Novel insights into DNA methylation and its critical implications in diabetic vascular complications

Zheng, Jia; Cheng, Jing; Zhang, Qian; Xiao, Xinhua

doi:10.1042/bsr20160611

Cited by 28 publications

(16 citation statements)

References 44 publications

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“…The elucidation of epigenetic changes involved in microvascular complications could improve our knowledge of pathophysiology and therapeutic management of these diseases, an important public health issue. The role of DNA methylation in vascular complications of diabetes has been recently reviewed [ 34 ]. Several lines of evidence described distinct methylation patterns in diabetes-associated cardiovascular complications [ 35 – 38 ], suggesting that high glucose-induced oxidative stress is an important mediator [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Curcumin Modulates DNA Methyltransferase Functions in a Cellular Model of Diabetic Retinopathy

Maugeri

Mazzone²,

Giuliano³

et al. 2018

Oxidative Medicine and Cellular Longevity

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Hyperglycaemia-induced oxidative stress appears to be involved in the aetiology of diabetic retinopathy (DR), a major public health issue, via altering DNA methylation process. We investigated the effect of hyperglycaemia on retinal DNA methyltransferase (DNMT) expression in diabetic mice, using Gene Expression Omnibus datasets. We also evaluated the effect of curcumin both on high glucose-induced reactive oxygen species (ROS) production and altered DNMT functions, in a cellular model of DR. We observed that three months of hyperglycaemia, in insulin-deficient Ins2Akita mice, decrease DNMT1 and DNMT3a expression levels. In retinal pigment epithelium (RPE) cells, we also demonstrated that high glucose-induced ROS production precedes upregulation of DNMT expression and activity, suggesting that changes in DNMT function could be mediated by oxidative stress via a potential dual effect. The early effect results in decreased DNMT activity, accompanied by the highest ROS production, while long-term oxidative stress increases DNMT activity and DNMT1 expression. Interestingly, treatment with 25 μM curcumin for 6 hours restores ROS production, as well as DNMT functions, altered by the exposure of RPE to acute and chronic high glucose concentration. Our study suggests that curcumin may represent an effective antioxidant compound against DR, via restoring oxidative stress and DNMT functions, though further studies are recommended.

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Section: Discussionmentioning

confidence: 99%

Curcumin Modulates DNA Methyltransferase Functions in a Cellular Model of Diabetic Retinopathy

Maugeri

Mazzone²,

Giuliano³

et al. 2018

Oxidative Medicine and Cellular Longevity

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“…DNA methylation in vascular complications of diabetes have been investigated and reviewed in a recent review ( 62 ). El-Osta ( 63 ) reported that short-term exposure of aortic endothelial cells to high glucose-induced promoter DNA methylation of NF-kB p65 subunit, an important mediator of cardiac fibrosis.…”

Section: Dna Methylation In Diabetes-induced Microvascular Complicatimentioning

confidence: 99%

Emerging Evidence of Epigenetic Modifications in Vascular Complication of Diabetes

2017

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Genes, dietary, and lifestyle factors have been shown to be important in the pathophysiology of diabetes and associated microvascular complications. Epigenetic modifications, such as DNA methylation, histone acetylation, and post-transcriptional RNA regulation, are being increasingly recognized as important mediators of the complex interplay between genes and the environment. Recent studies suggest that diabetes-induced dysregulation of epigenetic mechanisms resulting in altered gene expression in target cells can lead to diabetes-associated complications, such as diabetic cardiomyopathy, diabetic nephropathy, retinopathy, and so on, which are the major contributors to diabetes-associated morbidity and mortality. Thus, knowledge of dysregulated epigenetic pathways involved in diabetes can provide much needed new drug targets for these diseases. In this review, we constructed our search strategy to highlight the role of DNA methylation, modifications of histones and role of non-coding RNAs (microRNAs and long non-coding RNAs) in vascular complications of diabetes, including cardiomyopathy, nephropathy, and retinopathy.

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“…There is growing evidence that epigenetic dysregulation is involved in diabetes and its associated DN and DR [ 12 – 17 ]. In addition, epigenetic alterations and the C677T genotype were associated with risk for chronic renal failure and dialysis in patients with renal insufficiency due to low enzyme activity and global hypomethylation of DNA that alters the expression of different systemic alleles [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Hypermethylation in the promoter of the MTHFR gene is associated with diabetic complications and biochemical indicators

Nunes

Silva

Evangelista

et al. 2017

Diabetol Metab Syndr

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BackgroundDNA methylation is an epigenetic mechanism for regulating the transcription of many genes and has been linked to the development of various diseases. A promising gene to investigate is methylenetetrahydrofolate reductase (MTHFR), since the enzyme methylenetetrahydrofolate reductase (MTHFR) promotes methyl radical synthesis in the homocysteine cycle and can provide methyl groups for DNA methylation. In addition, several studies have correlated gene polymorphisms of this enzyme with a greater risk of diabetes, but little is known regarding the relationship between epigenetic changes in this gene and diabetes and its complications. The aim of this study was to investigate the relationship between methylation profile in the MTHFR gene promoter and biochemical, inflammatory and oxidative stress markers in individuals with type 2 diabetes (T2DM) who have been diagnosed for 5–10 years with or without diabetic retinopathy (DR) and nephropathy (DN).MethodsSpecific PCR for methylation (MSP) was used to analyze MTHFR methylation profile in leucocytes DNA. Biochemical markers (glycemia, glycated hemoglobin, total cholesterol, LDL, HDL, triglycerides, serum creatinine), inflammatory markers (C-reactive protein and alpha-1 acid glycoprotein) and oxidative stress (total antioxidant and malonaldehyde) were determined in peripheric blood samples and microalbuminuria in 24 h urine samples. The X2 and Mann–Whitney statistical tests were performed and p < 0.05 were considered significant.ResultsThe hypermethylated profile was most frequently observed in individuals with retinopathy (p < 0.01) and was associated with higher total cholesterol and LDL levels (p = 0.0046, 0.0267, respectively). Individuals with DN and hypermethylated profiles had higher levels of alpha-1 acid glycoprotein (p = 0.0080) and total antioxidant capacity (p = 0.0169) compared to subjects without complications.ConclusionsHypermethylation in the promoter of the MTHFR gene is associated with the occurrence of DR and with biochemical, inflammatory and oxidative stress parameters in the context of chronic complications

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Novel insights into DNA methylation and its critical implications in diabetic vascular complications

Cited by 28 publications

References 44 publications

Curcumin Modulates DNA Methyltransferase Functions in a Cellular Model of Diabetic Retinopathy

Curcumin Modulates DNA Methyltransferase Functions in a Cellular Model of Diabetic Retinopathy

Emerging Evidence of Epigenetic Modifications in Vascular Complication of Diabetes

Hypermethylation in the promoter of the MTHFR gene is associated with diabetic complications and biochemical indicators

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