Methylglyoxal induces cardiac dysfunction through mechanisms involving altered intracellular calcium handling in the rat heart.

Methylglyoxal (MGO) is an endogenous, highly reactive dicarbonyl metabolite generated under hyperglycaemic conditions. MGO plays a role in developing pathophysiological conditions, including diabetic cardiomyopathy. However, the mechanisms involved and the molecular targets of MGO in the heart have not been elucidated. In this work, we studied the exposure-related effects of MGO on cardiac function in an isolated perfused rat heart ex vivo model. The effect of MGO on calcium homeostasis in cardiomyocytes was studied in vitro by the fluorescence indicator of intracellular calcium Fluo-4. We demonstrated that MGO induced cardiac dysfunction, both in contractility and diastolic function. In rat heart, the effects of MGO treatment were significantly limited by aminoguanidine, a scavenger of MGO, ruthenium red, a general cation channel blocker, and verapamil, an L-type voltage-dependent calcium channel blocker, demonstrating that this dysfunction involved alteration of calcium regulation. MGO induced a significant concentration-dependent increase of intracellular calcium in neonatal rat cardiomyocytes, which was limited by aminoguanidine and verapamil. These results suggest that the functionality of various calcium channels is altered by MGO, particularly the L-type calcium channel, thus explaining its cardiac toxicity. Therefore, MGO could participate in the development of diabetic cardiomyopathy through its impact on calcium homeostasis in cardiac cells.

Anti-inflammatory effect of luteoloside against methylglyoxal induced human dental pulp cells.

PURPOSE: The aim of this study was to investigate whether luteoloside, a flavonoid, could protect human dental pulp cells (HDPCs) against inflammation and oxidative stress induced by methylglyoxal (MGO), one of the advanced glycated end products (AGE) substances. METHODS: HDPCs were stimulated with MGO and treated with luteoloside. MTT assay was used to determine cell viability. Protein expression was measured via western blotting. Reactive oxygen species (ROS) were measured with a Muse Cell Analyzer. Alkaline phosphatase activity (ALP) and Alizarin red staining were used for mineralization assay. RESULTS: Luteoloside down-regulated the expression of inflammatory molecules such as ICAM-1, VCAM-1, TNF-α, IL-1ß, MMP-2, MMP-9, and COX-2 in MGO-induced HDPCs without showing any cytotoxicity. It attenuated ROS formation and enhanced osteogenic differentiation such as ALP activity and Alizarin red staining in MGO-induced HDPCs. Overall, luteoloside showed protective actions against inflammation and oxidative stress in HDPCs induced by MGO through its anti-inflammatory, anti-oxidative, and osteogenic activities by down-regulating p-JNK in the MAPK pathway. CONCLUSION: These results suggest that luteoloside might be a potential adjunctive therapeutic agent for treating pulpal pathological conditions in patients with diabetes mellitus.

Chromate-induced methylglyoxal detoxification system drives cadmium and chromate immobilization by Cupriavidus sp. MP-37.

The detoxification of cadmium (Cd) or chromium (Cr) by microorganisms plays a vital role in bacterial survival and restoration of the polluted environment, but how microorganisms detoxify Cd and Cr simultaneously is largely unknown. Here, we isolated a bacterium, Cupriavidus sp. MP-37, which immobilized Cd(II) and reduced Cr(VI) simultaneously. Notably, strain MP-37 exhibited variable Cd(II) immobilization phenotypes, namely, cell adsorption and extracellular immobilization in the co-presence of Cd(II) and Cr(VI), while cell adsorption in the presence of Cd(II) alone. To unravel Cr(VI)-induced extracellular Cd(II) immobilization, proteomic analysis was performed, and methylglyoxal-scavenging protein (glyoxalase I, GlyI) and a regulator (YafY) showed the highest upregulation in the co-presence of Cd(II) and Cr(VI). GlyI overexpression reduced the intracellular methylglyoxal content and increased the immobilized Cd(II) content in extracellular secreta. The addition of lactate produced by GlyI protein with methylglyoxal as substrate increased the Cd(II) content in extracellular secreta. Reporter gene assay, electrophoretic mobility shift assay, and fluorescence quenching assay demonstrated that glyI expression was induced by Cr(VI) but not by Cd(II), and that YafY positively regulated glyI expression by binding Cr(VI). In the pot experiment, inoculation with the MP-37 strain reduced the Cd content of Oryza sativa L., and their secreted lactate reduced the Cr accumulation in Oryza sativa L. This study reveals that Cr(VI)-induced detoxification system drives methylglyoxal scavenging and Cd(II) extracellular detoxification in Cd(II) and Cr(VI) co-existence environment.

Methylglyoxal improves zirconium stress tolerance in Raphanus sativus seedling shoots by restricting zirconium uptake, reducing oxidative damage, and upregulating glyoxalase I.

Raphanus sativus also known as radish is a member of the Brassicaceae family which is mainly cultivated for human and animal consumption. R. sativus growth and development is negatively affected by heavy metal stress. The metal zirconium (Zr) have toxic effects on plants and tolerance to the metal could be regulated by known signaling molecules such as methylglyoxal (MG). Therefore, in this study we investigated whether the application of the signaling molecule MG could improve the Zr tolerance of R. sativus at the seedling stage. We measured the following: seed germination, dry weight, cotyledon abscission (%), cell viability, chlorophyll content, malondialdehyde (MDA) content, conjugated diene (CD) content, hydrogen peroxide (H2O2) content, superoxide (O2•-) content, MG content, hydroxyl radical (·OH) concentration, ascorbate peroxidase (APX) activity, superoxide dismutase (SOD) activity, glyoxalase I (Gly I) activity, Zr content and translocation factor. Under Zr stress, exogenous MG increased the seed germination percentage, shoot dry weight, cotyledon abscission, cell viability and chlorophyll content. Exogenous MG also led to a decrease in MDA, CD, H2O2, O2•-, MG and ·OH, under Zr stress in the shoots. Furthermore, MG application led to an increase in the enzymatic activities of APX, SOD and Gly I as well as in the complete blocking of cotyledon abscission under Zr stress. MG treatment decreased the uptake of Zr in the roots and shoots. Zr treatment decreased the translocation factor of the Zr from roots to shoots and MG treatment decreased the translocation factor of Zr even more significantly compared to the Zr only treatment. Our results indicate that MG treatment can improve R. sativus seedling growth under Zr stress through the activation of antioxidant enzymes and Gly I through reactive oxygen species and MG signaling, inhibiting cotyledon abscission through H2O2 signaling and immobilizing Zr translocation.

Methylglyoxal-induced neurotoxic effects in primary neuronal-like cells transdifferentiated from human mesenchymal stem cells: Impact of low concentrations.

In the last decades, advanced glycation end-products (AGEs) have aroused the interest of the scientific community due to the increasing evidence of their involvement in many pathophysiological processes including various neurological disorders and cognitive decline age related. Methylglyoxal (MG) is one of the reactive dicarbonyl precursors of AGEs, mainly generated as a by-product of glycolysis, whose accumulation induces neurotoxicity. In our study, MG cytotoxicity was evaluated employing a human stem cell-derived model, namely, neuron-like cells (hNLCs) transdifferentiated from mesenchymal stem/stromal cells, which served as a source of human based species-specific "healthy" cells. MG increased ROS production and induced the first characteristic apoptotic hallmarks already at low concentrations (≥10 µM), decreased the cell growth (≥5-10 µM) and viability (≥25 µM), altered Glo-1 and Glo-2 enzymes (≥25 µM), and markedly affected the neuronal markers MAP-2 and NSE causing their loss at low MG concentrations (≥10 µM). Morphological alterations started at 100 µM, followed by even more marked effects and cell death after few hours (5 h) from 200 µM MG addition. Substantially, most effects occurred as low as 10 µM, concentration much lower than that reported from previous observations using different in vitro cell-based models (e.g., human neuroblastoma cell lines, primary animal cells, and human iPSCs). Remarkably, this low effective concentration approaches the level range measured in biological samples of pathological subjects. The use of a suitable cellular model, that is, human primary neurons, can provide an additional valuable tool, mimicking better the physiological and biochemical properties of brain cells, in order to evaluate the mechanistic basis of molecular and cellular alterations in CNS.

The C-glucosyl flavone isoorientin pretreatment attenuates the methylglyoxal-induced mitochondrial dysfunction in the human neuroblastoma SH-SY5Y cells: role for the AMPK-PI3K/Akt/Nrf2/γ-GCL/GSH axis.

The reactive dicarbonyl methylglyoxal (MG) behaves as a pro-oxidant agent, causing redox dysfunction and cell death by different mechanisms in mammalian cells. MG is also a mitochondrial toxicant, impairing the oxidative phosphorylation (OXPHOS) system and leading to bioenergetics and redox collapses. MG induces glycation and exerts an important role in neurodegenerative and cardiovascular diseases. Isoorientin (ISO), a C-glucosyl flavone found in Aspalathus linearis, Fagopyrum esculentum, and Passiflora edulis, among others, is an antioxidant and anti-inflammatory molecule. ISO is a potent inducer of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), the master modulator of the redox environment in mammals. We investigated here whether ISO would prevent the mitochondria-related redox and bioenergetics impairments induced by MG in the human neuroblastoma SH-SY5Y cells. The cells were administrated with ISO at 20 µM for 18 h prior to the exposure to MG at 500 µM for further 24 h. It was observed that ISO efficiently prevented the mitochondrial impairments caused by MG. ISO upregulated the activity of the enzyme γ-glutamate-cysteine ligase (γ-GCL), consequently stimulating the synthesis of glutathione (GSH). The inhibition of γ-GCL, adenosine monophosphate-activated protein kinase (AMPK), and phosphoinositide 3-kinase/Akt (PI3K/Akt) suppressed the beneficial effects induced by ISO on the MG-challenged cells. Moreover, silencing of Nrf2 blocked the ISO-dependent γ-GCL and GSH upregulation and the effects on the mitochondria of the MG-challenged cells. Then, ISO caused mitochondrial protection by an AMPK-PI3K/Akt/Nrf2/γ-GCL/GSH-dependent manner in MG-administrated SH-SY5Y cells.

The process of methylglyoxal-induced retinal capillary endothelial cell degeneration in rats.

Methylglyoxal, a highly reactive dicarbonyl compound, is increased and accumulated in patients with diabetic mellitus. Methylglyoxal forms advanced glycation end products (AGE), contributing to the pathogenesis of diabetic complications, including diabetic retinopathy. Recent studies have shown that methylglyoxal induces diabetic retinopathy-like abnormalities in retinal vasculature. In this study, we investigated the processes and mechanisms of methylglyoxal-induced retinal capillary endothelial cell degeneration in rats. Morphological changes in vascular components (endothelial cells, pericytes, and basement membranes) were assessed in the retinas 2, 7, and 14 days after intravitreal injection of methylglyoxal. Intravitreal methylglyoxal injection induced retinal capillary endothelial cell degeneration in a dose- and time-dependent manner. Changes in the shape and distribution of pericytes occurred before the initiation of capillary regression in the retinas of methylglyoxal-injected eyes. The receptor for AGEs (RAGEs) antagonist FPS-ZM1, and the matrix metalloproteinase (MMP) inhibitor GM6001 significantly attenuated methylglyoxal-induced capillary endothelial cell degeneration. FPS-ZM1 failed to prevent pathological changes in pericytes in methylglyoxal-injected eyes. In situ zymography revealed that MMP activity was enhanced at sites of blood vessels with reduced pericyte coverage in methylglyoxal-injected eyes. These results suggest that intravitreal methylglyoxal injection induces pathological changes in pericytes before the initiation of capillary endothelial cell degeneration via an AGE-RAGE-independent pathway. The capillary endothelial cell degeneration is mediated by activating the AGE-RAGE pathway and increasing MMP activity in endothelial cells by impairing pericyte function in the retina.

Umbelliferone protects against methylglyoxal-induced HUVECs dysfunction through suppression of apoptosis and oxidative stress.

Methylglyoxal (MGO), a cytotoxic metabolite of glycolysis, can cause endothelial cells impairment, which is tightly associated with diabetic vascular complication. Umbelliferone, a derivative of coumarin, participates in various pharmacological activities. This study aimed to determine the effectiveness of umbelliferone in MGO-induced apoptosis and oxidative stress in endothelial cells. In this study, it has been indicated that umbelliferone inhibited MGO-induced human umbilical vein endothelial cells (HUVECs) cytotoxicity, apoptosis, Bax/Bcl-2 protein ratio, the activity of cleaved-caspase-3, and mitochondrial membrane potential loss. Furthermore, we found that umbelliferone inhibited MGO-induced activation of mitogen-activated protein kinases and nuclear factor-κB signaling pathways in HUVECs. In addition, umbelliferone could suppress oxidative stress, as evidenced by decrease of reactive oxygen species and malondialdehyde (MDA) generation, and increase of superoxide dismutase and glutathione peroxidase contents. Moreover, we found that umbelliferone can activate Nrf2/HO-1 signaling. Importantly, silencing of Nrf2 signaling clearly eliminated the anti-oxidative stress of umbelliferone, whereas umbelliferone pretreatment had no effect on Nrf2 overexpressing HUVECs. Altogether, this study suggested that umbelliferone pretreatment has a protective effect on MGO-induced endothelial cell dysfunction through inhibiting apoptosis and oxidative stress.

High pH Alleviated Sweet Orange (Citrus sinensis) Copper Toxicity by Enhancing the Capacity to Maintain a Balance between Formation and Removal of Reactive Oxygen Species and Methylglyoxal in Leaves and Roots.

The contribution of reactive oxygen species (ROS) and methylglyoxal (MG) formation and removal in high-pH-mediated alleviation of plant copper (Cu)-toxicity remains to be elucidated. Seedlings of sweet orange (Citrus sinensis) were treated with 0.5 (non-Cu-toxicity) or 300 (Cu-toxicity) µM CuCl2 × pH 4.8, 4.0, or 3.0 for 17 weeks. Thereafter, superoxide anion production rate; H2O2 production rate; the concentrations of MG, malondialdehyde (MDA), and antioxidant metabolites (reduced glutathione, ascorbate, phytochelatins, metallothioneins, total non-protein thiols); and the activities of enzymes (antioxidant enzymes, glyoxalases, and sulfur metabolism-related enzymes) in leaves and roots were determined. High pH mitigated oxidative damage in Cu-toxic leaves and roots, thereby conferring sweet orange Cu tolerance. The alleviation of oxidative damage involved enhanced ability to maintain the balance between ROS and MG formation and removal through the downregulation of ROS and MG formation and the coordinated actions of ROS and MG detoxification systems. Low pH (pH 3.0) impaired the balance between ROS and MG formation and removal, thereby causing oxidative damage in Cu-toxic leaves and roots but not in non-Cu-toxic ones. Cu toxicity and low pH had obvious synergistic impacts on ROS and MG generation and removal in leaves and roots. Additionally, 21 (4) parameters in leaves were positively (negatively) related to the corresponding root parameters, implying that there were some similarities and differences in the responses of ROS and MG metabolisms to Cu-pH interactions between leaves and roots.

Protective Effect of Flavonoids against Methylglyoxal-Induced Oxidative Stress in PC-12 Neuroblastoma Cells and Its Structure-Activity Relationships.

Methylglyoxal-induced oxidative stress and cytotoxicity are the main factors causing neuronal death-related, diabetically induced memory impairment. Antioxidant and anti-apoptotic therapy are potential intervention strategies. In this study, 25 flavonoids with different substructures were assayed for protecting PC-12 cells from methylglyoxal-induced damage. A structure-activity relationship (SAR) analysis indicated that the absence of the double bond at C-2 and C-3, substitutions of the gallate group at the 3 position, the pyrogallol group at the B-ring, and the R configuration of the 3 position enhanced the protection of flavan-3-ols, and a hydroxyl substitution at the 4' and meta-positions were important for the protection of flavonol. These SARs were further confirmed by molecular docking using the active site of the Keap1-Nrf2 complex as the receptor. The mechanistic study demonstrated that EGCG with the lowest EC50 protected the PC-12 cells from methylglyoxal-induced damage by reducing oxidative stress via the Nrf2/Keap1/HO-1 and Bcl-2/Bax signaling pathways. These results suggested that flavan-3-ols might be a potential dietary supplement for protection against diabetic encephalopathy.

Triphenylbismuth dichloride inhibits human glyoxalase I and induces cytotoxicity in cultured cancer cell lines.

Organobismuth compounds, i.e., organic-inorganic hybrid molecules composed of an organic structure and bismuth metal, have been reported to induce cytotoxicity in cancer cells; however, the target proteins associated with this cytotoxicity have not been elucidated. Herein, we investigated the inhibitory effect of five organobismuth compounds on human glyoxalase I (hGLO I), a promising target candidate for cancer therapy. Among these compounds, triphenylbismuth dichloride (Bi-05) exerted a strong inhibitory effect on hGLO I. Indeed, Bi-05 inhibited hGLO I in a dose-dependent manner with an IC50 value of 0.18 µM. Bi-05 also induced cytotoxicity in human leukemia HL-60 cells and human lung cancer NCI-H522 cells, both of which exhibit high expression levels of GLO I. However, the hGLO I-inhibiting and cytotoxic effects of Bi-05 disappeared when the bismuth atom was replaced with an antimony or phosphorus atom. Bismuth(III) nitrate had little inhibitory effect on hGLO I activity and only slightly reduced the viability of cancer cells. In the culture medium of Bi-05-treated HL-60 cells, the concentration of the GLO I substrate methylglyoxal was markedly elevated. In addition, Bi-05 treatment more strongly inhibited human lung cancer NCI-H522 cell (exhibiting high GLO I expression) proliferation than human lung cancer NCI-H460 cell (exhibiting low GLO I expression) proliferation. Furthermore, the cytotoxicity of Bi-05 was significantly decreased by pre- and co-treatment with the methylglyoxal scavengers N-acetyl-L-cysteine and aminoguanidine. Overall, these results suggest that Bi-05 treatment leads to the accumulation of methylglyoxal via GLO I inhibition, resulting in cytotoxic effects in cancer cells.

A lysosome-targeting fluorescent probe to visualize endogenous and exogenous methylglyoxal in live cells and zebrafish.

The development of a lysosome-targeting fluorescent probe to visualize endogenous and exogenous methylglyoxal (MGO) in live cells has important implications for associated diseases. Herein, a lysosome-targeting fluorescent probe MGO-Naph-A was designed and synthesized to detect MGO with high selectivity. The probe contained naphthalimide as the fluorescent group, o-phenylenediamine as the MGO recognition group, and morpholine as the lysosome targeting group. This fluorescent probe could detect endogenous and exogenous MGO in living cells by precisely targeting and staining lysosomes. It could also detect MGO in living zebrafish. The results showed that the probe MGO-Naph-A has the potential to visualize MGO in lysosomes.

Liraglutide reduces oxidative stress and improves energy metabolism in methylglyoxal-induced SH-SY5Y cells.

Diabetes mellitus can result in severe complications, such as neurodegenerative diseases including cognitive impairment and dementia. The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, is a novel antidiabetic drug with neuroprotective effects against neurodegenerative diseases. In this study, we explored the protective effect of liraglutide on SH-SY5Y cells exposed to methylglyoxal (MG), a byproduct of glucose metabolism that plays a key role in the development of diabetic encephalopathy. We found that liraglutide reduced the MG-induced oxidative stress, increased the activity of superoxide dismutase (SOD) and expression levels of P22phox, Gp91phox, and Xdh genes, and reduced reactive oxygen species (ROS) content. Metabolomics analysis based on 1H nuclear magnetic resonance showed that liraglutide induced alterations in metabolites involved in energy metabolism，including promotion of gluconeogenesis. Moreover, we found that liraglutide promoted oxidative phosphorylation and inhibited glycolysis in SH-SY5Y cells. This study revealed that liraglutide improved diabetes-related neuropathy damage by reducing the level of oxidative stress and maintaining the balance of energy metabolism, thus offering new insights into the potential mechanism of liraglutide in neuronal protection.

Lutein attenuated methylglyoxal-induced oxidative damage and apoptosis in PC12 cells via the PI3K/Akt signaling pathway.

Methylglyoxal (MGO), a cytotoxic byproduct of glycolysis, causes neuro oxidative damage and apoptosis, and plays key roles in diabetic encephalopathy (DE). The goal of this research was to evaluate the roles of lutein attenuated MGO-induced damage in PC12 cells as well as the underlying mechanisms. The findings of this study showed that lutein has a significant impact on reducing the generation of reactive oxygen species (ROS) and oxidative stress in MGO-induced PC12 cells, which may be attributed to the increased antioxidant enzymes activity and the decreased MDA levels. Moreover, treatment with lutein also alleviated cell apoptosis and mitochondrial damage. Real-time PCR and western blot analysis showed that lutein enhanced the Bcl-2:Bax ratio, inhibited the expression of caspase-3 and caspase-9, and increased the protein level of phosphorylated Akt. The network pharmacology and molecular docking prediction results suggested that the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway was a potential mechanism of lutein in DE treatment. Furthermore, LY294002, a specific PI3K inhibitor, partially abolished the protective effect of lutein. These results presented that lutein attenuated oxidative damage and apoptosis triggered by MGO in PC12 cells via the PI3K/Akt signaling pathway. PRACTICAL APPLICATIONS: Lutein is a common carotenoid dispersed in fruits and vegetables. This article confirmed a protective effect of lutein on oxidative damage and apoptosis in PC12 cells after MGO damage. These results indicated that lutein could potentially be developed as a nutraceutical or functional food in the prevention of diabetic-related neurodegenerative diseases.

Dietary Methylglyoxal Exposure Induces Alzheimer's Disease by Promoting Amyloid ß Accumulation and Disrupting Autophagy in Caenorhabditis elegans.

Methylglyoxal (MG) is a precursor of advanced glycation end products usually generated during cooking. The high level of MG in the brain is correlated to the pathogenesis of Alzheimer's disease (AD). However, it is not clear if MG consumed through the diet can cause AD-related toxicity. Herein, the Caenorhabditis elegans (C. elegans) AD model was used to investigate the neurotoxicity after long-term MG exposure at dietary levels. The results showed that C. elegans locomotive behaviors were significantly decreased after 0.1, 0.5, and 1 mM MG exposure (p < 0.001). In amyloid ß (Aß)-expressing transgenic C. elegans strains, 0.5 mM MG significantly promoted Aß accumulation by around 50% in day-8 CL2006 (p < 0.001), enhanced paralysis in CL4176 (p < 0.001) and CL2006 (p < 0.01), and made CL2355 around 17% more vulnerable to 5-HT, indicating impaired serotonin reuptake (p < 0.05). Additionally, 0.5 mM MG significantly increased the reactive oxygen species level (p < 0.001) by inhibiting the expression of stress-response genes including sod-3, gst-4, and hsp-16.2 in day-8 aged worms. Moreover, the autophagic pathway was disrupted through lgg-1, vps-34, and bec-1 expression after MG exposure and Aß accumulation. Treatment with the citrus flavonoid nobiletin reduced the MG-induced toxicity (p < 0.001). Overall, these findings imply that it is possible to exacerbate AD pathogenesis by MG exposure through the diet.

Therapeutic Potential of Phlorotannin-Rich Ecklonia cava Extract on Methylglyoxal-Induced Diabetic Nephropathy in In Vitro Model.

Advanced glycation end-products (AGEs) play a vital role in the pathogenesis of diabetic complications. Methylglyoxal (MGO), one of the major precursors of AGEs, is a highly reactive dicarbonyl compound that plays an important role in the pathogenesis of diabetic nephropathy. This study was designed to evaluate the therapeutic potential of phlorotannin-rich Ecklonia cava extract (ECE) on MGO-induced diabetic nephropathy in in vitro models using mouse glomerular mesangial cells. ECE showed anti-glycation activity via breaking of AGEs-collagen cross-links and inhibition of AGEs formation and AGE-collagen cross-linking formation. The renoprotective effects were determined by assessing intracellular reactive oxygen species (ROS) and MGO accumulation, cell apoptosis, and the Nrf-2/ARE signaling pathway. MGO-induced renal damage, intracellular ROS production level, and MGO-protein adduct accumulation were significantly decreased by pretreating ECE. Moreover, ECE pretreatment exhibited preventive properties against MGO-induced dicarbonyl stress via activation of the Nrf2/ARE signaling pathway and reduction of RAGE protein expression in mouse glomerular mesangial cells. Collectively, these results indicated potential anti-glycation properties and prominent preventive effects of ECE against MGO-induced renal damage. Additionally, ECE may be utilized for the management of AGE-related diabetic nephropathy.

Silicon-mediated metabolic upregulation of ascorbate glutathione (AsA-GSH) and glyoxalase reduces the toxic effects of vanadium in rice.

Although beneficial metalloid silicon (Si) has been proven to reduce the toxicity of several heavy metals, there is a lack of understanding regarding Si potential function in mitigating phytotoxicity induced by vanadium (V). In this study, effect of Si (1.5 mM) on growth, biomass production, V uptake, reactive oxygen species (ROS), methylglyoxal (MG) formation, selected antioxidants enzymes activities, glyoxalase enzymes under V stress (35 mg L-1) was investigated in hydroponic experiment. The results showed that V stress reduced rice growth, caused V accumulation in rice. Addition of Si to the nutritional medium increased plant growth, biomass yield, root length, root diameter, chlorophyll parameters, photosynthetic assimilation, ion leakage, antioxidant enzymes activities under V stress. Notably, Si sustained V-homeostasis and alleviated V caused oxidative stress by boosting ascorbate (AsA) levels and the activity of antioxidant enzymes in V stressed rice plants. Furthermore, Si protected rice seedlings against the harmful effects of methylglyoxal by increasing the activity of glyoxalase enzymes. Additionally, Si increased the expression of numerous genes involved in the detoxification of reactive oxygen species (e.g., OsCuZnSOD1, OsCaTB, OsGPX1, OsAPX1, OsGR2, and OsGSTU37) and methylglyoxal (e.g., OsGLYI-1 and OsGLYII-2). The findings supported that Si can be applied to plants to minimize the V availability to plant, and also induced V stress tolerance.

Ketogenic diet prevents methylglyoxal-evoked nociception by scavenging methylglyoxal.

ABSTRACT: Methylglyoxal (MGO) is a reactive dicarbonyl byproduct of glycolysis implicated in a growing number of neuropathic pain conditions, including chemotherapy-induced peripheral neuropathy, diabetic peripheral neuropathy, and radiculopathy with lumbar disk herniation. Recent studies show success in preclinical models treating these disorders with an interventional ketogenic diet. Here, we tested the hypothesis that a ketogenic diet modifies pathological MGO signaling as a mechanism underlying neuropathy improvement. We found that mice injected with MGO displayed nocifensive behaviors, whereas mice prefed a ketogenic diet were resistant to mechanical allodynia elicited by MGO. In addition, levels of circulating MGO were reduced in ketogenic diet-fed mice and negatively correlated with levels of the ketone body ß-hydroxybutyrate (ß-HB). Methylglyoxal is normally scavenged by the glyoxalase system, and ketogenic diet-fed mice displayed increased glyoxalase 1 activity compared with chow-fed control mice. Recent studies also suggest that ketone bodies contribute to MGO detoxification, consistent with a negative correlation between ß-HB and MGO. To assess whether ketone bodies modified MGO-evoked nociception through direct MGO detoxification, we coincubated either acetoacetate or ß-HB with MGO before injection. Mice receiving intraplantar MGO injection exhibit increased nociceptive behavior (lifting, licking, biting, and scratching), which was significantly reduced by coincubation with either acetoacetate or ß-HB. Methylglyoxal increased phospho-extracellular signal-regulated kinase-positive cells in the spinal dorsal horn, and this evoked spinal activation was ameliorated by preincubation with acetoacetate or ß-HB. These results suggest that a ketogenic diet and ketone bodies ameliorate MGO-evoked nociception, partially through detoxification of MGO, and provide rationale for therapeutic intervention with a ketogenic diet in MGO-driven pathologies.

Methylglyoxal Induces Inflammation, Metabolic Modulation and Oxidative Stress in Myoblast Cells.

Uremic sarcopenia is a serious clinical problem associated with physical disability and increased morbidity and mortality. Methylglyoxal (MG) is a highly reactive, dicarbonyl uremic toxin that accumulates in the circulatory system in patients with chronic kidney disease (CKD) and is related to the pathology of uremic sarcopenia. The pathophysiology of uremic sarcopenia is multifactorial; however, the details remain unknown. We investigated the mechanisms of MG-induced muscle atrophy using mouse myoblast C2C12 cells, focusing on intracellular metabolism and mitochondrial injury. We found that one of the causative pathological mechanisms of uremic sarcopenia is metabolic flow change to fatty acid synthesis with MG-induced ATP shortage in myoblasts. Evaluation of cell viability revealed that MG showed toxic effects only in myoblast cells, but not in myotube cells. Expression of mRNA or protein analysis revealed that MG induces muscle atrophy, inflammation, fibrosis, and oxidative stress in myoblast cells. Target metabolomics revealed that MG induces metabolic alterations, such as a reduction in tricarboxylic acid cycle metabolites. In addition, MG induces mitochondrial morphological abnormalities in myoblasts. These changes resulted in the reduction of ATP derived from the mitochondria of myoblast cells. Our results indicate that MG is a pathogenic factor in sarcopenia in CKD.

Acrylamide causes neurotoxicity by inhibiting glycolysis and causing the accumulation of carbonyl compounds in BV2 microglial cells.

Acrylamide is a potent neurotoxin produced during industrial production or food processing at high temperatures, and its effect on glycolytic processes may be critical in triggering neurotoxicity. Our work investigated the neurotoxic effects of acrylamide based on glycolysis using immortalized mouse microglia cell line BV2. The results showed that 1.5 mM acrylamide significantly inhibited the expression and activity of triphosphate isomerase and 3-phosphoglyceraldehyde dehydrogenase. Moreover, acrylamide limited the expression of pyruvate kinase and the decrease of pyruvate and lactate content of glycolysis products. In addition, acrylamide could increase intracellular methylglyoxal content and further affect its detoxification system. Not only that, subsequent cellular responses resulting from methylglyoxal accumulation, such as oxidative stress, activation of ERK, upregulation of NF-κB inflammatory signaling pathway, and elevated pro-inflammatory factor TNF-α, were found in the acrylamide-treated cell model. Therefore, we suggest that acrylamide's perturbation of the glycolytic process leads to methylglyoxal accumulation, which may be responsible for its key to neurotoxicity.