Powerful and prolonged protection of human retinal pigment epithelial cells, keratinocytes, and mouse leukemia cells against oxidative damage: The indirect antioxidant effects of sulforaphane

Gao, Xin-Yan; Dinkova‐Kostova, Albena T.; Talalay, Paul

doi:10.1073/pnas.261572998

Cited by 182 publications

(133 citation statements)

References 34 publications

(35 reference statements)

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“…HaCaT keratinocytes were chosen to examine this possibility because NQO1 is induced in this cell line by treatment with sulforaphane (Sul) (34). Initial experiments indicated that transfection of HaCaT cells with FITCtagged oligonucleotides resulted in 60-70% of cells staining positively under fluorescence microscopy.…”

Section: Resultsmentioning

confidence: 99%

Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype

Devling

Lindsay²,

McLellan³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

117

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A duplex 21 nucleotide small interfering RNA (siRNA) against human Keap1 is described that represents a unique class of cancer chemopreventive agent. This siRNA can knockdown Keap1 mRNA and thereby relieve negative regulation of nuclear factor erythroid 2 p45-related factor 2 (Nrf2)-mediated gene expression. The siRNA lowered endogenous Keap1 mRNA to <30% of control levels between 24 and 72 h after transfection in human HaCaT keratinocyte cells and was capable of blocking ectopic expression of FLAG-tagged human Keap1 protein but not that of ectopic V5-tagged mouse Keap1 protein. Transfection of human HaCaT cells with Keap1 siRNA markedly enhanced endogenous levels of nuclear factor erythroid 2 p45-related factor 2 (Nrf2) protein and increased transcription of an antioxidant response element-driven reporter gene by 2.3-fold. Furthermore, 48 h after transfection of these cells with Keap1 siRNA, expression of aldo-keto reductase 1C1͞2 and the glutamate cysteine ligase catalytic and modifier subunits was elevated between 5-and 14-fold. A modest increase of 3-fold in NAD(P)H:quinone oxidoreductase 1 was also observed. The Keap1 siRNA produced a 1.75-fold increase in intracellular glutathione 48 h after transfection. Thus, antagonism of Keap1 by siRNA can be used to preadapt human cells to oxidative stress without the need to expose them to redox stressors.antioxidant ͉ chemoprevention ͉ glutathione ͉ nuclear factor erythroid 2 p45-related factor 2 ͉ aldo-keto reductase

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Section: Resultsmentioning

confidence: 99%

Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype

Devling

Lindsay²,

McLellan³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

117

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“…The current literature describes the importance of Nrf2 for cellular resistance to pro-oxidant molecules (H 2 O 2 , tBHQ, and peroxynitrite), oxidant-generating molecules (menadione), in vivo situations that potentiate ROS-mediated damage (hyperoxic lung injury), as well as cytotoxic molecules that are neutralized by GSH detoxification or glucuronidation (4-hydroxynonenal, acetaminophen) (Duffy et al, 1998;Chan and Kan, 1999;Gao et al, 2001;Cho et al, 2002). However, it remains to be determined whether Nrf2 can provide resistance to relatively ROSindependent forms of cell death (i.e., excitotoxicity).…”

Section: Discussionmentioning

confidence: 99%

“…Now, there are ϳ2 dozen known phase II enzyme genes, with more to be elucidated via current technologies . Sharing common regulatory pathways, these enzymes possess chemically versatile antioxidant properties and are inducible by various agents, including those found in a normal diet (Fahey et al, 1997;Gao et al, 2001). Treatment of mammalian cells with electrophilic agents provokes a cellular response leading to the coordinated transcription of phase II genes (Prestera et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

Johnson²,

et al. 2003

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Astrocytes have a higher antioxidant potential in comparison to neurons. Pathways associated with this selective advantage include the transcriptional regulation of antioxidant enzymes via the action of the Cap'n'Collar transcription factor Nrf2 at the antioxidant response element (ARE). Here we show that Nrf2 overexpression can reengineer neurons to express this glial pathway and enhance antioxidant gene expression. However, Nrf2-mediated protection from oxidative stress is conferred primarily by glia in mixed cultures. The antioxidant properties of Nrf2-overexpressing glia are more pronounced than those of neurons, and a relatively small number of these glia (Ͻ 1% of total cell number added) could protect fully cocultured naive neurons from oxidative glutamate toxicity associated with glutathione (GSH) depletion. Microarray and biochemical analyses indicate a coordinated upregulation of enzymes involved in GSH biosynthesis (xCT cystine antiporter, ␥-glutamylcysteine synthetase, and GSH synthase), use (glutathione S-transferase and glutathione reductase), and export (multidrug resistance protein 1) with Nrf2 overexpression, leading to an increase in both media and intracellular GSH. Selective inhibition of glial GSH synthesis and the supplementation of media GSH indicated that an Nrf2-dependent increase in glial GSH synthesis was both necessary and sufficient for the protection of neurons, respectively. Neuroprotection was not limited to overexpression of Nrf2, because activation of endogenous glial Nrf2 by the small molecule ARE inducer, tert-butylhydroquinone, also protected against oxidative glutamate toxicity.

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“…Induction of the phase 2 response protects against reactive oxygen species (ROS) arising from exogenous oxidants and oxidative cycling in many cell lines, including ARPE-19 retinal pigment epithelial cells (26,27) and U937 leukemia cells (19). We examined this protection and its dependence on nrf2 gene function by measuring formation of fluorescent products from the oxidationsensitive dye 2Ј,7Ј-dichlorodihydrofluorescein diacetate (DCFH-DA) in RAW264.7 cells and peritoneal macrophages derived from WT and nrf2 Ϫ/Ϫ mice that were exposed to tert-butyl hydroperoxide ( Table 2).…”

Section: Protection Of Macrophages Against Oxidative Stress By Inducementioning

confidence: 99%

Coordinate regulation of enzyme markers for inflammation and for protection against oxidants and electrophiles

Liu

Dinkova‐Kostova

Talalay

2008

Proc. Natl. Acad. Sci. U.S.A.

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110

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Powerful and prolonged protection of human retinal pigment epithelial cells, keratinocytes, and mouse leukemia cells against oxidative damage: The indirect antioxidant effects of sulforaphane

Abstract: median effect plot ͉ tert-butylhydroperoxide ͉ peroxynitrite ͉ glutathione ͉ quinone reductase ͉ 4-hydroxynonenal

Cited by 182 publications

References 34 publications

Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype

Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

Coordinate regulation of enzyme markers for inflammation and for protection against oxidants and electrophiles

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