title: Tanshinone I activates the Nrf2-dependent antioxidant response and protects against As(III)-induced lung inflammation in vitro and in vivo.
abstract: OBJECTIVE
  The NF-E2 p45-related factor 2 (Nrf2) signaling pathway regulates the cellular antioxidant response and activation of Nrf2 has recently been shown to limit tissue damage from exposure to environmental toxicants, including As(III). In an attempt to identify improved molecular agents for systemic protection against environmental insults, we have focused on the identification of novel medicinal plant-derived Nrf2 activators.
  
  
  RESULTS
  Tanshinones [tanshinone I (T-I), tanshinone IIA, dihydrotanshinone, cryptotanshinone], phenanthrenequinone-based redox therapeutics derived from the medicinal herb Salvia miltiorrhiza, have been tested as experimental therapeutics for Nrf2-dependent cytoprotection. Using a dual luciferase reporter assay overexpressing wild-type or mutant Kelch-like ECH-associated protein-1 (Keap1), we demonstrate that T-I is a potent Keap1-C151-dependent Nrf2 activator that stabilizes Nrf2 by hindering its ubiquitination. In human bronchial epithelial cells exposed to As(III), T-I displays pronounced cytoprotective activity with upregulation of Nrf2-orchestrated gene expression. In Nrf2 wild-type mice, systemic administration of T-I attenuates As(III) induced inflammatory lung damage, a protective effect not observed in Nrf2 knockout mice.
  
  
  METHODS
  Tanshinones have been identified as a novel class of Nrf2-inducers for antioxidant tissue protection in an in vivo As(III) inhalation model, that is relevant to low doses of environmental exposure.
  
  
  CONCLUSIONS
  T-I represents a prototype Nrf2-activator that displays cytoprotective activity upon systemic administration targeting lung damage originating from environmental insults. T-I based Nrf2-directed systemic intervention may provide therapeutic benefit in protecting other organs against environmental insults.
authors: 1 Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona , Tucson, Arizona.
authors: Shasha
authors: S
authors: Tao
authors: Yi
authors: Y
authors: Zheng
authors: Alexandria
authors: A
authors: Lau
authors: Melba C
authors: MC
authors: Jaramillo
authors: Binh T
authors: BT
authors: Chau
authors: R Clark
authors: RC
authors: Lantz
authors: Pak K
authors: PK
authors: Wong
authors: Georg T
authors: GT
authors: Wondrak
authors: Donna D
authors: DD
authors: Zhang
mesh_terms: D045784:Abietanes / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001151:Arsenic / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010616:Phenanthrenes / Q000627:therapeutic use; D011014:Pneumonia / Q000139:chemically induced* / Q000188:drug therapy*; D027561:Salvia miltiorrhiza / Q000737:chemistry
chemical_list: D045784:Abietanes; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D010616:Phenanthrenes; C021751:tanshinone; C037886:cryptotanshinone; D001151:Arsenic
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