Oridonin confers protection against arsenic-induced toxicity through activation of the Nrf2-mediated defensive response

Yu Du, Nicole F. Villeneuve, Xiao Jun Wang, Zheng Sun, Weimin Chen, Jixue Li, Hongxiang Lou, Pak Kin Wong, Donna Zhang

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Background: Groundwater contaminated with arsenic imposes a big challenge to human health worldwide. Using natural compounds to subvert the detrimental effects of arsenic represents an attractive strategy. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical regulator of the cellular antioxidant response and xenobiotic metabolism. Recently, activation of the Nrf2 signaling pathway has been reported to confer protection against arsenic-induced toxicity in a cell culture model. Objectives: The goal of the present work was to identify a potent Nrf2 activator from plants as a chemopreventive compound and to demonstrate the efficacy of the compound in battling arsenic-induced toxicity. Results: Oridonin activated the Nrf2 signaling pathway at a low subtoxic dose and was able to stabilize Nrf2 by blocking Nrf2 ubiquitination and degradation, leading to accumulation of the Nrf2 protein and activation of the Nrf2-dependent cytoprotective response. Pretreatment of UROtsa cells with 1.4 μM oridonin significantly enhanced the cellular redox capacity, reduced formation of reactive oxygen species (ROS), and improved cell survival after arsenic challenge. Conclusions: We identified oridonin as representing a novel class of Nrf2 activators and illustrated the mechanism by which the Nrf2 pathway is activated. Furthermore, we demonstrated the feasibility of using natural compounds targeting Nrf2 as a therapeutic approach to protect humans from various environmental insults that may occur daily.

Original languageEnglish (US)
Pages (from-to)1154-1161
Number of pages8
JournalEnvironmental Health Perspectives
Volume116
Issue number9
DOIs
StatePublished - Sep 2008

Fingerprint

Arsenic
NF-E2 Transcription Factor
Ubiquitination
Groundwater
Xenobiotics
Oxidation-Reduction
Reactive Oxygen Species
Cell Survival
Cell Culture Techniques
Antioxidants
oridonin
Proteins

Keywords

  • Antioxidant responsive element
  • Antitumor
  • ARE
  • Arsenic
  • Chemoprevention
  • Diterpenoid
  • Keapl
  • Nrf2
  • Oridonin
  • Oxidative stress
  • Rubescensin

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Public Health, Environmental and Occupational Health

Cite this

Oridonin confers protection against arsenic-induced toxicity through activation of the Nrf2-mediated defensive response. / Du, Yu; Villeneuve, Nicole F.; Wang, Xiao Jun; Sun, Zheng; Chen, Weimin; Li, Jixue; Lou, Hongxiang; Wong, Pak Kin; Zhang, Donna.

In: Environmental Health Perspectives, Vol. 116, No. 9, 09.2008, p. 1154-1161.

Research output: Contribution to journalArticle

Du, Yu ; Villeneuve, Nicole F. ; Wang, Xiao Jun ; Sun, Zheng ; Chen, Weimin ; Li, Jixue ; Lou, Hongxiang ; Wong, Pak Kin ; Zhang, Donna. / Oridonin confers protection against arsenic-induced toxicity through activation of the Nrf2-mediated defensive response. In: Environmental Health Perspectives. 2008 ; Vol. 116, No. 9. pp. 1154-1161.
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