Table 2.
Effects of different phytochemicals on diabetic retinopathy pathogenesis.
| Phytochemical | Plant | Model | Dose/concentration | Study type | Mechanism | Reference |
|---|---|---|---|---|---|---|
| Aloe-emodin | — | ARPE-19 under hypoxia condition and OIR model rats | 0.2–5.0 µg/mL (in vitro) and 5.0 and 10.0 mg/kg/day (oral) | In vivo and in vitro | ↓ Retinal neovascularization and expressions of VEGFA, HIF-1α, and PHD-2 | Wu, 2016 |
| Alpha-mangostin | Garcinia mangostana | STZ-induced DR SD rat | 200 mg/kg/day | In vivo | ↓ MDA, AGE, RAGE, TNF-α, and VEGF | Jariyapongskul, 2015 |
| Andrographolide | Andrographis paniculata | STZ-induced NPDR and PDR C57BL/6 mice | 10 mg/kg/day (intraperitoneally) | In vivo | ↓ Retinal angiogenesis, inflammation, breakdown of BRB, VEGF, NF-κB, Egr-1 phospho-NF-κBp65, IKK, TNF-α, IL-6, IL-1β, serpine1, and TF | Yu, 2015 |
| Baicalein | — | STZ-induced DR SD female rats | 150 mg/kg/d orally | In vivo | ↓ Retinal inflammation, GFAP, VEGF, IL-18, TNF-a, IL-1, vascular abnormality, loss of ganglion cell layer (GCL), and microglial activation | Yang, 2009 |
| Biochanin | — | STZ-induced DR Wistar rats | 10 and 15 mg/kg/day (orally) | In vivo | ↓ Retinal angiogenesis, inflammation, VEGF, TNF-α, and IL-1β | Mehrabadi, 2018 |
| Blueberry anthocyanins | Vaccinium virgatum | High glucose-induced HRCECs | 10 μg/mL | In vitro | ↓ Retinal inflammation, oxidative stress, ROS, and VEGF production ↑ CAT and SOD activity BAE, Mv, and Mv-3-gal ↓ Nox4 protein expression BAE, Mv-3-glc, and Mv-3-gal ↓ Akt expression, Mv Mv-3-glc, and Mv-3-gal ↓ ICAM-1 levels and NF-κB | Huang, 2018 |
| Chebulagic acid (CA), chebulinic acid (CI), and gallic acid (GA) | — | RF/6A cells were stimulated with TNF-α CAM model | 1.0 to 100 µM; 25, 25, and 100 µM | In vivo and in vitro | ↓ CA, CI, and GA: retinal angiogenesis, inflammation, expression of MMP-9, IL-6, IL8, MCP-1, phosphorylation of p38, ERK and NF-κB CA, CI: eotaxin, MIP-1b, RANTES, PDGF-BB ↑ IL-10, and IL-13 | Shanmuga, 2018 |
| Chlorogenic acid | — | STZ-induced PDR C57BL/6 mice, HRECs, RF/6A cells, and microglia BV-2 cells | 1,10 mg/kg/day (oral); 0.3125–0.5 µM (in vitro) | In vivo and in vitro | ↓ Retinal angiogenesis, microglia cell activation, VEGF expression, phosphorylation of VEGFR-2, MEK1/2, ERK1/2, and p38 | Mei, 2018 |
| Chrysin | — | HRMVEC and adult male db/db mice C57BLKS | 1–20 µM (in vitro); 10 mg/kg (oral) | In vitro and in vivo | ↑ VE-cadherin, ZO-1 junction proteins, and PECAM-1 ↓ HIF-1α, VEGF, VEGF receptor-2, Ang-1, Ang-2, and Tie-2 proteins | Kang, 2016 |
| Chrysin | — | HRPE cell db/db mice | 1–20 µM; 10 mg/kg/day (oral) | In vivo and in vitro | ↓ Retinal neovascularization, VEGF, IGF-1, AGE secretion, RAGE, and ER stress ↑ Retinal thickness, PEDF, RPE65, LRAT, and RDH5 level | Kang, 2018 |
| Curcumin | — | STZ-induced DR Lewis rats | 0.5 g/kg, powdered diet | In vivo | ↓ Retinal inflammation, 8-OHdG, nitrotyrosine, IL-1β, VEGF, NF-κB, and ROS ↑ GSH activity | Kowluru, 2007 |
| Curcumin | — | STZ-induced DR male Wistar albino rats | 1g/kg body weight of rat orally | In vivo | ↓ Retinal inflammation, HbA1c level, vessel diameter, thickening of BM, TNF-a, and VEGF ↑ GSH, SOD, and CAT activities | Suresh,2011 |
| Curcumin | — | STZ-induced DR and rat retinal Müller cells | 100 mg/kg/day (oral); 5–15 μM | In vivo and in vitro | ↓ Retinal vascular leakage, inflammation, VEGF, iNOS, ICAM-1expession, phosphorylation of CaMKII, and NF-κB | Li, 2016 |
| Curcumin | Curcuma longa | Alloxan-induced DR in rats and RGC from diabetic and normal rats | 100 mg/kg/day (in vivo); 10–1000 nmol/mL (in vitro) | In vivo and in vitro | ↓ Retinal inflammation, oxidative stress, retinal capillary basement membrane thickness, phosphorylation p65subunit of NF-κB, CaMKII activity, VEGF, iNOS, and ICAM-1 expressions ↑ RecA and microvessel density, expression of Thy-1 and Brn3, and average neurite length | Pradhan, 2018 |
| Curcumin | — | STZ-induced PDR Wistar rat | 100 and 200 mg/kg/day (oral) | In vivo | ↓ Retinal angiogenesis, oxidative stress, apoptosis, retinal capillary basement membrane thickness, VEGF, and MDA ↑ Ratio of Bcl-2 to Bax, SOD, and T-AOC | Yang, 2018 |
| Curcumin | — | HG-induced ARPE-19 cells | 0–20 µmol/l | In vitro | ↓ TNF-α, IL-6, IL-1β, and ROS-AKT/mTOR | Ran, 2019 |
| Curcumolide | Curcuma wenyujin | STZ-induced DR, Wistar rats, and TNF-a-stimulated HUVECs | 2.5–20 μM intravitreal injection | In vivo and in vitro | ↓ Retinal inflammation, leukostasis, vascular permeability, TNF-a, ICAM-1, p38 MAPK, and NF-κB activation | Cai, 2017 |
| Decursin | Angelica gigas | HRMVEC cells and STZ-induced SD rats | 20 mg/kg/day (oral); 12.5–100 µM (in vitro) | In vivo and in vitro | ↓ Retinal proliferation and angiogenesis, VEGFR-2 expression, tube formation, and retinal neovascularization | Yang, 2013 |
| (1) Docosahexaenoic acid (2) β, ε-Carotene-3,3′-diol |
— | STZ-induced DR male Wistar rats | (1) CL and DL groups: 0.5 mg/kg (oral) (2) CDHA and DDHA groups: 13.3 mg/kg (oral) |
In vivo | (1) ↓ MDA (1,2) and nitrotyrosine level (2) ↑ GPX activity and GSH level (1, 2) |
Arnal, 2009 |
| Eriodictyol | — | HG-induced rat RGCs | 5–20 μM | In vitro | ↓ Retinal inflammation, production of ROS, TNF-α, IL-8, BAX, and cleaved caspase-3 ↑ SOD, GPX, CAT, Bcl-2, and activation of Nrf2/HO-1 | Lv, 2019 |
| Formononetin | Astragalus membranaceus | ARPE-19 cells under chemical hypoxia and OIR model rats | 5.0 and 10.0 mg/kg/day (intraperitoneal); 0.2–5 μg/mL (in vitro) | In vivo and in vitro | ↓ Retinal neovascularization, VEGF, HIF-1α, and PHD-2 | Wu, 2016 |
| Gastrodin | Gastrodia elata | HG-induced HRECs | 0.1–10 and 100 µM | In vitro | ↓ TLR4/NF-κB p65 signaling pathway, ROS, NADPH, NQO1, Nrf2, and GCLM ↑ SIRT1 | Zhang, 2018 |
| Genistein | — | ARPE-19 cells treated with normal and high glucose concentrations | 20 µM | In vitro | ↓ Retinal inflammation, angiogenesis, ALR, VEGF165, and VEGF secretion | Dongare, 2015 |
| Genistein combined polysaccharides | — | 12 postmenopausal Korean women | (Tablets) 2 g containing 120 mg of genistein and 57 mg of daidzein | In vivo | ↑ SHBG and GSH-Px activity | Oh, 2005 |
| Gentiopicroside | — | STZ-induced DR rats and rMC1 cells | 20–80 mg/kg/day; 10–100 µM (in vitro) | In vivo and in vitro | ↓ Retinal inflammation, oxidative stress, overexpression of HDAC, ROS expression, MDA, protein carbonyl expression, NF-κB, TNF-α, IL-1β, ICAM-1, GFAP, and VEGF expression ↑ HAT expression, GSH, SOD, CAT, and PEDF expression | Zhang, 2019 |
| Hesperetin | — | STZ-induced DR Wistar rats | 200 mg/kg/day (oral) | In vivo | ↓ Retinal angiogenesis, dilated vessels, VEGF, PKC-β, vascular permeability, and thickening of BM | Kumar, 2012 |
| Hesperetin | — | STZ-induced DR Wistar albino rats | 100 mg/kg body (oral) | In vivo | ↓ Retinal inflammation, ROS, TNF-α, IL-1β, caspase-3, GFAP, and AQP4 ↑ Retinal GSH SOD and CAT activity | Kumar, 2013 |
| Hesperidin | — | STZ-induced DR SD rats | 100 and 200 mg/kg/day (intragastrically) | In vivo | ↓ Retinal angiogenesis, oxidative stress, inflammation, permeability of the BRB, VEGF, ICAM-1, TNF-α, IL-1β, AGE, AR activity, and MDA ↑ SOD and retinal thickness | Shi, 2012 |
| Kaempferol | — | HRECs under high glucose condition | 5–25 µM | In vitro | ↓ Retinal angiogenesis, proliferative ability, migration, VEGF and PGF expression, expression of PI3K, activation of Erk1/2, Src, and Akt1 | Xu, 2017 |
| Lithospermic acid B | Salvia miltiorrhiza | OLETF rats | 10 or 20 mg/kg/day (oral) | In vivo | ↑ Thickness of the nerve layer, ganglion cells, and capillary BM layer ↓ VEGF, hsCRP, MCP1, TNF-α, and 8-OHdG | Jin, 2014 |
| Naringin | — | rMC1 STZ-induced DR rats | 20–80 mg/kg/day (intraperitoneally); 50 μM (in vitro) | In vivo and in vitro | ↓ Retinal inflammation, oxidative stress, TNF-α, IL-1β, IL-6, NF-κB level, and GFAP level ↑ SOD, GSH, GCL thickness, and ganglion cell number | Liu, 2017 |
| Paeoniflorin | — | Microglia BV-2 cells and STZ-induced DR CD-1 mice | 20 and 40 mg/kg/day (oral); 0.1–10 μM | In vivo and in vitro | ↓ Retinal inflammation, MMP-9 activation, expression of p-p38, NF-κB translocation, IBA-1, and IL-1β ↑SOCS3 expression and activating TLR4 | Zhu, 2017 |
| Physcion 8-O-Β-glucopyranoside | — | HG-disposed APRE-19 cell injury | 1.5 µM | In vitro | ↓ TNF-α, IL-1β, ROS generation, cell apoptosis, NORAD expression, and STAT3 ↑ miR-125 expression | Wan, 2020 |
| Pterostilbene | — | HRECs under high glucose environment | 1 mmol/l | In vitro | ↓ TNF-α, IL-1β, ROS production, and NF-κB mRNA and protein expression ↑ SOD activity | Shen, 2015 |
| Puerarin | — | AGE-RSA induced bovine retinal pericyte cells AGE-RSA injected to rat eyes | 1, 5, and 10 µM; 400 mM (intravitreally) | In vivo | ↓ NADPH oxidase activity, ROS, phosphorylation of p47 phox and Rac1, NF-κB, and 8-OHdG | Kim, 2012 |
| Quercetin | — | ARPE-19 cells were stimulated by high glucose | 30 μM | In vitro | ↓ Cell apoptosis, MCP-1, IL-6, ROS, PTEN, p-p65, and IκBα ↑ miR-29b expression and p-AKT | Wang, 2020 |
| Resveratrol (trans-3,5,40-trihydroxystilbene) | — | STZ-induced DR rats | 5 mg/kg per day orally | In vivo | ↓ Retinal inflammation, NF-κB, TNF-a, IL-6, and COX-2 | Ghadiri Soufi, 2015 |
| Sauchinone | — | Human RPE cell line/ARPE-19 | 5, 10, and 20 µM | In vitro | ↑ SOD, GPX, CAT, Bcl-2, P-Akt, nuclear nrf2, HO-1, and Akt/nrf2/HO-1 signaling pathway ↓ ROS and Bax | Shi, 2019 |
| Scutellarin | - | HRECs under high glucose and hypoxic condition | 0.1 nM; 1 µM | In vitro | ↓ Retinal angiogenesis and proliferation, tube formation, HIF-1α, VEGF, ROS, and NADPH oxidase activity | Wang, 2014 |
| Scutellarin | — | HRECs under high glucose and hypoxic condition and STZ-induced DR | 40 mg/kg/day (intragastrically); 10 μM (in vitro) | In vivo and in vitro | ↓ Retinal angiogenesis and proliferation, VEGF, phosphorylation of ERK, FAK, and Src | Long, 2019 |
| Sesamin | — | STZ-induced DR mice | 30 mg/kg BW (intraperitoneally), alternate day | In vivo | ↓ Retinal inflammation, TNF-α, ICAM, microglia activation, and iNOS | Ahmad, 2016 |
| Shikonin | — | STZ with whole-body hypoxia-induced DR in C57BL/6 mice and RPE cells | 0.5–50 mg/kg/day (oral); 0.1–10 μM (in vitro) | In vivo and in vitro | ↓ Retinal inflammation, vascular permeability, cell loss, COX-2, iNOS, Bax, MPO, and ZO-1 | Liao, 2017 |
| Silybin | — | STZ-induced DR SD rats | 15 and 30 mg/kg/day (orally) | In vivo | ↓ Retinal inflammation, obliterated retinal capillaries, retinal vascular leukostasis, and ICAM-1 | Zhang, 2014 |
| Sinomenine | Sinomenium acutum | Retinal microglia cells isolated from SD rats | 0.01–1 mM | In vitro | ↓ Retinal inflammation, microglial activation, IL-1β, TNF-α, IL-6, and ROS | Wang, 2007 |
| Sulforaphane | — | STZ-induced DR SD rats and rMC1 | 0.5 and 1 mg/kg/day 2.5 μM (in vitro) | In vivo and in vitro | ↓ Retinal inflammation, TNF-α, IL-6, IL-1β, NLRP3, ASC, and cleaved caspase-1 p20 level ↑Ganglion cells, antioxidant capacity, NRF2, transcriptions of HO-1, and NQO1 | Li, 2019 |
| Taxifolin | — | Alloxan-induced DR and albino Wistar male rats | 50 mg/kg/day (oral) | In vivo | ↓ Retinal inflammation, MDA, IL-1β, and TNF-α ↑ tGSH level | Ahiskali, 2019 |
| Zerumbone | Zingiber zerumbet | STZ-induced DR and male Wistar rats | 40 mg/kg once a day orally | In vivo | ↓ Retinal inflammation, NF-κB, apoptosis, thickness of retinal layers, AGEs, TNF-α, IL-1β, IL-6, VEGF, NF-κB, HbA1c, RAGE, ICAM-1, and VCAM-1 protein expression | Tzeng, 2016 |
∗ ↓: decrease; ↑: increase.