Table 1.

In vivo studies showing cytoprotective role of Nrf2 in CRC models

Testing model	Study design/testing compounds	Outcome effects	Reference
Nrf2 KO vs. C57BL/6 WT mice	DSS-induced colitis Gp 1: WT + 1% DSS Gp 2: KO + 1% DSS Gp 3: WT + water Gp 4: KO + water	Nrf2 KO mice had significant shorter colon as compared to Nrf2 WT mice (p<0.05). Nrf2 KO mice: ↑DSS-induced colitis ↓antioxidant/phase II detoxifying enzymes: HO-1, NQO1, UGT1A1, GSTM1 ↑proinflammatory mediators/cytokines: COX-2, iNOS, iL-1b, iL-6	[68]
Nrf2 KO vs. C57BL/6J WT mice	AOM/DSS-induced CRC Gp 1: WT + water Gp 2: KO + water Gp 3: WT + AOM/DSS Gp 4: KO + AOM/DSS	93% Nrf2 KO mice had colonic tumor vs. 53% Nrf2 WT (p<0.05), 80% were adenocarcinoma vs. 29% respectively. Nrf2 KO mice: ↑COX-2, 5-LOX, PGE2, LTB4, inflamed colonic mucosa (nitrotyrosine expression) Nrf2 WT mice: ↑NQO1, UGT1A1	[70]
Nrf2 KO vs. ICR/129S VJ WT mice	AOM/DSS-induced CRC Gp 1: WT + AOM Gp 2: KO + AOM Gp 3: WT + AOM/DSS Gp 4: KO + AOM/DSS	DSS treatment significantly increased ACF, inflammation and mucosal damage in Nrf2 KO mice but not WT (p<0.05).	[69]
BALB/cA nude mice	Gp 1: Basal diet Gp 2: IQ (50 mg/kg) Gp 3: IQ (50 mg/kg) + EGCG (5 mg/kg) Gp 4: IQ (50 mg/kg) + EGCG (10 mg/kg) Gp 5: IQ (50 mg/kg) + EGCG (20 mg/kg)	IQ suppressed Nrf2 and UGT1A10 expression. As compared to IQ treated, EGCG groups have: ↓atypical hyperplasia, total ACF and total AC significantly ↑Nrf2, UGT1A10 (all p<0.01)	[71]
Orthotopic HT-29 cancer cells implanted in the cecum of BALB/cA nude mice	Gp 1: Basal diet Gp 2: EGCG (5 mg/kg) Gp 3: EGCG (10 mg/kg) Gp 4: EGCG (20 mg/kg)	EGCG treated groups: ↓growth (all p<0.001, vs. control) and liver metastases (p<0.01 for Gp 3, p<0.05 for Gp 4 vs. control) ↑Nrf2, UGT1A, UGT1A8, UGT1A10 (all p<0.01)	[72]
Fischer 344 rats	Gp 1: Modified (high fat, fiber free) AIN76 diet Gp 2: IQ (100 mg/kg/day for 10 alternate days) Gp 3: IQ+Brussels sprouts juices 5 days before IQ and during IQ Gp 4: IQ+Red cabbage juices 5 days before IQ and during IQ	Brussels sprouts: ↓ACF /rat 41-52% in the colon, 85-91% liver GST-P+ foci Red cabbage: ↓ACF/rat 17-20%, 41-83% liver GST-P+ foci ↑UGT-2 & P4501A2 increased by both vegetables	[73]
F344 rats	2% curcumin in diet by oral, 500 mg/kg by i.g. gavage vs. control treated with CCl4	Curcumin treated rats: ↑16% Hepatic GST ↓36% Colon M1G	[74]

Abbreviations used: Nrf2 knockout (Nrf2 KO); Nrf2 wild-type (Nrf2 WT); Dextran sulfate sodium (DSS); Group (Gp); heme-oxygenase-1 (HO-1); NAD(P)H-quinone reductase-1 (NQO1); Uridine-diphospho-glucuronosyltransferase (UGT), glutathione S-transferase (GST); cyclo-oxygenase 2 (COX-2); inducible nitric oxide synthase (iNOS); interleukin-1beta (iL-1b); interleukin 6 (iL-6); azoxymethane (AOM); aberrant crypt foci (ACF); aberrant crypts (AC); 2-amino-3-methylimidazo[4,5-f]quinoline (IQ); epigallocatechin gallate (EGCG); liver glutathione-S-transferase placental positive (GST-P+, an early preneoplastic lesion in liver); cytochrome P4501A2 (P450, an enzyme catalyses the activation of HAA); adducts of malondialdehyde with DNA (M1G)