{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T21:09:22Z","timestamp":1788210562470,"version":"build-2803163510"},"reference-count":102,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,15]],"date-time":"2021-05-15T00:00:00Z","timestamp":1621036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY014370, EY017313 and EY022230"],"award-info":[{"award-number":["EY014370, EY017313 and EY022230"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Diabetic retinopathy remains the leading cause of vision loss in working-age adults. The multi-factorial nature of the disease, along with the complex structure of the retina, have hindered in elucidating the exact molecular mechanism(s) of this blinding disease. Oxidative stress appears to play a significant role in its development and experimental models have shown that an increase in cytosolic Reacttive Oxygen Speies (ROS) due to the activation of NADPH oxidase 2 (Nox2), is an early event, which damages the mitochondria, accelerating loss of capillary cells. One of the integral proteins in the assembly of Nox2 holoenzyme, Rac1, is also activated in diabetes, and due to epigenetic modifications its gene transcripts are upregulated. Moreover, addition of hyperlipidemia in a hyperglycemic milieu (type 2 diabetes) further exacerbates Rac1-Nox2-ROS activation, and with time, this accelerates and worsens the mitochondrial damage, ultimately leading to the accelerated capillary cell loss and the development of diabetic retinopathy. Nox2, a multicomponent enzyme, is a good candidate to target for therapeutic interventions, and the inhibitors of Nox2 and Rac1 (and its regulators) are in experimental or clinical trials for other diseases; their possible use to prevent\/halt retinopathy will be a welcoming sign for diabetic patients.<\/jats:p>","DOI":"10.3390\/antiox10050783","type":"journal-article","created":{"date-parts":[[2021,5,16]],"date-time":"2021-05-16T23:17:16Z","timestamp":1621207036000},"page":"783","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Diabetic Retinopathy and NADPH Oxidase-2: A Sweet Slippery Road"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3309-4942","authenticated-orcid":false,"given":"Renu A.","family":"Kowluru","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Visual and Anatomical Sciences, Kresge Eye Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1479-5868-11-26","article-title":"Physical activity and inactivity patterns in India\u2014Results from the ICMR-INDIAB study (Phase-1) [ICMR-INDIAB-5]","volume":"11","author":"Anjana","year":"2014","journal-title":"Int. J. Behav. Nutr. Phys. Act."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11892-015-0631-4","article-title":"Nutrition Transition and the Global Diabetes Epidemic","volume":"15","author":"Popkin","year":"2015","journal-title":"Curr. Diabetes Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1056\/NEJMra021678","article-title":"Diabetic Retinopathy","volume":"350","author":"Frank","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1001\/archopht.126.12.1740","article-title":"Projection of Diabetic Retinopathy and Other Major Eye Diseases Among People with Diabetes Mellitus: United States, 2005\u20132050","volume":"126","author":"Saaddine","year":"2008","journal-title":"Arch. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"151","DOI":"10.4103\/0974-9233.154388","article-title":"Diabetic Retinopathy and Systemic Factors","volume":"22","author":"Frank","year":"2015","journal-title":"Middle East Afr. J. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"32","DOI":"10.2174\/157339912798829188","article-title":"Diabetic retinopathy: Current and new treatment options","volume":"8","author":"Giuliari","year":"2012","journal-title":"Curr. Diabetes Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S113","DOI":"10.1046\/j.1523-1755.2000.07718.x","article-title":"Role of vascular endothelial growth factor in diabetic vascular complications","volume":"58","author":"Aiello","year":"2000","journal-title":"Kidney Int."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Diabetes Control and Complications Trial Research Group (1993). The effect of intensive treatment of diabetes on the development of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med., 329, 977\u2013986.","DOI":"10.1056\/NEJM199309303291401"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1001\/archopht.1996.01100140281004","article-title":"Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22","volume":"114","author":"Chew","year":"1996","journal-title":"Arch. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1016\/S0140-6736(07)61607-9","article-title":"Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): A randomised controlled trial","volume":"370","author":"Keech","year":"2007","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1007\/s00125-019-4959-1","article-title":"New insights into the mechanisms of diabetic complications: Role of lipids and lipid metabolism","volume":"62","author":"Eid","year":"2019","journal-title":"Diabetologia"},{"key":"ref_12","first-page":"3972","article-title":"Response of capillary cell death to aminoguanidine predicts the development of retinopathy: Comparison of diabetes and galactosemia","volume":"41","author":"Kern","year":"2000","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3233","DOI":"10.2337\/diabetes.53.12.3233","article-title":"Effect of Long-Term Administration of \u03b1-Lipoic Acid on Retinal Capillary Cell Death and the Development of Retinopathy in Diabetic Rats","volume":"53","author":"Kowluru","year":"2004","journal-title":"Diabetes"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Tonade, D., and Kern, T.S. (2020). Photoreceptor cells and RPE contribute to the development of diabetic retinopathy. Prog. Retin. Eye Res., 100919.","DOI":"10.1016\/j.preteyeres.2020.100919"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0014-4800(03)00035-2","article-title":"The role of advanced glycation in the pathogenesis of diabetic retinopathy","volume":"75","author":"Stitt","year":"2003","journal-title":"Exp. Mol. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.2337\/diabetes.54.6.1615","article-title":"The Pathobiology of Diabetic Complications: A Unifying Mechanism","volume":"54","author":"Brownlee","year":"2005","journal-title":"Diabetes"},{"key":"ref_17","first-page":"1","article-title":"The Polyol Pathway as a Mechanism for Diabetic Retinopathy: Attractive, Elusive, and Resilient","volume":"2007","author":"Lorenzi","year":"2007","journal-title":"Exp. Diabetes Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1161\/CIRCRESAHA.110.217117","article-title":"Activation of Protein Kinase C Isoforms and Its Impact on Diabetic Complications","volume":"106","author":"Geraldes","year":"2010","journal-title":"Circ. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.preteyeres.2004.06.002","article-title":"The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina","volume":"24","author":"SanGiovanni","year":"2005","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/S0891-5849(96)00347-4","article-title":"Abnormalities of Retinal Metabolism in Diabetes or Experimental Galactosemia. IV. Antioxidant Defense System","volume":"22","author":"Kowluru","year":"1997","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.2337\/diab.45.9.1233","article-title":"Abnormalities of retinal metabolism in diabetes or experimental galactosemia. III. Effects of antioxidants","volume":"45","author":"Kowluru","year":"1996","journal-title":"Diabetes"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3805","DOI":"10.1167\/iovs.06-1280","article-title":"Oxidative Damage in the Retinal Mitochondria of Diabetic Mice: Possible Protection by Superoxide Dismutase","volume":"48","author":"Kanwar","year":"2007","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"ref_23","first-page":"209","article-title":"Diabetic retinopathy, oxidative stress and antioxidants","volume":"3","author":"Kowluru","year":"2005","journal-title":"Curr. Top. Nutrac. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"241","DOI":"10.2337\/dbi18-0016","article-title":"Mitochondrial Stability in Diabetic Retinopathy: Lessons Learned from Epigenetics","volume":"68","author":"Kowluru","year":"2019","journal-title":"Diabetes"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1016\/j.bbadis.2015.08.001","article-title":"Oxidative stress, mitochondrial damage and diabetic retinopathy","volume":"1852","author":"Kowluru","year":"2015","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1152\/physrev.00018.2001","article-title":"Free Radicals in the Physiological Control of Cell Function","volume":"82","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1161\/CIRCRESAHA.116.309326","article-title":"Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis","volume":"120","author":"Xia","year":"2017","journal-title":"Circ. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1152\/physrev.00044.2005","article-title":"The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology","volume":"87","author":"Bedard","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1089\/ars.2008.2220","article-title":"NADPH Oxidase-Dependent Signaling in Endothelial Cells: Role in Physiology and Pathophysiology","volume":"11","author":"Frey","year":"2009","journal-title":"Antioxid. Redox Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.bcp.2011.01.013","article-title":"Friendly, and not so friendly, roles of Rac1 in islet \u03b2-cell function: Lessons learnt from pharmacological and molecular biological approaches","volume":"81","author":"Kowluru","year":"2011","journal-title":"Biochem. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1007\/s00125-014-3194-z","article-title":"TIAM1\u2013RAC1 signalling axis-mediated activation of NADPH oxidase-2 initiates mitochondrial damage in the development of diabetic retinopathy","volume":"57","author":"Kowluru","year":"2014","journal-title":"Diabetologia"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.cellsig.2011.08.011","article-title":"Rac signaling in breast cancer: A tale of GEFs and GAPs","volume":"24","author":"Wertheimer","year":"2012","journal-title":"Cell. Signal."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.tcb.2005.05.001","article-title":"GDIs: Central regulatory molecules in Rho GTPase activation","volume":"15","author":"DerMardirossian","year":"2005","journal-title":"Trends Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.bcp.2014.01.017","article-title":"Phagocyte-like NADPH oxidase [Nox2] in cellular dysfunction in models of glucolipotoxicity and diabetes","volume":"88","author":"Kowluru","year":"2014","journal-title":"Biochem. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"89","DOI":"10.4161\/21541248.2014.989785","article-title":"Regulation of phagocytosis by Rho GTPases","volume":"6","author":"Mao","year":"2015","journal-title":"Small GTPases"},{"key":"ref_36","first-page":"534","article-title":"A palmitoylation switch mechanism regulates Rac1 function and membrane organization","volume":"31","author":"Calvo","year":"2011","journal-title":"EMBO J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sahajpal, N., Kowluru, A., and Kowluru, R.A. (2019). The Regulatory Role of Rac1, a Small Molecular Weight GTPase, in the Development of Diabetic Retinopathy. J. Clin. Med., 8.","DOI":"10.3390\/jcm8070965"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.3390\/biom5042417","article-title":"Rho GTPases: Novel Players in the Regulation of the DNA Damage Response?","volume":"5","author":"Fritz","year":"2015","journal-title":"Biomolecules"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e00115","DOI":"10.1042\/BSR20140021","article-title":"Rho protein GTPases and their interactions with NF\u03baB: Crossroads of inflammation and matrix biology","volume":"34","author":"Tong","year":"2014","journal-title":"Biosci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1111\/j.1600-0854.2009.01015.x","article-title":"The Nuclear Import of the Small GTPase Rac1 is Mediated by the Direct Interaction with Karyopherin \u03b12","volume":"11","author":"Sandrock","year":"2010","journal-title":"Traffic"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1083\/jcb.200801047","article-title":"Rac1 accumulates in the nucleus during the G2 phase of the cell cycle and promotes cell division","volume":"181","author":"Michaelson","year":"2008","journal-title":"J. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3301","DOI":"10.1074\/jbc.M111.308387","article-title":"Mitochondrial Rac1 GTPase Import and Electron Transfer from Cytochrome c Are Required for Pulmonary Fibrosis","volume":"287","author":"Ryan","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"689","DOI":"10.2337\/db19-1009","article-title":"Retinopathy in a Diet-Induced Type 2 Diabetic Rat Model and Role of Epigenetic Modifications","volume":"69","author":"Kowluru","year":"2020","journal-title":"Diabetes"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/S0891-5849(98)00210-X","article-title":"Abnormalities of retinal metabolism in diabetes or experimental galactosemia. VI. Comparison of retinal and cerebral cortex metabolism, and effects of antioxidant therapy","volume":"26","author":"Kowluru","year":"1999","journal-title":"Free Radic. Biol. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"464","DOI":"10.2337\/diabetes.47.3.464","article-title":"Abnormalities of retinal metabolism in diabetes or experimental galactosemia: V. Relationship between protein kinase C and ATPases","volume":"47","author":"Kowluru","year":"1998","journal-title":"Diabetes"},{"key":"ref_46","first-page":"1","article-title":"Oxidative Stress and Diabetic Retinopathy","volume":"2007","author":"Kowluru","year":"2007","journal-title":"Exp. Diabetes Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"93751","DOI":"10.1172\/jci.insight.93751","article-title":"Diabetic retinopathy: Current understanding, mechanisms, and treatment strategies","volume":"2","author":"Duh","year":"2017","journal-title":"JCI Insight"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1023\/B:MCBI.0000044378.09409.b5","article-title":"Reactive oxygen species as mediators of angiogenesis signaling. Role of NAD(P)H oxidase","volume":"264","author":"Alexander","year":"2004","journal-title":"Mol. Cell. Biochem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5988","DOI":"10.2174\/1381612821666151029111127","article-title":"Redox mechanisms in pathological angiogenesis in the retina: Roles for NADPH oxidase","volume":"21","author":"Chan","year":"2015","journal-title":"Curr. Pharm. Des."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"8643","DOI":"10.1007\/s12035-019-01696-5","article-title":"Functional Regulation of an Oxidative Stress Mediator, Rac1, in Diabetic Retinopathy","volume":"56","author":"Mohammad","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1083\/jcb.200506001","article-title":"Sos-mediated activation of rac1 by p66shc","volume":"172","author":"Khanday","year":"2006","journal-title":"J. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1089\/ars.2018.7542","article-title":"Adaptor Protein p66Shc: A Link Between Cytosolic and Mitochondrial Dysfunction in the Development of Diabetic Retinopathy","volume":"30","author":"Mishra","year":"2019","journal-title":"Antioxid. Redox Signal."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1152\/physrev.00003.2012","article-title":"Regulation of Small GTPases by GEFs, GAPs, and GDIs","volume":"93","author":"Cherfils","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Abdrabou, A., and Wang, Z. (2018). Post-Translational Modification and Subcellular Distribution of Rac1: An Update. Cells, 7.","DOI":"10.3390\/cells7120263"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"60","DOI":"10.4161\/sgtp.19111","article-title":"Racing to the plasma membrane: The long and complex work commute of Rac1 during cell signaling","volume":"3","author":"Bustelo","year":"2012","journal-title":"Small GTPases"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.bcp.2012.09.024","article-title":"Upregulation of phagocyte-like NADPH oxidase by cytokines in pancreatic beta-cells: Attenuation of oxidative and nitrosative stress by 2-bromopalmitate","volume":"85","author":"Mohammed","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1159\/000374065","article-title":"Tiam1-Rac1 Axis Promotes Activation of p38 MAP Kinase in the Development of Diabetic Retinopathy: Evidence for a Requisite Role for Protein Palmitoylation","volume":"36","author":"Veluthakal","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.2337\/db09-1421","article-title":"Calcium Dobesilate Inhibits the Alterations in Tight Junction Proteins and Leukocyte Adhesion to Retinal Endothelial Cells Induced by Diabetes","volume":"59","author":"Leal","year":"2010","journal-title":"Diabetes"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1002\/jcp.25268","article-title":"Molecular Mechanism of Transcriptional Regulation of Matrix Metalloproteinase-9 in Diabetic Retinopathy","volume":"231","author":"Mishra","year":"2015","journal-title":"J. Cell. Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1038\/labinvest.2010.89","article-title":"Matrix metalloproteinase-2 in the development of diabetic retinopathy and mitochondrial dysfunction","volume":"90","author":"Mohammad","year":"2010","journal-title":"Lab. Investig."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"946","DOI":"10.2174\/1566524011313060007","article-title":"Triamcinolone Acetonide Inhibits p38MAPK Activation and Neuronal Apoptosis in Early Diabetic Retinopathy","volume":"13","author":"Zhang","year":"2013","journal-title":"Curr. Mol. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1007\/s00125-018-4560-z","article-title":"Role of endoplasmic reticulum stress in 12\/15-lipoxygenase-induced retinal microvascular dysfunction in a mouse model of diabetic retinopathy","volume":"61","author":"Elmasry","year":"2018","journal-title":"Diabetologia"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1194\/jlr.M056069","article-title":"A lipidomic screen of hyperglycemia-treated HRECs links 12\/15-Lipoxygenase to microvascular dysfunction during diabetic retinopathy via NADPH oxidase","volume":"56","author":"Ibrahim","year":"2015","journal-title":"J. Lipid Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1096\/fj.03-1476fje","article-title":"A central role for inflammation in the pathogenesis of diabetic retinopathy","volume":"18","author":"Joussen","year":"2004","journal-title":"FASEB J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1056\/NEJMra1005073","article-title":"Diabetic Retinopathy","volume":"366","author":"Antonetti","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_66","first-page":"1","article-title":"Contributions of Inflammatory Processes to the Development of the Early Stages of Diabetic Retinopathy","volume":"2007","author":"Kern","year":"2007","journal-title":"Exp. Diabetes Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1042\/CS20120212","article-title":"Reactive oxygen species, Nox and angiotensin II in angiogenesis: Implications for retinopathy","volume":"124","author":"Rana","year":"2013","journal-title":"Clin. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.exer.2016.04.014","article-title":"Diabetic retinopathy and transcriptional regulation of a small molecular weight G-Protein, Rac1","volume":"147","author":"Kowluru","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"4831","DOI":"10.1167\/iovs.18-24548","article-title":"Epigenetics and Regulation of Oxidative Stress in Diabetic Retinopathy","volume":"59","author":"Duraisamy","year":"2018","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1161\/CIRCRESAHA.110.223552","article-title":"Epigenetics: Mechanisms and implications for diabetic complications","volume":"107","author":"Cooper","year":"2010","journal-title":"Circ. Res."},{"key":"ref_71","first-page":"489","article-title":"Advances in epigenetics link genetics to the environment and disease","volume":"571","author":"Cavalli","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.1098\/rstb.2009.0125","article-title":"Epigenetic responses to environmental change and their evolutionary implications","volume":"364","author":"Turner","year":"2009","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"A160","DOI":"10.1289\/ehp.114-a160","article-title":"Epigenetics: The Science of Change","volume":"114","author":"Weinhold","year":"2006","journal-title":"Environ. Health Perspect."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nrg3142","article-title":"Epigenetics and the environment: Emerging patterns and implications","volume":"13","author":"Feil","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/hdy.2010.54","article-title":"Epigenetics and gene expression","volume":"105","author":"Gibney","year":"2010","journal-title":"Heredity"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2718","DOI":"10.2337\/db09-1003","article-title":"Epigenetics: A Molecular Link Between Environmental Factors and Type 2 Diabetes","volume":"58","author":"Ling","year":"2009","journal-title":"Diabetes"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"455","DOI":"10.3349\/ymj.2009.50.4.455","article-title":"Epigenetic Cross-Talk between DNA Methylation and Histone Modifications in Human Cancers","volume":"50","author":"Kondo","year":"2009","journal-title":"Yonsei Med. J."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1093\/jb\/mvu054","article-title":"Targeting histone methyltransferase EZH2 as cancer treatment","volume":"156","author":"Kondo","year":"2014","journal-title":"J. Biochem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1101\/gad.947102","article-title":"DNA methylation patterns and epigenetic memory","volume":"16","author":"Bird","year":"2002","journal-title":"Genes Dev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/35049533","article-title":"DNA methylation in health and disease","volume":"1","author":"Robertson","year":"2000","journal-title":"Nat. Rev. Genet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"670","DOI":"10.3390\/biology3040670","article-title":"DNA Modifications: Function and Applications in Normal and Disease States","volume":"3","author":"Liyanage","year":"2014","journal-title":"Biology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1038\/labinvest.2016.78","article-title":"Dynamic DNA methylation of matrix metalloproteinase-9 in the development of diabetic retinopathy","volume":"96","author":"Kowluru","year":"2016","journal-title":"Lab. Investig."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"5076","DOI":"10.1073\/pnas.0810362106","article-title":"Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells","volume":"106","author":"Chin","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Kowluru, R.A., Radhakrishnan, R., and Ghulam, M. (2021). Diabetic retinopathy and epigenetic modifications: Role of histone methylation and DNA methylation. Sci Rep., 2013, Under editorial review.","DOI":"10.1038\/s41598-021-93420-4"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.2337\/diacare.27.2007.S84","article-title":"Retinopathy in Diabetes","volume":"27","author":"Fong","year":"2003","journal-title":"Diabetes Care"},{"key":"ref_86","first-page":"42","article-title":"Lipid Profile in Childhood-and Youth-Onset Type 2 Diabetes and their Association with Microvascular Complications","volume":"65","author":"Amutha","year":"2017","journal-title":"J. Assoc. Phys. India"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2985","DOI":"10.1167\/iovs.15-16466","article-title":"Lipotoxicity Augments Glucotoxicity-Induced Mitochondrial Damage in the Development of Diabetic Retinopathy","volume":"56","author":"Kumar","year":"2015","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1016\/j.metabol.2016.07.012","article-title":"Hyperlipidemia and the development of diabetic retinopathy: Comparison between type 1 and type 2 animal models","volume":"65","author":"Kowluru","year":"2016","journal-title":"Metabolism"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e811","DOI":"10.1111\/aos.13769","article-title":"A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes","volume":"96","author":"Meng","year":"2018","journal-title":"Acta Ophthalmol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1111\/ceo.13155","article-title":"Effect of NADPH oxidase 1 and 4 blockade in activated human retinal endothelial cells","volume":"46","author":"Appukuttan","year":"2018","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1161\/HYPERTENSIONAHA.119.14100","article-title":"Nox (NADPH Oxidase) 1, Nox4, and Nox5 Promote Vascular Permeability and Neovascularization in Retinopathy","volume":"75","author":"Deliyanti","year":"2020","journal-title":"Hypertension"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.1158\/1535-7163.MCT-16-0915","article-title":"Dual Inhibition of NOX2 and Receptor Tyrosine Kinase by BJ-1301 Enhances Anticancer Therapy Efficacy via Suppression of Autocrine-Stimulatory Factors in Lung Cancer","volume":"16","author":"Gautam","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.ceb.2018.04.009","article-title":"Compartmentalisation of RAC1 signalling","volume":"54","author":"Payapilly","year":"2018","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s00005-012-0176-z","article-title":"The NADPH Oxidase Family and its Inhibitors","volume":"60","author":"Kleniewska","year":"2012","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2013\/462361","article-title":"NADPH Oxidase as a Therapeutic Target for Oxalate Induced Injury in Kidneys","volume":"2013","author":"Joshi","year":"2013","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1161\/hh1701.096037","article-title":"Novel Competitive Inhibitor of NAD(P)H Oxidase Assembly Attenuates Vascular O2\u2212and Systolic Blood Pressure in Mice","volume":"89","author":"Rey","year":"2001","journal-title":"Circ. Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1001\/jamaophthalmol.2018.6399","article-title":"Association of Statin Therapy with Prevention of Vision-Threatening Diabetic Retinopathy","volume":"137","author":"Kang","year":"2019","journal-title":"JAMA Ophthalmol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.biocel.2005.08.002","article-title":"Angiotensin and diabetic retinopathy","volume":"38","year":"2006","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1172\/JCI2425","article-title":"Neural apoptosis in the retina during experimental and human diabetes. Early onset and effect of insulin","volume":"102","author":"Barber","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1517\/13543784.2011.554822","article-title":"New nucleoside analogs for patients with hematological malignancies","volume":"20","author":"Robak","year":"2011","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1177271919846454","DOI":"10.1177\/1177271919846454","article-title":"Oncogenic Roles and Inhibitors of DNMT1, DNMT3A, and DNMT3B in Acute Myeloid Leukaemia","volume":"14","author":"Wong","year":"2019","journal-title":"Biomark. Insights"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.ijcard.2016.11.204","article-title":"Treatment of cardiovascular pathology with epigenetically active agents: Focus on natural and synthetic inhibitors of DNA methylation and histone deacetylation","volume":"227","author":"Chistiakov","year":"2017","journal-title":"Int. J. Cardiol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/5\/783\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:01:49Z","timestamp":1760162509000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/10\/5\/783"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,15]]},"references-count":102,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["antiox10050783"],"URL":"https:\/\/doi.org\/10.3390\/antiox10050783","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,15]]}}}