wasdetermined by a terminal deoxyribonucleotide transferase-mediated deoxy-uridine triphosphate nick-end labelling (TUNEL) assay. Cleaved caspase-3expression was determined by Western blotting. Reactive oxygen species(ROS) generation was fluorometrically measured using 2′,7′-dichlorodihy-drofluorescein diacetate. NADPH oxidase (NOX) activity was determinedby a lucigenin assay.Results: Vaspin significantly inhibited MGO-induced HUVEC death.Vaspin significantly attenuated MGO-increased TUNEL-positive ECs.Moreover, vaspin significantly inhibited MGO-induced caspase-3 cleavage.Vaspin significantly inhibited MGO-induced ROS generation as well asNOX activation.Conclusions: The present results for the first time demonstrate that vaspininhibits MGO-induced EC apoptosis by preventing caspase-3 activationvia the inhibition of NOX-derived ROS generation.Keywords adipocytokine, apoptosis, methylglyoxal, reactive oxygenspecies, vascular endothelial cell.
70 citations
TL;DR: Mangiferin can remarkably ameliorate DN in rats through inhibiting the AGEs/RAGE aix and oxidative stress damage, and Glo-1 may be a target for mangiferin action.
TL;DR: This study demonstrates that mangiferin can markedly ameliorate diabetes-associated cognitive decline in rats, which is done likely through suppressing methylglyoxal hyperactivity (promoting protein glycation, oxidative stress, and inflammation) mediated noxious effects.
Abstract: Evidences indicate that methylglyoxal, a highly reactive metabolite of hyperglycemia, can enhance protein glycation, oxidative stress, or inflammation. Mangiferin, a polyphenol compound of C-glucoside, has many beneficial biological activities, including anti-inflammation, anti-oxidation, neuroprotection, cognitive enhancement, etc. Whether mangiferin alleviates diabetes-associated cognitive impairment is still unclear. The present study was designed to investigate the effects of mangiferin on the behavioral deficits of diabetic rats induced by streptozotocin; the mechanisms associated with methylglyoxal toxicity are especially investigated. Diabetic rats were treated with mangiferin (15, 30, and 60 mg/kg, p.o.) for 9 weeks. Cognitive performances were evaluated with the Morris water maze. Hippocampus and blood were obtained for evaluation of the effects of mangiferin on protein glycation, oxidative stress, and inflammation in diabetic state. Mangiferin significantly improved the behavioral performances of diabetic rats, evidenced by a decrease in escape latency as well as increases in numbers of crossing the platform and percentage of time spent in the target quadrant, which were accompanied by decreases in the levels of advanced glycation end-products and their receptor (RAGE), interleukin-1β, TNF-α, and malondialdehyde and increases in the activity and expression of glyoxalase 1 as well as glutathione level in the hippocampus of diabetic rats. Furthermore, mangiferin produced a significant decrease in malondialdehyde level and increased glutathione level and superoxide dismutase activity in the serum of diabetic rats. This study demonstrates that mangiferin can markedly ameliorate diabetes-associated cognitive decline in rats, which is done likely through suppressing methylglyoxal hyperactivity (promoting protein glycation, oxidative stress, and inflammation) mediated noxious effects.
TL;DR: Results show that LSOPC has a significant anti-glycative activity in vitro and it can also effectively protect the secondary structure of BSA during glycation, which could be helpful to prevent AGEs-associated diseases, and with the potential to be used as functional food ingredients.
TL;DR: In this article, the cross-linked proteins in the insoluble fraction of reconstituted MPC80 contained all major caseins, with αS1-casein predominating, and a small amount of β-lactoglobulin.
TL;DR: It is demonstrated that methylglyoxal is cytotoxic on LNCaP and PC3 and that such cytotoxicity occurs not via cell proliferation but apoptosis control, and that this physiological compound merits investigation as a potential chemo-preventive/-therapeutic agent, in differently aggressive prostate cancers.
TL;DR: Cl cloning and characterization of a glyoxalase I from sugar beet M14 line are reported, suggesting an important role of BvM14-glyoxal enzyme I in cellular detoxification and tolerance to abiotic stresses.
Abstract: Glyoxalase I is the first enzyme of the glyoxalase system that can detoxify methylglyoxal, a cytotoxic compound increased rapidly under stress conditions. Here we report cloning and characterization of a glyoxalase I from sugar beet M14 line (an interspecific hybrid between a wild species Beta corolliflora Zoss and a cultivated species B. vulgaris L). The full-length gene BvM14-glyoxalase I has 1,449 bp in length with an open reading frame of 1,065 bp encoding 354 amino acids. Sequence analysis shows the conserved glyoxalase I domains, metal and glutathione binding sites and secondary structure (α-helixes and β-sheets). The BvM14-glyoxalase I gene was ubiquitously expressed in different tissues of sugar beet M14 line and up-regulated in response to salt, mannitol and oxidative stresses. Heterologous expression of BvM14-glyoxalase I could increase E. coli tolerance to methylglyoxal. Transgenic tobacco plants constitutively expressing BvM14-glyoxalase I were generated. Both leaf discs and seedlings showed significant tolerance to methylglyoxal, salt, mannitol and H2O2. These results suggest an important role of BvM14-glyoxalase I in cellular detoxification and tolerance to abiotic stresses.
TL;DR: Findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes.
TL;DR: A strong association is reported between elevated levels of methylglyoxal, RAGE, NF-κB, mediators of the renin angiotensin system and blood pressure in high fructose diet fed rats.
Abstract: The current epidemic of obesity and type 2 diabetes is attributed to a high carbohydrate diet, containing mainly high fructose corn syrup and sucrose. More than two thirds of diabetic patients have hypertension. Methylglyoxal is a highly reactive dicarbonyl generated during glucose and fructose metabolism, and a major precursor of advanced glycation end products (AGEs). Plasma methylglyoxal levels are increased in hypertensive rats and diabetic patients. Our aim was to examine the levels of methylglyoxal, mediators of the renin angiotensin system and blood pressure in male Sprague-Dawley rats treated with a high fructose diet (60% of total calories) for 4 months. The thoracic aorta and kidney were used for molecular studies, along with cultured vascular smooth muscle cells (VSMCs). HPLC, Western blotting and Q-PCR were used to measure methylglyoxal and reduced glutathione (GSH), proteins and mRNA, respectively. Fructose treated rats developed a significant increase in blood pressure. Methylglyoxal level and protein and mRNA for angiotensin II, AT1 receptor, adrenergic α1D receptor and renin were significantly increased, whereas GSH levels were decreased, in the aorta and/or kidney of fructose fed rats. The protein expression of the receptor for AGEs (RAGE) and NF-κB were also significantly increased in the aorta of fructose fed rats. MG treated VSMCs showed increased protein for angiotensin II, AT1 receptor, and α1D receptor. The effects of methylglyoxal were attenuated by metformin, a methylglyoxal scavenger and AGEs inhibitor. In conclusion, we report a strong association between elevated levels of methylglyoxal, RAGE, NF-κB, mediators of the renin angiotensin system and blood pressure in high fructose diet fed rats.
TL;DR: The results show that methylglyoxal covalently modifies Cyt c at a single residue and induces early conformational changes that lead to the formation of native-like aggregates, which shows a clear difference from the amyloid fibril mechanisms which involve partially or totally unfolded intermediates.
TL;DR: The modified protein was found to be more effective than HbA(0) in H(2)O(2)-mediated iron release and oxidative damages involving Fenton reaction and may enhance oxidative stress and associated complications, particularly in diabetes mellitus with increased level of MG.
TL;DR: The hypothesis that restoring brain glyoxalase activity would ameliorate neurogeneration stands validated, thus presenting a much needed new target for design of anti-Alzheimer's therapeutics.
Abstract: Pathologically high brain levels of reactive dicarbonyls such as methylglyoxal or glyoxal initiate processes that lead ultimately to neurodegeneration, presented clinically as Alzheimer's disease and other cognitive or motor impairment disorders. Methylglyoxal and glyoxal result from glycolysis and normal metabolic pathways. Their reaction products with proteins (advanced glycation end products), and their primary chemical toxicities are both linked unequivocally to the primary pathologies of Alzheimer's disease, namely, amyloid plaques and neurofibrillary tangles. Generation of dicarbonyls is countered through the reduction of dicarbonyls by the glutathione-dependent glyoxalase enzyme system. Although glyoxalase-I is overexpressed in early and middle stages of Alzheimer's disease, glutathione depletion in the Alzheimer's afflicted brain cripples its efficacy. Due to the lack of a suitable pharmacological tool, the restoration of glyoxalase enzyme activity in pre-Alzheimer's or manifest Alzheimer's remains yet unvalidated as a means for anti-Alzheimer's therapy development. Disclosed herein are the results of a preclinical study into the therapeutic efficacy of ψ-GSH, a synthetic cofactor of glyoxalase, in mitigating Alzheimer's indicators in a transgenic mouse model (APP/PS1) that is predisposed to Alzheimer's disease. ψ-GSH administration completely averts the development of spatial mnemonic and long-term cognitive/cued-recall impairment. Amyloid β deposition and oxidative stress indicators are drastically reduced in the ψ-GSH-treated APP/PS1 mouse. ψ-GSH lacks discernible toxicity at strikingly high doses of 2000 mg/kg. The hypothesis that restoring brain glyoxalase activity would ameliorate neurogeneration stands validated, thus presenting a much needed new target for design of anti-Alzheimer's therapeutics. Consequently, ψ-GSH is established as a candidate for drug-development.
TL;DR: Glyoxal and methylglyoxal formed more in acidic conditions than in basic conditions, whereas diacetyl formed the most at the highest basic condition of pH 12.
Abstract: Glyoxal, methylglyoxal, and diacetyl formed from sucrose alone and from a D-glucose/ammonia Maillard model system were analyzed by gas chromatography. They are known as precursors of 4(5)-methylimidazole (MI). Glyoxal and methylglyoxal formed more in acidic conditions than in basic conditions, whereas diacetyl formed the most at the highest basic condition of pH 12. Glyoxal formation from sucrose ranged from 0.33 to 32.90 μg/g under four different time and temperature conditions. Amounts of glyoxal, methylglyoxal, and diacetyl formed in Maillard model systems ranged from 2.98 to 46.12 μg/mL, from 8.27 to 156.61 μg/mL, and from 14.94 to 1588.45 μg/mL, respectively. 4(5)-MI formation in the same model systems ranged from 28.56 to 1269.71 μg/mL. Addition of sodium sulfite reduced formation of these chemicals significantly. Total α-dicarbonyl compounds in 12 commercial soft drinks ranged from 5.75 to 50.72 μg/mL. 4(5)-MI was found in levels ranging from 1.76 to 28.11 ng/mL in 10 commercial soft drinks.
TL;DR: Results showed that during gastroduodenal digestion α-DCs react with digestive enzymes to produce carbonylated proteins, and their ability to inhibit the function of human enzymes responsible for DNA repair were shown.
TL;DR: Results provide novel evidence that reactive carbonyl species can mediate occludin glycation in cerebral microvessels and in microvascular endothelial cells that contribute to barrier dysfunction, a process that was prevented by GSH through enhanced MG catabolism.
TL;DR: The results showed that monascin exerted anti-inflammatory and antioxidative effects mediated by Nrf2 to prevent the development of diseases such as type 2 diabetes caused by inflammation.
Abstract: Hyperglycemia is associated with advanced glycation end products (AGEs). This study was designed to evaluate the inhibitory effects of monascin on receptor for advanced glycation end product (RAGE) signal and THP-1 monocyte inflammation after treatment with S100b, a specific ligand of RAGE. Monascin inhibited cytokine production by S100b-treated THP-1 monocytes via up-regulation of nuclear factor-erythroid 2-related factor-2 (Nrf2) and alleviated p47phox translocation to the membrane. Methylglyoxal (MG, 600 mg/kg bw) was used to induce diabetes in Wistar rats. Inhibitions of RAGE and p47phox by monascin were confirmed by peripheral blood mononuclear cells (PBMCs) of MG-induced rats. Silymarin (SM) was used as a positive control group. It was found that monascin promoted heme oxygenase-1 (HO-1) expression mediated by Nrf2. Suppressions of AGEs, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-β) in serum of MG-induced rats were attenuated in the monascin administration group treated with retinoic ac...
TL;DR: The results indicate that DMA is a novel antioxidant and Nrf2 activator that lowers AGE levels and may prove to be an effective treatment for diabetes.
TL;DR: The analysis suggests that the transcriptional changes in response to MG are a culmination of the damage to DNA and proteins, but that some integrate specific functions, such as DNA repair, to augment the allosteric activation of the main protective system, KefGB.
Abstract: Methylglyoxal (MG) elicits activation of K+ efflux systems to protect cells against the toxicity of the electrophile. ChIP-chip targeting RNA polymerase, supported by a range of other biochemical measurements and mutant creation, was used to identify genes transcribed in response to MG and which complement this rapid response. The SOS DNA repair regulon is induced at cytotoxic levels of MG, even when exposure to MG is transient. Glyoxalase I alone among the core MG protective systems is induced in response to MG exposure. Increased expression is an indirect consequence of induction of the upstream nemRA operon, encoding an enzyme system that itself does not contribute to MG detoxification. Moreover, this induction, via nemRA only occurs when cells are exposed to growth inhibitory concentrations of MG. We show that the kdpFABCDE genes are induced and that this expression occurs as a result of depletion of cytoplasmic K+ consequent upon activation of the KefGB K+ efflux system. Finally, our analysis suggests that the transcriptional changes in response to MG are a culmination of the damage to DNA and proteins, but that some integrate specific functions, such as DNA repair, to augment the allosteric activation of the main protective system, KefGB.
TL;DR: It is shown for the first time an association between genetic variants with GLO1 enzyme activity in humans, which can be used to predict enzyme activity and detoxifying capabilities, but further studies are needed to link these SNPs with common complications in diabetes.
TL;DR: It is demonstrated that glycation of lipid-free apoA-I, particularly late glycation, modifies its structure, its capacity to bind phospholipids and but not ABCA1- or ABCG1-dependent cholesterol efflux from macrophages.
Abstract: Increased protein glycation in people with diabetes may promote atherosclerosis. This study examined the effects of non-enzymatic glycation on the association of lipid-free apolipoproteinA-I (apoA-I) with phospholipid, and cholesterol efflux from lipid-loaded macrophages to lipid-free and lipid-associated apoA-I. Glycation of lipid-free apoA-I by methylglyoxal and glycolaldehyde resulted in Arg, Lys and Trp loss, advanced glycation end-product formation and protein cross-linking. The association of apoA-I glycated by glucose, methylglyoxal or glycolaldehyde with phospholipid multilamellar vesicles was impaired in a glycating agent dose-dependent manner, with exposure of apoA-I to both 30 mM glucose (42% decrease in kslow) and 3 mM glycolaldehyde (50% decrease in kfast, 60% decrease in kslow) resulting is significantly reduced affinity. Cholesterol efflux to control or glycated lipid-free apoA-I, or discoidal reconstituted HDL containing glycated apoA-I (drHDL), was examined using cholesterol-loaded murine (J774A.1) macrophages treated to increase expression of ATP binding cassette transporters A1 (ABCA1) or G1 (ABCG1). Cholesterol efflux from J774A.1 macrophages to glycated lipid-free apoA-I via ABCA1 or glycated drHDL via an ABCG1-dependent mechanism was unaltered, as was efflux to minimally modified apoA-I from people with Type 1 diabetes, or controls. Changes to protein structure and function were prevented by the reactive carbonyl scavenger aminoguanidine. Overall these studies demonstrate that glycation of lipid-free apoA-I, particularly late glycation, modifies its structure, its capacity to bind phospholipids and but not ABCA1- or ABCG1-dependent cholesterol efflux from macrophages.
TL;DR: Investigation of in vitro simulated gastric and gastroduodenal digestion on MGO content ofuka honey showed that after digestion MGO concentration decreases because it reacts with digestive enzymes by carbonylating their free amino groups, and does not seem to interfere with the digestion process.
Abstract: Manuka honey (MH) is a functional food that shows in vitro antimicrobial activity and to which wound healing properties, positive effects on oral health, and beneficial properties during the treatment of gastrointestinal infection diseases and upper gastrointestinal dyspepsia are assigned. The antibacterial activity of MH is mainly due to its high concentration of methylglyoxal (MGO), a highly bifunctional alkylating agent that can induce rapid nonenzymatic modifications of proteins. The aim of the present study was to investigate the influence of in vitro simulated gastric and gastroduodenal digestion on MGO content of MH. To this aim commercial MH samples, with different MGO concentrations, were submitted to digestion, and MGO was determined before and after digestion by a validated RP-HPLC-DAD method. Moreover, the role of MGO in causing carbonylation of the digestive proteins and influencing their enzymatic activities was investigated. The results showed that after digestion MGO concentration decreases because it reacts with digestive enzymes by carbonylating their free amino groups. Nevertheless, carbonylation of pepsin and pancreatin does not influence their physiological activity and therefore does not seem to interfere with the digestion process.