Cellular targets in diabetic retinopathy therapy

Table 1 Summary of alterations, targets, and novel therapies

Contributors in DR development	Retinal alterations	Targets	Possible novel therapies
ROS accumulation	Low nuclear levels of Nrf2, antioxidant enzymes activities, and GLP1R expression. Retinal cell death, retinal ischemia, retinal neovascularization, DME	Nrf2 activation, Keap1 knockdown, inhibition and/or neutralization of ROS generation, GLP1R activation, reinforcement of the antioxidant defense system	Green tea polyphenols, resveratrol, curcumin, quercetin, tannins, pterostilbene, GLP1R agonist, RS9, dh404, triterpenoids, salvianolic acids, sulforaphane
Synthesis of proinflammatory molecules	Vascular permeability, BRB breakdown, capillary pericyte loss, neovascularization	Inhibition of inflammatory pathways	COX-2 inhibitors, tetracyclines (minocycline and doxycycline), IL-6 inhibitors (EBI-031 and tocilizumab), anti-TNF-α therapy, canakinumab (selective IL-1β antibody), fenofibrate (PPARα agonist)
Increased production of AGE/RAGE	Aberrant extracellular crosslinking of extracellular matrix proteins, increased vascular stiffness, release of proinflammatory cytokines and proangiogenic factors	Low the production of AGEs	Curcumin, epigallocatechin 3-gallate, quercetin, kaempferol and resveratrol
Activation of the polyol pathway	Retinal capillary osmotic damage and cell death	Inhibition of the polyol pathway	Pterostilbene
Increased flux through the hexosamine pathway	Neuro-vascular dysfunctions	Inhibition of the hexosamine pathway	Azaserine (antineoplastic), rhein (anthraquinone), benfotiamine (lipid-soluble thiamine derivative)
Activation of the PKC pathway	Endothelial alterations, cell demise of capillary cells and pericytes, formation of microaneurysms, VEGF-dependent retinal barrier alterations	Inhibition of PKC pathway	Ruboxistaurin mesylate (PKC-β inhibitor)
Lipid peroxidation	Generation of lipid radical species, apoptosis in retinal pigment epithelial cells, retinal vascular dysfunction, development of neovascularization	Inhibition of the formation of lipid peroxides in the retina	Fucoxanthin, pterostilbene
DNA methylation	Increased expression and activity of DNMTs	Inhibition of DNMTs	5-aza-2'-deoxycytidine
Histone methylation and acetylation	Decreased levels of H3K4me1 and H3K4me3 at glutamate-cysteine ligase promoter or decreased levels of H3K9me2 and increased levels in acetyl H3K9	Regulation of histone methylation/acetylation	Garcinol, resveratrol, curcumin, genistein
Regulation by ncRNA (miRNA and circular RNA)	Downregulation of miR126, miR-146a, and miR200b; retinal upregulation of miR-20b-5p, neovascularization and microvascular leakage	Modulation of miRNAs expression, overexpression of circular DNMT3B	siRNAs,double-stranded miRNA mimics and anti-mRNA antisense oligodeoxyribonucleotide

AGE/RAGE: Advanced glycation end products/receptors; BRB: Blood-retinal barrier; COX-2: Cyclooxygenase-2; dh404: Dihydro-CDDO-trifluoroethyl amide; DME: Diabetic macular edema; DNMT: DNA methyltransferases; GLP1R: Glucagon-like peptide-1 receptor; IL: Interleukin; Keap1: Kelch-like enoyl-CoA hydratase associated protein 1; miRNA: microRNA; ncRNA: noncoding RNAs; Nrf2: Nuclear factor erythroid 2-related factor 2; PKC: Protein kinase C; PPARα: Peroxisome proliferator-activated receptor α; ROS: Reactive oxygen species; TNF-α: Tumor necrosis factor α; VEGF: Vascular endothelial growth factor.