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 Ins2 Akita 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.

Department of General Surgery and Medical Surgical Specialties University of Catania Via Plebiscito 628 Catania 95124 Italy

Department of Medical and Surgical Sciences and Advanced Technologies GF Ingrassia University of Catania Via S Sofia 87 Catania 95123 Italy

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Research and Development Department SIFI SpA Via Ercole Patti 36 Catania 95025 Italy

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Flaxman S. R., Bourne R. R. A., Resnikoff S., et al. Global causes of blindness and distance vision impairment 1990-2020: a systematic review and meta-analysis. The Lancet Global Health. 2017;5(12):e1221–e1234. doi: 10.1016/S2214-109X(17)30393-5. PubMed DOI

Congdon N., Zheng Y., He M. The worldwide epidemic of diabetic retinopathy. Indian Journal of Ophthalmology. 2012;60(5):428–431. doi: 10.4103/0301-4738.100542. PubMed DOI PMC

Yau J. W., Rogers S. L., Kawasaki R., et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556–564. doi: 10.2337/dc11-1909. PubMed DOI PMC

Madsen-Bouterse S. A., Kowluru R. A. Oxidative stress and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Reviews in Endocrine & Metabolic Disorders. 2008;9(4):315–327. doi: 10.1007/s11154-008-9090-4. PubMed DOI

Santos J. M., Mohammad G., Zhong Q., Kowluru R. A. Diabetic retinopathy, superoxide damage and antioxidants. Current Pharmaceutical Biotechnology. 2011;12(3):352–361. doi: 10.2174/138920111794480507. PubMed DOI PMC

Aiello L. P., DCCT/EDIC Research Group Diabetic retinopathy and other ocular findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37(1):17–23. doi: 10.2337/dc13-2251. PubMed DOI PMC

Kowluru R. A., Santos J. M., Mishra M. Epigenetic modifications and diabetic retinopathy. BioMed Research International. 2013;2013:9. doi: 10.1155/2013/635284.635284 PubMed DOI PMC

Mishra M., Kowluru R. A. Epigenetic modification of mitochondrial DNA in the development of diabetic retinopathy. Investigative Ophthalmology & Visual Science. 2015;56(9):5133–5142. doi: 10.1167/iovs.15-16937. PubMed DOI PMC

Pelzel H. R., Schlamp C. L., Waclawski M., Shaw M. K., Nickells R. W. Silencing of Fem1cR3 gene expression in the DBA/2J mouse precedes retinal ganglion cell death and is associated with histone deacetylase activity. Investigative Ophthalmology & Visual Science. 2012;53(3):1428–1435. doi: 10.1167/iovs.11-8872. PubMed DOI PMC

Zhong Q., Kowluru R. A. Epigenetic changes in mitochondrial superoxide dismutase in the retina and the development of diabetic retinopathy. Diabetes. 2011;60(4):1304–1313. doi: 10.2337/db10-0133. PubMed DOI PMC

Zhong Q., Kowluru R. A. Epigenetic modification of Sod2 in the development of diabetic retinopathy and in the metabolic memory: role of histone methylation. Investigative Ophthalmology & Visual Science. 2013;54(1):244–250. doi: 10.1167/iovs.12-10854. PubMed DOI PMC

Auclair G., Weber M. Mechanisms of DNA methylation and demethylation in mammals. Biochimie. 2012;94(11):2202–11. doi: 10.1016/j.biochi.2012.05.016. PubMed DOI

Barchitta M., Quattrocchi A., Maugeri A., Vinciguerra M., Agodi A. LINE-1 hypomethylation in blood and tissue samples as an epigenetic marker for cancer risk: a systematic review and meta-analysis. PLoS One. 2014;9(10, article e109478) doi: 10.1371/journal.pone.0109478. PubMed DOI PMC

Carreira P. E., Richardson S. R., Faulkner G. J. L1 retrotransposons, cancer stem cells and oncogenesis. The FEBS Journal. 2014;281(1):63–73. doi: 10.1111/febs.12601. PubMed DOI PMC

Fabris S., Ronchetti D., Agnelli L., et al. Transcriptional features of multiple myeloma patients with chromosome 1q gain. Leukemia. 2007;21(5):1113–1116. doi: 10.1038/sj.leu.2404616. PubMed DOI

Rodić N., Burns K. H. Long interspersed element-1 (LINE-1): passenger or driver in human neoplasms? PLoS Genetics. 2013;9(3, article e1003402) doi: 10.1371/journal.pgen.1003402. PubMed DOI PMC

Amalraj A., Pius A., Gopi S., Gopi S. Biological activities of curcuminoids, other biomolecules from turmeric and their derivatives - a review. Journal of Traditional and Complementary Medicine. 2017;7(2):205–233. doi: 10.1016/j.jtcme.2016.05.005. PubMed DOI PMC

Akbik D., Ghadiri M., Chrzanowski W., Rohanizadeh R. Curcumin as a wound healing agent. Life Sciences. 2014;116(1):1–7. doi: 10.1016/j.lfs.2014.08.016. PubMed DOI

Zhang Y., McClain S. A., Lee H.-M., et al. A novel chemically modified curcumin “normalizes” wound-healing in rats with experimentally induced type I diabetes: initial studies. Journal of Diabetes Research. 2016;2016:11. doi: 10.1155/2016/5782904.5782904 PubMed DOI PMC

Epstein J., Sanderson I. R., Macdonald T. T. Curcumin as a therapeutic agent: the evidence from in vitro, animal and human studies. The British Journal of Nutrition. 2010;103(11):1545–1557. doi: 10.1017/S0007114509993667. PubMed DOI

Osawa T., Kato Y. Protective role of antioxidative food factors in oxidative stress caused by hyperglycemia. Annals of the New York Academy of Sciences. 2005;1043(1):440–451. doi: 10.1196/annals.1333.050. PubMed DOI

Woo J. M., Shin D. Y., Lee S. J., et al. Curcumin protects retinal pigment epithelial cells against oxidative stress via induction of heme oxygenase-1 expression and reduction of reactive oxygen. Molecular Vision. 2012;18:901–908. PubMed PMC

Kowluru R. A., Kanwar M. Effects of curcumin on retinal oxidative stress and inflammation in diabetes. Nutrition & Metabolism. 2007;4(1):p. 8. doi: 10.1186/1743-7075-4-8. PubMed DOI PMC

Freeman W. M., Bixler G. V., Brucklacher R. M., et al. Transcriptomic comparison of the retina in two mouse models of diabetes. Journal of Ocular Biology, Diseases, and Informatics. 2009;2(4):202–213. doi: 10.1007/s12177-009-9045-3. PubMed DOI PMC

Bogdanov P., Corraliza L., Villena J. A., et al. The db/db mouse: a useful model for the study of diabetic retinal neurodegeneration. PLoS One. 2014;9(5, article e97302) doi: 10.1371/journal.pone.0097302. PubMed DOI PMC

Candiloros H., Muller S., Zeghari N., Donner M., Drouin P., Ziegler O. Decreased erythrocyte membrane fluidity in poorly controlled IDDM. Influence of ketone bodies. Diabetes Care. 1995;18(4):549–551. doi: 10.2337/diacare.18.4.549. PubMed DOI

Chen Y. H., Chou H. C., Lin S. T., Chen Y. W., Lo Y. W., Chan H. L. Effect of high glucose on secreted proteome in cultured retinal pigmented epithelium cells: its possible relevance to clinical diabetic retinopathy. Journal of Proteomics. 2012;77:111–128. doi: 10.1016/j.jprot.2012.07.014. PubMed DOI

Jouven X., Lemaître R. N., Rea T. D., Sotoodehnia N., Empana J. P., Siscovick D. S. Diabetes, glucose level, and risk of sudden cardiac death. European Heart Journal. 2005;26(20):2142–2147. doi: 10.1093/eurheartj/ehi376. PubMed DOI

Agodi A., Barchitta M., Quattrocchi A., et al. Low fruit consumption and folate deficiency are associated with LINE-1 hypomethylation in women of a cancer-free population. Genes & Nutrition. 2015;10(5):p. 480. doi: 10.1007/s12263-015-0480-4.. PubMed DOI PMC

Barchitta M., Quattrocchi A., Maugeri A., et al. LINE-1 hypermethylation in white blood cell DNA is associated with high-grade cervical intraepithelial neoplasia. BMC Cancer. 2017;17(1):p. 601. doi: 10.1186/s12885-017-3582-0.. PubMed DOI PMC

Khullar M., Cheema B. S., Raut S. K. Emerging evidence of epigenetic modifications in vascular complication of diabetes. Frontiers in Endocrinology. 2017;8 doi: 10.3389/fendo.2017.00237. PubMed DOI PMC

Gilbert E. R., Liu D. Epigenetics: the missing link to understanding β-cell dysfunction in the pathogenesis of type 2 diabetes. Epigenetics. 2012;7(8):841–852. doi: 10.4161/epi.21238. PubMed DOI PMC

Ling C., Groop L. Epigenetics: a molecular link between environmental factors and type 2 diabetes. Diabetes. 2009;58(12):2718–2725. doi: 10.2337/db09-1003. PubMed DOI PMC

Zheng J., Cheng J., Zhang Q., Xiao X. Novel insights into DNA methylation and its critical implications in diabetic vascular complications. Bioscience Reports. 2017;37(2):p. BSR20160611. doi: 10.1042/BSR20160611. PubMed DOI PMC

El-Osta A., Brasacchio D., Yao D., et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. The Journal of Experimental Medicine. 2008;205(10):2409–2417. doi: 10.1084/jem.20081188. PubMed DOI PMC

Movassagh M., Choy M.-K., Goddard M., Bennett M. R., Down T. A., Foo R. S.-Y. Differential DNA methylation correlates with differential expression of angiogenic factors in human heart failure. PLoS One. 2010;5(1, article e8564) doi: 10.1371/journal.pone.0008564. PubMed DOI PMC

Mönkemann H., De Vriese A. S., Blom H. J., et al. Early molecular events in the development of the diabetic cardiomyopathy. Amino Acids. 2002;23(1–3):331–336. doi: 10.1007/s00726-001-0146-y. PubMed DOI

Pirola L., Balcerczyk A., Tothill R. W., et al. Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells. Genome Research. 2011;21(10):1601–1615. doi: 10.1101/gr.116095.110. PubMed DOI PMC

Liu Z. Z., Zhao X. Z., Zhang X. S., Zhang M. Promoter DNA demethylation of Keap1 gene in diabetic cardiomyopathy. International Journal of Clinical and Experimental Pathology. 2014;7(12):8756–8762. PubMed PMC

Zhong J., Agha G., Baccarelli A. A. The role of DNA methylation in cardiovascular risk and disease: methodological aspects, study design, and data analysis for epidemiological studies. Circulation Research. 2016;118(1):119–131. doi: 10.1161/CIRCRESAHA.115.305206. PubMed DOI PMC

Bell C. G., Teschendorff A. E., Rakyan V. K., Maxwell A. P., Beck S., Savage D. A. Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus. BMC Medical Genomics. 2010;3(1, article 33) doi: 10.1186/1755-8794-3-33. PubMed DOI PMC

Peng R., Liu H., Peng H., et al. Promoter hypermethylation of let-7a-3 is relevant to Its down-expression in diabetic nephropathy by targeting UHRF1. Gene. 2015;570(1):57–63. doi: 10.1016/j.gene.2015.05.073. PubMed DOI

Sapienza C., Lee J., Powell J., et al. DNA methylation profiling identifies epigenetic differences between diabetes patients with ESRD and diabetes patients without nephropathy. Epigenetics. 2011;6(1):20–28. doi: 10.4161/epi.6.1.13362. PubMed DOI

Agardh E., Lundstig A., Perfilyev A., et al. Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy. BMC Medicine. 2015;13(1, article 182) doi: 10.1186/s12916-015-0421-5. PubMed DOI PMC

Kowluru R. A., Shan Y. Role of oxidative stress in epigenetic modification of MMP-9 promoter in the development of diabetic retinopathy. Graefe's Archive for Clinical and Experimental Ophthalmology. 2017;255(5):955–962. doi: 10.1007/s00417-017-3594-0. PubMed DOI PMC

Wang J., Takeuchi T., Tanaka S., et al. A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse. The Journal of Clinical Investigation. 1999;103(1):27–37. doi: 10.1172/JCI4431. PubMed DOI PMC

Hong E. G., Jung D. Y., Ko H. J., et al. Nonobese, insulin-deficient Ins2Akita mice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling. American Journal of Physiology Endocrinology and Metabolism. 2007;293(6):E1687–E1696. doi: 10.1152/ajpendo.00256.2007. PubMed DOI

Kowluru R. A., Kowluru A., Mishra M., Kumar B. Oxidative stress and epigenetic modifications in the pathogenesis of diabetic retinopathy. Progress in Retinal and Eye Research. 2015;48:40–61. doi: 10.1016/j.preteyeres.2015.05.001. PubMed DOI PMC

Tewari S., Zhong Q., Santos J. M., Kowluru R. A. Mitochondria DNA replication and DNA methylation in the metabolic memory associated with continued progression of diabetic retinopathy. Investigative Ophthalmology & Visual Science. 2012;53(8):4881–4888. doi: 10.1167/iovs.12-9732. PubMed DOI PMC

Mishra M., Kowluru R. A. The role of DNA methylation in the metabolic memory phenomenon associated with the continued progression of diabetic retinopathy. Investigative Ophthalmology & Visual Science. 2016;57(13):5748–5757. doi: 10.1167/iovs.16-19759. PubMed DOI PMC

Olsen A. S., Sarras M. P., Leontovich A., Intine R. V. Heritable transmission of diabetic metabolic memory in zebrafish correlates with DNA hypomethylation and aberrant gene expression. Diabetes. 2012;61(2):485–491. doi: 10.2337/db11-0588. PubMed DOI PMC

Afanas’ev I. New nucleophilic mechanisms of ros-dependent epigenetic modifications: comparison of aging and cancer. Aging and Disease. 2014;5(1):52–62. doi: 10.14336/AD.2014.050052. PubMed DOI PMC

Tokarz P., Kaarniranta K., Blasiak J. Inhibition of DNA methyltransferase or histone deacetylase protects retinal pigment epithelial cells from DNA damage induced by oxidative stress by the stimulation of antioxidant enzymes. European Journal of Pharmacology. 2016;776:167–175. doi: 10.1016/j.ejphar.2016.02.049. PubMed DOI

Kant V., Gopal A., Kumar D., et al. Curcumin-induced angiogenesis hastens wound healing in diabetic rats. The Journal of Surgical Research. 2015;193(2):978–988. doi: 10.1016/j.jss.2014.10.019. PubMed DOI

Shah A., Amini-Nik S. The role of phytochemicals in the inflammatory phase of wound healing. International Journal of Molecular Sciences. 2017;18(5) doi: 10.3390/ijms18051068. PubMed DOI PMC

Thangapazham R. L., Sharad S., Maheshwari R. K. Phytochemicals in wound healing. Advances in Wound Care. 2016;5(5):230–241. doi: 10.1089/wound.2013.0505. PubMed DOI PMC

Abe Y., Hashimoto S., Horie T. Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacological Research. 1999;39(1):41–47. doi: 10.1006/phrs.1998.0404. PubMed DOI

Balogun E., Hoque M., Gong P., et al. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. The Biochemical Journal. 2003;371(3):887–895. doi: 10.1042/BJ20021619.. PubMed DOI PMC

Huang M. T., Lysz T., Ferraro T., Abidi T. F., Laskin J. D., Conney A. H. Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis. Cancer Research. 1991;51(3):813–819. PubMed

Reddy A. C., Lokesh B. R. Studies on spice principles as antioxidants in the inhibition of lipid peroxidation of rat liver microsomes. Molecular and Cellular Biochemistry. 1992;111(1-2):117–124. PubMed

Scapagnini G., Colombrita C., Amadio M., et al. Curcumin activates defensive genes and protects neurons against oxidative stress. Antioxidants & Redox Signaling. 2006;8(3-4):395–403. doi: 10.1089/ars.2006.8.395. PubMed DOI

Singh S., Aggarwal B. B. Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected] The Journal of Biological Chemistry. 1995;270(42):24995–25000. doi: 10.1074/jbc.270.42.24995. PubMed DOI

Susan M., Rao M. N. Induction of glutathione S-transferase activity by curcumin in mice. Arzneimittel-Forschung. 1992;42(7):962–964. PubMed

Woo J. H., Kim Y. H., Choi Y. J., et al. Molecular mechanisms of curcumin-induced cytotoxicity: induction of apoptosis through generation of reactive oxygen species, down-regulation of Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt. Carcinogenesis. 2003;24(7):1199–1208. doi: 10.1093/carcin/bgg082. PubMed DOI

Howell J. C., Chun E., Farrell A. N., et al. Global microRNA expression profiling: curcumin (diferuloylmethane) alters oxidative stress-responsive microRNAs in human ARPE-19 cells. Molecular Vision. 2013;19:544–560. PubMed PMC

Pittalà V., Fidilio A., Lazzara F., et al. Effects of novel nitric oxide-releasing molecules against oxidative stress on retinal pigmented epithelial cells. Oxidative Medicine and Cellular Longevity. 2017;2017:11. doi: 10.1155/2017/1420892.1420892 PubMed DOI PMC

Sharma R. A., Euden S. A., Platton S. L., et al. Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clinical Cancer Research. 2004;10(20):6847–6854. doi: 10.1158/1078-0432.CCR-04-0744. PubMed DOI

Ravindranath V., Chandrasekhara N. Absorption and tissue distribution of curcumin in rats. Toxicology. 1980;16(3):259–265. doi: 10.1016/0300-483X(80)90122-5. PubMed DOI

Ravindranath V., Chandrasekhara N. Metabolism of curcumin–studies with [3H] curcumin. Toxicology. 1981;22(4):337–344. doi: 10.1016/0300-483X(81)90027-5. PubMed DOI

Mandal M. N. A., Patlolla J. M. R., Zheng L., et al. Curcumin protects retinal cells from light-and oxidant stress-induced cell death. Free Radical Biology & Medicine. 2009;46(5):672–679. doi: 10.1016/j.freeradbiomed.2008.12.006. PubMed DOI PMC

Suryanarayana P., Saraswat M., Mrudula T., Krishna T. P., Krishnaswamy K., Reddy G. B. Curcumin and turmeric delay streptozotocin-induced diabetic cataract in rats. Investigative Ophthalmology & Visual Science. 2005;46(6):p. 2092. doi: 10.1167/iovs.04-1304. PubMed DOI

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