KMID : 0620920120440060369
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Experimental & Molecular Medicine 2012 Volume.44 No. 6 p.369 ~ p.377
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A new synthetic chalcone derivative, 2-hydroxy-3',5,5'-trimethoxychalcone (DK-139), suppresses the Toll-like receptor 4-mediated inflammatory response through inhibition of the Akt/NF-¥êB pathway in BV2 microglial cells
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Lee Young-Han
Jeon Seung-Hyun Kim Se-Hyun Kim Chang-Youn Lee Seung-Jae Koh Dong-Soo Lim Yoong-Ho Ha Kyoo-Seob Shin Soon-Young
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Abstract
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Microglial cells are the resident innate immune cells that sense pathogens and tissue injury in the central nervous system (CNS). Microglial activation is critical for neuroinflammatory responses. The synthetic compound 2-hydroxy-3',5,5'-trimethoxychalcone (DK-139) is a novel chalcone-derived compound. In this study, we investigated the effects of DK-139 on Toll-like receptor 4 (TLR4)-mediated inflammatory responses in BV2 microglial cells. DK-139 inhibited lipopolysaccharide (LPS)-induced TLR4 activity, as determined using a cell-based assay. DK-139 blocked LPS-induced phosphorylation of I¥êB and p65/RelA NF-¥êB, resulting in inhibition of the nuclear translocation and trans-acting activity of NF-¥êB in BV2 microglial cells. We also found that DK-139 reduced the expression of NF-¥êB target genes, such as those for COX-2, iNOS, and IL-1¥â, in LPS-stimulated BV2 microglial cells. Interestingly, DK-139 blocked LPS-induced Akt phosphorylation. Inhibition of Akt abrogated LPS-induced phosphorylation of p65/RelA, while overexpression of dominant-active p110CAAX enhanced p65/RelA phosphorylation as well as iNOS and COX2 expression. These results suggest that DK-139 exerts an anti-inflammatory effect on microglial cells by inhibiting the Akt/I¥êB kinase (IKK)/NF-¥êB signaling pathway.
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KEYWORD
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chalcone, lipopolysaccharides, microglia, NF-¥êB, proto-oncogene proteins c-akt, Toll-like receptor 4
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