Table 5.

Effects of flavonols on cellular and molecular mechanisms affected by diabetic retinopathy.

Name of Substances/Compound	Dose	Model	Observations	Reference
Kaempferol	5 and 25 μM for 24 h	High glucose-stimulated HRECs	↓ VEGF and PGF mRNA levels	[100]
			↓ cell proliferation, migration, migration distance and sprouting of HRECs
			↓ PI3K expression and ERK1/2, Src, and Akt1 activation
	10, 15, 20, 25, 30 and 35 µM	N/A	↓ α-glucosidase and α-amylase activities	[101]
Quercetin	25 and 50 mg/kg orally administered for 24 weeks	STZ-induced T1DM rats	↑ GSH levels	[103]
			↑ SOD and CAT activities
			↑ ganglion cells number and retinal thickness
			↓ TNF-α and IL-1β levels
			↓ NF-kB and caspase-3 levels
			↓ GFAP and aquaporin-4 levels
	150 mg/kg by intragastric injection for 20 weeks	STZ-induced T1DM rats	↓ MMP-9 and VEGF serum levels	[102]
			↓ MMP-9 and VEGF RNA and protein levels
	10, 20, 30, 40 and 50 μM for 24 h	High glucose-exposed ARPE-19 cells	↑ CyclinD1, CDK4 and Bcl-2 levels	[104]
			↑ MiR-29b expression
			↑ PTEN/AKT pathway
			↓ NF-κB pathway via a miR-29b-dependent way
			↓ viability loss, apoptosis, MCP-1 and IL-6 production and ROS generation
			↓ p53, Bax and cleaved-caspase-3 expression
Rutin	100 mg/kg orally administered for 5 weeks	STZ-induced T1DM rats	↑ blood insulin levels	[106]
			↑ Bcl-2 levels
			↑ BDNF, NGF and GSH
			↓ blood glucose levels
			↓ TBARs
			↓ caspase-3 levels
	50 mg/kg orally administered for 24 weeks	STZ-induced T1DM rats	↑ total antioxidant capacity of the retinas	[107]
			↓ VEGF, TNF-α and aldose reductase protein levels
			↓ vascular leakage of fluorescein
Galangin	20 and 50 μM for 6 h	D-glucose-stimulated microglial BV2 cells	↓ BRB damage	[108]
			↓ ROS formation
			↓ microglia cells activation
			↓ ERK1/2 phosphorylation
			↓ NF-κB and Egr1 protein levels
			↓ TNF-α levels
	20 and 50 μM for 6 h	TNF-α-exposed HRECs and ARPE-19 cells	↑ claudin-1 and occludin levels
			↑ Nrf2 activation
			↓ BRB damage
			↓ ROS formation
	1 and 10 mg/kg injection for 1 month	STZ-induced T1DM mice	↓ BRB damage
			↓ ROS formation
			↓ microglia cells activation
			↓ ERK1/2 phosphorylation, NF-κB Egr1 protein
			↓ TNF-α levels
Myricetin	N/A	AGE-BSA-exposed bovine retinal pericytes	↓ pericytes migration	[109]
			↓ ERK1/2-FAK-1-paxillin phosphorylation
	5 or 10 mM intravitreally injection	AGE-BSA-intravitreally injected rats	↓ pericytes migration
			↓ ERK1/2-FAK-1-paxillin phosphorylation
	2.5, 5, 10, 20 and 40 μg/mL for 4 h	Glucose oxidase-exposed ARPE-19 cells	↑ Nrf2 and SOD2 levels	[110]
			↓ production of H2O2 and intracellular ROS
			↓ nitric oxide producer transcription
	0.02, 0.2, 2, 20 and 40 μg/mL for 48 h	High glucose-exposed ARPE-19 cells	↑ antioxidant proteins and other protective factors	[111]
			↑ Nrf2 pathway
			↓ intracellular ROS levels and
			AGE formation
			↓ NFkB1 expression
			and RAGE
Icariin	5 mg/kg orally administered for 12 weeks	STZ-induced T1DM rats	↑ RECA, Thy-1, Brn3a, and Collagen IV and CA-II levels	[112]
			↑ VEGF levels
	0, 10, 100 and 1000 nmol/mL for 3 days	RGC cells from control and diabetic rats	↑ neurite growth

AGE: advanced glycation end products, AKT: protein kinase B, ARPE-19: human retinal pigment epithelial cell line, Bax: Bcl-2 associated X protein, Bcl-2: B cell lymphoma-2 protein, BDNF: brain-derived neurotrophic factor, BRB: blood–retinal barrier, Brn3a: brain-specific homeobox/POU domain protein 3A, BSA: bovine serum albumin, CA-II: carbonic anhydrase II, CAT: catalase, CDK4: cyclin-dependent kinase 4, Egr1: early growth response protein 1, ERK1/2: extracellular signal-regulated protein kinases 1 and 2, FAK-1: focal adhesion kinase 1, GFAP: glial fibrillary acidic protein, GSH: glutathione, H₂O₂: hydrogen peroxide, HRECs: human retinal endothelial cells, IL-1β: interleukin-1β, IL-6: interleukin-6, MCP-1: monocyte chemoattractant protein, miR-29b, microRNA-29b, MMP-9: metalloproteinase-9, N/A: not applicable, NF-κB: nuclear factor kappa-B, NFkB1, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1, NGF: nerve growth factor, Nrf2: nuclear factor erythroid 2-related factor-2, PGF: placenta growth factor, PI3K: phosphoinositide 3-kinase, PTEN, phosphatase and tensin homolog deleted on chromosome 10, RAGE: AGE receptor, RECA: rat endothelial cell antigen, RGC: retinal ganglion cell, ROS: reactive oxygen species, SOD: superoxide dismutase, STZ: streptozotocin, T1DM: type 1 diabetes mellitus, TBARs: thiobarbituric acid reactive substances, TNF-α: tumor necrosis factor alfa, VEGF: vascular endothelial growth factor, ↑: increase, ↓ decrease.