Sulforaphane protects against ethanol‐induced oxidative stress and apoptosis in neural crest cells by the induction of Nrf2‐mediated antioxidant response

Abstract

BACKGROUND AND PURPOSENuclear factor erythroid 2-related factor (Nrf2) is a transcription factor that up-regulates a diverse array of antioxidant genes and protects cells from oxidative damage. This study is designed to determine whether D-L-sulforaphane (SFN) can protect neural crest cells (NCCs), an ethanol-sensitive cell population implicated in fetal alcohol spectrum disorders, against ethanolinduced apoptosis and whether protective effects of SFN are mediated by the induction of Nrf2-mediated antioxidant response. EXPERIMENTAL APPROACHControl, SFN-treated or Nrf2-siRNA transfected NCCs were exposed to ethanol. Nrf2 activation, the expression and activities of Nrf2 downstream antioxidant proteins, reactive oxygen species generation and apoptosis were determined in control and ethanol-exposed NCCs. KEY RESULTSExposure of NCCs to SFN alone significantly increased Nrf2 activation and the expression of Nrf2 downstream antioxidants as well as the activities of the antioxidant enzymes. Treatment of NCCs with SFN along with ethanol significantly decreased ethanol-induced oxidative stress and apoptosis. In contrast, knockdown of Nrf2 by siRNA significantly increased the sensitivity of NCCs to ethanol-induced oxidative stress and apoptosis. Suppression of Nrf2 signalling in NCCs also significantly diminished SFN-mediated antioxidant response and abolished the protective effects of SFN on ethanol-induced oxidative stress and apoptosis. CONCLUSIONS AND IMPLICATIONSThese results demonstrated that Nrf2-mediated antioxidant response plays an important role in the susceptibility of NCCs to ethanol-induced oxidative stress and apoptosis and that the protection of SFN against ethanol-induced oxidative stress and apoptosis in NCCs is mediated by the induction of Nrf2 signalling. AbbreviationsARE, antioxidant response element; D3T, 3H-1,2-dithiole-3-thione; DCHFDA, 2′,7′-dichlorodihydrofluoroscein diacetate; FASD, fetal alcohol spectrum disorder; MTS, 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt; NCC, neural crest cell; NQO1, NAD(P)H:quinone oxidoreductase 1; Nrf2, nuclear factor erythroid 2-related factor; ROS, reactive oxygen species; SFN, D-L-sulforaphane; SOD, superoxide dismutase BJP British Journal of Pharmacology

Sulforaphane Inhibits the Proliferation of the BIU87 Bladder Cancer Cell Line via IGFBP-3 Elevation

“…It has been reported that sulforaphane functions as an antioxidant in skin and neural tissue (Kleszczynski et al, 2013;Chen et al, 2013). Moreover, anticancer potential of sulforaphane by suppressing cancer cell proliferation has also been well documented in breast, prostate and colon cancer cells (Johnston et al, 2004;Frydoonfar et al, 2004;HermanAntosiewicz et al, 2007).…”

A Glance at… Broccoli, glucoraphanin, and sulforaphane

“…A similar release of Nrf2 from the gatekeeper complex is produced by the binding of sulforaphane to the complex [4,26,27,[46][47][48]. Following its release, free Nrf2 undergoes translocation to the nucleus where it accumulates and forms complexes with small transcription factors (such as the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog; Maf) that bind to the genomic antioxidant response element (ARE), activating the expression of both phase 2 detoxification systems and the complete armamentarium of endogenous antioxidant enzymes [4,26,27,36,[46][47][48][49][50][51][52][53][54][55][56].…”

“…Nrf2 activation and the indirect antioxidant effects of sulforaphane appear to be ubiquitous; they have been observed in the liver [30][31][32]41,59,60], kidney [60], lungs [60][61][62][63], lens [58], central nervous system [49,60], immune system [50], choroid plexus [51], small intestine [9], large intestine [60], prostate [60], retinal pigment epithelial cells [34,39,64], corneal epithelial cells [55], astroglial cells [54], fetal neural crest cells [52], neuroblastoma cells [36], insulin-secreting pancreatic cells [65], differentiated peripheral blood neutrophils [53], endothelial cells [40], osteoblasts [37], and keratinocytes [33][34][35].…”

Stress Response of Dietary Phytochemicals in a Hormetic Manner for Health and Longevity

“…Sulforaphane may prevent diabetic auric damage and cardiomyopathy by increasing Nrf2 activation in mice [104,105]. Sulforaphane showed protective effect against ethanol-induced oxidative stresses and apoptosis in neural crest cells by generating an antioxidant response with Nrf2 activation [106]. Sulforaphane activates the Nrf2/ARE pathway and inhibits 3-nitropropionic acidinduced toxicity in striatal cells by inhibiting MAPKs and NF-κB pathways [107].…”