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.

Virus	Pharmacologic or genetic modulation	Target cells or animals	Effect on Nrf2	Effect on Nrf2 target genes	ROS level	Effect on pathogenesis	Effect on virus	Effect on others	Reference
MoMuLV ts1	α-Luminol	Astrocytes, FVB/N mice	↑	GPx↓, xCT↓	H2O2↓	↓	Replication↓, gPr80env↓	Cellular DNA synthesis↑, GSH↑	Jiang et al. [40]
		Thymocyte, FVB/N mice	↑	ND	↓	↓	gPr80env↓	CK8/5 gradient↑, caspase-3↓, cell number↑	Scofield et al. [129, 130]
		Intestinal lymphoid cells, FVB/N mice	↑	ND	ND	↓	gPr80env↓, gp70↓	CD4 T cell number↑, CD8 T cell number↑, caspase-3↓, TSH gradient↑, Ki67 gradient↑	Scofield et al. [129, 130]
		Astrocytes, neurons, FVB/N mice	↑	ND	ND	↓	ND	ND	Reddy et al., 2010
	Minocycline	Astrocytes, neurons, thymocytes	↑	ND	↓	↓	↓ in CNS	GFAP↓, astrocyte cell number↑, MDA↓, Ik-Bα↑, p65↓, COX-2↓, CD68↓, caspase-3↓, p53↓	Kuang et al. [131]
HIV	EGCG	HeLa-CD4-LTR-β-galactosidase indicator cells	↑	↑	↓	ND	ND	Tat-induced LTR transactivation↓, GSH↑, NF-κB↓, NOX2↓, AKT↓, AMPK↑	Zhang et al. [64]
	Tanshinone II A	HeLa cells	↑	↑	↓	ND	ND	GSH↑, Nampt↑, NAD+↑, AMPK↑, SIRT1↑, Tat-induced LTR transactivation↓	Zhang et al. [62, 186]
	Nrf2 silencing, BSO	Alveolar epithelial cells, HIV transgenic rats	↓	GSSG↓, GCLC↓, GST↓, GSR↓, NQO1↓	ND	↓	ND	Paracellular permeability↑, TER↓, ZO-1↓, occludin↓, claudin-18↓	Fan et al. [51]
	Nrf2 overexpression, SFN, GSH	Alveolar epithelial cells, HIV transgenic rats	↑	NQO1↑, GSH↑	ND	↓	ND	Paracellular permeability↓, TER↑, ZO-1↑, occludin↑	Fan et al. [51]
	DMF	Monocyte-derived macrophages	↑	HO-1↑, GPx↑, NQO1↑	ND	↓	↓	NF-κB↓, TNF-α↓	Cross et al. [146]
	Sulforaphane, EGCG, DMF	Primary macrophage	↑	ND	ND	ND	↓ in macrophage after entry	ND	Furuya et al. [145]
	Sulforaphane	Monocyte-derived macrophage	↑	NQO1↑, GCLC↑	ND	ND	ND	Phagocytic function↑	Staitieh et al. [53]
HCV	Biliverdin	Hepatoma cells	ND	ND	ND	ND	NS3/4A protease↓, replication↓	ND	Zhu et al. [148]
	HO-1 induction by CoPP, HO-1 overexpression, CO, Fe	Hepatoma cells	ND	HO-1↑	ND	ND	↓	OAS↑, PKR↑, IFN-α↑, HRI↑	Lehmann et al. [149]
	Lucidone	Hepatoma cells	↑	HO-1↑	ND	ND	Replication↓	OAS↑, PKR↑, IFN-α↑, bilirubin↑	Chen et al., 2013
	Andrographolide	Hepatoma cells	↑	HO-1↑	ND	ND	NS3/4A protease↓, replication↓	p38↑, bilirubin↑, OAS↑, PKR↑, IFN-α↑, HRI↑	Lee et al. [153]
	Fluvastatin	Hepatoma cells		HO-1↑			Replication↓	Bach1↓, KLF2↑, matrix stiffness↑	Wuestenberg et al. [157]
	SFN	Hepatoma cells	↑	HO-1↑	ND	ND	NS3/4A protease↓, replication↓	PI3K↑, PKR↑, OAS↑, IFN-α↑, bilirubin↑	Yu et al. [158]
	Celastrol	Hepatoma cells	↑	HO-1↑	ND	ND	NS3/4A protease↓, replication↓	JNK↑, IFN-α↑, OAS↑	Tseng et al. [162]
	Nrf2 silencing	Hepatoma cells	↓	NQO1↓, GCLC↓, G6PD↓	ND	ND	Replication↓	LD↓, cholesterol↓, triacylglycerol↓, phospholipid↓	Sugiyama et al. [77]
	K67	Hepatoma cells	↓	NQO1↓, GCLC↓, UGDH↓		↓	ND	KEAP1-phospho-p62 interaction↓, tumor growth↓, tolerance to anticancer agents↓	Saito et al. [78]
Influenza virus	Nrf2 silencing	Nasal epithelial cell	↓	HO-1↓	ND	ND	Replication↑, titer↑	ND	Kesic et al. [163]
	EGCG and SFN	Nasal epithelial cell	↑	HO-1↑	↓	↓	Replication↓, entry↓	IFN-α↑, RIG-I↑, MxA↑	Kesic et al. [163]
	Nrf2 deficiency and cigarette smoke	Nrf2-deficient mice	↓	NQO1↓, GCLC↓, HO-1↓	↑	↑	ND	TNF-α ↑, KC↑, IFN-α, NF-κB↑, lung permeability damage↑, mucus production↑, macrophages↑, neutrophils↑, cell injury↑	Yageta et al. [127]
	Nrf2 expression	Human primary alveolar type I-like cells	↑	HO-1↑	↓	↓	Replication↓	GSH↑, IL-8↑, cell injury↓	Kosmider et al. [44]
	Nrf2 deficiency	Human primary alveolar type I-like cells	↓	HO-1↓, MX1↓, OAS1↓	↓	↓	Replication↓	Caspases 1 and 3↑, cell injury↓	Kosmider et al. [44]
	Carbocisteine	Nrf2-deficient mice, macrophages	↑	GCLC↑, GCLM↑, HO-1↑	↓	↓	Replication↓	PI3K↑, 8-OHdG↓, mucus production↓	Yageta et al. [166]
	Broccoli sprouts (SFN)	Human subjects (smoker, nonsmoker)	↑	ND	ND	↓	Replication↓	Inflammation↓, IL-6↓	Noah et al. [167]
	Compounds from S. baicalensis	Nrf2/ARE luciferase reporter (HepG2C8), MDCK	↑	ND	ND	ND	Replication↓	ND	Ji et al. [168]
	Bakuchiol	MDCK	↑	NQO1↑, GST↑	ND	ND	Infection↓, viral titer↓	IFN-α↓, Mx1↓	Shoji et al. [172]
	Compounds from licorice (echinatin)	HepG2	↑	HO-1↑, NQO1↑	ND	ND	Replication↓	ALT↓, AST↓, GSH↓	Ji et al. [173]
	Rupestonic acid deriv, YZH-106 from CYZH pellet	MDCK, RAW264.7	Nuclear translocation↑	HO-1↑	↓	↓	Replication↓	p38↑, ERK1/2↑, IFN-α↑, IFN-β↑, IFIT1↑, IFITM3↑, OAS1↑, PKR↑	Ma et al. [176], Yin et al. [177]
	Emodin	A549 cells	↑	HO-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]
	Curcumin	A549 cells	↑	HO-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]
RSV	Nrf2 deficiency	Bronchoalveolar lavage fluid of Nrf2-deficient mice	↓	GCLC↓, UGT1↓, NQO1↓, HO-1↓, GST↓, GPx↓	ND	↑	Replication↑, viral titer↑	Nasal airway injury↑, mucus production↑, IL-6↑, IL-13↑, GSH↓, GSSG↓, protein oxidation↑, AP-1↑, NF-κB↑, DNP↑	Cho et al. [19]
	SFN	Bronchoalveolar lavage fluid	↑	NQO1↑, GST↑, HO-1↑, GPx↑	ND	ND	Replication↓	Neutrophils↓, eosinophils↓	Cho et al. [19]
	Roflumilast N-oxide	Bronchial epithelia cell	↑	HO-1↑, GPx↑	↓	↓	Replication↓	ICAM-1↓, β-tubulin↑, Foxj1↑, Dnai2↑, MUC5AC↓, hCLCA1↓, IL-13↓, IL-8↓, IL-6↓, TNF-α↓	Mata et al. [88]
	Butylated hydroxyanisole	Bronchial epithelia cell	↑	HO-1↑, NQO1↑, CAT↑, SOD1↑	↓	↓	ND	8-Isoprostaine↓	Komaravelli et al. [90]
HBV	HO-1 induction (CoPP)	Mouse infection model, HepG2 cells		HO-1↑	ND	↓	Core↓, HBeAg↓, HBV DNA↓	ALT↓	Protzer et al. [185]
Herpes virus	Sulforaphane	Astrocyte, mixed neural culture	↑	HO-1↑, GPx↑, GCLM↑, GSH↑	↓	↓	↔	Macrophage infiltration↓	Schachtele et al. [105]
DENV	ATRA	Mononuclear phagocytes	↓	ND	ND	↓	CLEC5A↓, TNF-α↓	ND	Cheng et al. [47]
	HO-1 induction CoPP, andrographolide	Huh-7 cells	ND	HO-1↑	ND	↓	↓	Biliverdin↑, NS2B/NS3 protease↓, IFN-α↑, OASs↑, PKR↑	Tseng et al., 2016
	Nrf2 and HO-1 induction (lucidone)	Huh-7 cells	↑	HO-1↑	ND	↓	Replication↓	Biliverdin↑, NS2B/NS3 protease↓, IFN-α↑, OASs↑, PKR↑	Chen et al. [150]
SVCV	SFN bardoxolone		↑	SOD↑, HO-1↑	ND	ND	↓	Total antioxidant capacity↑	Yang et al. [117], Shao et al. [116]
Coxsackievirus	Isatin derivative 45	HeLa and HL-1 cells	Nuclear localization↑	NQO1↑, GCLM↑	ND	ND	↓	Procaspase 3 cleavage↓, GRP78↑, UPR↑, p-PERK↑, eIF4GI↑, cap-dependent translation↑	Zhang et al. [62, 186]
Coxsackievirus	Melittin	HeLa cells	↑	HO-1↑, NQO1↑, GCL↑	ND	↓	↓	Apoptosis↓, 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 virus	HO-1 induction (hemin)	Human monocyte-derived macrophage	ND	HO-1↑	ND		↓	ND	Huang et al. [188]
VSV	SFN	PC-3	↑	HO-1↑, NQO1, GCLC↑, GCLM↑, SQSTM1↑		↓	↑	Oncolytic activity↑, tumor progression↓, LC3↑, p62↑, autophagy↑, innate antiviral response↓, IRF3↓, STAT1↓, STING↓	Olagnier et al., 2017
Theiler virus	DMF	TMEV-infected mice	↑	HO-1↑, NQO1↑, GCLC↑	ND	↓	↑	IFN-γ, IL-17a, IL-4, IL-10 and TNF-α, T cell response↓	Kobayashi et al. [193]
RHDV	Melatonin	New Zealand white rabbits	↑	SOD↑, GPx↑, GST↑	ND	↓	ND	ND	Crespo et al. [195]
PCV2	Selenium, selenoprotein S	PK15	↑	GCL↑, GCSL↑, GSH↑	↓	ND	Ochratoxin 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.