Review Article

Collaborative Power of Nrf2 and PPARγ Activators against Metabolic and Drug-Induced Oxidative Injury

Table 1

Summary of Nrf2 and PPARγ pathway activators studied for their potential protective effects on various disease models. Nrf2 and PPARγ pathway activators are categorized based on their target specificities and origin of synthesis. Their compound names, target diseases, effects on experimental models, effect on Nrf2, PPARγ, and other relevant molecules, and their related references are listed accordingly. Abbreviations used within the table are as follows. Nrf2: nuclear factor erythroid 2p45-related factor 2; PPARγ: peroxisome proliferator-activated receptor γ; HO-1: heme oxygenase-1; CNS: central nerve system; ARE-luc: antioxidant response element-containing luciferase reporter; PI3K: phosphatide 3-kinase; PKC: protein kinase C; LPS: lipopolysaccharide; NF-κB: nuclear factor kappa B; COX-2: cyclooxygenase-2; MAPK: mitogen-activated protein kinase; iNOS: inducible nitric oxide synthase; GST-α: glutathione S-transferase-α; ABCA1: ATP-binding cassette transporter 1; MAPKAPK: mitogen-activated protein kinase-activated protein kinase; Bcl-xL: B-cell lymphoma-extra large; NQO-1: NAD(P)H quinone oxidoreductase-1; SOD: superoxide dismutase; GPX: glutathione peroxidase; GST: glutathione; TNF-α: tumor necrosis factor-α; MDA: malondialdehyde; CAT: catalase; NO: nitric oxide; SIRT1: silent information regulator 2 (Sir2) protein 1; γ-GCL: γ-glutamyl cysteine ligase.

CategoryCompound nameTarget diseaseEffects on experimental modelsEffect on Nrf2Effect on PPARγEffect on othersReference

Nrf2 activatorsBardoxolone methylKidney diseaseAmelioration of ischemic acute kidney injury in miceNrf2 ↑PPARγHO-1 ↑Wu et al. [69]
CurcuminMalariaIncreased nonopsonic phagocytosis of Plasmodium falciparum in monocytes/macrophages and hepatoma cellsNrf2 ↑PPARγCD36 ↑Mimche et al. [73]

Endogenous PPARγ activators15-Deoxy-D12, 14-prostaglandin J2CNS diseaseProtection against homocysteic acid-induced oxidative death in neuronsARE-luc ↑IndependentHO-1 ↑Haskew-Layton et al. [75]
Not specifiedAttenuation of cell death in RAW264.7 mouse macrophagesNrf2 ↑IndependentHO-1 ↑Gong et al. [76]
Nitroalkene fatty acidsNot specifiedActivation of Nrf2 and PPARγ pathways in human MCF7 breast cancer cellsNrf2 ↑ (<1 μM)PPARγ ↑ (>1 μM)PI3K, PKC ↑Bates et al. [78]
Nitrated fatty acidsRespiratory diseaseDecreased severity of LPS-induced acute lung injury in miceNrf2 ↑PPARγNF-κB ↓Reddy et al. [80]

Synthetic PPARγ activatorsRosiglitazoneDiabetesProtection against high glucose-induced toxicity in hepatocytesNrf2, ARE ↑IndependentHO-1 ↑
PKC, COX-2 ↓
Wang et al. [67]
Respiratory diseaseProtection against paraquat-induced acute lung injury in ratsNrf2 ↑PPARγNF-κB ↓Liu et al. [83]
Troglitazone and cyanidinLiver diseaseProtection against H2O2-induced cytotoxicity in human hepatoblastoma HepG2 and rat normal hepatocytesNrf2 and ARE ↑PPARγMAPK ↑Shih et al. [84]
Arylidene-thiazolidinedioneDiabetesBlockage of LPS-induced inflammation and oxidative stress in RAW mouse macrophagesIndependentPPARγCD36, HO-1 ↑
iNOS, COX-2 ↓
Faine et al. [82]

Natural PPARγ activatorsCarotenoidsCancerInhibition of proliferation of K562 myelogenous leukemia cellsNrf2 ↑PPARγp21 ↑, cyclin D1 ↓Zhang et al. [85]
MonascinDiabetesProtection against methylglyoxal-induced toxicity in HepG2 cells and ratsNrf2 ↑PPARγPKC ↓Hsu et al. [88]
Hsu et al. [87]
AnkaflavinDiabetesProtection against methylglyoxal-induced toxicity in HepG2 cells and ratsNrf2 ↑PPARγGlyoxalase, HO-1 ↑Lee et al. [90]
Hsu and Pan [89]

Dual Nrf2 and PPARγ activatorsGenisteinAtherosclerosisAttenuation of H2O2-induced endothelial cell injury in transformed human umbilical vein endothelial cellsNrf2 ↑PPARγHO-1 ↑Zhang et al. [92]
Vitamin EAtherosclerosisProtection against hypercholesterolemia-induced atherosclerosis in rabbit aortaeNrf2 ↑PPARγGST, ABCA1 ↑Bozaykut et al. [94]
OlmesartanKidney diseaseProtection against oxidative and inhibition of inflammation in daunorubicin-induced nephrotoxicity in ratsNrf2 ↑PPARγMAPKAPK, caspase-12, p47, p67 ↓
Bcl-xL, GST ↑
Gounder et al. [96]
α-Methylene-γ-lactonesKidney diseaseActivation of Nrf2 and PPARγ pathways in mouse peritoneal macrophages from normal and PPARγ-knockout mice againstNrf2 ↑PPARγDectin-1, CD36, NQO-1, HO-1 ↑Le Lamer et al. [97]
18β-Glycyrrhetinic acidKidney diseaseProtection against methotrexate-induced kidney injury in ratsNrf2 ↑IndependentGSH, SOD, GPX, GST, HO-1 ↑, TNF-α, MDA, NO ↓Abd El-Twab et al. [100]
Liver diseaseProtection against cyclophosphamide-induced hepatotoxicity in ratsNrf2 ↑PPARγMDA, NF-κB, iNOS ↓, GSH, GPX, SOD, CAT ↑Mahmoud and Al Dera [102]
(−)-Epigallocatechin-3-gallateKidney diseaseProtection against crescentic glomerulonephritis induced by administration of rabbit anti-mouse glomerular basement membrane antibody in miceNrf2 ↑PPARγSIRT1, γ-GCL, GPX1, NQO-1↑, AKT, JNK, ERK, p38 ↓Ye et al. [103]
MangiferinGastrointestinal diseaseProtection against gastric ulcer in ischemia/reperfused ratsNrf2 ↑PPARγHO-1 ↑, NF-κB ↓Mahmoud-Awny et al. [104]
3-O-Lauryl glyceryl ascorbateSkin diseaseSuppression of oxidative damage induced by H2O2 and UVB in normal human epidermal keratinocytesNrf2 ↑PPARγγ-GCS, HO-1, NQO-1, GSH ↑Katsuyama et al. [105]
UmbelliferoneLiver diseaseProtection against cyclophosphamide-induced hepatotoxicity in ratsNrf2 ↑PPARγHO-1 ↑Mahmoud et al. [106]
Graptopetalum paraguayense and resveratrolDiabetesProtection against carboxymethyllysine-induced pancreas dysfunction and hyperglycemia in miceNrf2 ↑PPARγPDX-1, GSH, GCL ↑Lee et al. [109]
Cyanidin-3-glucose and resveratrolGastrointestinal diseaseProtection against cytokine-stimulated oxidative stress in human colon cancer cellsNrf2 ↑PPARγHO-1, γ-GCS, GSH ↑Serra et al. [110]