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1.
Food Chem ; 366: 130601, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34298391

RESUMO

An analytical method was developed and validated for simultaneous identification and quantification of advanced glycation end products (AGEs), amino acid cross-links, lysine and arginine in foodstuffs based on acid hydrolysis, hydrophilic interaction chromatography and high-resolution mass spectrometry. The method proved to be sensitive, reproducible and accurate for furosine, N-Ɛ-(carboxymethyl)lysine, N-Ɛ-(carboxyethyl)lysine, methylglyoxal and glyoxal-derived hydroimidazolones (MG-H and GO-H isomers, respectively), glyoxal lysine dimer, lysinoalanine, lanthionine, lysine and arginine. LOD and LOQ values in water were found to be 0.9-15.5 ng/mL and 2.8-47 ng/mL, respectively, and increased to 1.4-60 ng/mL and 4.4-182 ng/mL in liquid infant formula. Recovery values ranged from 76 to 118% in four different food matrices. Microwave-assisted hydrolysis for 11 min had similar efficiency as conventional hydrolysis, which requires overnight incubation. Acid stability of each compound was determined during microwave and conventional hydrolysis, and showed that the MG-H1 isomer is partially converted to the MG-H3 isomer during acid hydrolysis.


Assuntos
Aminoácidos , Produtos Finais de Glicação Avançada , Hidrólise , Espectrometria de Massas , Aldeído Pirúvico
2.
Food Chem ; 373(Pt A): 131451, 2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-34717081

RESUMO

The present study investigated the influence of in vitro stimulated digestion system on the content of glyoxal and methylglyoxal in commercial cookies. Glyoxal and methylglyoxal levels in different cookie samples were analyzed before and after in vitro digestion with High Performance Liquid Chromatography. Initial glyoxal and methylglyoxal values ranged between 42.9 and 126.6 µg/100 g, and between 22.9 and 507.3 µg/100 g, respectively. After in vitro digestion, formation of glyoxal and methylglyoxal values were increased up to 645% and 698%, respectively. The results revealed that in vitro stimulated digestion conditions strongly increased the amount of glyoxal and methylglyoxal in cookies. The amount of fructose was found to be more effective on the formation of both GO and MGO than those of glucose and sucrose. Further studies are needed to extensively investigate glyoxal and methylglyoxal formation under in vitro conditions in such foods.


Assuntos
Glioxal , Aldeído Pirúvico , Cromatografia Líquida de Alta Pressão , Alimentos , Glucose
3.
Food Chem ; 369: 130884, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34455317

RESUMO

This study aimed at investigating the effects of interactions between dietary dicarbonyl scavengers coexisting in human plasma on the overall methylglyoxal scavenging potential. Apart from being the most effective dicarbonyl scavengers, epicatechin or cysteine, which can be easily oxidized by other compounds, was reacted with methylglyoxal in the presence of certain other dicarbonyl scavengers under simulated physiological conditions (pH 7.4, 37 °C). Methylglyoxal was monitored kinetically in the presence of the individual scavengers or in their combinations with epicatechin or cysteine. The observed and estimated reaction rate constants were calculated for each combination. As the observed rate constant for the reaction between cysteine and epicatechin was found to be significantly greater (p < 0.05) than the estimated rate constant, the results suggest synergism occurred in this combination. Epicatechin was found to interact antagonistically with scavengers that stimulate its oxidation such as creatine, quercetin, and gallic acid during methylglyoxal scavenging.


Assuntos
Catequina , Aldeído Pirúvico , Cisteína , Ácido Gálico , Humanos , Quercetina
4.
Food Chem ; 369: 130952, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34474283

RESUMO

l-glycine and l-serine are the building blocks of proteins and exhibit various biological activities. This work found that l-glycine and l-serine show low scavenging capacity for methylglyoxal at moderate conditions (pH 7.0, 37 °C). However, they efficiently eliminate methylglyoxal and formaldehyde when the two aldehydes co-exist, via generation of imidazole salt, a compound formed by one molecule of methylglyoxal and formaldehyde, and two molecules of amino acids. The imidazole salts were identified in biscuits and fried potato crisps. Moreover, the formation of imidazole salts greatly decreased the cytotoxicity of their precursors, methylglyoxal and formaldehydes. This finding suggests that glycine and serine can be used to scavenge these two harmful aldehydes both after intake and during food processing.


Assuntos
Glicina , Aldeído Pirúvico , Formaldeído , Imidazóis , Sais , Serina
5.
Food Chem ; 371: 131141, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34598119

RESUMO

The aim of this study was to investigate sourdough impact on the in vitro bioaccessibility of Glyoxal (GO) and methylglyoxal (MGO). Five sourdough bread and one white bread (control bread) were prepared to observe sourdough influence on GO and MGO levels before and after in vitro digestion. GO and MGO levels increased in all breads after in vitro digestion. The highest increase in GO and MGO levels was realized in the control bread with bioaccessibility indexes (BIGO and BIMGO) of 8.67 and 4.14, respectively, whereas BIGO and BIMGO in sourdough breads were found in the range of 1.65 to 2.65 and 1.73 to 2.97, respectively. The extent of Maillard reaction (MR) in control bread was confirmed by FAST method. The lower increase in GO and MGO compounds after in vitro digestion thanks to sourdough addition may reduce bread's contribution of AGEs accumulation in the body.


Assuntos
Pão , Aldeído Pirúvico , Digestão , Fermentação , Glioxal , Triticum
6.
J Agric Food Chem ; 69(50): 15374-15383, 2021 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-34905354

RESUMO

The reaction of the N6-amino group of lysine residues and 1,2-dicarbonyl compounds during Maillard processes leads to advanced glycation end products (AGEs). In the present work, we deliver a comprehensive analysis of changes of carbohydrates, dicarbonyl structures, and 11 AGEs during the grilling of porcine meat patties. While raw meat contained mainly glyoxal-derived N6-carboxymethyl lysine (CML), grilling led to an increase of predominantly methylglyoxal-derived AGEs N6-carboxyethyl lysine (CEL), N6-lactoyl lysine, methylglyoxal lysine dimer (MOLD), and methylglyoxal lysine amide (MOLA). Additionally, we identified and quantitated a novel methylglyoxal-derived amidine compound N1,N2-di-(5-amino-5-carboxypentyl)-2-lactoylamidine (methylglyoxal lysine amide, MGLA) in heated meat. Analysis of carbohydrates suggested that approximately 50% of the methylglyoxal stemmed from the fragmentation of triosephosphates during the heat treatment. Surprisingly, N6-lactoyl lysine was the major AGE, and based on model incubations, we propose that approximately 90% must be explained by the nonenzymatic acylation of lysine through S-lactoylglutathione, which was quantitated for the first time in meat herein.


Assuntos
Culinária , Produtos Finais de Glicação Avançada/análise , Glioxal , Carne de Porco , Aldeído Pirúvico , Animais , Reação de Maillard , Suínos
7.
Cells ; 10(12)2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34943806

RESUMO

Meningiomas are the most common non-malignant intracranial tumors and prefer, like most tumors, anaerobic glycolysis for energy production (Warburg effect). This anaerobic glycolysis leads to an increased synthesis of the metabolite methylglyoxal (MGO) or glyoxal (GO), which is known to react with amino groups of proteins. This reaction is called glycation, thereby building advanced glycation end products (AGEs). In this study, we investigated the influence of glycation on sialylation in two meningioma cell lines, representing the WHO grade I (BEN-MEN-1) and the WHO grade III (IOMM-Lee). In the benign meningioma cell line, glycation led to differences in expression of sialyltransferases (ST3GAL1/2/3/5/6, ST6GAL1/2, ST6GALNAC2/6, and ST8SIA1/2), which are known to play a role in tumor progression. We could show that glycation of BEN-MEN-1 cells led to decreased expression of ST3Gal5. This resulted in decreased synthesis of the ganglioside GM3, the product of ST3Gal5. In the malignant meningioma cell line, we observed changes in expression of sialyltransferases (ST3GAL1/2/3, ST6GALNAC5, and ST8SIA1) after glycation, which correlates with less aggressive behavior.


Assuntos
Meningioma/enzimologia , Sialiltransferases/metabolismo , Linhagem Celular Tumoral , Gangliosídeo G(M3)/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicosilação/efeitos dos fármacos , Humanos , Meningioma/genética , Ácido N-Acetilneuramínico/biossíntese , Aldeído Pirúvico/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sialiltransferases/genética
8.
J Mol Evol ; 89(9-10): 618-638, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34718825

RESUMO

In the chemoautotrophic theory for the origin of life, offered as an alternative to broth theory, the archaic reductive citric acid cycle operating without enzymes is in the center. The non-enzymatic (methyl)glyoxalase pathway has been suggested to be the anaplerotic route for the reductive citric acid cycle. In the recent years, much has been learned about methylglyoxal, but its importance in the metabolic machinery is still uncovered. If methylglyoxal had been essential participant of the early stage of evolution, then it is a legitimate question whether it might have played a role in the early oxido-reduction network, too. Therefore, an oxido-reduction network of methylglyoxal that might have functioned under ancient circumstances without enzymes was constructed and analyzed by virtue of group contribution method. Taking methylglyoxal as input material, it turned out that the evolutionary value of reactions and biomolecules were not similar. Glycerol, glycerate, and tartonate, the output components, were conserved to different degrees. Although the tartonate route was similarly favorable from energetic point of view, its intermediates are almost not present in extant biochemistry. The presence of two carboxyl or aldehyde groups, or their combination in tricarbons of the constructed network seemed disadvantageous for selection, and the inductive effect, resulting in an asymmetry in electron cloud of chemicals, might have been important. The evolutionary role for cysteine, H2S, and formaldehyde in the emergence of high-energy bonds in the form of thioesters and in Fe-S cluster formation as well as in imidazole synthesis was shown to bridge the gap between prebiotic chemistry and contemporary biochemistry. Overall, the ideas developed here represent an approach fitting to chemoautotrophic origin of life and implying to the role of methylglyoxal in triose formation. The proposed network is expected to have an impact upon how one may think of prebiological chemical processes on methylglyoxal, too. Finally, along the evolutionary time line, the network functioning without enzymes is situated between the formation of simple organic compounds and primeval cells, being closer to the former and well preceding the last common metabolic ancestor developed after primitive cells emerged.


Assuntos
Lactoilglutationa Liase , Aldeído Pirúvico , Humanos
9.
J Agric Food Chem ; 69(40): 11960-11970, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34591478

RESUMO

Despite more than 100 years of research, formation of food melanoidins from carbohydrates and amino acids in the course of the Maillard reaction is still not fully understood. Experiments with relevant precursors are commonly used to limit the pathways of the complex reaction and to elucidate the formation mechanisms of the colored end-products. Here as a simple model, methylglyoxal was incubated with l-alanine or l-lysine in aqueous solutions at 100 °C and pH 5. The reaction mixtures were analyzed for color formation, molecular weight distribution, and conversion of methylglyoxal. High-resolution mass spectrometry was used to characterize the variety of products formed. With the help of Kendrick and van Krevelen analyses, the complex data sets were investigated for common substructures and reaction patterns. This study revealed that methylglyoxal forms oligomers via aldol reaction under involvement of its prevalent reaction products such as formaldehyde, acetaldehyde, acetol, and aminoacetone with amino acids.


Assuntos
Lisina , Reação de Maillard , Alanina , Espectrometria de Massas , Polímeros , Aldeído Pirúvico
10.
eNeuro ; 8(5)2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531281

RESUMO

Recent evidence suggests that alteration of axon initial segment (AIS) geometry (i.e., length or location along the axon) contributes to CNS dysfunction in neurological diseases. For example, AIS length is shorter in the prefrontal cortex of type 2 diabetic mice with cognitive impairment. To determine the key type 2 diabetes-related factor that produces AIS shortening we modified levels of insulin, glucose, or the reactive glucose metabolite methylglyoxal in cultures of dissociated cortices from male and female mice and quantified AIS geometry using immunofluorescent imaging of the AIS proteins AnkyrinG and ßIV spectrin. Neither insulin nor glucose modification altered AIS length. Exposure to 100 but not 1 or 10 µm methylglyoxal for 24 h resulted in accumulation of the methylglyoxal-derived advanced glycation end-product hydroimidazolone and produced reversible AIS shortening without cell death. Methylglyoxal-evoked AIS shortening occurred in both excitatory and putative inhibitory neuron populations and in the presence of tetrodotoxin (TTX). In single-cell recordings resting membrane potential was depolarized at 0.5-3 h and returned to normal at 24 h. In multielectrode array (MEA) recordings methylglyoxal produced an immediate ∼300% increase in spiking and bursting rates that returned to normal within 2 min, followed by a ∼20% reduction of network activity at 0.5-3 h and restoration of activity to baseline levels at 24 h. AIS length was unchanged at 0.5-3 h despite the presence of depolarization and network activity reduction. Nevertheless, these results suggest that methylglyoxal could be a key mediator of AIS shortening and disruptor of neuronal function during type 2 diabetes.


Assuntos
Segmento Inicial do Axônio , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animais , Feminino , Masculino , Camundongos , Neurônios , Aldeído Pirúvico
11.
Int J Mol Sci ; 22(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34576189

RESUMO

Reactive carbonyl species (RCS) such as methylglyoxal (MGO) or glyoxal (GO) are the main precursors of the formation of advanced glycation end products (AGEs). AGEs are a major factor in the development of vascular complications in diabetes. Vasoprotectives (VPs) exhibit a wide range of activities beneficial to cardiovascular health. The present study aimed to investigate selected VPs and their structural analogs for their ability to trap MGO/GO, inhibit AGE formation, and evaluate their antioxidant potential. Ultra-high-performance liquid chromatography coupled with an electrospray ionization mass spectrometer (UHPLC-ESI-MS) and diode-array detector (UHPLC-DAD) was used to investigate direct trapping capacity and kinetics of quenching MGO/GO, respectively. Fluorimetric and colorimetric measurements were used to evaluate antiglycation and antioxidant action. All tested substances showed antiglycative effects, but hesperetin was the most effective in RCS scavenging. We demonstrated that rutin, diosmetin, hesperidin, and hesperetin could trap both MGO and GO by forming adducts, whose structures we proposed. MGO-derived AGE formation was inhibited the most by hesperetin, and GO-derived AGEs by diosmetin. High reducing and antiradical activity was confirmed for quercetin, rutin, hesperetin, and calcium dobesilate. Therefore, in addition to other therapeutic applications, some VPs could be potential candidates as antiglycative agents to prevent AGE-related complications of diabetes.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Animais , Antioxidantes/metabolismo , Cromatografia Líquida de Alta Pressão , Hesperidina/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Aldeído Pirúvico/farmacologia , Espectrometria de Massas por Ionização por Electrospray
12.
Anal Chim Acta ; 1181: 338902, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34556229

RESUMO

Methylglyoxal (MGO) is the primary material basis for the non-peroxide antibacterial activity (NPA) of manuka honey from New Zealand. Therefore, it is necessary to identify the quality or discriminate the grade of honey because no all manuka honeys on the market display the NPA. The current routine method employed for the detection of MGO involves high-performance liquid chromatography (HPLC) test. However, it requires long time (∼8 h) for sample derivatization. Herein, we report an intrinsic Raman signal amplification strategy for the rapid identification and detection of MGO by using silver-coated gold nanoparticles (Au@Ag NPs) along with a high selective surface-enhanced Raman scattering (SERS) probe 8-thioguanosine (8-TG). 8-TG is synthesized via the derivatization of 8-bromoguanosine (8-BG) with thiourea, and its Raman peak assignments were confirmed by computer simulation. The detection is performed through the Raman intensity ratio (I631/I700) variation of N2-(1-carboxyethyl)-thioguanosine (CETG) formed by the reaction between 8-TG and MGO on surface of Au@Ag NPs, where one CETG Raman intensity at 631 cm-1 increases while the other one at 700 cm-1 decreases oppositely. The opposite change not only yields an intrinsic Raman signal amplification, but also provides built-in correction. As a result, the proposed SERS method exhibits high sensitivity and accuracy. In addition, the whole analytical test is achieved within ∼20 min. The method can be used for the fast detection of MGO in manuka honey and discrimination of the honey grade.


Assuntos
Mel , Nanopartículas Metálicas , Simulação por Computador , Ouro , Mel/análise , Aldeído Pirúvico , Análise Espectral Raman
13.
Nutrients ; 13(7)2021 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-34371884

RESUMO

The dietary supplement, trans-resveratrol and hesperetin combination (tRES-HESP), induces expression of glyoxalase 1, countering the accumulation of reactive dicarbonyl glycating agent, methylglyoxal (MG), in overweight and obese subjects. tRES-HESP produced reversal of insulin resistance, improving dysglycemia and low-grade inflammation in a randomized, double-blind, placebo-controlled crossover study. Herein, we report further analysis of study variables. MG metabolism-related variables correlated with BMI, dysglycemia, vascular inflammation, blood pressure, and dyslipidemia. With tRES-HESP treatment, plasma MG correlated negatively with endothelial independent arterial dilatation (r = -0.48, p < 0.05) and negatively with peripheral blood mononuclear cell (PBMC) quinone reductase activity (r = -0.68, p < 0.05)-a marker of the activation status of transcription factor Nrf2. For change from baseline of PBMC gene expression with tRES-HESP treatment, Glo1 expression correlated negatively with change in the oral glucose tolerance test area-under-the-curve plasma glucose (ΔAUGg) (r = -0.56, p < 0.05) and thioredoxin interacting protein (TXNIP) correlated positively with ΔAUGg (r = 0.59, p < 0.05). Tumor necrosis factor-α (TNFα) correlated positively with change in fasting plasma glucose (r = 0.70, p < 0.001) and negatively with change in insulin sensitivity (r = -0.68, p < 0.01). These correlations were not present with placebo. tRES-HESP decreased low-grade inflammation, characterized by decreased expression of CCL2, COX-2, IL-8, and RAGE. Changes in CCL2, IL-8, and RAGE were intercorrelated and all correlated positively with changes in MLXIP, MAFF, MAFG, NCF1, and FTH1, and negatively with changes in HMOX1 and TKT; changes in IL-8 also correlated positively with change in COX-2. Total urinary excretion of tRES and HESP metabolites were strongly correlated. These findings suggest tRES-HESP counters MG accumulation and protein glycation, decreasing activation of the unfolded protein response and expression of TXNIP and TNFα, producing reversal of insulin resistance. tRES-HESP is suitable for further evaluation for treatment of insulin resistance and related disorders.


Assuntos
Hesperidina/administração & dosagem , Resistência à Insulina , Obesidade/terapia , Sobrepeso/terapia , Resveratrol/administração & dosagem , Adulto , Pressão Sanguínea/efeitos dos fármacos , Índice de Massa Corporal , Proteínas de Transporte/sangue , Correlação de Dados , Estudos Cross-Over , Suplementos Nutricionais , Método Duplo-Cego , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/terapia , Feminino , Transtornos do Metabolismo de Glucose/sangue , Transtornos do Metabolismo de Glucose/terapia , Glicosilação/efeitos dos fármacos , Humanos , Inflamação , Mediadores da Inflamação/sangue , Leucócitos Mononucleares/metabolismo , Masculino , Obesidade/sangue , Sobrepeso/sangue , Aldeído Pirúvico/sangue , Fator de Necrose Tumoral alfa/sangue
14.
Plant Foods Hum Nutr ; 76(3): 340-346, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34342789

RESUMO

Brassica vegetables are common in cuisines worldwide. The aim of this study was to investigate the antiglycation, methylglyoxal (MG)-trapping action and antioxidant activity of Brassica vegetable extract (BVE) from cabbage, cauliflower and Chinese cabbage. The results showed that cauliflower had the highest phenolic content with the strongest DPPH radical scavenging activity, ferric reducing antioxidant power and oxygen radical absorbance capacity. Seven phenolic acids and three flavonoids were identified by ESI-Q-TOF-MS analysis. The common phenolic compounds in all BVE were sinapic acid and p-hydroxybenzoic acid. The BVE (0.5 mg/mL) showed significant inhibitory activity against glucose-induced fluorescent advanced glycation end products (AGEs) formation (34 - 67%) and preserved the amount of protein thiol group (30 - 35%). In addition, all extracts (0.125 - 4 mg/mL) also had the ability to trap MG, a reactive glycating agent. Total phenolic content of BVE exhibited a positive correlation with DPPH radical scavenging activity (r = 0.524) and % inhibition of AGE formation (r = 0.570) and % MG-trapping capacity (r = 0.786). These findings suggest that the BVE possesses antioxidant and antiglycating activity that may help to protect against protein glycation and oxidation mediated by glycation reaction.


Assuntos
Antioxidantes , Brassica , Antioxidantes/farmacologia , Produtos Finais de Glicação Avançada , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Aldeído Pirúvico , Verduras
15.
PLoS Pathog ; 17(8): e1009819, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34407151

RESUMO

Listeria monocytogenes is a Gram-positive, food-borne pathogen that lives a biphasic lifestyle, cycling between the environment and as a facultative intracellular pathogen of mammals. Upon entry into host cells, L. monocytogenes upregulates expression of glutathione synthase (GshF) and its product, glutathione (GSH), which is an allosteric activator of the master virulence regulator PrfA. Although gshF mutants are highly attenuated for virulence in mice and form very small plaques in host cell monolayers, these virulence defects can be fully rescued by mutations that lock PrfA in its active conformation, referred to as PrfA*. While PrfA activation can be recapitulated in vitro by the addition of reducing agents, the precise biological cue(s) experienced by L. monocytogenes that lead to PrfA activation are not known. Here we performed a genetic screen to identify additional small-plaque mutants that were rescued by PrfA* and identified gloA, which encodes glyoxalase A, a component of a GSH-dependent methylglyoxal (MG) detoxification system. MG is a toxic byproduct of metabolism produced by both the host and pathogen, which if accumulated, causes DNA damage and protein glycation. As a facultative intracellular pathogen, L. monocytogenes must protect itself from MG produced by its own metabolic processes and that of its host. We report that gloA mutants grow normally in broth, are sensitive to exogenous MG and severely attenuated upon IV infection in mice, but are fully rescued for virulence in a PrfA* background. We demonstrate that transcriptional activation of gshF increased upon MG challenge in vitro, and while this resulted in higher levels of GSH for wild-type L. monocytogenes, the glyoxalase mutants had decreased levels of GSH, presumably due to the accumulation of the GSH-MG hemithioacetal adduct. These data suggest that MG acts as a host cue that leads to GSH production and activation of PrfA.


Assuntos
Proteínas de Bactérias/metabolismo , Glutationa/metabolismo , Lactoilglutationa Liase/metabolismo , Listeria monocytogenes/fisiologia , Listeriose/microbiologia , Aldeído Pirúvico/metabolismo , Virulência , Animais , Proteínas de Bactérias/genética , Feminino , Regulação Bacteriana da Expressão Gênica , Inativação Metabólica , Lactoilglutationa Liase/genética , Listeriose/metabolismo , Camundongos , Mutação , Aldeído Pirúvico/química , Substâncias Redutoras/química , Ativação Transcricional
16.
Heart Lung Circ ; 30(11): 1681-1693, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34393049

RESUMO

BACKGROUND: Arterial stiffening is a hallmark of vascular ageing and a consequence of many diseases including diabetes mellitus. Methylglyoxal (MGO), a highly reactive α-dicarbonyl mainly formed during glycolysis, has emerged as a potential contributor to the development of arterial stiffness. MGO reacts with arginine and lysine residues in proteins to form stable advanced glycation endproducts (AGEs). AGEs may contribute to arterial stiffening by increased cross-linking of collagen within the extracellular matrix (ECM), by altering the vascular structure, and by triggering inflammatory and oxidative pathways. Although arterial stiffness is mainly determined by ECM and vascular smooth muscle cell function, the effects of MGO and MGO-derived AGEs on these structures have not been thoroughly reviewed to date. METHODS AND RESULTS: We conducted a PubMed search without filtering for publication date which resulted in 16 experimental and 22 clinical studies eligible for inclusion. Remarkably, none of the experimental and only three of the clinical studies specifically mentioned MGO-derived AGEs. Almost all studies reported an association between arterial stiffness and AGE accumulation in the arterial wall or increased plasma AGEs. Other studies report reduced arterial stiffness in experimental models upon administration of AGE-breakers. CONCLUSIONS: No papers published to date directly show an association between MGO or MGO-derived AGEs and arterial stiffening. The relevance of the various underlying mechanisms is not yet clear, which is particularly due to methodological challenges in the detection of MGO and MGO-derived AGEs at the molecular, intra- and pericellular, and structural levels, as well as in challenges in the assessment of intrinsic arterial wall properties at ECM- and tissue levels.


Assuntos
Aldeído Pirúvico , Rigidez Vascular , Matriz Extracelular
17.
Int J Mol Sci ; 22(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207084

RESUMO

Advanced glycation end products (AGEs) are formed via nonenzymatic reactions between reducing sugars and proteins. Recent studies have shown that methylglyoxal, a potent precursor for AGEs, causes a variety of biological dysfunctions, including diabetes, inflammation, renal failure, and cancer. However, little is known about the function of methylglyoxal-derived AGEs (AGE4) in kidney cells. Therefore, we verified the expression of endoplasmic reticulum (ER) stress-related genes and apoptosis markers to determine the effects of AGE4 on human proximal epithelial cells (HK-2). Moreover, our results showed that AGE4 induced the expression of apoptosis markers, such as Bax, p53, and kidney injury molecule-1, but downregulated Bcl-2 and cyclin D1 levels. AGE4 also promoted the expression of NF-κB, serving as a transcription factor, and the phosphorylation of c-Jun NH2-terminal kinase (JNK), which induced cell apoptosis and ER stress mediated by the JNK inhibitor. Furthermore, AGE4 induced mitochondrial dysfunction by inducing the permeabilization of the mitochondrial membrane and ATP synthesis. Through in vitro and in vivo experiments, this study provides a new perspective on renal dysfunction with regard to the AGE4-induced RAGE /JNK signaling pathway, which leads to renal cell apoptosis via the imbalance of mitochondrial function and ER stress in kidney damage.


Assuntos
Apoptose , Estresse do Retículo Endoplasmático , Produtos Finais de Glicação Avançada/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mitocôndrias/metabolismo , Aldeído Pirúvico/metabolismo , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/metabolismo , Produtos Finais de Glicação Avançada/farmacologia , Humanos , Rim/metabolismo , Camundongos , Mitocôndrias/efeitos dos fármacos , Modelos Biológicos , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo
18.
PLoS One ; 16(7): e0253840, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34314429

RESUMO

Laminitis is one of the most devastating diseases in equine medicine, and although several etiopathogenetic mechanisms have been proposed, few clear answers have been identified to date. Several lines of evidence point towards its underlying pathology as being metabolism-related. In the carbonyl stress pathway, sugars are converted to methylglyoxal (MG)-a highly reactive α-oxoaldehyde, mainly derived during glycolysis in eukaryotic cells from the triose phosphates: D-glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. One common hypothesis is that MG could be synthesized during the digestive process in horses, and excessive levels absorbed into peripheral blood could be delivered to the foot and lead to alterations in the hoof lamellar structure. In the present study, employing an ex vivo experimental design, different concentrations of MG were applied to hoof explants (HE), which were then incubated and maintained in a specific medium for 24 and 48 h. Macroscopic and histological analyses and a separation force test were performed at 24 and 48 h post-MG application. Gene expression levels of matrix metalloproteinase (MMP)-2 and -14 and tissue inhibitor of metalloproteinase (TIMP)-2 were also measured at each time point for all experimental conditions. High concentrations of MG induced macroscopic and histological changes mimicking laminitis. The separation force test revealed that hoof tissue samples incubated for 24 h in a high concentration of MG, or with lower doses but for a longer period (48 h), demonstrated significant weaknesses, and samples were easily separated. All results support that high levels of MG could induce irreversible damage in HEs, mimicking laminitis in an ex vivo model.


Assuntos
Casco e Garras/metabolismo , Modelos Biológicos , Aldeído Pirúvico/metabolismo , Animais , Expressão Gênica/efeitos dos fármacos , Casco e Garras/citologia , Casco e Garras/patologia , Cavalos , Masculino , Metaloproteinase 14 da Matriz/genética , Metaloproteinase 14 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Aldeído Pirúvico/análise , Aldeído Pirúvico/farmacologia , Açúcares/metabolismo , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo
19.
Chem Commun (Camb) ; 57(66): 8166-8169, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34318802

RESUMO

An "AND"-logic-gate-based fluorescent probe NAP-DCP-4 with dual reactive sites is reported, which has improved selectivity for methylglyoxal over glyoxal, featuring formaldehyde-enhanced methylglyoxal detection and irreversible and reversible turn-on fluorescence responses at different excitation wavelengths. Its cell-impermeability enables facile monitoring of extracellular methylglyoxal level changes in the supernatant of activated macrophages.


Assuntos
Corantes Fluorescentes/química , Macrófagos/química , Aldeído Pirúvico/análise , Animais , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Aldeído Pirúvico/metabolismo , Células RAW 264.7
20.
Nat Commun ; 12(1): 3316, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083524

RESUMO

The methylglyoxal-derived hydroimidazolone isomer, MGH-1, is an abundant advanced glycation end-product (AGE) associated with disease and age-related disorders. As AGE formation occurs spontaneously and without an enzyme, it remains unknown why certain sites on distinct proteins become modified with specific AGEs. Here, we use a combinatorial peptide library to determine the chemical features that favor MGH-1. When properly positioned, tyrosine is found to play an active mechanistic role that facilitates MGH-1 formation. This work offers mechanistic insight connecting multiple AGEs, including MGH-1 and carboxyethylarginine (CEA), and reconciles the role of negative charge in influencing glycation outcomes. Further, this study provides clear evidence that glycation outcomes can be influenced through long- or medium-range cooperative interactions. This work demonstrates that these chemical features also predictably template selective glycation on full-length protein targets expressed in mammalian cells. This information is vital for developing methods that control glycation in living cells and will enable the study of glycation as a functional post-translational modification.


Assuntos
Produtos Finais de Glicação Avançada/metabolismo , Proteínas/metabolismo , Sequência de Aminoácidos , Arginina/análogos & derivados , Arginina/química , Arginina/metabolismo , Produtos Finais de Glicação Avançada/química , Glicosilação , Células HEK293 , Humanos , Imidazóis/química , Imidazóis/metabolismo , Isomerismo , Biblioteca de Peptídeos , Processamento de Proteína Pós-Traducional , Proteínas/química , Proteínas/genética , Aldeído Pirúvico/análogos & derivados , Aldeído Pirúvico/química , Aldeído Pirúvico/metabolismo
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