Table 1.

Activators of the Nrf2/ARE pathway in non-cancer experimental models: phytochemicals and other signal molecules.

Group	Compound	Effective Concentration	Experimental Model	Mode of Action	Reference
Phytochemicals–Polyphenols
Phenolic acid	Ellagic acid	25–50 µM	Human keratinocyte HaCaT cells	↑ Nrf2 nuclear translocation. ↑ SOD enzyme activity.	[141]
	Chlorogenic acid	100 µM	Human retinal pigment epithelial ARPE-19 cells	↑ mRNA expression of Nrf2 and SOD.	[142]
		500 mg/kg of body weight orally	Sprague-Dawley rats	↑ mRNA expression of Nrf2. ↑ SOD and GSH activities.	[143]
Proanthocyanidin	Procyanidin C1	5–10 µM	Mouse hippocampal neuronal HT22 cells	↑ Nrf2 nuclear translocation. ↑ HO-1 protein.	[144]
Lignans	Sesamin	100 mg/kg body weight intraperitoneally	C57BL/6 mice	↑ SOD and CAT activities. ↑ GSH and Nrf2 protein.	[145]
		10 µM	Primary chondrocytes	↑ Nrf2 and HO-1 proteins.	[146]
Coumarins	Fraxin	50 mg/kg of body weight up to 5 days orally	Sprague-Dawley rats	↑ cellular GSH levels.	[147]
Stilbene derivative	Resveratrol	5 µM	Primary human coronary artery endothelial cells	↑ mRNA expression of NQO1.	[148]
		500 mg in a tablet/day up to 30 days in the morning fasting	Phase 3 clinical trial on chronic subclinical inflammation and redox status	↑ electrophilic modification of Keap1-Cys-151	[47,85]
		215 mg in a tablet/day up to 52 weeks	Phase 2 clinical trials on Alzheimer’s disease	↑ electrophilic modification of Keap1-Cys-151	[47,149]
Curcumminoid	Curcumin	5 µM	Human extravillous trophoblast HTR8/Sveo cells	↑ CAT and GSH activities.	[150]
		400 mg/kg body weight/day orally up to 21 days	White Pekin ducklings	↑ CAT, SOD, and GPx activities.	[151]
		800 mg/day in two capsules up to 7 days	Phase 3 clinical on diabetic nephropathy	↑ electrophilic modifications of Keap1-Cys-151	[47,82]
		15 µM	Human retinal pigment epithelial ARPE-19 cells	↑ Nrf2 protein. ↑ HO-1 activity.	[152]
		15–30 µM	Porcine renal epithelial proximal tubule LLC PK1 cells	↑ ARE binding activity. ↑ Nrf2 protein. ↑ HO-1 activity.	[153]
		10 µM	Rat kidney epithelial NRK-52E cells	↑ ARE binding activity.	[153]
		200 mg/kg body weight twice a week for 6 weeks	Kunming (KM) mice	↑ Nrf2 nuclear translocation. ↑ HO-1 and NQO-1 proteins.	[154]
Phytochemicals–Polyphenols–Flavonoids
Flavone	Luteolin	0.1 mg/kg body weight/day for 7 days at two time points orally.	ICR mice	↑ Nrf2 nuclear translocation. ↑ HO-1 and NQO-1 proteins.	[51]
		10 mg/kg body weight intracerebrally injected	Sprague-Dawley rats	↑ Nrf2 nuclear translocation. ↑ HO-1 and NQO-1 proteins.	[131]
		5–10 µM	Rat myoblast H9c2 cells	↑ Nrf2 protein. ↑ mRNA expression of SOD, NQO-1 and HO-1.	[93]
		5 µM	Mouse testis sertoli TM4 cells	↑ Nrf2 nuclear translocation.	[121]
	3,5-di-O-Methyl Gossypetin	10–25 µg/mL	Human keratinocyte HaCaT cells	↑ Nrf2 nuclear translocation. ↑ GSH, SOD and HO-1 proteins.	[55]
	Baicalein	160 mg/kg/day for 8 weeks orally	T2DM Kunming mice	↑ Nrf2 nuclear translocation. ↑ SOD, CAT, GSH proteins.	[120]
		50 µM	Human liver L-02 cells	↑ p62 protein. ↑ Nrf2 dissociation from Keap1. ↑ Nrf2 phosphorylation via phosphorylation of ERK1/2 and protein kinase C.	[117]
		20 µM	Human liver HL-7702 cells	↑ Nrf2 nuclear translocation. ↑ SOD, CAT, GSH protein.	[120]
	Baicalin	50 mg/kg body weight twice after 2 and 12 h of subarachnoid hemorrhage intraperitoneally.	Sprague-Dawley rats	↑ SOD, GSH, NQO-1, and Nrf2 proteins. ↑ mRNA expression of HO-1.	[94]
		75 µM	Rat myoblast H9C2 cells	↑ Nrf2 and HO-1 proteins.	[97]
		450 mg/kg body weight/day up to 7 days orally.	Chicken	↑ Nrf2 and HO-1 proteins. ↑ mRNA expression of Nrf2 and HO-1.	[116]
		50 µM	Human liver L-02 cells	↑ p62 protein. ↑ Nrf2 dissociation from Keap1. ↑ Nrf2 phosphorylation via phosphorylation of ERK1/2 and protein kinase C.	[117]
	Chrysin	10–25 µM	Rat hepatocytes	↑ Nrf2 nuclear translocation via ERK2 signaling. ↑cellular GSH protein. ↑ ARE binding ability.	[124]
	Apigenin	400 µM	Human retinal pigment epithelial ARPE-19 cells	↑ mRNA expression of Nrf2. ↑ Nrf2 protein. ↑ Nrf2 nuclear translocation. ↑SOD, CAT, and GPx activities.	[95]
		200 µM	Human renal tubular epithelial HK-2 cells	↑ mRNA expression of Nrf2 and HO-1. ↑ Nrf2 protein.	[100]
Flavonol	Myricetin	100 mg/kg/day for 6 weeks orally	Kungming mice	↑ Nrf2 nuclear translocation.	[132]
	Quercetin	30 µM	Human keratinocyte HaCaT and BJ foreskin fibroblast cells	↑ Nrf2 protein.	[102]
		200 mg/kg body weight/day for 20 days orally	Broiler chicken	↑ Nrf2 protein. ↑ Nrf2 nuclear translocation. ↑ SOD and CAT proteins.	[111]
		100 µM	Intestinal epithelial IEC-6 cells	↑ Nrf2 nuclear translocation.	[155]
		10 µM	Human umbilical endothelial cells	↑ Nrf2 protein.	[108]
	Rutin	44 µM	Human keratinocyte HaCaT cells	↑ mRNA expression of HO-1 and NQO-1.	[140]
Flavanone	Naringenin	80 µM	Sprague-Dawley rat neuron cells	↑ Nrf2, HO-1, and NQO-1 proteins.	[103]
		70 mg/kg body weight/day up to 4 days orally	C57BL/6 mice	↑ Nrf2 protein.	[112]
	Hesperidin	50 mg/kg body weight for 28 days orally	Sprague-Dawley rat	↑ Nrf2 and HO-1 proteins. ↑ mRNA expression of HO-1.	[104]
Flavan-3-ol	Epicatechin	10–100 µM	Primary astrocytes from WT and Nrf2 deficient KO mice	↑ Nrf2 nuclear translocation.	[122]
	Epigallocatechin-3-gallate (EGCG)	40 mg/kg body weight/day for 3 days intraperitoneally or a single dose of 50 mg/kg body weight intraperitoneally	Sprague-Dawley rat	↑ Nrf2 protein.	[105,156]
Isoflavones	Genistein	1 mg/kg body weight intraperitoneally	Sprague-Dawley rat	↑ Nrf2 nuclear translocation. ↑ HO-1 protein.	[138]
Anthocyanin	Cyanidin-3-O-glucoside (C3G)	20–40 µM	Human umbilical vein epithelial cells	↑ Nrf2 nuclear translocation. ↑mRNA expression of NQO-1 and HO-1.	[128]
Chalcone	Butein	20 µM	Human dental pulp cells	↑ Nrf2 nuclear translocation.	[130]
Other Phytochemicals
Sulfur-containing	Sulforaphane	5 µM	Mouse skin JB6 P+ cells	↑ Nrf2 nuclear translocation. ↑ HO-1 and NQO-1 proteins.	[157]
	Diallyl sulfide	15 µM	Human embryonic lung MRC-5 cells	Dissociates Nrf2 from Keap1 through phosphorylated ERK and p38 interactions. ↑ Nrf2 nuclear translocation.	[89]
		150 mg/kg body weight/day intraperitoneally for 6 days	Wistar rats	↑ Nrf2 protein. ↑SOD, CAT, GPx, GR, GST, and quinone reductase activities.	[158]
Alkaloids	Berberine	200 mg/kg body weight/day orally for 16 weeks	Wistar rats	↑ mRNA expression of Nrf2.	[159]
Vitamins
Fat-soluble vitamins	Vitamin D	40 000 U/kg/week of body weight intratracheally for 8 weeks	C57BL/6 mice	↑ mRNA expression Aldo-keto reductase family 1 member C1 (AKR1C1) and GCLM.	[160]
	Vitamin E	100 mg/kg body weight/day intraperitoneally for 6 days	Balb/c mice	↑ Nrf2 and HO-1 protein levels.	[161]
	Vitamin A	100,000 U/kg body weight/day subcutaneously for 14 days	Wistar rats	↑ Nrf2 nuclear translocation. ↑ HO-1 and NQO 1 proteins.	[162]
Water-soluble vitamins	Vitamin C	27–65 mg/kg body feed twice a day for 8 weeks	Juvenile Sillago sihama	↑ mRNA expression of Nrf2, CAT, SOD, GPx, GR, and GST in intestine and liver cells.	[163]
	Vitamin B2	30 mg/kg body weight/day intra-gastrically	APP/PS1 double transgenic mice	↑ SOD, CAT, GSH, and GPx activities. ↑ Nrf2 expression. ↓ Keap1 expression.	[164,165]
Endogenous Signaling Molecules
Protein kinases	PI3K	N/A	Human retinal pigment epithelial RPE-19 cells	↑ Nrf2 nuclear translocation.	[92]
	JNK 1 & 2	N/A	Human embryonic kidney HEK 293T cells	Phosphorylates Nrf2 at S212, S408, S558, S577, and T559.	[80]
	p38	N/A	Human embryonic kidney HEK 293T cells	Phosphorylates Nrf2 at Ser212, Ser408, Ser558, Ser577, and Thre559.	[80]
	AMPK	N/A	Human embryonic kidney HEK 293T cells	Phosphorylates Nrf2 at the Ser558 residue. ↑ Nrf2 nuclear translocation.	[49]
	ERK2	N/A	Human embryonic kidney HEK 293T cells	Phosphorylates Nrf2 at Ser212, Ser408, Ser558, Ser577, and Thre559.	[80]
	Casein kinase 2	N/A	Human embryonic kidney HEK 293T cells	↑ Nrf2 phosphorylation. ↑ Nrf2 nuclear translocation.	[90]
	PKC	N/A	New Zealand white rabbits	↑ Nrf2 nuclear translocation.	[91]
	PERK	N/A	Mouse embryonic fibroblasts	Dissociates Nrf2 from Keap1 by phosphorylation of Nrf2.	[79]
Autophagy-substrate proteins	Sequestosome 1 (p62)	N/A	Human aortic smooth muscle cells	Competes with Nrf2 to bind with Keap1.	[88]
Synthetic compounds
Synthetic triterpenoids	Bradoxolone-methyl (CDDO-Me)	25–50 mg/day for 52 weeks	Phase 2 clinical on diabetic nephropathy	↑ electrophilic modification of Keap1-Cys-151.	[47,84]
Synthetic triterpenoids	RTA-408 (omaveloxolone)	1% ophthalmic suspension for twice a day for 14 days	Phase 2 clinical trial on inflammation and pain following ocular surgery	↑ electrophilic modification of Keap1-Cys-151.	[47,83]
Synthetic lignans	LGM2605 (Secoisolariciresinol diglucoside)	50 µM	Murine peritoneal macrophages derived from C57BL/6J mice	↑ mRNA expression of GST and redoxin reductase 1.	[166]

Abbreviations—HaCaT: human skin keratinocytes; ARPE-19: human retinal pigment epithelial cell line; HT22: mouse hippocampal neuronal cell line; LLC PK₁: porcine renal epithelial proximal tubule cell line; NRK-52E: rat kidney epithelial cell line; IEC-6: intestinal epithelial cell line; HK-2: human renal tubular epithelial cell line; HL-7702/ L-02: human liver cell line; MRC5: human embryonic lung cell line; HTR8/Sveo: extravillous trophoblast cell line; HEK 293T: human embryonic kidney 293T cell line; HT22: mouse neuronal cell line; H9C2: rat myoblast cell line: TM4: mouse Sertoli cell line; T2DM mice: type 2 diabetes mellitus mice; BJ: human foreskin fibroblast cell line; WT: wild type; KO: knock-out; JB6 P+: mouse skin cells; APP/PSI: ARTE1; GCLM: glutamate-cysteine ligase modifier; GSH: glutathione; CAT: catalase; SOD; superoxide dismutase; GPx: glutathione peroxidase; ARE: antioxidant response element; ERK: extracellular signal-regulated protein kinase; GSK-3β: glycogen synthase kinase 3; Akt: protein kinase B; GR: glutathione reductase; NQO-1: NAD(P)H quinone dehydrogenase 1; HO-1: heme oxygenase 1; GST- glutathione S-transferase; Ser212: serine residue 212; Ser408: serine residue; Ser558: serine residue 558; Ser577: serine residue 577; Thre559: threonine residue 559; PI3K: phosphorylation of phosphatidylinositol 3-kinase; JNK: N-terminal kinase; AMPK: 5′ adenosine monophosphate-activated protein kinase; PKC: protein kinase C; PERK: protein kinase-like endoplasmic reticulum-resident kinase; p62: sequestosome 1; Keap1: Kelch-like ECH-associated protein 1; Nrf2: Nuclear factor erythroid 2 p45 (NF-E2)-related factor; ↑ increase; ↓ decrease.