title: A purified feverfew extract protects from oxidative damage by inducing DNA repair in skin cells via a PI3-kinase-dependent Nrf2/ARE pathway.
abstract: BACKGROUND
  Environmental factors such as solar ultraviolet (UV) radiation and other external aggressors provide an oxidative challenge that is detrimental to skin health. The levels of endogenous antioxidants decrease with age, thus resulting in less protection and a greater potential for skin damage. The NF-E2-related factor-2 (Nrf2) - antioxidant response element (ARE) pathway is a primary defense mechanism against oxidative stress, and induces the expression of antioxidant, detoxification and repair genes. Activation of ARE-Nrf2 can help restore oxidative homeostasis of the skin and play a role in inflammatory response and DNA repair mechanisms.
  
  
  OBJECTIVE
  To evaluate the role of a purified parthenolide-depleted Feverfew (PD-Feverfew) extract on the ARE-Nrf2 pathway and DNA repair in skin cells.
  
  
  METHODS
  These studies were undertaken in primary human keratinocytes or KB cells using Luciferase Promoter assay, siRNA transfection studies, Western blot analyses, Immunofluorescence microscopy, comet assay and quantitative real-time PCR.
  
  
  RESULTS
  PD-Feverfew was found to induce Nrf2 nuclear translocation and to increase ARE activity in a dose dependent manner. Furthermore, knockdown of Nrf2 resulted in suppression of PD-Feverfew-induced ARE activity. PD-Feverfew was also found to induce phosphorylation of Akt, a kinase downstream of PI3K. Inhibition of PI3K via pre-treatment with the selective pharmacological inhibitor, LY294002, abolished PD-Feverfew-induced Nrf2/ARE activation. PD-Feverfew also reduced UV-induced DNA damage in a PI3K and Nrf2-dependent manner.
  
  
  CONCLUSIONS
  Therefore, by increasing endogenous defense mechanisms and aid in DNA repair of damaged skin cells via activation of a PI3K-dependent Nrf2/ARE pathway, PD-Feverfew may help protect the skin from numerous environmental aggressors.
authors.affiliation: Skin Biology and Pharmacology, Johnson and Johnson Skin Research Center, Skillman, NJ, USA.
authors.forename: Karien J
authors.initials: KJ
authors.lastname: Rodriguez
authors.forename: Heng-Kuan
authors.initials: HK
authors.lastname: Wong
authors.forename: Thierry
authors.initials: T
authors.lastname: Oddos
authors.forename: Michael
authors.initials: M
authors.lastname: Southall
authors.forename: Balz
authors.initials: B
authors.lastname: Frei
authors.forename: Simarna
authors.initials: S
authors.lastname: Kaur
mesh_terms: D061745:Antioxidant Response Elements / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007624:KB Cells; D015603:Keratinocytes / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010936:Plant Extracts / Q000494:pharmacology*; D020903:Tanacetum parthenium
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010936:Plant Extracts; D019869:Phosphatidylinositol 3-Kinases
keywords: ARE; Antioxidants; DNA repair; Feverfew; Nrf2