Document Detail

Willow bark extract increases antioxidant enzymes and reduces oxidative stress through activation of Nrf2 in vascular endothelial cells and Caenorhabditis elegans.
MedLine Citation:
PMID:  23277146     Owner:  NLM     Status:  MEDLINE    
Willow bark extract (WBE) is listed in the European Pharmacopoeia and has been traditionally used for treating fever, pain, and inflammation. Recent studies have demonstrated its clinical usefulness. This study investigated the antioxidative effects of WBE in human umbilical vein endothelial cells (HUVECs) and Caenorhabditis elegans. WBE prevented oxidative-stress-induced cytotoxicity of HUVECs and death of C. elegans. WBE dose-dependently increased mRNA and protein expression levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) target genes heme oxygenase-1, γ-glutamylcysteine ligase modifier and catalytic subunits, and p62 and intracellular glutathione (GSH) in HUVECs. In the nematode C. elegans, WBE increased the expression of the gcs-1::green fluorescent protein reporter, a well-characterized target of the Nrf2 ortholog SKN-1, in a manner that was SKN-1-dependent. WBE increased intranuclear expression and DNA binding of Nrf2 and the activity of an antioxidant response element (ARE) reporter plasmid in HUVECs. WBE-induced expression of Nrf2-regulated genes and increased GSH levels in HUVECs were reduced by Nrf2 and p38 small interfering (si) RNAs and by the p38-specific inhibitor SB203580. Nrf2 siRNA reduced the cytoprotective effect of WBE against oxidative stress in HUVECs. Salicin, a major anti-inflammatory ingredient of WBE, failed to activate ARE-luciferase activity, whereas a salicin-free WBE fraction showed intensive activity. WBE induced antioxidant enzymes and prevented oxidative stress through activation of Nrf2 independent of salicin, providing a new potential explanation for the clinical usefulness of WBE.
Atsushi Ishikado; Yoko Sono; Motonobu Matsumoto; Stacey Robida-Stubbs; Aya Okuno; Masashi Goto; George L King; T Keith Blackwell; Taketoshi Makino
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-12-28
Journal Detail:
Title:  Free radical biology & medicine     Volume:  65     ISSN:  1873-4596     ISO Abbreviation:  Free Radic. Biol. Med.     Publication Date:  2013 Dec 
Date Detail:
Created Date:  2013-12-10     Completed Date:  2014-09-02     Revised Date:  2014-10-03    
Medline Journal Info:
Nlm Unique ID:  8709159     Medline TA:  Free Radic Biol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1506-15     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
Antioxidant Response Elements / genetics
Benzyl Alcohols / pharmacology
Caenorhabditis elegans / enzymology*
Caenorhabditis elegans Proteins / biosynthesis,  genetics
Carboxylic Ester Hydrolases / metabolism
Cells, Cultured
Cyclooxygenase Inhibitors / pharmacology
DNA-Binding Proteins / biosynthesis,  genetics
Endothelial Cells / enzymology
Enzyme Activation
Enzyme Inhibitors / pharmacology
Glucosides / pharmacology
Glutamate-Cysteine Ligase / biosynthesis,  genetics
Glutathione / biosynthesis,  genetics
Heme Oxygenase-1 / biosynthesis,  genetics
Human Umbilical Vein Endothelial Cells / enzymology*
Imidazoles / pharmacology
NF-E2-Related Factor 2 / genetics,  metabolism*
Oxidative Stress / drug effects
Plant Bark / chemistry
Plant Extracts / pharmacology*
Proto-Oncogene Proteins c-myc / biosynthesis,  genetics
Pyridines / pharmacology
RNA Interference
RNA, Messenger / biosynthesis
RNA, Small Interfering
Salix / chemistry*
Transcription Factors / biosynthesis,  genetics
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors,  genetics
Grant Support
Reg. No./Substance:
0/Antioxidants; 0/Benzyl Alcohols; 0/Caenorhabditis elegans Proteins; 0/Cyclooxygenase Inhibitors; 0/DNA-Binding Proteins; 0/Enzyme Inhibitors; 0/Glucosides; 0/Imidazoles; 0/NF-E2-Related Factor 2; 0/Plant Extracts; 0/Proto-Oncogene Proteins c-myc; 0/Pyridines; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/SB 203580; 0/Transcription Factors; 148733-36-2/skn-1 protein, C elegans; 4649620TBZ/salicin; EC Oxygenase-1; EC Mitogen-Activated Protein Kinases; EC 3.1.1.-/Carboxylic Ester Hydrolases; EC; EC Ligase; GAN16C9B8O/Glutathione

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