Table 3.

Examples of bioactive compounds from natural products that have been shown to have a protective effect on RPE or retina against UVR, white light, or chemically induced oxidative stress.

Bioactive compounds of natural product	Source of natural product	Subject of study	Protective effect on RPE	Citations
3H-1,2-dithiole-3-thione	Cruciferous vegetables	(1) In vitro studies: (i) ARPE-19 and primary murine RPE cells from C57/B6 mice (2) In vivo studies: (i) Male BALB/c mice	(1) In vitro studies (a) Protection against UVB+UVA2: (i) Inhibits cell death (ii) Attenuated cell apoptosis, caspase-9 activation, and mitochondrial membrane potential reduction (iii) Inhibits ROS production (iv) Increases Nrf2 and HO-1 protein expression dose- and time-dependently. HO-1 (but not Nrf2) mRNA was also increased (v) Increase in Nrf2 phosphorylation and nuclear accumulation (vi) Increase in γ-glutamyl-cysteine ligase catalytic subunit (GCLC), γ-glutamyl-cysteine ligase modifying subunit (GCLM), and NAD(P)H:quinone oxidase-1 (NQO-1) (vii) Disruption of Nrf2-Keap1 association in the cytosol (viii) Activated AKT-mTORC1 signaling time- and dose-dependently by upregulating phosphorylation of AKT, S6, and 4E-BP1 (b) Protection against H2O2: (i) Inhibits H2O2-induced cell death, cell apoptosis, and ROS production (2) In vivo studies of the retina exposed to white light (i) Attenuated the decrease in a- and b-wave amplitudes on the electroretinography (ERG) (ii) Decrease in light-induced apoptosis of the outer nuclear layer of the retina	[159, 160]
Escin	Seed of horse chestnut	ARPE-19 and primary murine RPE cells from C57/B6 mice	(1) In vitro studies (a) Protection against H2O2: (i) Inhibit cell death induced by H2O2 dose-dependently (ii) Decrease H2O2-induced cell apoptosis and caspase-3 activity (iii) Decrease in H2O2-induced ROS levels and lipid peroxidation (iv) Activation of Nrf2-ARE genes by increasing HO-1, SRXN-1, and NQO-1 mRNA (v) Induction and accumulation of Nrf2 phosphorylation at serine 40. The nuclear level of Nrf2 was also increased (vi) Induce AKT activation by inducing Ser-473 and Thr-308 phosphorylation	[161]
Salvianolic acid A	Root of Salvia miltiorrhiza	ARPE-19 and primary murine RPE cells from aged male C57BL/6 mice	(1) In vitro studies (a) Protection against H2O2: (i) Dose-dependently increase cell viability despite H2O2 treatment (ii) Decrease in H2O2-induced cell apoptosis and caspase-3 cleavage (iii) Inhibit MAPK activation by inhibiting the phosphorylation of ERK1, p38, and JNK (iv) Restore mTORC1 activation by increasing the phosphorylation of p-S6 and p-4E-BP1 (v) Inhibit H2O2-induced phosphorylation of AMP-activated protein kinase (AMPK) and ACC (vi) Increase protein expression of Nrf2 and HO-1 (vii) Increase phosphorylation of AKT and S6, indicating the activation of the AKT/mTOR pathway	[162]
Fucoxanthin	Laminaria japonica (marine brown alga)	(1) In vitro studies: (i) ARPE-19 cell line (2) In vivo studies: (i) Rabbit	(1) In vitro studies (a) Before the introduction of white light to RPE cells (i) Inhibit VEGF overexpression (b) Protection against white light exposure (i) Significantly improve the phagocytotic activity of RPE (ii) Inhibit RPE cell senescence (iii) Decrease ROS levels (2) In vivo studies of the retina exposed to white light (i) Prevent light-induced damage and improve microcirculation of the retina based on ERG datas	[163]
Resveratrol	Red grapes	ARPE-19	(1) In vitro studies (a) Protection against UVA (i) Increase survival rate of RPE cells (ii) Reduce the production of UVA-induced intracellular H2O2 (iii) Inhibit the induction of ERK1/2, JNK, and p38 (iv) Reduces the increase of COX-2 expression	[164]
Ginsenoside Rg-1	Ginseng	ARPE-19	(1) In vitro studies (a) Protection against CoCl2 (i) Increase the cell viability and inhibit cell apoptosis of RPE by decreasing caspase-3 activity (ii) Inhibit the production of ROS (iii) Inhibit the activation of JNK and p38 (iv) Activate mTORC1 by increasing the phosphorylation of S6 and 4E-BP1 (v) Increases the phosphorylation of AKT (vi) Inhibit the activation of AMPK (b) Protection against cell hypoxia (i) Restored cell viability and decreased cell apoptosis	[165]
Ginsenoside Rh3	Ginseng	(1) In vitro studies: (i) ARPE-19 (2) In vivo studies: (i) BALB/c male mice	(1) In vitro studies (a) Protection against UVB+UVA2 (i) Inhibit cell death caused by the exposure (ii) Attenuate cell apoptosis and cell necrosis (iii) Inhibits caspase-3 activity and histone-bound DNA accumulation (iv) Increases HO-1, NQO-1, and GCLC mRNA (v) Elevates Nrf2 protein level and translocation into the cell nuclei (vi) Attenuates ROS production (vii) Increases the expression of miR-141and decreases Keap1 mRNA, suggesting the activation of the Nrf2 pathway (2) In vivo studies of the retina exposed to white light (i) Increase both ERG a- and b-wave amplitude, protecting the retina against light-induced damage (ii) Increase of HO-1, NQO-1, and GCLC mRNA and protein levels in the retinal tissue (iii) Upregulation of Nrf2 protein in the retinal tissue (iv) Elevated miR-141 and decrease in Keap1 mRNA was detected	[166]
Luteolin	Platycodon grandiflorum	ARPE-19	(1) In vitro studies (a) Protection against T-butyl hydroxide (i) Attenuation of T-butyl hydroxide-induced cell death (ii) Reduced the ROS level (iii) Inhibit caspase-3 activation and reduced apoptotic nuclei and DNA fragmentation	[167]