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

Abstract

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.

Mediterranean Diet and Particulate Matter Exposure Are Associated With LINE-1 Methylation: Results From a Cross-Sectional Study in Women

“…This study had some limitations. Although hypomethylation of transposable repetitive elements, including LINE-1 sequences, has been associated with chromosomal instability and aberrant genome function ( Schulz, 2006 ; Slotkin and Martienssen, 2007 ) and with different chronic degenerative diseases ( Baccarelli et al, 2010 ; Woo and Kim, 2012 ; Barchitta et al, 2014b ; Maugeri et al, 2018b ), mechanisms of DNA hypomethylation are not fully understood. Therefore, the cross-sectional design of our analysis arises the need of further prospective studies and of functional test to explore the causes and the consequences of these modifications and to better understood the biological significance of LINE-1 methylation alterations.…”

“…Methylation level of transposable sequences, including both long interspersed nucleotide elements 1 (LINE-1) and Alu sequences, has been used as a surrogate marker of global genomic DNA methylation ( Yang et al, 2004 ). Although LINE-1 methylation is not an universally accepted marker of global methylation, aberrant methylation of these sequences was shown to be associated with cancer ( Woo and Kim, 2012 ; Barchitta et al, 2014b ), CVD ( Baccarelli et al, 2010 ), and degenerative diseases ( Maugeri et al, 2018a , b ).…”

Bioactivity, Health Benefits, and Related Molecular Mechanisms of Curcumin: Current Progress, Challenges, and Perspectives

“…Quinocetone causes genotoxicity and oxidative stress in human hepatocyte L02 cells, and curcumin pretreatment markedly inhibits excessive ROS generation, with the suppression of the decrease in the activity of antioxidant enzymes, like superoxide dismutase (SOD), and levels of antioxidant constituents, such as glutathione (GSH) [ 29 ]. In addition, in diabetic mice, curcumin treatment inhibits ROS production and hyperglycemia-induced oxidative stress by restoring the functions of DNA methyltransferase (DNMT) [ 30 ].…”

Dietary antioxidants remodel DNA methylation patterns in chronic disease

“…Another member of the antioxidant network, GSTP1 , was also found to be demethylated and activated upon exposure of breast cancer cells to curcumin (Kumar, Sharma, & Rathi, ). Furthermore, Maugeri et al () reported up‐regulation of DNMT1 expression and activity along with oxidative stress induced by chronic high glucose levels in a cellular model of diabetic retinopathy (Maugeri et al, ). Interestingly, curcumin restored normal levels of DNMT1 and inhibited the overproduction of ROS (Maugeri et al, ).…”

“…Furthermore, Maugeri et al () reported up‐regulation of DNMT1 expression and activity along with oxidative stress induced by chronic high glucose levels in a cellular model of diabetic retinopathy (Maugeri et al, ). Interestingly, curcumin restored normal levels of DNMT1 and inhibited the overproduction of ROS (Maugeri et al, ).…”