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Methylglyoxal (MGO) is an active metabolite of glucose and plays a prominent role in the pathogenesis of diabetic vascular complications, including endothelial cell apoptosis induced by oxidative stress. Metformin (MET), a widely prescribed antidiabetic agent, appears to reduce excessive reactive oxygen species (ROS) generation and limit cell apoptosis. However, the molecular mechanisms underlying this process are still not fully elucidated. We reported here that MET prevents MGO-induced apoptosis by suppressing oxidative stress in vitro and in vivo. Protein expression and protein phosphorylation were investigated using western blotting, ELISA, and immunohistochemical staining, respectively. Cell viability and apoptosis were assessed by the MTT assay, TUNEL staining, and Annexin V-FITC and propidium iodide double staining. ROS generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Our results revealed that MET prevented MGO-induced HUVEC apoptosis, inhibited apoptosis-associated biochemical changes such as loss of MMP, the elevation of the Bax/Bcl-2 ratio, and activation of cleaved caspase-3, and attenuated MGO-induced mitochondrial morphological alterations in a dose-dependent manner. MET pretreatment also significantly suppressed MGO-stimulated ROS production, increased signaling through the ROS-mediated PI3K/Akt and Nrf2/HO-1 pathways, and markedly elevated the levels of its downstream antioxidants. Finally, similar results were obtained in vivo, and we demonstrated that MET prevented MGO-induced oxidative damage, apoptosis, and inflammation. As expected, MET reversed MGO-induced downregulation of Nrf2 and p-Akt. In addition, a PI3K inhibitor (LY-294002) and a Nrf2 inhibitor (ML385) observably attenuated the protective effects of MET on MGO-induced apoptosis and ROS generation by inhibiting the Nrf2/HO-1 pathways, while a ROS scavenger (NAC) and a permeability transition pores inhibitor (CsA) completely reversed these effects. Collectively, these findings broaden our understanding of the mechanism by which MET regulates apoptosis induced by MGO under oxidative stress conditions, with important implications regarding the potential application of MET for the treatment of diabetic vascular complications.

Increased glucose uptake and metabolism is a prominent phenotype of most cancers, but efforts to clinically target this metabolic alteration have been challenging. Here, we present evidence that lactoylglutathione (LGSH), a byproduct of methylglyoxal detoxification, is elevated in both human and murine non-small cell lung cancers (NSCLC). Methylglyoxal is a reactive metabolite byproduct of glycolysis that reacts non-enzymatically with nucleophiles in cells, including basic amino acids, and reduces cellular fitness. Detoxification of methylglyoxal requires reduced glutathione (GSH), which accumulates to high levels in NSCLC relative to normal lung. Ablation of the methylglyoxal detoxification enzyme glyoxalase I (Glo1) potentiates methylglyoxal sensitivity and reduces tumor growth in mice, arguing that targeting pathways involved in detoxification of reactive metabolites is an approach to exploit the consequences of increased glucose metabolism in cancer. Glycolysis is elevated in many cancers. In this study, the authors show that lactoylglutathione, a by-product of methylglyoxal produced from increased glycolysis, is elevated in lung cancer in mouse models and humans, arguing reactive metabolite production can be a liability for cancers.

Tumours are a low-oxygen environment, in this study glioblastoma cells are found to overexpress the serine hydroxymethyltransferase SHMT2; SHMT acts to reduce oxygen consumption, which confers the tumour cells with a survival advantage. Low oxygen gives tumour cells an edge Tumour cells thrive in a low-oxygen environment, and in this study David Sabatini and colleagues demonstrate a mechanism that operates in the ischaemic zone of glioblastoma cells to give tumour cells a survival advantage. Glioblastoma cells are shown to overexpress the serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC). SHMT2 favours poorly vascularized tumour cells by reducing oxygen consumption but at the same time it exposes a selective vulnerability. Glycine, the product of SHMT2 activity, if allowed to accumulate in excess within the cell can be converted into toxic molecules, hence it may be possible to target tumorigenic glioblastoma cells by inhibiting GLDC. Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment 1 , 2 , 3 . Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition.

Age-associated dementia and Alzheimer's disease (AD) are currently epidemic. Neither their cause nor connection to the metabolic syndrome (MS) is clear. Suppression of deacetylase survival factor sirtuin 1 (SIRT1), a key host defense, is a central feature of AD. Age-related MS and diabetes are also causally associated with suppressed SIRT1 partly due to oxidant glycotoxins [advanced glycation end products (AGEs)]. Changes in the modern diet include excessive nutrient-bound AGEs, such as neurotoxic methyl-glyoxal derivatives (MG). To determine whether dietary AGEs promote AD, we evaluated WT mice pair-fed three diets throughout life: low-AGE (MG-), MG-supplemented low-AGE (MG+), and regular (Reg) chow. Older MG+-fed mice, similar to old Reg controls, developed MS, increased brain amyloid-β42, deposits of AGEs, gliosis, and cognitive deficits, accompanied by suppressed SIRT1, nicotinamide phosphoribosyltransferase, AGE receptor 1, and PPARγ. These changes were not due to aging or caloric intake, as neither these changes nor the MS were present in age-matched, pair-fed MGmice. The mouse data were enhanced by significant temporal correlations between high circulating AGEs and impaired cognition, as well as insulin sensitivity in older humans, in whom dietary and serum MG levels strongly and inversely associated with SIRT1 gene expression. The data identify a specific AGE (MG) as a modifiable risk factor for AD and MS, possibly acting via suppressed SIRT1 and other host defenses, to promote chronic oxidant stress and inflammation. Because SIRT1 deficiency in humans is both preventable and reversible by AGE reduction, a therapeutic strategy that includes AGE reduction may offer a new strategy to combat the epidemics of AD and MS.

Integrity of epithelial and endothelial cell barriers is of critical importance for health, barrier disruption is a hallmark of numerous diseases, of which many are driven by carbonyl stressors such as methylglyoxal (MG). Carnosine and anserine exert some MG-quenching activity, but the impact of these and of other histidine containing dipeptides on cell barrier integrity has not been explored in detail. In human proximal tubular (HK-2) and umbilical vein endothelial (HUVEC) cells, exposure to 200 µM MG decreased transepithelial resistance (TER), i.e. increased ionic permeability and permeability for 4-, 10- and 70-kDa dextran, membrane zonula occludens (ZO-1) abundance was reduced, methylglyoxal 5-hydro-5-methylimidazolones (MG-H1) formation was increased. Carnosine, balenine (ß-ala-1methyl-histidine) and anserine (ß-ala-3-methyl-histidine) ameliorated MG-induced reduction of TER in both cell types. Incubation with histidine, 1-/3-methylhistidine, but not with ß-alanine alone, restored TER, although to a lower extent than the corresponding dipeptides. Carnosine and anserine normalized transport and membrane ZO-1 abundance. Aminoguanidine, a well-described MG-quencher, did not mitigate MG-induced loss of TER. Our results show that the effects of the dipeptides on epithelial and endothelial resistance and junction function depend on the methylation status of histidine and are not exclusively explained by their quenching activity.

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.

Methylglyoxal (MGO)-induced cellular apoptosis, oxidative stress, inflammation, and AGE formation are specific events that induce vascular endothelial cell (EC) toxicity in endothelial dysfunction (ED). MGO accumulates quickly in various tissues and plays a prominent role in the pathogeneses of several diabetic complications. Unbalanced angiogenesis is a gateway to the development of diabetic complications. EC apoptosis and autophagy work together to regulate angiogenesis by interacting with different angiogenic factors. In addition to understanding the deep mechanism regarding MGO-dependent autophagy/apoptosis may provide new therapeutic applications to treat diabetes and diabetic complications. Therefore, the present study aimed to investigate the regulatory effects of MGO-induced autophagy and apoptosis on angiogenesis in HAoEC and to elucidate the molecular mechanisms to discover new target base therapy for diabetes and diabetic complications. In MGO-stimulated HAoEC, protein expression was identified using a western blot, autophagosomes were observed by bio-transmission electron microscopy (TEM), and cell autophagic vacuoles and flux were measured using a confocal microscope. We found that MGO significantly induced autophagy, declined the pro-angiogenic effect, decreased proliferation, migration, and formation of tube-like structures, and increased autophagic vacuoles, flux and autophagosomes in the HAoEC in a dose-dependent manner. We observed that MGO-induced autophagic cell death and inhibited the ROS-mediated Akt/mTOR signaling pathway. MGO also triggered apoptosis by elevating the cleaved caspase-3 to Bax/Bcl-2 ratio and through activation of the ROS-mediated MAPKs (p-JNK, p-p38, and p-ERK) signaling pathway. Collectively, these findings suggest that autophagy and apoptosis inhibit angiogenesis via the ROS-mediated Akt/mTOR and MAPKs signaling pathways, respectively, when HAoEC are treated with MGO.

Dicarbonyl stress, characterized by the abnormal accumulation of reactive dicarbonyl metabolites and advanced glycation end-products (AGEs), is implicated in various pathological conditions, including obesity, diabetes, and reproductive disorders. Methylglyoxal (MGO), a highly reactive dicarbonyl metabolite, has been shown to compromise oocyte quality and developmental competence. In this study, we investigated the protective role of punicic acid (PA), a potent antioxidant found in pomegranate seed oil, against MGO-induced oocyte dysfunction. Our findings revealed that 75 µM MGO exposure during in vitro oocyte maturation significantly reduced the maturation rate and impaired subsequent embryonic development, characterized by decreased pronucleus formation and blastocyst rates. Interestingly, PA supplementation partially ameliorated these adverse effects of MGO, highlighting its potential as a protective agent against dicarbonyl-induced oocyte dysfunction. Co-treatment with PA restored the imbalanced redox state induced by MGO, leading to reduction in ROS levels and an increase in GSH levels in matured oocytes. Additionally, co-supplementation with PA preserved mitochondrial distribution in oocytes challenged with MGO, further contributing to improved oocyte quality. At the molecular level, PA co-treatment modulated the expression of genes involved in dicarbonyl stress and oxidative responses, including Glo1 , Rage , Nrf2 , and Nf- κ B , potentially regulating the detoxification of MGO and mitigating its harmful effects. Lastly, PA supplementation improved cell lineage allocation in blastocysts developed from MGO-challenged oocytes, emphasizing its role in enhancing the quality of preimplantation embryos. In conclusion, our study provides novel insights into the protective effects of punicic acid as an antioxidant against MGO-induced oocyte dysfunction, suggesting its potential as a dietary intervention to enhance reproductive health, particularly in individuals facing dicarbonyl stress-associated conditions such as obesity and diabetes.

Chalcones belong to a class of biologically active polyphenolic natural products. As a result of their simple chemical nature, they are easily synthesized and show a variety of promising biological activities. 2-Hydroxy-4′-methoxychalcone (AN07) is a synthetic chalcone derivate with potential anti-atherosclerosis effects. In this study, we demonstrated the novel antioxidant, anti-inflammatory, and neuroprotective effects of AN07. In RAW 264.7 macrophages, AN07 attenuated lipopolysaccharide (LPS)-induced elevations in reactive oxygen species (ROS) level and oxidative stress via down-regulating gp91phox expression and stimulating the antioxidant system of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) pathways, which were accompanied by increased glutathione (GSH) levels. Additionally, AN07 attenuated LPS-induced inflammatory factors, including NO, inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and phosphorylated inhibitor of nuclear factor kappa B-alpha (p-IκBα) in RAW 264.7 macrophages. However, the effects of AN07 on promoting nuclear Nrf2 levels and decreasing COX-2 expressions were significantly abrogated by the peroxisome proliferator-activated receptor-γ (PPARγ) antagonist GW9662. In human dopaminergic SH-SY5Y cells treated with or without methylglyoxal (MG), a toxic endogenous by-product of glycolysis, AN07 up-regulated neurotrophic signals including insulin-like growth factor 1 receptor (IGF-1R), p-Akt, p-GSK3β, glucagon-like peptide 1 receptor (GLP-1R), and brain-derived neurotrophic factor (BDNF). AN07 attenuated MG-induced apoptosis by up-regulating the B-cell lymphoma 2 (Bcl-2) protein and down-regulating the cytosolic expression of cytochrome c. AN07 also attenuated MG-induced neurite damage via down-regulating the Rho-associated protein kinase 2 (ROCK2)/phosphorylated LIM kinase 1 (p-LIMK1) pathway. Moreover, AN07 ameliorated the MG-induced down-regulation of neuroprotective Parkinsonism-associated proteins parkin, pink1, and DJ-1. These findings suggest that AN07 possesses the potentials to be an anti-inflammatory, antioxidant, and neuroprotective agent

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 (H 2 O 2 ) content, superoxide (O 2 •− ) 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, H 2 O 2 , O 2 •− , 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 H 2 O 2 signaling and immobilizing Zr translocation.