Oxidative Medicine and Cellular Longevity / 2018 / Article / Tab 2

Review Article

Therapeutic Modulation of Virus-Induced Oxidative Stress via the Nrf2-Dependent Antioxidative Pathway

Table 2

Summary of pharmacologic and genetic Nrf2 modulators and their effects on Nrf2, cellular ROS level, viral pathogenesis, virus replication, and other parameters.

VirusPharmacologic or genetic modulationTarget cells or animalsEffect on Nrf2Effect on Nrf2 target genesROS levelEffect on pathogenesisEffect on virusEffect on othersReference

MoMuLV ts1α-LuminolAstrocytes, FVB/N miceGPx↓, xCT↓H2O2Replication↓, gPr80env↓Cellular DNA synthesis↑, GSH↑Jiang et al. [40]
Thymocyte, FVB/N miceNDgPr80env↓CK8/5 gradient↑, caspase-3↓, cell number↑Scofield et al. [129, 130]
Intestinal lymphoid cells, FVB/N miceNDNDgPr80env↓, gp70↓CD4 T cell number↑, CD8 T cell number↑, caspase-3↓, TSH gradient↑, Ki67 gradient↑Scofield et al. [129, 130]
Astrocytes, neurons, FVB/N miceNDNDNDNDReddy et al., 2010
MinocyclineAstrocytes, neurons, thymocytesND↓ in CNSGFAP↓, astrocyte cell number↑, MDA↓, Ik-Bα↑, p65↓, COX-2↓, CD68↓, caspase-3↓, p53↓Kuang et al. [131]

HIVEGCGHeLa-CD4-LTR-β-galactosidase indicator cellsNDNDTat-induced LTR transactivation↓, GSH↑, NF-κB↓, NOX2↓, AKT↓, AMPK↑Zhang et al. [64]
Tanshinone II AHeLa cellsNDNDGSH↑, Nampt↑, NAD+↑, AMPK↑, SIRT1↑, Tat-induced LTR transactivation↓Zhang et al. [62, 186]
Nrf2 silencing, BSOAlveolar epithelial cells, HIV transgenic ratsGSSG↓, GCLC↓, GST↓, GSR↓, NQO1↓NDNDParacellular permeability↑, TER↓, ZO-1↓, occludin↓, claudin-18↓Fan et al. [51]
Nrf2 overexpression, SFN, GSHAlveolar epithelial cells, HIV transgenic ratsNQO1↑, GSH↑NDNDParacellular permeability↓, TER↑, ZO-1↑, occludin↑Fan et al. [51]
DMFMonocyte-derived macrophagesHO-1↑, GPx↑, NQO1↑NDNF-κB↓, TNF-αCross et al. [146]
Sulforaphane, EGCG, DMFPrimary macrophageNDNDND↓ in macrophage after entryNDFuruya et al. [145]
SulforaphaneMonocyte-derived macrophageNQO1↑, GCLC↑NDNDNDPhagocytic function↑Staitieh et al. [53]

HCVBiliverdinHepatoma cellsNDNDNDNDNS3/4A protease↓, replication↓NDZhu et al. [148]
HO-1 induction by CoPP, HO-1 overexpression, CO, FeHepatoma cellsNDHO-1↑NDNDOAS↑, PKR↑, IFN-α↑, HRI↑Lehmann et al. [149]
LucidoneHepatoma cellsHO-1↑NDNDReplication↓OAS↑, PKR↑, IFN-α↑, bilirubin↑Chen et al., 2013
AndrographolideHepatoma cellsHO-1↑NDNDNS3/4A protease↓, replication↓p38↑, bilirubin↑, OAS↑, PKR↑, IFN-α↑, HRI↑Lee et al. [153]
FluvastatinHepatoma cellsHO-1↑Replication↓Bach1↓, KLF2↑, matrix stiffness↑Wuestenberg et al. [157]
SFNHepatoma cellsHO-1↑NDNDNS3/4A protease↓, replication↓PI3K↑, PKR↑, OAS↑, IFN-α↑, bilirubin↑Yu et al. [158]
CelastrolHepatoma cellsHO-1↑NDNDNS3/4A protease↓, replication↓JNK↑, IFN-α↑, OAS↑Tseng et al. [162]
Nrf2 silencingHepatoma cellsNQO1↓, GCLC↓, G6PD↓NDNDReplication↓LD↓, cholesterol↓, triacylglycerol↓, phospholipid↓Sugiyama et al. [77]
K67Hepatoma cellsNQO1↓, GCLC↓, UGDH↓NDKEAP1-phospho-p62 interaction↓, tumor growth↓, tolerance to anticancer agents↓Saito et al. [78]

Influenza virusNrf2 silencingNasal epithelial cellHO-1↓NDNDReplication↑, titer↑NDKesic et al. [163]
EGCG and SFNNasal epithelial cellHO-1↑Replication↓, entry↓IFN-α↑, RIG-I↑, MxA↑Kesic et al. [163]
Nrf2 deficiency and cigarette smokeNrf2-deficient miceNQO1↓, GCLC↓, HO-1↓NDTNF-α ↑, KC↑, IFN-α, NF-κB↑, lung permeability damage↑, mucus production↑, macrophages↑, neutrophils↑, cell injury↑Yageta et al. [127]
Nrf2 expressionHuman primary alveolar type I-like cellsHO-1↑Replication↓GSH↑, IL-8↑, cell injury↓Kosmider et al. [44]
Nrf2 deficiencyHuman primary alveolar type I-like cellsHO-1↓, MX1↓, OAS1↓Replication↓Caspases 1 and 3↑, cell injury↓Kosmider et al. [44]
CarbocisteineNrf2-deficient mice, macrophagesGCLC↑, GCLM↑, HO-1↑Replication↓PI3K↑, 8-OHdG↓, mucus production↓Yageta et al. [166]
Broccoli sprouts (SFN)Human subjects (smoker, nonsmoker)NDNDReplication↓Inflammation↓, IL-6↓Noah et al. [167]
Compounds from S. baicalensisNrf2/ARE luciferase reporter (HepG2C8), MDCKNDNDNDReplication↓NDJi et al. [168]
BakuchiolMDCKNQO1↑, GST↑NDNDInfection↓, viral titer↓IFN-α↓, Mx1↓Shoji et al. [172]
Compounds from licorice (echinatin)HepG2HO-1↑, NQO1↑NDNDReplication↓ALT↓, AST↓, GSH↓Ji et al. [173]
Rupestonic acid deriv, YZH-106 from CYZH pelletMDCK, RAW264.7Nuclear translocation↑HO-1↑Replication↓p38↑, ERK1/2↑, IFN-α↑, IFN-β↑, IFIT1↑, IFITM3↑, OAS1↑, PKR↑Ma et al. [176], Yin et al. [177]
EmodinA549 cellsHO-1↑, NQO1↑, GSH↑, SOD↑, GR↑, CAT↑, GPx↑Replication↓TLR2/3/4/7↓, MyD88↓, TRAF6↓, phospho-p38↓, phospho-JNK↓, p65↓, IL-1β↓, TNF-α↓, IL-6↓Dai et al. [180]
CurcuminA549 cellsHO-1↑, GSH↑, NQO1↑, GSTA3↑Replication↓, viral titer↓IFN-β↑, TLR2/3/4/7↓, MyD88↓, TRAF6↓, phospho-Akt↓, phospho-p38↓, phospho-JNK↓, TNF-α↓, IL-1β↓, IL-6↓, IL-8↓, NF-κB↓, MMP-2↓, MMP-9↓Dai et al. [183]

RSVNrf2 deficiencyBronchoalveolar lavage fluid of Nrf2-deficient miceGCLC↓, UGT1↓, NQO1↓, HO-1↓, GST↓, GPx↓NDReplication↑, viral titer↑Nasal airway injury↑, mucus production↑, IL-6↑, IL-13↑, GSH↓, GSSG↓, protein oxidation↑, AP-1↑, NF-κB↑, DNP↑Cho et al. [19]
SFNBronchoalveolar lavage fluidNQO1↑, GST↑, HO-1↑, GPx↑NDNDReplication↓Neutrophils↓, eosinophils↓Cho et al. [19]
Roflumilast N-oxideBronchial epithelia cellHO-1↑, GPx↑Replication↓ICAM-1↓, β-tubulin↑, Foxj1↑, Dnai2↑, MUC5AC↓, hCLCA1↓, IL-13↓, IL-8↓, IL-6↓, TNF-αMata et al. [88]
Butylated hydroxyanisoleBronchial epithelia cellHO-1↑, NQO1↑, CAT↑, SOD1↑ND8-Isoprostaine↓Komaravelli et al. [90]

HBVHO-1 induction (CoPP)Mouse infection model, HepG2 cellsHO-1↑NDCore↓, HBeAg↓, HBV DNA↓ALT↓Protzer et al. [185]

Herpes virusSulforaphaneAstrocyte, mixed neural cultureHO-1↑, GPx↑, GCLM↑, GSH↑Macrophage infiltration↓Schachtele et al. [105]

DENVATRAMononuclear phagocytesNDNDCLEC5A↓, TNF-αNDCheng et al. [47]
HO-1 induction CoPP, andrographolideHuh-7 cellsNDHO-1↑NDBiliverdin↑, NS2B/NS3 protease↓, IFN-α↑, OASs↑, PKR↑Tseng et al., 2016
Nrf2 and HO-1 induction (lucidone)Huh-7 cellsHO-1↑NDReplication↓Biliverdin↑, NS2B/NS3 protease↓, IFN-α↑, OASs↑, PKR↑Chen et al. [150]

SVCVSFN bardoxoloneSOD↑, HO-1↑NDNDTotal antioxidant capacity↑Yang et al. [117], Shao et al. [116]

CoxsackievirusIsatin derivative 45HeLa and HL-1 cellsNuclear localization↑NQO1↑, GCLM↑NDNDProcaspase 3 cleavage↓, GRP78↑, UPR↑, p-PERK↑, eIF4GI↑, cap-dependent translation↑Zhang et al. [62, 186]

CoxsackievirusMelittinHeLa cellsHO-1↑, NQO1↑, GCL↑NDApoptosis↓, Bax↓, caspase-3↓, bcl-2↑, HDAC2↑, GSK-3β↑, AST, CK, HBDH and LDH↑, IL-1β↓, IL-6↓, TNF-α↓, MCP-1↓Wang et al. [187]

ZIKA virusHO-1 induction (hemin)Human monocyte-derived macrophageNDHO-1↑NDNDHuang et al. [188]

VSVSFNPC-3HO-1↑, NQO1, GCLC↑, GCLM↑, SQSTM1↑Oncolytic activity↑, tumor progression↓, LC3↑, p62↑, autophagy↑, innate antiviral response↓, IRF3↓, STAT1↓, STING↓Olagnier et al., 2017

Theiler virusDMFTMEV-infected miceHO-1↑, NQO1↑, GCLC↑NDIFN-γ, IL-17a, IL-4, IL-10 and TNF-α, T cell response↓Kobayashi et al. [193]
RHDVMelatoninNew Zealand white rabbitsSOD↑, GPx↑, GST↑NDNDNDCrespo et al. [195]
PCV2Selenium, selenoprotein SPK15GCL↑, GCSL↑, GSH↑NDOchratoxin A-induced replication↓Ochratoxin A-induced ROS↓, ochratoxin A-induced p38 phosphorylation↓Gan et al. [197]

ND indicates “not determined.” Abbreviations used within the table are as follows. Akt: protein kinase B; ALT: alanine aminotransferase; AMPK: AMP-activated protein kinase; AST: aspartate aminotransferase; ATRA: all-trans retinoic acid; BACH1: basic leucine zipper transcription factor; Bax: bcl-2-like protein 4; Bcl-2: B-cell lymphoma 2; BSO: buthionine sulfoximine; CK8/5: casein kinase 8 and 5; CNS: central nerve system; CoPP: cobalt-protoporphyrin-IX; DMF: dimethyl fumarate; Dnai2: dynein intermediate chain 2; DNP: dinitrophenyl; EGCG: epigallocatechin-3-gallate; eIF4GI: eukaryotic translation initiation factor; Foxj1: forkhead box protein J1; G6PD: glucose 6 phosphate dehydrogenase; GCLC: glutamate cysteine ligase catalytic subunit; GCLM: glutamate cysteine ligase regulatory subunit; GFAP: glial fibrillary acid protein; GPx: glutathione peroxidase; GR: glutathione reductase; GRP78: glucose-responsive proteins 78; GSH: glutathione; GSK: glycogen synthase kinase; GSR: glutathione reductase; GSSG: intracellular reduced glutathione-to-glutathione disulfide; GST: glutathione S transferase; HBDH: β-hydroxybutyrate dehydrogenase; hCLCA1: human chloride channel accessory 1; HDAC: histone deacetylase; HO-1: heme oxygenase; HRI: heme-regulated eIF2alpha kinase; ICAM-1: intercellular adhesion molecule 1; IFIT1: IFN-induced protein with tetratricopeptider repeats 1; IFITM3: IFN-inducible transmembrane protein 3; IFN: IFN; Ik-Bα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; IL-13: interleukin 13; IL-6: interleukin 6; IL-8: interleukin 8; IRF3: IFN regulatory factor 3; JNK: c-Jun kinase; KC: keratinocyte-derived chemokine; Ki67: antigen KI-67; KLF2: Krueppel-like factor 2; LDH: lactate dehydrogenase; MCP-1: monocyte chemoattractant protein-1; MDA: malondialdehyde; MUC5AC: mucin 5AC; MX1: IFN-induced GTP-binding protein; MxA: MxGTPases; NAD+: nicotinamide adenine dinucleotide; Nampt: nicotinamide phosphoribosyltransferase; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NOX: NADPH oxidase; NQO1: NAD(P)H dehydrogenase quinone 1; NS3/4A: nonstructural protein 3/4A; OAS: oligoadenylate synthetase; PCV2: porcine circovirus type 2; PERK: protein kinase R-like ER kinase; PI3K: phosphatidyl inositol 3 kinase; PKR: protein kinase R; RHDV: rabbit hemorrhagic disease virus; SFN: sulforaphane; SIRT1: NAD+-dependent histone deacetylase sirtuin1; SQSTM1: sequestosome-1; STAT1: signal transducer and activator of transcription 1; STING: stimulator of IFN genes; SVCV: spring viremia of carp virus; tBHQ: tert-butyl hydroquinone; TER: transepithelial electrical resistance; TMEV: Theiler’s murine encephalomyelitis virus; TNF-α: tumor necrosis factor alpha; TSH: thyroid stimulating hormone; UGDH: UDP-glucose dehydrogenase; UPR: unfold protein response; VSV: vascular stomatitis virus; xCT: cell surface cysteine-glutamate antiporter; ZO-1: zonula occludens-1.

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