Antioxidant mechanism of isoflavone metabolites in hydrogen peroxide-stimulated rat primary astrocytes: Critical role of hemeoxygenase-1 and NQO1 expression

Jin Sun Park, Ji Sun Jung, Yeon Hui Jeong, Jin Won Hyun, Thi Kim Van Le, Dong Hyun Kim, Eung Chil Choi, Hee Sun Kim

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

The brain is highly vulnerable to oxidative stress, thus controlling oxidative stress is considered to be an important therapeutic target for neurodegenerative diseases. In this study, we found that two isoflavone metabolites (tectorigenin and glycitein) inhibited hydrogen peroxide-induced reactive oxygen species (ROS) generation and subsequent cell death in rat primary astrocytes. The isoflavone metabolites increased the expression of phase II antioxidant enzymes, such as hemeoxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), and pre-treatment of cells with their specific inhibitors or small interfering RNA (siRNA) reversed the antioxidant and cytoprotective effects of isoflavones. The results suggest that the antioxidant/cytoprotective effects of isoflavone metabolites are at least because of increased HO-1 and NQO1 expression. Further mechanistic studies revealed that isoflavones increase the binding of transcription factors [nuclear factor-E2-related factor 2 (Nrf2) and c-Jun] to the antioxidant response element (ARE) on HO-1 and NQO1 promoters. Down-regulation of Nrf2 and/or c-Jun using dominant-negative mutants (DNMs) or siRNA diminished the expression of HO-1 and NQO1, suggesting that Nrf2 and c-Jun are key transcription factors modulating HO-1/NQO1 expression. Moreover, PI3 kinase and mitogen-activated protein kinase (MAPK) signaling pathways were shown to be involved in HO-1 and/or NQO1 expression by isoflavones. Our data collectively suggest that HO-1 and NQO1 play a critical role in antioxidant effects of isoflavone metabolites in rat brain astrocytes.

Original languageEnglish
Pages (from-to)909-919
Number of pages11
JournalJournal of Neurochemistry
Volume119
Issue number5
DOIs
StatePublished - Dec 2011

Keywords

  • astrocytes
  • isoflavone metabolites
  • phase II antioxidant enzymes
  • signaling pathway
  • transcription factors

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