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


OBJECTIVE
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 muM 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.
Du
Yu
Y
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
Villeneuve
Nicole F
NF
Wang
Xiao-Jun
XJ
Sun
Zheng
Z
Chen
Weimin
W
Li
Jixue
J
Lou
Hongxiang
H
Wong
Pak Kin
PK
Zhang
Donna D
DD
D001151:Arsenic / Q000633:toxicity*; D045744:Cell Line, Tumor; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination
D045786:Diterpenes, Kaurane; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C011959:oridonin; D001151:Arsenic
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