Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Pyrrole-Derivative of Chalcone, (E)-3-Phenyl-1-(2-Pyrrolyl)-2-Propenone, Inhibits Inflammatory Responses via Inhibition of Src, Syk, and TAK1 Kinase Activities

  • Yang, Sungjae (Department of Genetic Engineering, Sungkyunkwan University) ;
  • Kim, Yong (Department of Genetic Engineering, Sungkyunkwan University) ;
  • Jeong, Deok (Department of Genetic Engineering, Sungkyunkwan University) ;
  • Kim, Jun Ho (Department of Genetic Engineering, Sungkyunkwan University) ;
  • Kim, Sunggyu (Research and Business Foundation, Sungkyunkwan University) ;
  • Son, Young-Jin (College of Pharmacy, Sunchon National University) ;
  • Yoo, Byong Chul (Colorectal Cancer Branch, Research Institute, National Cancer Center) ;
  • Jeong, Eun Jeong (Department of Science Education, Kangwon National University) ;
  • Kim, Tae Woong (Department of Biochemistry, Kangwon National University) ;
  • Han Lee, In-Sook (Department of Science Education, Kangwon National University) ;
  • Cho, Jae Youl (Department of Genetic Engineering, Sungkyunkwan University)
  • Received : 2016.02.11
  • Accepted : 2016.04.21
  • Published : 2016.11.01
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Abstract

(E)-3-Phenyl-1-(2-pyrrolyl)-2-propenone (PPP) is a pyrrole derivative of chalcone, in which the B-ring of chalcone linked to ${\beta}$-carbon is replaced by pyrrole group. While pyrrole has been studied for possible Src inhibition activity, chalcone, especially the substituents on the B-ring, has shown pharmaceutical, anti-inflammatory, and anti-oxidant properties via inhibition of NF-${\kappa}B$ activity. Our study is aimed to investigate whether this novel synthetic compound retains or enhances the pharmaceutically beneficial activities from the both structures. For this purpose, inflammatory responses of lipopolysaccharide (LPS)-treated RAW264.7 cells were analyzed. Nitric oxide (NO) production, inducible NO synthase (iNOS) and tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) mRNA expression, and the intracellular inflammatory signaling cascade were measured. Interestingly, PPP strongly inhibited NO release in a dose-dependent manner. To further investigate this anti-inflammatory activity, we identified molecular pathways by immunoblot analyses of nuclear fractions and whole cell lysates prepared from LPS-stimulated RAW264.7 cells with or without PPP pretreatment. The nuclear levels of p50, c-Jun, and c-Fos were significantly inhibited when cells were exposed to PPP. Moreover, according to the luciferase reporter gene assay after cotransfection with either TRIF or MyD88 in HEK293 cells, NF-${\kappa}B$-mediated luciferase activity dose-dependently diminished. Additionally, it was confirmed that PPP dampens the upstream signaling cascade of NF-${\kappa}B$ and AP-1 activation. Thus, PPP inhibited Syk, Src, and TAK1 activities induced by LPS or induced by overexpression of these genes. Therefore, our results suggest that PPP displays anti-inflammatory activity via inhibition of Syk, Src, and TAK1 activity, which may be developed as a novel anti-inflammatory drug.

Keywords

References

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