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Project description:Aims: Evaluate the genome-wide gene expression and epigenomic alterations caused by transient high glucose (HG) in endothelial cells (ECs), and to assess NRF2 pathway activation as a potential treatment for the diabetes-associated transcriptional memory. Methods and results: We exposed human umbilical vein endothelial cells (HUVEC) to three different glucose treatments: control (5.5 mM for 8 days), HG (30 mM for 8 days) and memory (5.5 mM for 4 days followed by 30 mM for 4 days). After these treatments we conducted a series of experiments, first we found that cells in the HG treatment had sustained alterations in both glycolytic and respiratory rates that persisted in the memory treatment, this without changes in proliferation or cell viability. Similarly, HG provoked substantial changes in the expression of genes belonging to pathways known to be impaired in diabetes, like the TGF-beta, TNF, foxO, p53 and NRF2 pathways, many of which were still present in memory. In addition, we found persistent changes in chromatin accessibility located mainly in non-promoter regions, some of which we identified as putative enhancer regions neighboring genes altered in memory. Finally, we demonstrated that activation of the NRF2 pathway through either NRF2 overexpression or sulforaphane treatment was able to substantially revert the glucose-induced transcriptional memory in ECs. Conclusions: Our results demonstrate that transient HG induces persistent changes in both the transcriptomic and chromatin accessibility profiles of ECs, and that pharmacological NRF2 pathway activation through sulforaphane supplementation is able to prevent and revert the glucose-induced transcriptional memory.
2024-04-29 | GSE241565 | GEO
Project description:Aims: Evaluate the genome-wide gene expression and epigenomic alterations caused by transient high glucose (HG) in endothelial cells (ECs), and to assess NRF2 pathway activation as a potential treatment for the diabetes-associated transcriptional memory. Methods and results: We exposed human umbilical vein endothelial cells (HUVEC) to three different glucose treatments: control (5.5 mM for 8 days), HG (30 mM for 8 days) and memory (5.5 mM for 4 days followed by 30 mM for 4 days). After these treatments we conducted a series of experiments, first we found that cells in the HG treatment had sustained alterations in both glycolytic and respiratory rates that persisted in the memory treatment, this without changes in proliferation or cell viability. Similarly, HG provoked substantial changes in the expression of genes belonging to pathways known to be impaired in diabetes, like the TGF-beta, TNF, foxO, p53 and NRF2 pathways, many of which were still present in memory. In addition, we found persistent changes in chromatin accessibility located mainly in non-promoter regions, some of which we identified as putative enhancer regions neighboring genes altered in memory. Finally, we demonstrated that activation of the NRF2 pathway through either NRF2 overexpression or sulforaphane treatment was able to substantially revert the glucose-induced transcriptional memory in ECs. Conclusions: Our results demonstrate that transient HG induces persistent changes in both the transcriptomic and chromatin accessibility profiles of ECs, and that pharmacological NRF2 pathway activation through sulforaphane supplementation is able to prevent and revert the glucose-induced transcriptional memory.
2024-04-29 | GSE241564 | GEO
Project description:Reversal of high-glucose-induced transcriptional and epigenetic memories through NRF2 pathway activation
| PRJNA1008705 | ENA
Project description:Reversal of high-glucose-induced transcriptional and epigenetic memories through NRF2 pathway activation (RNA-seq).
| PRJNA1008711 | ENA
Project description:Reversal of high-glucose-induced transcriptional and epigenetic memories through NRF2 pathway activation (ATAC-seq).
| PRJNA1008709 | ENA
Project description:Our previous studies have assessed ginsenoside Rg1 (Rg1)-mediated protection in a type 1 diabetes rat model. To uncover the mechanism through which Rg1 protects against cardiac injury induced by diabetes, we mimicked diabetic conditions by culturing H9C2 cells in high glucose/palmitate. Rg1 had no toxic effect, and it alleviated the high glucose/palmitate damage in a dose-dependent manner, as indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and lactate dehydrogenase release to the culture medium. Rg1 prevented high glucose/palmitate-induced cell apoptosis, assessed using cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labelling staining. Rg1 also reduced high glucose-/palmitate-induced reactive oxygen species formation and increased intracellular antioxidant enzyme activity. We found that Rg1 activates protein kinase B (AKT)/glycogen synthase kinase-3 (GSK-3β) pathway and antioxidant nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, indicated by increased phosphorylation of AKT and GSK-3β, and nuclear translocation of Nrf2. We used phosphatidylinositol-3-kinase inhibitor Ly294002 to block the activation of the AKT/GSK-3β pathway and found that it partially reversed the protection by Rg1 and decreased Nrf2 pathway activation. The results suggest that Rg1 exerts a protective effect against high glucose and palmitate damage that is partially AKT/GSK-3β/Nrf2-mediated. Further studies are required to validate these findings using primary cardiomyocytes and animal models of diabetes.
| S-EPMC7348154 | biostudies-literature
Project description:Diabetic encephalopathy (DE) is a severe complication of diabetes, but its pathogenesis remains unclear. This study aimed to investigate the roles and underlying mechanisms of high glucose (HG)- and advanced glycosylation end product (AGE)-induced oxidative stress (OS) in the cognitive decline in DE. The DE mouse model was established using a high-fat diet and streptozotocin, and its cognitive functions were evaluated using the Morris Water Maze, novel object recognition, and Y-maze test. The results revealed increased reactive oxygen species (ROS) generation, mitophagy inhibition, and decreased prohibitin 2 (PHB2) expression in the hippocampal neurons of DE mice and HG- or AGE-treated HT-22 cells. However, overexpression of PHB2 reduced ROS generation, reversed mitophagy inhibition, and improved mitochondrial function in the HG- or AGE-treated HT-22 cells and ameliorated cognitive decline, improved mitochondrial structural damage, and reversed mitophagy inhibition of hippocampal neurons in DE mice. Further analysis revealed that the Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was involved in the HG- or AGE-mediated downregulation of PHB2 in HT-22 cells. These results demonstrate that HG- or AGE-induced OS inhibits the mitophagy of hippocampal neurons via the Keap1-Nrf2-PHB2 pathway, thereby contributing to the cognitive decline in DE.
| S-EPMC11473637 | biostudies-literature
Project description:Hyperglycemia, as well as diabetes mellitus, has been shown to trigger cardiac cell apoptosis. We have previously demonstrated that myricitrin prevents endothelial cell apoptosis. However, whether myricitrin can attenuate H9c2 cell apoptosis remains unknown. In this study, we established an experiment model in H9c2 cells exposed to high glucose. We tested the hypothesis that myricitrin may inhibit high glucose (HG)-induced cardiac cell apoptosis as determined by TUNEL staining. Furthermore, myricitrin promoted antioxidative enzyme production, suppressed high glucose-induced reactive oxygen species (ROS) production and decreased mitochondrial membrane potential (MMP) in H9c2 cells. This agent significantly inhibited apoptotic protein expression, activated Akt and facilitated the transcription of NF-E2-related factor 2 (Nrf2)-mediated protein (heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO-1) expression as determined by Western blotting. Significantly, an Akt inhibitor (LY294002) or HO-1 inhibitor (ZnPP) not only inhibited myricitrin-induced HO-1/NQO-1 upregulation but also alleviated its anti-apoptotic effects. In summary, these observations demonstrate that myricitrin activates Nrf2-mediated anti-oxidant signaling and attenuates H9c2 cell apoptosis induced by high glucose via activation of Akt signaling.
| S-EPMC6274128 | biostudies-literature
Project description:ObjectivesDiabetic nephropathy is a major complication of diabetes and a frequent cause of end-stage renal disease and recent studies suggest that podocyte damage may play a role in the pathogenesis of this. At early onset of diabetic nephropathy there is podocyte drop-out, which is thought to provoke glomerular albuminuria and subsequent glomerular injury; however, the underlying molecular mechanisms of this remain poorly understood. Here we report that we tested the hypothesis that early diabetic podocyte injury is caused, at least in part, by up-regulation of transient receptor potential cation channel 6 (TRPC6), which is regulated by the canonical Wnt signalling pathway, in mouse podocytes.Materials and methodsMechanism of injury initiation in mouse podocytes, by high concentration of D-glucose (HG, 30 mM), was investigated by MTT, flow cytometry, real-time quantitative PCR, and western blot analysis.ResultsHG induced apoptosis and reduced viability of differentiated podocytes. It caused time-dependent up-regulation of TRPC6 and activation of the canonical Wnt signalling pathway, in mouse podocytes. In these cells, blockade of the Wnt signalling pathway by dickkopf related protein 1 (Dkk1) resulted in effective reduction of TRPC6 up-regulation and amelioration of podocyte apoptosis. Furthermore, reduction of cell viability induced by HG was attenuated by treatment with Dkk1.ConclusionThese findings indicate that the Wnt/β-catenin signalling pathway may potentially be active in pathogenesis of TRPC6-mediated diabetic podocyte injury.
| S-EPMC6496492 | biostudies-literature
Project description:BackgroundHigh glucose levels are key factors and key contributors to several cardiovascular diseases associated with cardiomyocyte injury. Ferroptosis, which was identified in recent years, is a mode of cell death caused by the iron-mediated accumulation of lipid peroxides. Neuregulin-4 (Nrg4) is an adipokine that has protective effects against metabolic disorders and insulin resistance. Our previous study revealed that Nrg4 has a protective effect against diabetic myocardial injury, and the aim of this study was to investigate whether Nrg4 could attenuate the occurrence of high glucose-induced ferroptosis in cardiomyocytes.MethodsWe constructed an in vivo diabetic myocardial injury model in which primary cardiomyocytes were cultured in vitro and treated with Nrg4. Changes in ferroptosis-related protein levels and ferroptosis-related indices in cardiomyocytes were observed. In addition, we performed back-validation and explored signalling pathways that regulate ferroptosis in primary cardiomyocytes.ResultsNrg4 attenuated cardiomyocyte ferroptosis both in vivo and in vitro. Additionally, the AMPK/NRF2 signalling pathway was activated during this process, and when the AMPK/NRF2 pathway was inhibited, the beneficial effects of Nrg4 were attenuated.ConclusionNrg4 antagonizes high glucose-induced ferroptosis in cardiomyocytes via the AMPK/NRF2 signalling pathway.
| S-EPMC11295585 | biostudies-literature