Oxidative Medicine and Cellular Longevity / 2016 / Article / Tab 1

Review Article

Naturally Occurring Nrf2 Activators: Potential in Treatment of Liver Injury

Table 1

Various Nrf2 activator phytochemicals and their role in liver injury.

PhytochemicalsEffective dosesExperimental procedure (injury model)OutcomesReferences

Acetaminophen toxicity
Ginsenoside Rg33 μg/mLRat hepatocytes treated with 200 μM NAPQIRepletion of GSH content and enhanced expression of Mrp expression[39]
Oleanolic acid90 mg/kgMice injected with 330 μmol/kg APAP into the right femoral veinEnhanced antioxidant response to reduce hepatocyte necrosis[37]
Salvianolic acid B25 and 50 mg/kgMice treated with single dose of 300 mg/kg APAP (i.g.)Antioxidant response and phase II enzyme induction via activation of PI3K/Akt and PKC signaling to reduce liver injury[35]
Sauchinone30 mg/kgMice treated with single dose of 500 mg/kg APAP (i.p.)Induction of antioxidant genes to reduce hepatocyte necrosis[34]
Oleanolic acid5 mg/kgMice treated with single dose of 300 mg/kg APAP (i.p.)Reduction of ROS generation, GSH depletion, and lipid peroxidation coupled with upregulation of antioxidant genes[36]
Withaferin A40 mg/kgMice treated with single dose of 250 mg/kg APAP (i.p.)Reduced hepatocyte injury by reducing GSH depletion[38]

Inflammatory injury
Ellagic acid5, 10, and 20 mg/kgMice treated with single dose of 800 mg/kg Gal + 50 μg/kg LPS (i.p.)Reduced LPS/GalN-induced NF-κB activation and increased antioxidant genes[43]
Linalool10, 20, and 40 mg/kgMice treated with single dose of 800 mg/kg Gal + 50 μg/kg LPS (i.p.)Reduced LPS/GalN-induced NF-κB activation and induction of cytoprotective genes[44]
Mangiferin5, 10, and 20 mg/kgMice treated with single dose of 800 mg/kg Gal + 50 μg/kg LPS (i.p.)Reduced liver injury by activating antioxidant pathway and inhibiting NLRP3 inflammasome activation[45]
Oroxylin A15, 30, and 60 mg/kgMice treated with single dose of 800 mg/kg Gal + 50 μg/kg LPS (i.p.)Decreased liver injury by activating antioxidant genes and inhibiting TLR4 signaling-mediated inflammation[46]

Chemical toxicity
Tungtungmadic acid5 and 20 μMHepa1c1c7 cells treated with 250 μM t-BHPHO-1 induction via the PI3K/Akt signaling pathway to reduce hepatocyte death[47]
Antcin C20 μM in cells, 100 mg/kg in miceHepG2 cells treated with 10 mM AAPH, mice treated with single dose of 80 mg/kg AAPH (i.p.)Induction of antioxidant response via increase of JNK1/2 and PI3K/Akt activities[48]
Butein and phloretin25 μM in vitro, 30 mg/kg in vivoMouse hepatocytes treated with 0.5 mM t-BHP, rats treated with single dose of 1 mL/kg CCl4 (i.p.)Upregulation of HO-1 and GCLC expression through ERK2 pathway[49]
Carthamus red10 and 20 mg/kgMice treated with two doses of 2 mL/kg CCl4-olive oil mixture (1 : 1)Upregulation of Nrf2, GSTα, and NQO1 expressions associated with decreased hepatocyte injury and ALT levels[50]
Curcumin200 mg/kgMice treated with single dose of 20 mg/kg DEN (i.p.)Nrf2-mediated HO-1 induction and amelioration of hepatocyte injury[51]
Diallyl disulfide50 and 100 mg/kgRats treated with single dose of 2 mL/kg CCl4 (i.g.)Induction of antioxidant and detoxifying enzyme activities and suppressing of inflammatory cytokines production by reducing NF-κB activation[52, 53]
Ginsenoside Rg120 and 40 mg/kgRats treated with 2 mL/kg of 50% CCl4 (s.c.) twice a week for 8 weeksReduced liver fibrosis by augmented antioxidant systems[54]
Glycyrrhetinic acid25 and 50 mg/kgMice treated with 6.4 g/kg CCl4 (s.c.) for 30 daysEnhanced antioxidant genes expression to reduce hepatocyte injury[55]
Hesperidin40 and 80 μMLO-2 cells treated with 150 μM t-BHPERK-mediated nuclear translocation of Nrf2 to induce HO-1 gene expression and antioxidant response[56]
Isoorientin5 μg/mLHepG2 cells treated with 200 μM t-BHPUpregulation of antioxidant enzyme expression through PI3K/Akt pathway[57]
Naringenin50 mg/kgRats treated with 2 mL/kg CCl4-olive oil mixture (1 : 1) on days 2 and 5 (i.p.)Increase in Nrf2 and HO-1 expression to reduce liver injury[58]
Oxyresveratrol10 μM for in vitro study, 10 and 30 mg/kg for in vivo study200 μM t-BHP treatment to HepG2 cells, ice treated with single dose of 0.5 mL/kg CCl4 (i.p.)ERK phosphorylation-mediated induction of antioxidant pathway to protect hepatocytes against oxidative stress, mitochondrial damage, and resultant cell death[59]
Puerarin100 μM500 μM t-BHP treatment to Hepa1c1c7 and HepG2 cellsAugmentation of cellular antioxidant defenses through Nrf2-dependent HO-1 induction via PI3K pathway[60]
Resveratrol50 and 75 μMPrimary rat hepatocytes treated with 500 μM t-BHPReduced hepatocyte death by improving antioxidant status[61]
Schisandrin B15 μMAML12 cells treated with 20 μM menadione for 1 hInduction of ERK/Nrf2 signaling to enhance glutathione-mediated antioxidant response to protect hepatocytes against menadione-induced apoptosis[62]

Metal toxicity
Curcumin200 mg/kgExposure of mice to NaAsO2 (100 mg/L) in drinking waterInduction of antioxidant genes and enhanced methylation and elimination of arsenic[63]
Lutein40 mg/kgMice treated with 4 mg/kg As2O3 (i.g.)Reduced liver injury by induction of antioxidant response[64]
S-Allylcysteine100 mg/kgMice treated with single dose of 17 mg/kg K2Cr2O7 (s.c.)Induction of antioxidant response to reduce liver injury[65]

Alcohol toxicity
Lucidone1, 5, and 10 μg/mLHepG2 cells treated with 100 mM ethanolInduction of HO-1 via Nrf2 signaling pathway to enhance antioxidant response[66]
Quercetin100 μMPrimary human hepatocytes treated with 100 mM ethanolERK- and p38-mediated Nrf2 nuclear translocation and subsequent induction of HO-1 activity[67, 68]
Quercetin50 μMLO-2 cells treated with 100 mM ethanolPreventing hepatotoxicity by inducing p62 expression and induction of antioxidant response[69]
Sulforaphane50 mg/kgMice treated with 3 g/kg ethanol (30%) for 5 days (i.g.)Decreased hepatocyte lipid accumulation and injury without altering CYP2E1 expression[70]

Nonalcoholic steatohepatitis
Baicalein10 mg/kgRats fed with MCD diet for 8 weeksReduction in inflammation and oxidative hepatocyte injury[71]
Curcumin50 mg/kgRats fed with HFD for 6 weeksReduced hepatocyte lipid accumulation and improved insulin resistance and anti-inflammatory and antioxidant effects[72]
Gastrodin10, 20, and 50 mg/kgHL-7702 cells treated with 0.6 mM of OA for 24 h, mice fed with HFD for 10 weeksAMPK-mediated induction of Nrf2 pathway to enhance expression of antioxidant enzymes[73]
Lycopene15 mg/kgMice fed with HFD for the next 6 weeks following a single dose of 30 mg/kg DEN injectionReduction in hepatocyte injury by induction of antioxidant pathway along with a decrease in CY2E1 expression[74]

Cholestatic liver injury
Oleanolic acid20 mg/kgMice treated with 125 mg/kg LCA (i.p.)Upregulation of Mrp2, Mrp3, and Mrp4 to reduce cholestatic liver injury[75]
Oleanolic acid20 mg/kgBile duct ligation in miceInduction of Mrps and FXR antagonism to reduce cholestatic liver injury[76]
Paeoniflorin200 mg/kgRats treated with 50 mg/kg ANIT for 4 days (i.g.)Enhanced GSH synthesis by activating Nrf2 through PI3K/Akt-dependent pathway[8]
Sulforaphane50 mg/kgMice treated with 3 g/kg ethanol (30%) for 5 days (i.g.)Decreased hepatocyte lipid accumulation and injury without altering CYP2E1 expression[70]
Sulforaphane25 mg/kgBile duct ligation in miceAntifibrotic response by inhibition of TGF-β/Smad signaling pathway[77]

AAPH: 2,2′-azobis(2-amidinopropane) dihydrochloride; MCD: methionine and choline deficient; CCl4: carbon tetrachloride; DEN: dimethylnitrosamine; HFD: high-fat diet; Gal: galactosamine; LPS: lipopolysaccharide; OA: oleic acid; NAPQI: N-acetylbenzoquinoneimine; i.p.: intraperitoneal; s.c.: subcutaneous; i.g.: intragastric; t-BHP: tert-butyl hydroperoxide; APAP: acetaminophen; LCA: lithocholic acid; ANIT: alpha-naphthylisothiocyanate; Nrf2: nuclear factor (erythroid-derived 2)-like 2; JNK1/2: c-Jun N-terminal kinases 1/2; PI3K/AKT: phosphoinositide 3-kinase/protein kinase B; HO-1: heme oxygenase-1; GCLC: glutamate-cysteine ligase catalytic subunit; ALT: alanine transaminase; GST: glutathione S-transferase; NQO1: NAD(P)H quinone dehydrogenase 1; AMPK: 5′ AMP-activated protein kinase; GSH: glutathione; CYP2E1: cytochrome P450 2E1; NLRP3: NLR family pyrin domain containing 3; Mrp: multidrug resistance-associated protein; TLR4: Toll-like receptor 4; Keap1: Kelch-like ECH-associated protein 1.

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