Methylglyoxal Down-Regulates the Expression of Cell Cycle Associated Genes and Activates the P53 Pathway in Human Endothelial Cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE111123 | GEO | 2019/02/13
REPOSITORIES: GEO
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Project description:In diabetic nephropathy (DN), glomerular endothelial cells (GECs) and podocytes undergo pathological alterations, which are influenced by metabolic changes characteristic of diabetes, including hyperglycaemia (HG) and elevated methylglyoxal (MGO) levels. However, it remains insufficiently understood what effects these metabolic factors have on GEC and podocytes and to what extent the interactions between the two cell types can modulate these effects. To address these questions, we established a co-culture system in which GECs and podocytes were grown together in close proximity, and assessed transcriptional changes in each cell type after exposure to HG and MGO. We found that HG and MGO had distinct effects on gene expression and that the effect of each treatment was markedly different between GECs and podocytes. HG treatment led to upregulation of “immediate early response” genes, particularly those of the EGR family, as well as genes involved in inflammatory responses (in GECs) or DNA replication/cell cycle (in podocytes). Interestingly, both HG and MGO led to downregulation of genes related to extracellular matrix organisation in podocytes. Crucially, the transcriptional responses of GECs and podocytes were dependent on their interaction with each other, as many of the prominently regulated genes in co-culture of the two cell types were not significantly changed when monocultures of the cells were exposed to the same stimuli. Finally, the changes in the expression of selected genes were validated in BTBR ob/ob mice, an established model of DN. This work highlights the molecular alterations in GECs and podocytes in response to the key diabetic metabolic triggers HG and MGO, as well as the central role of GEC-podocyte crosstalk in governing these responses.
2023-11-09 | GSE220226 | GEO
Project description:Diabetes is one of the major risk factors for Alzheimer’s disease (AD) development. The role of elevated levels of glucose, methylglyoxal (MGO), and advanced glycation end products (AGEs) in diabetes in the pathogenesis of the AD is not well understood. In this pursuit, we studied the role of methylglyoxal in the pathogenesis of AD in rat models. The elevated plus-maze (EPM) behavioural study indicated that MGO induces anxiety. Treatment of telmisartan (RAGE expression inhibitor) and aminoguanidine (MGO quencher) attenuated MGO induced anxiety. Further, hippocampal proteomics demonstrated that MGO treated rats differentially regulate proteins involved in calcium homeostasis, mitochondrial functioning, and apoptosis which may affect neurotransmission and neuronal plasticity. Hippocampal tau phosphorylation level was increased in MGO treated rats which was reduced in presence in aminoguanidine and telmisartan. Plasma fructosamine level was increased upon MGO treatment. Hippocampal histochemistry showed vascular degeneration and neuronal loss upon MGO treatment. This study provides mechanistic insight into the role of MGO in the diabetes-associated development of AD.
2024-01-26 | PXD037673 | Pride
Project description:Methylglyoxal (MGO) is a highly reactive cellular metabolite that glycates lysine and arginine residues to form post-translational modifications known as advanced glycation end products. Because of their low abundance and low stoichiometry, few studies have reported their occurrence and site-specific locations in proteins. Proteomic analysis of WIL2-NS B lymphoblastoid cells in the absence and presence of exogenous MGO was conducted to investigate the extent of MGO modi-fications. We found over 500 MGO modified proteins, revealing an over-representation of these modifications on many glycolytic enzymes, as well as ribosomal and spliceosome proteins. Moreover, MGO modifications were observed on the active site residues of glycolytic enzymes that could alter their activity. We similarly observed modification of glycolytic enzymes across several epithelial cell lines and peripheral blood lymphocytes, with modification of fructose bisphosphate aldolase being observed in all samples. These results indicate that glycolytic proteins could be particularly prone to the formation of MGO adducts.
2022-05-20 | PXD032812 | Pride
Project description:We compared the transcriptome profile of M. tuberculosis-infected murine bone marrow derived macrophages (BMM) treated or not with 200 uM methylglyoxal (MGO) and uninfected controls as described below. We found 3606 differentially expressed genes (DEGs) between uninfected and M. tuberculosis-infected BMM, being approximately half of these upregulated . 1699 DEGs were determined by comparing Mtb-MGO vs M. tuberculosis BMM, with 2/3 of these DEGs downregulated. Genes in the glyoxalate, glutathione and selenocompound metabolic KEEG pathways were increased comparing Mtb-MGO vs M. tuberculosis BMM. Instead genes involved in type I IFN responses, cytokine receptor and chemokine signalling gene ontology clusters (GO) were increased after infection with Mtb as compared to uninfected controls and decreased in Mtb-MGO vs M. tuberculosis BMM.
2024-07-20 | GSE271061 | GEO
Project description:Mass Spectrometry data showing MICA crosslinking of NLRP3 Pyrin cysteines and arginines induced by methylglyoxal (MGO)
2024-08-01 | MSV000095503 | MassIVE
Project description:Major depressive disorder (MDD) is a severe psychiatric illness that affects about 16 percent of the global population. Despite massive efforts, unravelling the pathophysiology of MDD and developing effective treatments is still a huge challenge. Here, we report a novel therapeutic axis of methylglyoxal (MGO)/tropomyosin receptor kinase B (TrkB) for treating MDD. As an endogenous metabolite, MGO was demonstrated directly binding to the extracellular domain of TrkB, provoking its dimerization and autophosphorylation. This rapidly enhances the expression of brain-derived neurotrophic factor (BDNF) and forms a BDNF-positive feedback loop. Low-dose treatment of MGO effectively promotes the hippocampal neurogenesis and exhibits sustained antidepressant effects in chronic unpredictable mild stress rat models. In addition, the modulation on MGO concentration by overexpression or inhibition of Glyoxalase 1 (GLO1) has been demonstrated associated with depression behaviors in rats. Furthermore, we also identified a natural product luteolin and its derivative lutD as potent inhibitors of GLO1 and explored their precise binding modes. Our findings reveal a novel regulatory mechanism underlying MDD and depict principles for the rational design of new antidepressants targeting GLO1.
2018-09-06 | GSE119482 | GEO
Project description:In diabetic nephropathy (DN), glomerular endothelial cells (GECs) and podocytes undergo pathological alterations, which are influenced by metabolic changes characteristic of diabetes, including hyperglycaemia (HG) and elevated methylglyoxal (MGO) levels. However, it remains insufficiently understood what effects these metabolic factors have on GEC and podocytes and to what extent the interactions between the two cell types can modulate these effects. To address these questions, we established a co-culture system in which GECs and podocytes were grown together in close proximity, and assessed transcriptional changes in each cell type after exposure to HG and MGO. We found that HG and MGO had distinct effects on gene expression and that the effect of each treatment was markedly different between GECs and podocytes. HG treatment led to upregulation of “immediate early response” genes, particularly those of the EGR family, as well as genes involved in inflammatory responses (in GECs) or DNA replication/cell cycle (in podocytes). Interestingly, both HG and MGO led to downregulation of genes related to extracellular matrix organisation in podocytes. Crucially, the transcriptional responses of GECs and podocytes were dependent on their interaction with each other, as many of the prominently regulated genes in co-culture of the two cell types were not significantly changed when monocultures of the cells were exposed to the same stimuli. Finally, the changes in the expression of selected genes were validated in BTBR ob/ob mice, an established model of DN. This work highlights the molecular alterations in GECs and podocytes in response to the key diabetic metabolic triggers HG and MGO, as well as the central role of GEC-podocyte crosstalk in governing these responses.
2023-11-09 | GSE220228 | GEO
Project description:In diabetic nephropathy (DN), glomerular endothelial cells (GECs) and podocytes undergo pathological alterations, which are influenced by metabolic changes characteristic of diabetes, including hyperglycaemia (HG) and elevated methylglyoxal (MGO) levels. However, it remains insufficiently understood what effects these metabolic factors have on GEC and podocytes and to what extent the interactions between the two cell types can modulate these effects. To address these questions, we established a co-culture system in which GECs and podocytes were grown together in close proximity, and assessed transcriptional changes in each cell type after exposure to HG and MGO. We found that HG and MGO had distinct effects on gene expression and that the effect of each treatment was markedly different between GECs and podocytes. HG treatment led to upregulation of “immediate early response” genes, particularly those of the EGR family, as well as genes involved in inflammatory responses (in GECs) or DNA replication/cell cycle (in podocytes). Interestingly, both HG and MGO led to downregulation of genes related to extracellular matrix organisation in podocytes. Crucially, the transcriptional responses of GECs and podocytes were dependent on their interaction with each other, as many of the prominently regulated genes in co-culture of the two cell types were not significantly changed when monocultures of the cells were exposed to the same stimuli. Finally, the changes in the expression of selected genes were validated in BTBR ob/ob mice, an established model of DN. This work highlights the molecular alterations in GECs and podocytes in response to the key diabetic metabolic triggers HG and MGO, as well as the central role of GEC-podocyte crosstalk in governing these responses.
2023-11-09 | GSE220227 | GEO
Project description:Diabetic kidney disease (DKD) remains the number one cause of end-stage renal disease in the western world. Currently there is no treatment to cure diabetes or deal effectively with its complications. In experimental diabetes, mitochondrial dysfunction in the kidney has been widely reported with changes in mitochondrial bioenergetics preceding the development of the renal lesion. Glucose-derived molecules generated during diabetes, known as dicarbonyls, such as methylglyoxal, are thought to impair mitochondrial function and may contribute to the pathogenesis of DKD. Here, we sought to target methylglyoxal within the mitochondria using MitoGamide, the novel mitochondria-targeted dicarbonyl scavenger, in an experimental model of diabetes. Male 6-week-old heterozygous Akita mice (C57BL/6-Ins2-Akita/J) or wildtype littermates were randomized to receive MitoGamide (10mg/kg/day) or vehicle by oral gavage for 16 weeks. MitoGamide did not alter blood glucose control or body composition. Akita mice exhibited hallmarks of DKD including albuminuria, hyperfiltration, glomerulosclerosis and renal fibrosis, however, after 16 weeks of treatment, MitoGamide did not substantially improve the renal phenotype. Complex-I-linked mitochondrial respiration was increased in the kidney of Akita mice which was unaffected by MitoGamide. Exploratory studies using transcriptomics identified that MitoGamide induced changes to olfactory signalling, immune system, respiratory electron transport and post-translational protein modification pathways. These findings indicate that targeting methylglyoxal within the mitochondria using MitoGamide is not a valid therapeutic approach for DKD and that other mitochondrial targets or processes upstream should be the focus of therapy.
2020-10-23 | GSE159882 | GEO
Project description:To clarify the effect of intrauterine methylglyoxal (MGO) administration on the endometrium, mRNA expression profiles of bovine endometrium were investigated. Hierarchical cluster analysis with the expression levels of all genes was divided these cows into two clusters. First cluster was composed of control cows, second cluster contained MGO (5 mM) treated cows.
2021-01-19 | GSE165039 | GEO