Search

The present investigation was carried out to study the leaf composition and methylglyoxal pathway in four barley genotypes on infection with Bipolaris sorokiniana. PL 891 was found to be highly resistant, followed by PL 807 as a resistant cultivar, while PL 426 and RD 2786 depicted susceptible behavior to spot blotch disease. Total soluble sugars increased by more than 1.4 folds in resistant genotypes at the growth stage (GS) 55 (half inflorescence emerged) while declined in the sensitive ones. However, control leaves of the latter had more total soluble sugars and cholorophyll contents at GS 55 but declined after infection. Glyoxalase I activity increased in the lower leaves of PL 807, PL 891 and PL 426 on infection with Bipolaris sorokiniana at GS 87 (hard dough). Glyoxalase II activity increased in the infected leaves of PL 891, PL 807, and PL 426 by 1.3, 1.1 and 1.4 folds respectively at GS 55 stage while declined by more than 1.3 folds in the susceptible genotype RD 2786. Glyoxalase III activity increased in the flag and lower leaves of PL 807 at both stages while declined or remained unaffected in other genotypes indicating the action of glutathione independent pathway in this genotype. Methylglyoxal reductase activity increased by more than 1.3 and 1.9 folds respectively in the flag and lower leaves of both the resistant genotypes. Negative correlation of MG with Gly I (-0.431**) and with methylglyoxal reductase (-0.274*) verified the role of these enzymes in its detoxification in response to leaf blight disease. Analysis of the data shows that the rise in total soluble sugars at initial stages and the activities of Gly III and methylglyoxal reductase at later stages along with the maintenance of redox pool could be responsible for the resistant nature of PL 891 and PL 807. [ABSTRACT FROM AUTHOR]

Bioproduction of industrially relevant chemicals such as 1,2-propanediol (1,2-PD) is central to decarbonization of the economy. Currently, 1,2-PD is produced from fossil-derived feedstocks, contributing to CO 2 emission and generation of hazardous wastes. In this study, Clostridium beijerinckii NCIMB 8052 (Cbei) , C. pasteurianum ATCC 6013 (Cpas), and Clostridium tyrobutyricum ATCC 25755 (Ctyro) were screened for the ability to transform methylglyoxal and acetol—precursors of 1,2-PD—to 1,2-PD in cultures exogenously supplemented with both compounds. Only Cbei transformed methylglyoxal to 1,2-PD (0.08 g/L). Subsequently, multiple recombinant strains of Cbei were engineered to express methylglyoxal-targeting aldo-keto reductases [ mgR , yeaE , yhdN (from Cpas), yqhD , and ydjG (from Enterobacter hormaechei UW0SKVC1), and glycerol dehydrogenase (gldA ; from Ctyro ]. With exogenous supplementation of methylglyoxal, the growth of the control strain of Cbei was impaired. Conversely, Cbei_ydjG , Cbei_yqhD , and Cbei_gldA showed 19.3 %, 130 % and 162 % enhanced growth following methylglyoxal challenge, respectively, whilst producing 0.100, 0.032, and 0.042 g/L 1,2-PD. Wildtype or recombinant strains of Cbei , Cpas , and Ctyro transformed ∼100 % of exogenously supplemented acetol to 1,2-PD. Cbei _ mgsA + mgR co-expressing methylglyoxal synthase (mgsA) and mgR (both from Cpas) produced up to 88 % more butanol on both glucose and lactose than the control strains. [Display omitted] • Clostridium beijerinckii transformed a fraction of exogenously supplemented methylglyoxal to 1,2-propanediol. • Two aldo-keto reductases and a glycerol dehydrogenase that transform cloning and heterologous expression. • YdjG from Enterobacter hormaechei UW0SKVC1 exhibited the highest 1,2-propandiol production from exogenous methylglyoxal. • Heterologous expression of mgR from Clostridium pasteurianum in Clostridium beijerinckii enhanced butanol production. [ABSTRACT FROM AUTHOR]

Methylglyoxal (MG) is responsible for advanced glycation end‐product formation, the mechanisms leading to diabetes pathogenesis and complications like acute coronary syndrome (ACS). Sugar metabolites, amino acids and fatty acids are possible substrates for MG. The study aimed to measure plasma MG substrate levels using a validated gas chromatography–mass spectrometry (GC–MS) method and explore their association with ACS risk in type 2 diabetes mellitus (T2DM). The study included 150 T2DM patients with ACS as cases and 150 T2DM without ACS as controls for the analysis of glucose, fructose, ribulose, sorbitol, glycerol, pyruvate, lactate, glycine, serine, threonine, C16:0, C16:1, C18:0, C18:1, C18:2, C18:3, C20:0 and C22:6 by GC–MS. Validated GC–MS methods were accurate, precise and sensitive. Cases significantly differed in plasma MG and metabolite levels except for lactate, C16:0, C18:0, C18:2, and C18:3 levels compared with controls. On multivariable logistic regression, plasma C20:0, C18:1, glycine and glycerol levels had increased odds of ACS risk. On multivariate receiver operating characteristic analysis, a model containing plasma C20:0, C16:1, C18:1, C18:2, serine, glycerol, lactate and threonine levels had the highest area under the curve value (0.932) for ACS diagnosis. In conclusion, plasma C20:0, C16:1, C18:1, glycine, glycerol and sorbitol levels were associated with ACS risk in T2DM. Highlights: MG is a determinant of carbonyl stress in T2DM patients.The substrates of MG were analysed by GC–MS in T2DM with and without ACS.The validated GC–MS methods were sensitive, accurate, precise and reliable.Plasma C20:0, C16:1, C18:1, glycine, glycerol and sorbitol are associated with ACS risk in T2DM. [ABSTRACT FROM AUTHOR]

Methylglyoxal (MGO) triggers oxidative stress responses in vascular endothelial cells, leading to apoptosis linked to diabetic vascular complications. Total flavonoids of Eucommia ulmoides leaves (TFEL) display antioxidant activity, yet its prevention of MGO‐induced apoptosis and mechanisms are unclear. Our study used western blotting and ELISA to evaluate protein levels and enzyme activities. Cell viability and apoptosis were evaluated using CCK8 assay and PE Annexin V/7‐AAD double staining. Reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) were measured using fluorescence probes. Vascular pathological changes and apoptosis were analyzed through H&E and TUNEL staining. In vitro, MGO‐stimulated human umbilical vein endothelial cells (HUVECs) were treated with varying TFEL concentrations. Our results demonstrated that TFEL significantly enhanced cell viability, reduced apoptosis, downregulated caspase‐3 activity, and Bax/Bcl‐2 ratio. Moreover, TFEL markedly suppressed MGO‐induced ROS and malondialdehyde (MDA) production while restoring antioxidant enzyme activity and MMP. TFEL pretreatment promoted the expression of p‐Akt, Nrf2, and HO‐1 proteins. Pharmacological inhibition of p‐Akt significantly suppressed the upregulation of Nrf2 and HO‐1 protein levels mediated by TFEL. Consistently, pharmacological inhibition of Nrf2 or p‐Akt partially abrogated the protective effects of TFEL against MGO‐induced damage in HUVECs. In vivo studies revealed that TFEL (100 and 200 mg/kg) partially restored antioxidant capacity and reduced aortic thickness and apoptosis in MGO‐injured mice. In conclusion, the findings indicate that TFEL mitigates MGO‐induced apoptosis via activation of p‐Akt/Nrf2/HO‐1 and scavenging of oxidative stress, highlighting its potential in diabetic vascular complication management. [ABSTRACT FROM AUTHOR]

Advanced glycation end products (AGEs) are the final products of the Maillard reaction, formed through the interaction of carbohydrates and proteins. Reactive dicarbonyl compounds such as methylglyoxal (MGO) serve as precursors for AGEs formation. Elevated levels of MGO/AGEs are observed in conditions like obesity, polycystic ovarian syndrome (PCOS), and diabetes, negatively impacting oocyte development. Previous studies have shown that hydrogen sulfide, a gasotransmitter with anti-AGEs effects, is produced in a process influenced by vitamin B6. R-α-lipoic acid (ALA) inhibits protein glycation and AGEs formation while stimulating glutathione (GSH) production. Taurine mitigates oxidative stress and acts as an anti-glycation compound, preventing in vitro glycation and AGEs accumulation. This study aimed to explore the ameliorative effects of a micronutrient support (Taurine, ALA and B6: TAB) on mouse oocytes challenged with MGO. Our results indicate that MGO reduces oocyte developmental competence, while TAB supplementation improves maturation, fertilization, and blastocyst formation rates. TAB also restores cell lineage allocation, redox balance and mitigates mitochondrial dysfunction in MGO-challenged oocytes. Furthermore, cumulus cells express key enzymes in the transsulfuration pathway, and TAB enhances their mRNA expression. However, TAB does not rescue MGO-induced damage in denuded oocytes, emphasizing the supportive role of cumulus cells. Overall, these findings suggest that TAB interventions may have significant implications for addressing reproductive dysfunctions associated with elevated MGO/AGEs levels. This study highlights the potential of TAB supplementation in preserving the developmental competence of COCs exposed to MGO stress, providing insights into mitigating the impact of dicarbonyl stress on oocyte quality and reproductive outcomes. [ABSTRACT FROM AUTHOR]

The damage caused by oxidative and glycative stress to cells accumulates on a daily basis and accelerates aging. Glutathione (GSH), a major antioxidant molecule in living organisms, plays a crucial role in detoxifying the stress-causing substances inherent in cells, such as H2O2 and methylglyoxal (MG), an important intermediate of advanced glycation end-products (AGEs). In this study, we focused on the enhanced antioxidant capacity of the selenium analog of GSH, i.e., selenoglutathione (GSeH), compared to GSH, and examined its effects on the detoxification of stress-causing substances and improvement in cell viability. In cell-free systems, GSeH (1 mM) generated in situ from GSeSeG in the presence of NADPH and glutathione reductase (GR) rapidly reduced more than 80% of 0.1 mM H2O2, indicating the significant glutathione peroxidase (GPx)-like antioxidant activity of GSeSeG. Similarly, around 50% of 0.5 mM MG was degraded by 0.5 mM GSeH within 30 min through a non-enzymatic mechanism. It was also found that GSeSeG (0.05–0.5 mM) showed glutathione S-transferase (GST)-like activity against 1-chloro-2,4-dinitrobenzene (CDNB), a model substance of oxidative stress-causing toxic materials in cells. Meanwhile, HeLa cells that had been pre-treated with GSeSeG exhibited increased viability against 1.2 mM H2O2 (at [GSeSeG] = 0.5–50 μM) and 4 mM MG (at [GSeSeG] = 3 μM), and the latter effect was maintained for two days. Thus, GSeSeG is a potential antioxidant and antiglycative stress agent for cells. [ABSTRACT FROM AUTHOR]

Context: Carbonyl compounds, especially aldehydes, emitted to the atmosphere, may suffer hydration in aerosols or water droplets in clouds. At the same time, they can react with hydroxyl radicals which may add or abstract hydrogen atoms from these species. The interplay between hydration and hydrogen abstraction is studied using density functional and quantum composite theoretical methods, both in the gas phase and in simulated bulk water. The H-abstraction from the aldehydic and geminal diol forms of formaldehyde, acetaldehyde, glycolaldehyde, glyoxal, methylglyoxal, and acrolein is studied to determine whether the substituent has any noticeable effect in the preference for the abstraction of one form or another. It is found that abstraction of the H-atom adjacent to the carbonyl group gives a more stable radical than same abstraction from the geminal diol in the case of formaldehyde, acetaldehyde, and glycolaldehyde. The presence of a delocalizing group in the Cα (a carbonyl group in glyoxal and methylglyoxal, and a vinyl group in acrolein), reverts this trend, and now the abstraction of the H-atom from the geminal diol gives more stable radicals. A further study was conducted abstracting hydrogen atoms from the other different positions in the species considered, both in the aldehydic and geminal diol forms. Only in the case of glycolaldehyde, the radical formed by H-abstraction from the –CH2OH group is more stable than any of the other radical species. Abstraction of the hydrogen atom in one of the hydroxyl groups in the geminal diol is equivalent to the addition of the •OH radical to the aldehyde. It leads, in some cases, to decomposition into a smaller radical and a neutral molecule. In these cases, some interesting theoretical differences are observed between the results in gas phase and (simulated) bulk solvent, as well as with respect to the method of calculation chosen. Methods: DFT (M06-2X, B2PLYP, PW6B95), CCSD(T), and composite (CBS-QB3, jun-ChS, SCVECV-f12) methods using Dunning basis sets and extrapolation to the CBS limit were used to study the energetics of closed shell aldehydes in their keto and geminal-diol forms, as well as the radical derived from them by hydrogen abstraction. Both gas phase and simulated bulk solvent calculations were performed, in the last case using the Polarizable Continuum Model. [ABSTRACT FROM AUTHOR]

This review summarises the data from long-term experimental studies and literature data on the role of oxidatively modified low-density lipoproteins (LDL) in atherogenesis and diabetogenesis. It was shown that not “oxidized” (lipoperoxide-containing) LDL, but dicarbonylmodified LDL are atherogenic (actively captured by cultured macrophages with the help of scavenger receptors), and also cause expression of lectin like oxidized low density lipoprotein receptor 1 (LOX-1) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX-1) genes in endotheliocytes, which stimulate apoptosis and endothelial dysfunction. The obtained data allowed us to justify new approaches to pharmacotherapy of atherosclerosis and diabetes mellitus. [ABSTRACT FROM AUTHOR]

Diabetes is commonly associated with an elevated level of reactive carbonyl species due to alteration of glucose and fatty acid metabolism. These metabolic changes cause an abnormality in cardiac Ca2+ regulation that can lead to cardiomyopathies. In this study, we explored how the reactive α-dicarbonyl methylglyoxal (MGO) affects Ca2+ regulation in mouse ventricular myocytes. Analysis of intracellular Ca2+ dynamics revealed that MGO (200 μM) increases action potential (AP)-induced Ca2+ transients and sarcoplasmic reticulum (SR) Ca2+ load, with a limited effect on L-type Ca2+ channel-mediated Ca2+ transients and SERCA-mediated Ca2+ uptake. At the same time, MGO significantly slowed down cytosolic Ca2+ extrusion by Na+/Ca2+ exchanger (NCX). MGO also increased the frequency of Ca2+ waves during rest and these Ca2+ release events were abolished by an external solution with zero [Na+] and [Ca2+]. Adrenergic receptor activation with isoproterenol (10 nM) increased Ca2+ transients and SR Ca2+ load, but it also triggered spontaneous Ca2+ waves in 27% of studied cells. Pretreatment of myocytes with MGO increased the fraction of cells with Ca2+ waves during adrenergic receptor stimulation by 163%. Measurements of intracellular [Na+] revealed that MGO increases cytosolic [Na+] by 57% from the maximal effect produced by the Na+-K+ ATPase inhibitor ouabain (20 μM). This increase in cytosolic [Na+] was a result of activation of a tetrodotoxin-sensitive Na+ influx, but not an inhibition of Na+-K+ ATPase. An increase in cytosolic [Na+] after treating cells with ouabain produced similar effects on Ca2+ regulation as MGO. These results suggest that protein carbonylation can affect cardiac Ca2+ regulation by increasing cytosolic [Na+] via a tetrodotoxin-sensitive pathway. This, in turn, reduces Ca2+ extrusion by NCX, causing SR Ca2+ overload and spontaneous Ca2+ waves. [ABSTRACT FROM AUTHOR]

Methylglyoxal (MG) is considered a classical biomarker of diabetes mellitus and its comorbidities. However, a role for this compound in exacerbated immune responses, such as septicemia, is being increasingly observed and requires clarification, particularly in the context of neuroinflammatory responses. Herein, we used two different approaches (in vivo and acute hippocampal slice models) to investigate MG as a biomarker of neuroinflammation and the neuroimmunometabolic shift to glycolysis in lipopolysaccharide (LPS) inflammation models. Our data reinforce the hypothesis that LPS-induced neuroinflammation stimulates the cerebral innate immune response by increasing IL-1β, a classical pro-inflammatory cytokine, and the astrocyte reactive response, via elevating S100B secretion and GFAP levels. Acute neuroinflammation promotes an early neuroimmunometabolic shift to glycolysis by elevating glucose uptake, lactate release, PFK1, and PK activities. We observed high serum and cerebral MG levels, in association with a reduction in glyoxalase 1 detoxification activity, and a close correlation between serum and hippocampus MG levels with the systemic and neuroinflammatory responses to LPS. Findings strongly suggest a role for MG in immune responses. [ABSTRACT FROM AUTHOR]

Background: Advanced glycation end products (AGEs) that accompany many metabolic disorders including diabetes, obesity, and a wide range of dyslipidemia conditions, are strongly associated with adverse effects on cell and tissue homeostasis. Accordingly, our objective was to investigate the impact of AGE-promoting diets on mouse models, considering both scenarios with and without methylglyoxal (MGO) as a primary precursor of AGEs. Materials and Methods: In this experimental study, 5-week-old C57BL/6 mice were split into four groups as a control group (n=5), AGE (n=5), MGO (n=8), and AGE-MGO-diets (n=8). After five weeks the level of fasting blood sugar (FBS), body weight, food intake, sperm parameters, and functional tests were evaluated. Furthermore, testicular superoxide dismutase (SOD) activity, malondialdehyde, and total antioxidant capacity (TAC) were assessed. Results: After five weeks, AGE, AGE-MGO, and MGO groups showed the highest level of body weight and FBS in comparison to the control group. Mean sperm concentration, sperm malondialdehyde, testicular lipid peroxidation, and TAC did not differ significantly among the study groups. While, AGE, MGO, and AGE-MGO groups showed a significant reduction in sperm motility and progressive motility compared to the control group (P<0.05). The greatest increases in abnormal sperm morphology and intracytoplasmic reactive oxygen species (ROS) were observed in the MGO and AGE-MGO groups than in the control group (P<0.05). Sperm protamine deficiency and residual histone were significantly increased in the three treatment groups compared to the control group (P<0.05). Regarding the DNA damage, the AGE and AGE-MGO groups showed the most severe damage. The lowest amount of testicular superoxide dismutases (SOD, P<0.001) was observed in the AGE-MGO group. Conclusion: AGEs and MGO have a negative influence on sperm function and reproductive potential. These effects could be possibly attributed to both increased oxidative stress (OS) and inflammation. [ABSTRACT FROM AUTHOR]

The 1,2‐dicarbonyl compound methylglyoxal (MGO) can react with and thereby impair the function of proteins and DNA, leading to pathophysiological pathways in vivo. However, studies on the bioavailability of dietary MGO and its reactions during digestion have diverging results. Therefore, simulated digestion experiments of MGO, protein, and creatine were performed in the dynamic, in vitro model of the upper gastrointestinal tract (TIM‐1). This multicompartment model continuously adjusts pH values and has realistic gastrointestinal transit times while also removing water and metabolites by dialysis. Samples were analyzed with HPLC‐UV for MGO and HPLC–MS/MS for creatine and glycated amino compounds. MGO reacted with creatine during simulated digestion in TIM‐1 to form the hydroimidazolone MG‐HCr in similar amounts as in a human intervention study. 28%–69% of MGO from the meal were passively absorbed in TIM‐1, depending on the addition of creatine and protein. Simultaneous digestion of MGO with ovalbumin led to the formation of the lysine adduct Nε‐carboxyethyllysine (CEL) and the methylglyoxal‐derived hydroimidazolone of arginine (MG‐H1). The formation of both compounds decreased with added creatine. Hence, glycation compounds are formed during digestion and significantly contribute to other ingested dietary glycation compounds, whose physiological consequences are critically discussed. [ABSTRACT FROM AUTHOR]

BACKGROUND: Preeclampsia is a multifaceted syndrome that includes maternal vascular dysfunction. We hypothesize that increased placental glycolysis and hypoxia in preeclampsia lead to increased levels of methylglyoxal (MGO), consequently causing vascular dysfunction. METHODS: Plasma samples and placentas were collected from uncomplicated and preeclampsia pregnancies. Uncomplicated placentas and trophoblast cells (BeWo) were exposed to hypoxia. The reactive dicarbonyl MGO and advanced glycation end products (Nε-(carboxymethyl)lysine [CML], Nε-(carboxyethyl)lysine [CEL], and MGO-derived hydroimidazolone [MG-H]) were quantified using liquid chromatography-tandem mass spectrometry. The activity of GLO1 (glyoxalase-1), that is, the enzyme detoxifying MGO, was measured. The impact of MGO on vascular function was evaluated using wire/pressure myography. The therapeutic potential of the MGO-quencher quercetin and mitochondrial-specific antioxidant mitoquinone mesylate (MitoQ) was explored. RESULTS: MGO, CML, CEL, and MG-H2 levels were elevated in preeclampsia-placentas (+36%, +36%, +25%, and +22%, respectively). Reduced GLO1 activity was observed in preeclampsia-placentas (−12%) and hypoxia-exposed placentas (−16%). Hypoxia-induced MGO accumulation in placentas was mitigated by the MGO-quencher quercetin. Trophoblast cells were identified as the primary source of MGO. Reduced GLO1 activity was also observed in hypoxia-exposed BeWo cells (−26%). Maternal plasma concentrations of CML and the MGO-derived MG-H1 increased as early as 12 weeks of gestation (+16% and +17%, respectively). MGO impaired endothelial barrier function, an effect mitigated by MitoQ, and heightened vascular responsiveness to thromboxane A2. CONCLUSIONS: This study reveals the accumulation of placental MGO in preeclampsia and upon exposure to hypoxia, demonstrates how MGO can contribute to vascular impairment, and highlights plasma CML and MG-H1 levels as promising early biomarkers for preeclampsia. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the antibacterial activity of two types of Manuka honey with varying concentrations of methylglyoxal (MGO), 70 and 1050 mg/kg against S. aureus in vitro. Methods: Two types of Manuka honey were purchased and tested for their antimicrobial activities. The Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) were determined using the broth tube dilution method. Results: The results revealed that both concentrations of Manuka honey exhibited antibacterial activity against S. aureus, with the higher concentration (1050 mg/kg) exhibiting enhanced antibacterial activity. The MIC was determined to be 100% v/v (undiluted) for the initial concentration and 1:2 (50% v/v) for the higher concentration. The MBC was not reached at the dilution level used in this experiment for the initial concentration, but it was inferred to be at a dilution of 1:2 for the higher concentration. Conclusion: These findings suggest that Manuka honey with a higher concentration of MGO may be more effective in inhibiting the growth of S. aureus and potentially killing bacteria present. The results of this study highlight the potential use of a high concentration of Manuka honey as an alternative antimicrobial agent against S. aureus. Further investigation into its efficacy in various clinical settings is required. [ABSTRACT FROM AUTHOR]

Background: Though maternal diabetes effects are well described in the literature, the effects of maternal diabetes in postnatal phases are often overlooked. Diabetic individuals have higher levels of circulating glycotoxins, and there is a positive correlation between maternal-derived glycotoxins and circulating glycotoxins in their progeny. Previous studies evaluated the metabolic effects of high glycotoxin exposure during lactation in adult animals. However, here we focus on the cardiovascular system of juvenile rats. Methods: For this, we used two experimental models: 1. High Methylglyoxal (MG) environment: pregnant Wistar rats were injected with PBS (VEH group) or Methylglyoxal (MG group; 60 mg/kg/day; orally, postnatal day (PND) 3 to PND14). 2. GLO-1 inhibition: pregnant Wistar rats were injected with dimethyl sulfoxide (VEH group) or a GLO-1 inhibitor (BBGC group; 5 mg/kg/day; subcutaneously, PND1–PND5). The offspring were evaluated at PND45. Results: MG offspring presented cardiac dysfunction and subtly worsened vasomotor responses in the presence of perivascular adipose tissue, without morphological alterations. In addition, an endogenous increase in maternal glycotoxins impacts offspring vasomotricity due to impaired redox status. Conclusions: Our data suggest that early glycotoxin exposure led to cardiac and vascular impairments, which may increase the risk for developing cardiovascular diseases later in life. [ABSTRACT FROM AUTHOR]

Abstract Advanced glycation end products (AGEs) are the final products of the Maillard reaction, formed through the interaction of carbohydrates and proteins. Reactive dicarbonyl compounds such as methylglyoxal (MGO) serve as precursors for AGEs formation. Elevated levels of MGO/AGEs are observed in conditions like obesity, polycystic ovarian syndrome (PCOS), and diabetes, negatively impacting oocyte development. Previous studies have shown that hydrogen sulfide, a gasotransmitter with anti-AGEs effects, is produced in a process influenced by vitamin B6. R-α-lipoic acid (ALA) inhibits protein glycation and AGEs formation while stimulating glutathione (GSH) production. Taurine mitigates oxidative stress and acts as an anti-glycation compound, preventing in vitro glycation and AGEs accumulation. This study aimed to explore the ameliorative effects of a micronutrient support (Taurine, ALA and B6: TAB) on mouse oocytes challenged with MGO. Our results indicate that MGO reduces oocyte developmental competence, while TAB supplementation improves maturation, fertilization, and blastocyst formation rates. TAB also restores cell lineage allocation, redox balance and mitigates mitochondrial dysfunction in MGO-challenged oocytes. Furthermore, cumulus cells express key enzymes in the transsulfuration pathway, and TAB enhances their mRNA expression. However, TAB does not rescue MGO-induced damage in denuded oocytes, emphasizing the supportive role of cumulus cells. Overall, these findings suggest that TAB interventions may have significant implications for addressing reproductive dysfunctions associated with elevated MGO/AGEs levels. This study highlights the potential of TAB supplementation in preserving the developmental competence of COCs exposed to MGO stress, providing insights into mitigating the impact of dicarbonyl stress on oocyte quality and reproductive outcomes.

Abstract The 1,2‐dicarbonyl compound methylglyoxal (MGO) can react with and thereby impair the function of proteins and DNA, leading to pathophysiological pathways in vivo. However, studies on the bioavailability of dietary MGO and its reactions during digestion have diverging results. Therefore, simulated digestion experiments of MGO, protein, and creatine were performed in the dynamic, in vitro model of the upper gastrointestinal tract (TIM‐1). This multicompartment model continuously adjusts pH values and has realistic gastrointestinal transit times while also removing water and metabolites by dialysis. Samples were analyzed with HPLC‐UV for MGO and HPLC–MS/MS for creatine and glycated amino compounds. MGO reacted with creatine during simulated digestion in TIM‐1 to form the hydroimidazolone MG‐HCr in similar amounts as in a human intervention study. 28%–69% of MGO from the meal were passively absorbed in TIM‐1, depending on the addition of creatine and protein. Simultaneous digestion of MGO with ovalbumin led to the formation of the lysine adduct Nε‐carboxyethyllysine (CEL) and the methylglyoxal‐derived hydroimidazolone of arginine (MG‐H1). The formation of both compounds decreased with added creatine. Hence, glycation compounds are formed during digestion and significantly contribute to other ingested dietary glycation compounds, whose physiological consequences are critically discussed.

Background: Advanced glycation end products (AGEs) that accompany many metabolic disorders including diabetes,obesity, and a wide range of dyslipidemia conditions, are strongly associated with adverse effects on cell and tissuehomeostasis. Accordingly, our objective was to investigate the impact of AGE-promoting diets on mouse models,considering both scenarios with and without methylglyoxal (MGO) as a primary precursor of AGEs.Materials and Methods: In this experimental study, 5-week-old C57BL/6 mice were split into four groups as a controlgroup (n=5), AGE (n=5), MGO (n=8), and AGE-MGO-diets (n=8). After five weeks the level of fasting blood sugar (FBS),body weight, food intake, sperm parameters, and functional tests were evaluated. Furthermore, testicular superoxide dismutase(SOD) activity, malondialdehyde, and total antioxidant capacity (TAC) were assessed.Results: After five weeks, AGE, AGE-MGO, and MGO groups showed the highest level of body weight and FBS incomparison to the control group. Mean sperm concentration, sperm malondialdehyde, testicular lipid peroxidation,and TAC did not differ significantly among the study groups. While, AGE, MGO, and AGE-MGO groups showed asignificant reduction in sperm motility and progressive motility compared to the control group (P

Manuka honey (MH) is considered a superfood mainly because of its various health-promoting properties, including its anti-cancer, anti-inflammatory, and clinically proven antibacterial properties. A unique feature of Manuka honey is the high content of methylglyoxal, which has antibacterial potential. Additionally, it contains bioactive and antioxidant substances such as polyphenols that contribute to its protective effects against oxidative stress. In this study, commercially available Manuka honey was tested for its total polyphenol content and DPPH radical scavenging ability. It was then tested in vitro on human fibroblast cells exposed to UV radiation to assess its potential to protect cells against oxidative stress. The results showed that the honey itself significantly interfered with cell metabolism, and its presence only slightly alleviated the effects of UV exposure. This study also suggested that the MGO content has a minor impact on reducing oxidative stress in UV-irradiated cells and efficiency in scavenging the DPPH radical.

Reactive carbonyl species such as methylglyoxal (MGO) act as potent glycating agents that are implicated in several oxidative stress-induced diseases, including, but not limited to, cancer, diabetes and neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. In the present study, a combined approach of initial computational studies and in vitro analysis was utilized to investigate the therapeutic benefit of L-cysteine (CYS), a thiol-containing compound. Based on the reactive analysis using global and local density functional theory (DFT) descriptors, the data reported here has revealed that CYS matches its electron-donating capacity with the electron acceptor, methylglyoxal, making the former a good candidate sequestering agent for the latter. Furthermore, in vitro analysis shows that CYS exhibits significant inhibitory effects towards damaging protein structural alteration and formation of advanced glycation end products (AGEs). Such assessment came about through Congo red binding Assay and Antiglycation Assay using BSA-MGO and BSA-glucose model systems. Additionally, CYS also demonstrates a significant protective effect towards MGO-induced oxidative stress in mouse C2C12 myotubes. Therefore, this thiol-containing compound is a promising therapeutic tool for several glycation or AGEs-induced pathological conditions. The use of more relevant cellular and animal models of desired disease studies is recommended to better understand the mechanistic basis of CYS’s potential therapeutic effect. This study utilizing the combined approach of computational and in-vitro analysis, provides helpful data to maximize the potential impact of CYS by designing related molecules that could serve as novel treatment strategies that are effective, safe, and accessible to all in the future.

Modern crops exhibit diverse sensitivities to ammonium as the primary nitrogen source, influenced by environmental factors such as external pH and nutrient availability. Despite its significance, there is currently no systematic classification of plant species based on their ammonium sensitivity. We conducted a meta-analysis of 50 plant species and present a new classification method based on the comparison of fresh biomass obtained under ammonium and nitrate nutrition. The classification uses the natural logarithm of the biomass ratio as the size effect indicator of ammonium sensitivity. This numerical parameter is associated with critical factors for nitrogen demand and form preference, such as Ellenberg indicators and the repertoire of nitrogen transporters for ammonium and nitrate uptake. Finally, a comparative analysis of the developmental and metabolic responses, including hormonal balance, is conducted in two species with divergent ammonium sensitivity values in the classification. Results indicate that nitrate has a key role in counteracting ammonium toxicity in species with a higher abundance of genes encoding NRT2-type proteins and fewer of those encoding the AMT2-type proteins. Additionally, the study demonstrates the reliability of the phytohormone balance and methylglyoxal content as indicators for anticipating ammonium toxicity. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) is often associated with metabolic disorders. Statin drugs are potent inhibitors of cholesterol biosynthesis. Objective: The aim of this study was to evaluate the effect of atorvastatin on the concentrations of methylglyoxal (MGO), glyoxalase 1 (GLO-1), and aldo–keto reductase family 1 member B10 (AKR1B10) in patients with T2DM and prediabetes. Methods: This study was conducted on 80 subjects with and without T2DM and prediabetics divided into 5 groups: patients with T2DM receiving statins (group A, n = 17), patients with T2DM not receiving statins (group B, n = 17), patients with prediabetes receiving statins (group C, n = 12), patients with prediabetes not receiving statins (group D, n = 17), and healthy controls without T2DM (control group, n = 17). Patients with T2DM and prediabetes received atorvastatin 20 mg/day for 3 months. The measurement of MGO and AKR1B10 was performed with a non-competitive sandwich-type enzyme-linked immunosorbent assay (ELISA) at 450 nm. The measurement of GLO-1 was performed by an enzymatic method at 240 nm. Results: The serum level of MGO was significantly higher in patients with T2DM and prediabetes than that of healthy controls (p = 0.001). In patients with T2DM, statins decreased the serum level of MGO, but in patients with prediabetes, statins increased the serum level of MGO (p = 0.001). The level of GLO-1 activity was significantly higher in healthy controls than that of patients with T2DM and prediabetes (p = 0.001). Furthermore, the level of GLO-1 activity was significantly higher in patients with T2DM and prediabetes receiving statins than that of patients with T2DM and prediabetes not receiving statins (p = 0.002). The serum level of AKR1B10 was significantly higher in groups C and D than that of the other groups (p = 0.001). Conclusion: Atorvastatin can improve the level of GLO-1 activity and thereby prevent diabetic complications. [ABSTRACT FROM AUTHOR]

Introduction: Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, often characterised by severe course and unclear etiopathogenesis. The reaction of protein glycoxidation, also known as glycation, may be linked to etiopathogenesis of SLE. Advanced glycation end-products (AGEs) exhibit cytotoxic properties, affect cellular signalling, impair functions of extracellular proteins, and may act as neoepitopes. Glucosone (GS), glyoxal (GO), and methylglyoxal (MGO) are examples of α-dicarbonyl compounds (α-DCs) partaking in glycoxidation. The study aimed to evaluate concentrations of these three compounds in blood serum of SLE patients, and to compare the results with healthy individuals. Material and methods: 31 women suffering from SLE and 26 healthy individuals were included in the study. High-performance liquid chromatography with fluorescence detection was applied to evaluate concentrations of α-DCs in their serum samples. Correlations between the results and parameters such as disease duration time, age, glomerular filtration rate (GFR), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), and creatinine were analysed. Results: The SLE patients exhibited lower concentrations of glucosone, glyoxal, and methylglyoxal than the control group. Analysis of correlations showed a difference between the examined groups. Conclusions: In women suffering from SLE the course of α-DCs metabolism is altered. SLE patients are characterised by low serum levels of α-DCs. We hypothesise that either hindered proteasomal degradation or fast consumption of α-DCs in oxidative conditions may cause the observed low concentration of these compounds. [ABSTRACT FROM AUTHOR]

Obesity is a complex condition associated with disruptions in carbohydrate, protein, and fat metabolism, linked to increased insulin resistance and glucose intolerance. High levels of Advanced Glycation End-products (AGEs) are associated with a range of chronic diseases, including kidney diseases, diabetic complications, cardiovascular diseases, and neurodegenerative diseases. Our study aims to investigate the accumulation of AGEs in the liver, renal and adipose tissues of mice fed a high-fat diet, contributing to a deeper understanding of obesity and its related metabolic disorders. Our study consists of three different groups fed with diets containing 60% and 10% fat. The Experiment 1 group was maintained on their diet for 12 weeks, while the obese 2 and control groups continued their diets for 24 weeks. AGEs in the liver and kidney tissues obtained were measured using the High-performance liquid chromatography grade (HPLC) method. Higher accumulation of AGEs has been observed in kidney tissue compared to adipose and liver tissues (p < 0.05). Moreover, the GO levels were notably higher in liver tissue than in adipose tissue of the D1 and D2 groups (p < 0.0001). Our results suggest that particularly in kidney tissue, increased filtration burden, functional impairment, and receptor interaction due to obesity may be effective. The lower levels of AGEs detected, especially in the obese groups compared to the control, can be attributed to the inability to metabolize AGEs due to tissue damage caused by obesity. [ABSTRACT FROM AUTHOR]

Metformin, a biguanide compound (N-1,1-dimethylbiguanide), is widely prescribed for diabetes mellitus type 2 (T2D) treatment. It also presents a plethora of properties, such as anti-oxidant, anti-inflammatory, anti-apoptosis, anti-tumorigenic, and anti-AGE formation activity. However, the precise mechanism of action of metformin in the central nervous system (CNS) needs to be clarified. Herein, we investigated the neuroprotective role of metformin in acute hippocampal slices exposed to methylglyoxal (MG), a highly reactive dicarbonyl compound and a key molecule in T2D developmental pathophysiology. Metformin protected acute hippocampal slices from MG-induced glutamatergic neurotoxicity and neuroinflammation by reducing IL-1β synthesis and secretion and RAGE protein expression. The drug also improved astrocyte function, particularly with regard to the glutamatergic system, increasing glutamate uptake. Moreover, we observed a direct effect of metformin on glutamate transporters, where the compound prevented glycation, by facilitating enzymatic phosphorylation close to Lys residues, suggesting a new neuroprotective role of metformin via PKC ζ in preventing dysfunction in glutamatergic system induced by MG. Proposed neuroprotection role of metformin in acute hippocampal slices against impairment in glutamatergic system induced in a model of methylglyoxal glycotoxicity. Metformin reversed methylglyoxal (MG)-induced neuroinflammation by reducing pro-inflammatory IL-1β synthesis and secretion and RAGE protein expression. Metformin did not alter the effect of MG on S100B secretion (1). Both MG and metformin also influenced astrocyte function in hippocampal slices. Metformin did not reverse the elevation in GLO1 activity induced by glycotoxicity; however, it abrogated the high GSH level and the expression of the co-factor of GLO1 (2). Both treatments per se changed bioenergetic metabolism and increased glucose uptake, extracellular lactate content, and pyruvate kinase (PK) activity. The increment in glucose uptake and lactate levels ceased during the co-incubation of MG with metformin. Metformin reversed the elevation of hexokinase activity by MG (3). We suggest a new role of metformin in the glutamate system, whereby it protects the hippocampus against the derangements of the glutamatergic system induced by MG, possibly by phosphorylation via PKC ζ (4). The neuroprotective action of metformin may be mediated by the phosphorylation of specific amino acid residues (Lysine) of the glutamate transporters (GLAST and GLT-1), since metformin activated the PKC ζ signaling and promoted cascades of phosphorylation in p38 MAPK and Akt proteins. The transporter protein phosphorylation prevented the Lys-glycation and the impairment of glutamate uptake induced by MG (5). [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events, culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC), has a narrow therapeutic window, and early treatment is essential for a satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end products (AGEs) and the consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase 1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in the APAP-mediated activation of RAGE and downstream cell death cascades. Constitutive Glo-1-knockout mice (GKO) and a cofactor of Glo-1, ψ-GSH, were used as tools. Our findings showed elevated oxidative stress resulting from the activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild-type controls. A unique feature of the hepatic necrosis in GKO mice was the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than the inflammation seen in the wild type. The GSH surrogate and general antioxidant ψ-GSH alleviated APAP toxicity irrespective of the Glo-1 status, suggesting that oxidative stress is the primary driver of APAP toxicity. Overall, the exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against the initial stages of APAP overdose. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes mellitus patients have been reported to have a higher incidence of Parkinson's disease. This study aimed to explore the effect of advanced glycation end products precursor methylglyoxal (MGO) on the pathophysiology of Parkinson's disease in a rotenone model. Materials and Methods: Adult female Wistar rats (n=42) were divided into four groups. Rotenone toxicity was assessed by daily weight measurements and mortality rates. Effect of MGO on blood glucose was evaluated. Locomotor activity, rearing, and rotarod tests were performed to evaluate motor functions, and for neurodegeneration, tyrosine hydroxylase immunoreactivity in the striatum and substantia nigra regions was assessed. Results: The mortality rate was 9% in the rotenone-applied rats. The mean weight, locomotor activity, rearing activity, and longest time spent on a rotarod were lower in the MGO+Rotenone group than in the Control group. Tyrosine hydroxylase immunoreactivity in the striatum rostral to the anterior commissure in the MGO+Rotenone group was lower than that in the Control and MGO groups. The number of tyrosine hydroxylase positive cells in the substantia nigra pars compacta was comparable among the groups. Conclusion: When nigrostriatal degeneration was triggered, MGO was found to worsen motor dysfunction and increase damage to dopaminergic neuron projections. [ABSTRACT FROM AUTHOR]

Methylglyoxal (MG), a reactive metabolic byproduct of glycolysis, is a causative of painful diabetic neuropathy. Patients with diabetes are associated with more frequent severe asthma exacerbation. Stimulation of capsaicin-sensitive lung vagal (CSLV) afferents may contribute to the pathogenesis of hyperreactive airway diseases such as asthma. However, the possibility of the stimulatory effect of MG on CSLV afferents and the underlying mechanisms remain unknown. Our results showed that intravenous injection of MG (25 mg/kg, MG25) in anesthetized, spontaneously breathing rats elicited pulmonary chemoreflexes characterized by apnea, bradycardia, and hypotension. The MG-induced apneic response was reproducible and dose dependent. MG25 no longer evoked these reflex responses after perineural capsaicin treatment of both cervical vagi to block C-fibers’ conduction, suggesting that the reflexes were mediated through the stimulation of CSLV afferents. Pretreatment with HC030031 [an antagonist of transient receptor potential ankyrin subtype 1 protein (TRPA1)] or AP18 (another TRPA1 antagonist), but not their vehicle, markedly attenuated the apneic response induced by MG25. Consistently, electrophysiological results showed that pretreatment with HC030031 largely attenuated the intense discharge in CSLV afferents induced by injection of MG25 in openchest and artificially ventilated rats. In isolated CSLV neurons, the perfusion of MG evoked an abrupt and pronounced increase in calcium transients in a concentration-dependent manner. This stimulatory effect on CSLV neurons was also abolished by HC030031 treatment but not by its vehicle. In conclusion, these results suggest that MG exerts a stimulatory effect on CSLV afferents, inducing pulmonary chemoreflexes, and such stimulation is mediated through the TRPA1 activation. NEW & NOTEWORTHY Methylglyoxal (MG) is implicated in the development of painful diabetic neuropathy. A retrospective cohort study revealed an increased incidence of asthma exacerbations in patients with diabetes. This study demonstrated that elevated circulating MG levels stimulate capsaicin-sensitive lung vagal afferents via activation of TRPA1, which in turn triggers respiratory reflexes. These findings provide new information for understanding the pathogenic mechanism of diabetes-associated hyperreactive airway diseases and potential therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Key message: Methylglyoxal and glyoxalase function a significant role in plant response to heavy metal stress. We update and discuss the most recent developments of methylglyoxal and glyoxalase in regulating plant response to heavy metal stress. Methylglyoxal (MG), a by-product of several metabolic processes, is created by both enzymatic and non-enzymatic mechanisms. It plays an important role in plant growth and development, signal transduction, and response to heavy metal stress (HMS). Changes in MG content and glyoxalase (GLY) activity under HMS imply that they may be potential biomarkers of plant stress resistance. In this review, we summarize recent advances in research on the mechanisms of MG and GLY in the regulation of plant responses to HMS. It has been discovered that appropriate concentrations of MG assist plants in maintaining a balance between growth and development and survival defense, therefore shielding them from heavy metal harm. MG and GLY regulate plant physiological processes by remodeling cellular redox homeostasis, regulating stomatal movement, and crosstalking with other signaling molecules (including abscisic acid, gibberellic acid, jasmonic acid, cytokinin, salicylic acid, melatonin, ethylene, hydrogen sulfide, and nitric oxide). We also discuss the involvement of MG and GLY in the regulation of plant responses to HMS at the transcriptional, translational, and metabolic levels. Lastly, considering the current state of research, we present a perspective on the future direction of MG research to elucidate the MG anti-stress mechanism and offer a theoretical foundation and useful advice for the remediation of heavy metal-contaminated environments in the future. [ABSTRACT FROM AUTHOR]

Purpose: Alzhеimеr's disеasе (AD) is thе most prеvalеnt form of dеmеntia globally. Rеsеarch links thе incrеasе of rеactivе oxidativе spеciеs (ROS) to thе pathogеnеsis of AD; thus, this study invеstigatеd thе impact of mеthylglyoxal (MGO) on thе еxprеssion of miR-125b, miR-107, and gеnеs involvеd in oxidativе strеss signaling in SH-SY5Y cеlls. Methods: Thе MTT assay assеssеd MGO's еffеcts on SH-SY5Y viability. miR-125b and miR-107 еxprеssion was analyzеd via rеal-timе PCR. Additionally, thе Human Oxidativе Strеss Pathway Plus RT2 Profilеr PCR array quantifiеd oxidativе pathway gеnе еxprеssion. Results: MGO concеntrations undеr 700μM did not significantly rеducе SH–SY5Y viability. MiR-125b and miR-107 еxprеssion in SH-SY5Y cеlls incrеasеd and dеcrеasеd rеspеctivеly (P <0.05).>P<0.05).>P<0.05).> Conclusion: MGO altеrs oxidativе strеss pathway gеnе, miR-125b, and miR-107 еxprеssion in SH-SY5Y cеlls. Targеting MGO or miR-125b and miR-107 may providе novеl AD thеrapеutic stratеgiеs or improvе sеvеrе symptoms. Furthеr rеsеarch should еlucidatе thе prеcisе mеchanisms. [ABSTRACT FROM AUTHOR]

Exposure to abiotic stresses leads to elevated methylglyoxal (MG) levels in plants, impacting seed germination and root growth. In response, the activation of NADPH-dependent aldo-keto reductase and glutathione (GSH)-dependent glyoxalase enzymes helps to regulate MG levels and reduce its toxic efects. However, detoxifcation may not be carried out efectively due to the limitation of GSH and NADPH in plants under stress. Recently, a novel enzyme called glyoxalase III (GLY III) has been discovered which can detoxify MG in a single step without needing GSH. To understand the physiological importance of this pathway in rice, we overexpressed the gene encoding GLYIII enzyme (OsDJ-1C) in rice. It was observed that OsDJ-1C overexpression in rice regulated MG levels under stress conditions thus, linked well with plants' abiotic stress tolerance potential. The OsDJ-1C overexpression lines displayed better root architecture, improved photosynthesis, and reduced yield penalty compared to the WT plants under salinity, and drought stress conditions. These plants demonstrated an improved GSH/GSSG ratio, reduced level of reactive oxygen species, increased antioxidant capacity, and higher anti-glycation activity thereby indicating that the GLYIII mediated MG detoxifcation plays a signifcant role in plants' ability to reduce the impact of abiotic stress. Furthermore, these fndings imply the potential of OsDJ-1C in crop improvement programs. [ABSTRACT FROM AUTHOR]

Glyoxalase I (GLO1) is the primary enzyme for detoxification of the reactive dicarbonyl methylglyoxal (MG). Loss of GLO1 promotes accumulation of MG resulting in a recapitulation of diabetic phenotypes. We previously demonstrated attenuated GLO1 protein in skeletal muscle from individuals with type 2 diabetes (T2D). However, whether GLO1 attenuation occurs prior to T2D and the mechanisms regulating GLO1 abundance in skeletal muscle are unknown. GLO1 expression and activity were determined in skeletal muscle tissue biopsies from 15 lean healthy individuals (LH, BMI: 22.4 ± 0.7) and 5 individuals with obesity (OB, BMI: 32.4 ± 1.3). GLO1 protein was attenuated by 26 ± 0.3 % in OB compared to LH skeletal muscle (p = 0.019). Similar reductions for GLO1 activity were observed (p = 0.102). NRF2 and Keap1 expression were equivocal between groups despite a 2-fold elevation in GLO1 transcripts in OB skeletal muscle (p = 0.008). GLO1 knock-down (KD) in human immortalized myotubes promoted downregulation of muscle contraction and organization proteins indicating the importance of GLO1 expression for skeletal muscle function. SIRT1 KD had no effect on GLO1 protein or activity whereas, SIRT2 KD attenuated GLO1 protein by 28 ± 0.29 % (p

Abstract Background 1,2-propanediol (1,2-PDO) is widely used in the cosmetic, food, and drug industries with a worldwide consumption of over 1.5 million metric tons per year. Although efforts have been made to engineer microbial hosts such as Corynebacterium glutamicum to produce 1,2-PDO from renewable resources, the performance of such strains is still improvable to be competitive with existing petrochemical production routes. Results In this study, we enabled 1,2-PDO production in the genome-reduced strain C. glutamicum PC2 by introducing previously described modifications. The resulting strain showed reduced product formation but secreted 50 ± 1 mM d-lactate as byproduct. C. glutamicum PC2 lacks the d-lactate dehydrogenase which pointed to a yet unknown pathway relevant for 1,2-PDO production. Further analysis indicated that in C. glutamicum methylglyoxal, the precursor for 1,2-PDO synthesis, is detoxified with the antioxidant native mycothiol (MSH) by a glyoxalase-like system to lactoylmycothiol and converted to d-lactate which is rerouted into the central carbon metabolism at the level of pyruvate. Metabolomics of cell extracts of the empty vector-carrying wildtype, a 1,2-PDO producer and its derivative with inactive d-lactate dehydrogenase identified major mass peaks characteristic for lactoylmycothiol and its precursors MSH and glucosaminyl-myo-inositol, whereas the respective mass peaks were absent in a production strain with inactivated MSH synthesis. Deletion of mshA, encoding MSH synthase, in the 1,2-PDO producing strain C. glutamicum ΔhdpAΔldh(pEKEx3-mgsA-yqhD-gldA) improved the product yield by 56% to 0.53 ± 0.01 mM1,2−PDO mMglucose −1 which is the highest value for C. glutamicum reported so far. Conclusions Genome reduced-strains are a useful basis to unravel metabolic constraints for strain engineering and disclosed in this study the pathway to detoxify methylglyoxal which represents a precursor for 1,2-PDO production. Subsequent inactivation of the competing pathway significantly improved the 1,2-PDO yield.

Introduction Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease, often characterised by severe course and unclear etiopathogenesis. The reaction of protein glycoxidation, also known as glycation, may be linked to etiopathogenesis of SLE. Advanced glycation end-products (AGEs) exhibit cytotoxic properties, affect cellular signalling, impair functions of extracellular proteins, and may act as neoepitopes. Glucosone (GS), glyoxal (GO), and methylglyoxal (MGO) are examples of α-dicarbonyl compounds (α-DCs) partaking in glycoxidation. The study aimed to evaluate concentrations of these three compounds in blood serum of SLE patients, and to compare the results with healthy individuals. Material and methods 31 women suffering from SLE and 26 healthy individuals were included in the study. High-performance liquid chromatography with fluorescence detection was applied to evaluate concentrations of α-DCs in their serum samples. Correlations between the results and parameters such as disease duration time, age, glomerular filtration rate (GFR), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), and creatinine were analysed. Results The SLE patients exhibited lower concentrations of glucosone, glyoxal, and methylglyoxal than the control group. Analysis of correlations showed a difference between the examined groups. Conclusions In women suffering from SLE the course of α-DCs metabolism is altered. SLE patients are characterised by low serum levels of α-DCs. We hypothesise that either hindered proteasomal degradation or fast consumption of α-DCs in oxidative conditions may cause the observed low concentration of these compounds.

ABSTRACTObjectives To analyze contributions to microbial ecology of Reactive Electrophile Species (RES), including methylglyoxal, generated during glycolysis.Methods Genetic analyses were performed on the glyoxalase pathway in Streptococcus mutans (SM) and Streptococcus sanguinis (SS), followed by phenotypic assays and transcription analysis.Results Deleting glyoxalase I (lguL) reduced RES tolerance to a far greater extent in SM than in SS, decreasing the competitiveness of SM against SS. Although SM displays a greater RES tolerance than SS, lguL-null mutants of either species showed similar tolerance; a finding consistent with the ability of methylglyoxal to induce the expression of lguL in SM, but not in SS. A novel paralogue of lguL (named gloA2) was identified in most streptococci. SM mutant ∆gloA2SM showed little change in methylglyoxal tolerance yet a significant growth defect and increased autolysis on fructose, a phenotype reversed by the addition of glutathione, or by the deletion of a fructose: phosphotransferase system (PTS) that generates fructose-1-phosphate (F-1-P).Conclusions Fructose contributes to RES generation in a PTS-specific manner, and GloA2 may be required to degrade certain RES derived from F-1-P. This study reveals the critical roles of RES in fitness and interbacterial competition and the effects of PTS in modulating RES metabolism.

Drought-induced leaf senescence is associated with high sugar levels, which bears some resemblance to the syndrome of diabetes in humans; however, the underlying mechanisms of such 'plant diabetes' on carbon imbalance and the corresponding detoxification strategy are not well understood. Here, we investigated the regulatory mechanism of exogenous methylglyoxal (MG) on 'plant diabetes' in maize plants under drought stress applied via foliar spraying during the grain-filling stage. Exogenous MG delayed leaf senescence and promoted photoassimilation, thereby reducing the yield loss induced by drought by 14%. Transcriptome and metabolite analyses revealed that drought increased sugar accumulation in leaves through inhibition of sugar transporters that facilitate phloem loading. This led to disequilibrium of glycolysis and overaccumulation of endogenous MG. Application of exogenous MG up-regulated glycolytic flux and the glyoxalase system that catabolyses endogenous MG and glycation end-products, ultimately alleviating 'plant diabetes'. In addition, the expression of genes facilitating anabolism and catabolism of trehalose-6-phosphate was promoted and suppressed by drought, respectively, and exogenous MG reversed this effect, implying that trehalose-6-phosphate signaling in the mediation of 'plant diabetes'. Furthermore, exogenous MG activated the phenylpropanoid biosynthetic pathway, promoting the production of lignin and phenolic compounds, which are associated with drought tolerance. Overall, our findings indicate that exogenous MG activates defense-related pathways to alleviate the toxicity derived from 'plant diabetes', thereby helping to maintain leaf function and yield production under drought. [ABSTRACT FROM AUTHOR]

Background: The formation of advanced glycation end products (AGEs) is the central process contributing to diabetic complications in diabetic individuals with sustained and inconsistent hyperglycemia. Methylglyoxal, a reactive carbonyl species, is found to be a major precursor of AGEs, and its levels are elevated in diabetic conditions. Dysfunction of pancreatic beta cells and impairment in insulin secretion are the hallmarks of diabetic progression. Exposure to methylglyoxal-induced AGEs alters the function and maintenance of pancreatic beta cells. Hence, trapping methylglyoxal could be an ideal approach to alleviate AGE formation and its influence on beta cell proliferation and insulin secretion, thereby curbing the progression of diabetes to its complications. Methods and results: In the present study, we have explored the mechanism of action of (+)-Catechin against methylglyoxal-induced disruption in pancreatic beta cells via molecular biology techniques, mainly western blot. Methylglyoxal treatment decreased insulin synthesis (41.5%) via downregulating the glucose-stimulated insulin secretion pathway (GSIS). This was restored upon co-treatment with (+)-Catechin (29.9%) in methylglyoxal-induced Beta-TC-6 cells. Also, methylglyoxal treatment affected the autocrine function of insulin by disrupting the IRS1/PI3k/Akt pathway. Methylglyoxal treatment suppresses Pdx-1 and Maf A levels, which are responsible for beta cell maintenance and cell proliferation. (+)-Catechin could significantly augment the levels of these transcription factors. Conclusion: This is the first study to examine the impact of a natural compound on methylglyoxal with the insulin-mediated autocrine and paracrine activities of pancreatic beta cells. The results indicate that (+)-Catechin exerts a protective effect against methylglyoxal exposure in pancreatic beta cells and can be considered a potential anti-glycation agent in further investigations on ameliorating diabetic complications. [ABSTRACT FROM AUTHOR]

Objective: To determine the association of diabetic nephropathy with glyoxalase-1 enzyme levels and a genetic missense variation (SNP rs4746) in its gene (GLO-1). Methods: This cross-sectional comparative study was conducted at the Department of Biochemistry and Molecular Biology, Army Medical College, Rawalpindi from November 2020 to December 2022. One hundred patients and one hundred and thirteen healthy controls were enrolled using the nonprobability convenience sampling method. Medical history and 10ml blood were obtained from each individual after written informed consent. Blood samples were subjected to biochemical tests and DNA extraction which was later used for single nucleotide polymorphism (SNP) analysis (C332C variant of rs4741 GLO-1 gene) using Tetra primer ARMS PCR and gel electrophoresis. Glyoxalase-1 enzyme activity in serum was measured using ELISA. Results: There was a significant difference in serum glyoxalase-1 levels in the two groups (p-value< 0.001). The patient group had lower levels (16.24 ± 22.51mg/dl) of glyoxalase-1 as compared to the control group (48.70 ± 42.54mg/dl). In genotypic analysis, 98 out of 100 control individuals had AA genotype-while only one had CC and another AC genotype. In the patient group, 94 out of 100 patients showed AA genotype, three AC, and three CC genotypes. As the statistical significance (p-value) was 0.37, there was no significant association found between AC or CC genotype and diabetic nephropathy. Conclusion: Glyoxalase-1 levels are linked to the development of diabetic nephropathy in our patients while a known missense variant rs4746 in the GLO-1 gene is not associated with increased risk. [ABSTRACT FROM AUTHOR]

Copyright of Ege Journal of Medicine is the property of Ege University, Faculty of Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Astrocytes play fundamental roles in the maintenance of brain homeostasis. The dysfunction of these cells is widely associated with brain disorders, which are often characterized by variations in the astrocyte protein markers GFAP and S100B, in addition to alterations in some of its metabolic functions. To understand the role of astrocytes in neurodegeneration mechanisms, we induced some of these metabolic alterations, such as energy metabolism, using methylglyoxal (MG) or fluorocitrate (FC); and neuroinflammation, using lipopolysaccharide (LPS) and streptozotocin (STZ), which is used for inducing Alzheimer's disease (AD) in animal models. We showed that MG, LPS, STZ and FC similarly caused astrocyte dysfunction by increasing GFAP and reducing S100B secretion. In the context of AD, STZ caused an amyloid metabolism impairment verified by increases in Aβ1-40 peptide content and decreases in the amyloid degradation enzymes, IDE and NEP. Our data contribute to the understanding of the role of astrocytes in brain injury mechanisms and suggest that STZ is suitable for use in vitro models for studying the role of astrocytes in AD. [ABSTRACT FROM AUTHOR]

Background: 1,2-propanediol (1,2-PDO) is widely used in the cosmetic, food, and drug industries with a worldwide consumption of over 1.5 million metric tons per year. Although efforts have been made to engineer microbial hosts such as Corynebacterium glutamicum to produce 1,2-PDO from renewable resources, the performance of such strains is still improvable to be competitive with existing petrochemical production routes. Results: In this study, we enabled 1,2-PDO production in the genome-reduced strain C. glutamicum PC2 by introducing previously described modifications. The resulting strain showed reduced product formation but secreted 50 ± 1 mM d-lactate as byproduct. C. glutamicum PC2 lacks the d-lactate dehydrogenase which pointed to a yet unknown pathway relevant for 1,2-PDO production. Further analysis indicated that in C. glutamicum methylglyoxal, the precursor for 1,2-PDO synthesis, is detoxified with the antioxidant native mycothiol (MSH) by a glyoxalase-like system to lactoylmycothiol and converted to d-lactate which is rerouted into the central carbon metabolism at the level of pyruvate. Metabolomics of cell extracts of the empty vector-carrying wildtype, a 1,2-PDO producer and its derivative with inactive d-lactate dehydrogenase identified major mass peaks characteristic for lactoylmycothiol and its precursors MSH and glucosaminyl-myo-inositol, whereas the respective mass peaks were absent in a production strain with inactivated MSH synthesis. Deletion of mshA, encoding MSH synthase, in the 1,2-PDO producing strain C. glutamicum ΔhdpAΔldh(pEKEx3-mgsA-yqhD-gldA) improved the product yield by 56% to 0.53 ± 0.01 mM1,2−PDO mMglucose−1 which is the highest value for C. glutamicum reported so far. Conclusions: Genome reduced-strains are a useful basis to unravel metabolic constraints for strain engineering and disclosed in this study the pathway to detoxify methylglyoxal which represents a precursor for 1,2-PDO production. Subsequent inactivation of the competing pathway significantly improved the 1,2-PDO yield. [ABSTRACT FROM AUTHOR]

Methylglyoxal (MGO), a highly reactive dicarbonyl metabolite of glucose primarily formed during the glycolytic pathway, is a precursor of advanced glycation end-products (AGEs). Recently, numerous studies have shown that MGO accumulation can cause pain and hyperalgesia. However, the mechanism through which MGO induces pain in the spinal dorsal horn remains unclear. The present study investigated the effect of MGO on spontaneous excitatory postsynaptic currents (sEPSC) in rat spinal dorsal horn neurons using blind whole-cell patch-clamp recording. Perfusion of MGO increased the frequency and amplitude of sEPSC in spinal horn neurons in a concentration-dependent manner. Additionally, MGO administration increased the number of miniature EPSC (mEPSC) in the presence of tetrodotoxin, a sodium channel blocker. However, 6-cyano-7-nitroqiunocaline-2,3-dione (CNQX), an AMPA/kainate receptor antagonist, blocked the enhancement of sEPSC by MGO. HC-030031, a TRP ankyrin-1 (TRPA1) antagonist, and capsazepine, a TRP vanilloid-1 (TRPV1) antagonist, inhibited the action of MGO. Notably, the effects of MGO were completely inhibited by HC-030031 and capsazepine. MGO generates reactive oxygen species (ROS) via AGEs. ROS also potentially induce pain via TRPA1 and TRPV1 in the spinal dorsal horn. Furthermore, we examined the effect of MGO in the presence of N-tert-butyl-α-phenylnitrone (PBN), a non-selective ROS scavenger, and found that the effect of MGO was completely inhibited. These results suggest that MGO increases spontaneous glutamate release from the presynaptic terminal to spinal dorsal horn neurons through TRPA1, TRPV1, and ROS and could enhance excitatory synaptic transmission. [ABSTRACT FROM AUTHOR]

Xanthomonas oryzae pv. oryzae (Xoo) causes bacterial blight (BB), a globally devastating disease of rice (Oryza sativa) that is responsible for significant crop loss. Sugars and sugar metabolites are important for pathogen infection, providing energy and regulating events associated with defense responses; however, the mechanisms by which they regulate such events in BB are unclear. As an inevitable sugar metabolite, methylglyoxal (MG) is involved in plant growth and responses to various abiotic stresses, but the underlying mechanisms remain enigmatic. Whether and how MG functions in plant biotic stress responses is almost completely unknown. Here, we report that the Xoo strain PXO99 induces OsWRKY62.1 to repress transcription of OsGLY II genes by directly binding to their promoters, resulting in overaccumulation of MG. MG negatively regulates rice resistance against PXO99: osglyII2 mutants with higher MG levels are more susceptible to the pathogen, whereas OsGLYII2- overexpressing plants with lower MG content show greater resistance than the wild type. Overexpression of OsGLYII2 to prevent excessive MG accumulation confers broad-spectrum resistance against the biotrophic bacterial pathogens Xoo and Xanthomonas oryzae pv. oryzicola and the necrotrophic fungal pathogen Rhizoctonia solani , which causes rice sheath blight. Further evidence shows that MG reduces rice resistance against PXO99 through CONSTITUTIVE DISEASE RESISTANCE 1 (OsCDR1). MG modifies the Arg97 residue of OsCDR1 to inhibit its aspartic protease activity, which is essential for OsCDR1-enhanced immunity. Taken together, these findings illustrate how Xoo promotes infection by hijacking a sugar metabolite in the host plant. Sugars and sugar metabolites are important for plant–pathogen interactions. This study demonstrates that Xoo , which causes rice bacterial blight disease, upregulates OsWRKY62.1 expression to promote the accumulation of MG and that MG negatively regulates rice resistance by modifying and inhibiting OsCDR1 protease activity. The study reveals how bacterial pathogens promote their infection by manipulating the accumulation of a sugar metabolite in the host plant. [ABSTRACT FROM AUTHOR]

Therapeutic proteins are potent, fast-acting drugs that are highly effective in treating various conditions. Medicinal protein usage has increased in the past 10 years, and it will evolve further as we better understand disease molecular pathways. However, it is associated with high processing costs, limited stability, difficulty in being administered as an oral medication, and the inability of large proteins to penetrate tissue and reach their target locations. Many methods have been developed to overcome the problems with the stability and chaperone activity of therapeutic proteins, viz., the addition of external agents (changing the properties of the surrounding solvent by using stabilizing excipients, e.g., amino acids, sugars, polyols) and internal agents (chemical modifications that influence its structural properties, e.g., mutations, glycosylation). However, these methods must completely clear protein instability and chaperone issues. There is still much work to be done on finetuning chaperone proteins to increase their biological efficacy and stability. Methylglyoxal (MGO), a potent dicarbonyl compound, reacts with proteins and forms covalent cross-links. Much research on MGO scavengers has been conducted since they are known to alter protein structure, which may result in alterations in biological activity and stability. MGO is naturally produced within our body, however, its impact on chaperones and protein stability needs to be better understood and seems to vary based on concentration. This review highlights the efforts of several research groups on the effect of MGO on various proteins. It also addresses the impact of MGO on a client protein, α-crystallin, to understand the potential solutions to the protein's chaperone and stability problems. [ABSTRACT FROM AUTHOR]

This comprehensive exploration delves into the intricate interplay of methylglyoxal (MG) and glyoxalase 1 (GLO I) in various physiological and pathological contexts. The linchpin of the narrative revolves around the role of these small molecules in age-related issues, diabetes, obesity, cardiovascular diseases, and neurodegenerative disorders. Methylglyoxal, a reactive dicarbonyl metabolite, takes center stage, becoming a principal player in the development of AGEs and contributing to cell and tissue dysfunction. The dual facets of GLO I—activation and inhibition—unfold as potential therapeutic avenues. Activators, spanning synthetic drugs like candesartan to natural compounds like polyphenols and isothiocyanates, aim to restore GLO I function. These molecular enhancers showcase promising outcomes in conditions such as diabetic retinopathy, kidney disease, and beyond. On the contrary, GLO I inhibitors emerge as crucial players in cancer treatment, offering new possibilities in diseases associated with inflammation and multidrug resistance. The symphony of small molecules, from GLO I activators to inhibitors, presents a nuanced understanding of MG regulation. From natural compounds to synthetic drugs, each element contributes to a molecular orchestra, promising novel interventions and personalized approaches in the pursuit of health and wellbeing. The abstract concludes with an emphasis on the necessity of rigorous clinical trials to validate these findings and acknowledges the importance of individual variability in the complex landscape of health. [ABSTRACT FROM AUTHOR]

Tissue engineering approaches aim to provide biocompatible scaffold supports that allow healing to progress often in healthy tissue. In diabetic foot ulcers (DFUs), hyperglycemia impedes ulcer regeneration, due to complications involving accumulations of cellular methylglyoxal (MG), a key component of oxidated stress and premature cellular aging which further limits repair. In this study, we aim to reduce MG using a collagen-chondroitin sulfate gene-activated scaffold (GAS) containing the glyoxalase-1 gene (GLO-1) to scavenge MG and anti-fibrotic β-klotho to restore stem cell activity in diabetic adipose-derived stem cells (dADSCs). dADSCs were cultured on dual GAS constructs for 21 days in high-glucose media in vitro. Our results show that dADSCs cultured on dual GAS significantly reduced MG accumulation (−84%; p < 0.05) compared to the gene-free controls. Similar reductions in profibrotic proteins α-smooth muscle actin (−65%) and fibronectin (−76%; p < 0.05) were identified in dual GAS groups. Similar findings were observed in the expression of pro-scarring structural proteins collagen I (−62%), collagen IV (−70%) and collagen VII (−86%). A non-significant decrease in the expression of basement membrane protein E-cadherin (−59%) was noted; however, the dual GAS showed a significant increase in the expression of laminin (+300%). We conclude that dual GAS-containing Glo-1 and β-klotho had a synergistic MG detoxification and anti-fibrotic role in dADSC's. This may be beneficial to provide better wound healing in DFUs by controlling the diabetic environment and rejuvenating the diabetic stem cells towards improved wound healing. [ABSTRACT FROM AUTHOR]