Table 4.
Effects of flavones on cellular and molecular mechanisms affected by diabetic retinopathy.
| Name of Substances/Compound | Dose | Model | Observations | Reference |
|---|---|---|---|---|
| Baicalein | 75, 150 and 300 mg/kg orally administered for 24 weeks | STZ-induced T1DM rats | ↓ microglial activation and IL-18, TNF-α and IL-1β expression | [81] |
| ↓ GFAP and VEGF expression in Müller cells | ||||
| ↓ vascular abnormality and ganglion cell loss | ||||
| 75 mg/kg in drinking water | Ins2Akita mice | ↑ pSHP1 levels | [83] | |
| ↓ HETE, ICAM-1, VCAM-1 and IL-6 levels | ||||
| ↓ ROS generation, and NOX2 expression | ||||
| ↓ pVEGF-R2 levels | ||||
| Baicalin | 2.5, 5, 10, 50 and 100 μM for 12 h | High glucose-exposed ARPE-19 and HRMECs | ↑ miR-145 levels | [84] |
| ↑ cell proliferation | ||||
| ↓ apoptosis | ||||
| ↓ IL-1β, IL-6 and IL-8 release and ROS levels | ||||
| ↓ NF-κB and p38 MAPK pathways | ||||
| Scutellarin | 0.1, 1, 10 or 100 nM; 0,1 or 1 μM for 48 h | High glucose and hypoxia-mimetic agent-exposed HRECs | ↓ cell proliferation, migration, and tube formation | [90] |
| ↓ VEGF levels | ||||
| ↓ HIF-1α protein and mRNA levels | ||||
| ↓ NADPH oxidase activity | ||||
| 20 and 50 μM for 6 h | High glucose-exposed BV-2 cells | ↓ NF-κB and TNF-α expression | [89] | |
| ↓ microglia cell activation | ||||
| ↓ BRB damage | ||||
| ↓ ERK1/2 phosphorylation | ||||
| 20 and 50 μM for 6 h | TNF-α-exposed HRECs and ARPE-19 cells | ↑ claudin-1 and claudin-19 expression | ||
| ↑ Nrf2 nuclear accumulation | ||||
| ↓ ROS formation and BRB damage | ||||
| 5 and 10 mg/kg intragastric administration for 1 month | STZ-induced T1DM rats | ↑ claudin-1 and claudin-19 expression | ||
| ↓ microglia cell activation | ||||
| ↓ BRB breakdown | ||||
| ↓ ERK1/2 phosphorylation | ||||
| Nepetin | 2.5, 5 and 10 µM for 24 h | IL-1β-exposed ARPE-19 cells | ↓ IL-6, IL-8 and MCP-1 levels | [91] |
| ↓ nuclear translocation of NF-κB p65 | ||||
| ↓ phosphorylation of inhibitor of nuclear factor kappa B and IκB kinase | ||||
| ↓ phosphorylation of ERK1/2, JNK and p38 MAPK | ||||
| Silybin | 15 and 30 mg/kg orally administered for 22 weeks | STZ and high-fat diet-induced T2DM rats | ↓ obliterated retinal capillaries | [92] |
| ↓ leukostasis and ICAM-1 levels | ||||
| Chrysin | 1, 10 and 20 µM for 3 days | Glucose-exposed RPE cells | ↑ PEDF levels | [93] |
| ↓ VEGF and IGF-1 levels | ||||
| ↓ AGE secretion and RAGE induction | ||||
| ↓ ER stress | ||||
| 1, 10 and 20 µM for 3 days | AGE-BSA-exposed RPE cells | ↑ PEDF, RPE65, LRAT and RDH5 levels | ||
| ↓ ER stress | ||||
| 10 mg/kg orally administered for 10 weeks | db/db mice | ↑ ONL thickness | ||
| ↑ RPE65, LRAT, RDH5, CRBP, CRALBP, IRBP, STRA6 and rhodopsin levels | ||||
| ↓ AGE secretion and RAGE induction | ||||
| ↓ ER stress | ||||
| Diosmin | 100 mg/kg intragastric administration | Retinal ischemia/reperfusion in rats | ↑ SOD, GPx and CAT activities | [97] |
| ↑ retinal a- and b-wave amplitudes | ||||
| ↑ INL, IPL, ONL and total retinal thicknesses | ||||
| ↑ ganglion cells number | ||||
| ↓ edema | ||||
| ↓ MDA | ||||
| ↑ retinal a- and b-wave amplitudes | [96] | |||
| ↑ ZO-1 and occludin levels | ||||
| ↓ VEGF levels | ||||
| ↓ Evans blue leakage | ||||
| 0.1, 1 and 10 µg/mL | High glucose-exposed ARPE-19 cells | ↑ cell viability | [98] | |
| ↑ Bcl-2/Bax | ||||
| ↓ capase-3 activity and cytochrome c release | ||||
| ↓ ROS levels | ||||
| ↓ JNK and p38 phosphorylation |
AGE: advanced glycation end products, ARPE-19: human retinal pigment epithelial cell line, Bax: Bcl-2 associated X protein, Bcl-2: B cell lymphoma-2 protein, BRB: blood–retinal barrier, BSA: bovine serum albumin, CAT: catalase, CRALBP: cellular retinaldehyde-binding protein-1, CRBP: cellular retinol-binding protein, ER: endoplasmic reticulum, ERK1/2: extracellular signal-regulated protein kinases 1 and 2, GFAP: glial fibrillary acidic protein, GPx: glutathione peroxidase, HETE: hydroxyeicosatetraenoic acids, HIF1-α: hypoxia inducible factor 1α, HRECs: human retinal endothelial cells, HRMECs: human retinal microvascular endothelial cells, ICAM-1: intercellular adhesion molecule 1, IGF-1: insulin-like growth factor-1, IκB kinase: inhibitor of κB kinase, IL-1β: interleukin-1β, IL-6: interleukin-6, IL-8: interleukin-8, IL-18: interleukin-18, INL: inner nuclear layer, Ins2Akita, genetic animal model of T!DM, IPL: inner plexiform layer, IRBP: interphotoreceptor retinoid-binding protein, JNK: c-Jun N-terminal kinases, LRAT: lecithin retinol acyltransferase, MAPK: mitogen-activated protein kinase, MCP-1: monocyte chemoattractant protein, MDA: malondialdehyde, miR-145, microRNA-145, NADPH: Nicotinamide adenine dinucleotide phosphate, NF-κB: nuclear factor kappa-B, NF-κB p65: NF-κB p65 subunit, Nox2: NADPH oxidase 2, Nrf2: nuclear factor erythroid 2-related factor-2, ONL: outer nuclear layer, PEDF: pigment epithelium-derived factor, pVEGF-R2, phosphorylated VEGF receptor 2, RAGE: AGE receptor, RDH5: retinol dehydrogenase 5, ROS: reactive oxygen species, RPE: retinal pigment epithelium, SOD: superoxide dismutase, STRA6: stimulated by retinoic acid 6, STZ: streptozotocin, T1DM: type 1 diabetes mellitus, T2DM: type 2 diabetes mellitus TNF-α: tumor necrosis factor alfa, VCAM-1: vascular cell adhesion molecule-1, VEGF: vascular endothelial growth factor, ZO-1: zonula occludens-1, ↑: increase, ↓ decrease.