Table 1.
Effects of various phytochemical compounds/extracts on ethanol-induced liver injury via regulating Nrf-2 signaling pathways
| Compounds | ALD models | Improved parameters | Evidences of Nrf-2 in the protection against ALD | References |
|---|---|---|---|---|
| Sulforaphane | Sprague–Dawley rats exposed to ethanol (5 g/kg bw) twice daily for 16 days | Serum ALT, AST, LDH; histological changes | Increased Nrf-2 nucleus translocation; increased mRNA and protein levels of HO-2, NQO-1, and GST-P | [70] |
| Sulforaphane | CYP2E1-expressing HepG2; Male SV129 humanized CYP2E1 knockin mice exposed to 3 g/kg bw ethanol twice daily for 5 days | Liver TC and TG levels; liver steatosis | Increased protein levels of Nrf-2 and HO-1; increased Nrf-2 activity | [64] |
| Curcumin | Sprague–Dawley rats exposed to ethanol (56%, 10 ml/kg bw) twice daily for 4 weeks; LO2 cells exposed to 100 mM ethanol | Necroptosis; serum ALT | Nrf-2 knockdown by shRNA lentivirus abrogated the hepatoprotective effect of curcumin | [66] |
| Curcumin | Sprague–Dawley rats exposed to ethanol (56%, 10 ml/kg bw) once daily for 9 weeks; LO2 cells exposed to 100 mM ethanol | Serum ALT, AST, ALP, LDH, TG, TC, LDL-C, HDL-C; Liver TG, TC; ALT, AST, and LDH in culture medium; Cellular lipid level; Steatosis | Increased protein levels of Nrf-2; Nrf-2 siRNA attenuated the protective effects, while Nrf-2 overexpression enhanced the protection. | [67] |
| Curcumin | Male Balb/C mice exposed to ethanol (56%, 10 ml/kg bw) orally for 6 weeks | Serum ALT, AST; Liver TG, TC, LDL-C, HDL-C; Steatosis | Increased Nrf-2 nucleus translocation; increased mRNA levels of NQO1, HO-1, and GCLc | [80] |
| Quercetin | LO2 cells exposed to ethanol | Cell viability | Induced nucleus translocation of Nrf-2 and p62; increased expression of GCL and HO-1; p62 siRNA blocked the protective effects | [76] |
| Quercetin | Human hepatocytes exposed to ethanol | GSH and MDA, LDH and AST activity in culture medium, and EC50 of ethanol | Nrf-2/HO-1 inhibitor abrogated the protective effects of quercetin | [75] |
| Diallyl disulfide | Male Kunming mice exposed to 3 doses of ethanol (5 g/kg bw); LO2 cells exposed to 25–200 μM ethanol | LDH, AST in culture medium; apoptosis | Increased the Nrf-2 nucleus translocation; increased protein and mRNA levels of HO-1; HO-1 inhibitor abrogated the protective effects of DADS | [25] |
| Dihydromyricetin | C57BL/6 mice fed with Lieber–DeCarli liquid diet for 6 weeks | Hepatic enzyme release, lipid peroxidation; TG deposition; inflammatory cytokines; hepatic pathological changes | Increased the protein levels of Nrf-2 and p62 | [97] |
| Wuzhi tablet | Male C57BL/6 mice exposed to chronic-plus-binge model; or exposed to 6 g/kg bw ethanol for 3 times | Serum ALT and AST; Liver steatosis | Increase the protein levels of Nrf-2, GCLc, GCLm and HO-1 | [99] |
| Triticum aestivum sprout-derived polysaccharide | Male C57BL/6 mice were exposed to ethanol for 10 days | Serum ALT and AST; Liver TG and TG; steatosis; apoptosis | Upregulated the expression of Nrf-2 and HO-1 | [96] |
| Ligustrazine | Male ICR mice exposed to ethanol (56%, v/v, 10 ml/kg bw) once daily for 4 weeks; LO2 cell exposed to ethanol (100 mM) | Serum ALT, AST, ALP, LDH; liver inflammation and steatosis | Nrf-2 knockdown abrogated the hepatoprotective effects | [91] |
| Polydatin | Male Wistar rats exposed to ethanol (7 ml/kg bw) orally every 12 h at 5 different time points | Serum ALT, AST, ALP, LDH; liver inflammation, steatosis, necrosis, apoptosis | Increased protein levels of Nrf-2 and Nrf-2-targeted HO-1 | [65] |
| Baicalin | Chronic-plus-binge model (Gao-Bin model) | Serum ALT and AST; liver TG; liver steatosis, inflammation, apoptosis, necrosis | Enhanced nuclear translocation of Nrf-2 and increased mRNA levels of Nrf-2 target genes including HO-1 and NQO-1 | [92] |
| Hoveniae semen cum fructus extracts | Male C57BL/6 mice exposed to ethanol (5 g/kg bw) for 14 days | Serum ALT, AST, albumin, ALP, TG, γ-GT (γ-glutamyl transferase); liver TG, TNF-α; liver steatosis | Suppressed ethanol-induced decline of Nrf2 mRNA level and the decrease of hepatic GSH level and SOD and CAT activity | [93] |
| Glycycoumarin | Chronic plus binge drinking-induced chronic ALD and acute ALD model in C57BL/6 mice | Serum ALT and AST; liver TG level | Increased the protein levels of Nrf-2, HO-1, and GCLc; Nrf-2 activation lead to upregulation of p62. | [102] |
| Ethanolic extract of Sida cordifolia | Male Sprague–Dawley rats were gavaged with ethanol (4 g/kg bw) for 90 days | Serum ALT, AST, GGT; liver ALT, AST | Increased the nucleus translocation of Nrf-2 and the mRNA level of γ-GCS. | [94] |
| Tetramethylpyrazine | Ethanol-exposed LO2 cells | Cell viability, ALT and AST in culture medium; cellular TG, TC; apoptosis, | Increased Nrf-2 expression and nucleus translocation; overexpression of Nrf-2 enhanced the protective effects, while Nrf-2 siRNA eliminated the protective effects. | [68] |
| Citrus aurantium extract | Male C57BL/6 mice exposed to 5 g/kg bw ethanol for 3 doses | Serum ALT, AST, TG; liver steatosis, necrosis, apoptosis | Increased the protein levels of Nrf-2, NQO-1 and γ-GCSc | [63] |
| Chlorella ethanol extract | Sprague–Dawley rats were gavaged with ethanol 5 g/kg bw twice daily for 16 days | Serum ALT, AST, γ-GT, LDH | Increased Nrf-2 nucleus translocation and increased mRNA and protein levels of HO-2, NQO-1, and GST-P. | [70] |
| Oleanolic acid | Sprague–Dawley rats were gavaged with 4 g/kg bw ethanol for 30 days | Serum ALT, AST; liver ATP, TG, MDA | Increased the nucleus translocation of Nrf-2, and the protein expression of HO-1, SOD, and GR | [70] |
| Antroquinonol | Ethanol-exposed HepG2 cells | ALT, AST, ROS, MDA, NO | Increased the mRNA and protein levels of HO-1, Nrf-2 nucleus translocation, and ARE binding activity | [100] |
| Lucidone | Ethanol-exposed HepG2 cells | ALT, AST, NO, TNF-α, MDA, ROS | Increased the mRNA and protein levels of HO-1, Nrf-2 nucleus translocation and ARE binding activity | [101] |
ALD alcoholic liver disease; ALP alkaline phosphatase; ALT alanine aminotransferase; ARE antioxidant response element; AST aspartate aminotransferase; CAT catalase; GCL glutamate–cysteine ligase; GR glutathione reductase; GSH glutathione; GST glutathione S-transferase; γ-GT γ-glutamyl transferase; HDL-C high-density lipoprotein cholesterol; HO-1 heme oxygenase 1; LDH lactic dehydrogenase; LDL-C low-density lipoprotein cholesterol; MDA malondialdehyde; NO nitrogen oxide; NQO-1 NAD(P)H quinone oxidoreductase 1; Nrf-2 nuclear factor erythroid-derived 2-like 2; ROS reactive oxygen species; SOD superoxide dismutase; TG triglyceride; TC total cholesterol; TNF-α tumor necrosis factor α