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Anti-inflammatory effects of beta-hydroxyisovalerylshikonin in BV2 microglia are mediated through suppression of the PI3K/Akt/NF-kB pathway and activation of the Nrf2/HO-1 pathway
- Anti-inflammatory effects of beta-hydroxyisovalerylshikonin in BV2 microglia are mediated through suppression of the PI3K/Akt/NF-kB pathway and activation of the Nrf2/HO-1 pathway
- Jayasooriya, RGPT[Jayasooriya, Rajapaksha Gedara Prasad Tharanga]; Lee, KT[Lee, Kyoung-Tae]; Lee, HJ[Lee, Hak-Ju]; Choi, YH[Choi, Yung Hyun]; Jeong, JW[Jeong, Jin-Woo]; Kim, GY[Kim, Gi-Young]
- DGIST Authors
- Jeong, JW[Jeong, Jin-Woo]
- Issue Date
- Food and Chemical Toxicology, 65, 82-89
- Article Type
- (3 Hydroxyisovaleryl)Shikonin; Animals; Anti-Inflammatory Activity; Anti-Inflammatory Agent; Beta-Hydroxyisovalerylshikonin; Beta Hydroxyisovalerylshikonin; Cell Line; Concentration Response; Controlled Study; COX 2 Gene; Cyclooxygenase 2; Dinoprostone; DNA; DNA-Binding; Down-Regulation; Drug Mechanism; Drug Research; Drug Structure; Enzyme Induction; Gene Expression Regulation; Heme Oxygenase-1; I Kappa B Alpha; Immunoglobulin Enhancer Binding Protein; Inducible Nitric Oxide Synthase; Inos Gene; Lipopolysaccharide; Lipopolysaccharides; Magnetic Resonance Spectroscopy; Mice; Microglia; Molecular Structure; Naphthoquinones; Nerve Cell Culture; NF-E2-Related Factor 2; NF-Kappa B; Nitric Oxide; Nuclear Factor-Erythroid 2-Related Factor 2; nuclear factor-Kappa B; Phosphatidylinositol 3-Kinases; Phosphatidylinositol 3 Kinase; Phosphorylation; Prostaglandin E2; Prostaglandin Synthesis Inhibition; Protein Degradation; Protein DNA Binding; Protein Expression; Protein Kinase B; Protein Phosphorylation; Protein Secretion; Proto-Oncogene Proteins C-AKT; Pyrrolidines; Shikonin Derivative; Thiocarbamates; Transcription Factor Nrf2; Unclassified Drug; Upregulation
- In the present study, we investigated whether β-hydroxyisovalerylshikonin (β-HIVS) affects the production of proinflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2) in BV2 microglial cells. Our data showed that β-HIVS inhibited secretion of NO and PGE2 and downregulated expression of their main regulatory genes, inducible NO synthesis (iNOS) and cyclooxygenase-2 (COX-2). β-HIVS also reduced the LPS-induced DNA-binding activity of nuclear factor-κB (NF-κB) by suppressing nuclear translocation of the NF-κB subunits and inhibiting the degradation and phosphorylation of IκBα. Furthermore, an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), attenuated LPS-stimulated iNOS and COX-2 expression, suggesting that NF-κB inhibition is a main effector in the expression of iNOS and COX-2. We also found that LPS-induced NF-κB activation is regulated through inhibition of PI3K/Akt phosphorylation in response to β-HIVS. Additionally, β-HIVS caused the induction of heme oxygenase-1 (HO-1) via upregulation of nuclear factor-erythroid 2-related factor 2 (Nrf2), both of which are involved in the secretion of proinflammatory mediators such as NO and PGE2. Taken together, our data indicate that β-HIVS diminishes the proinflammatory mediators NO and PGE2 and the expression of their regulatory genes, iNOS and COX-2, in LPS-stimulated BV2 microglial cells by inhibiting PI3K/Akt-dependent NF-κB activation and inducing Nrf2-mediated HO-1 expression. © 2013 Elsevier Ltd.
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