Pyrrole-Derivative of Chalcone, (E)-3-Phenyl-1-(2-Pyrrolyl)-2-Propenone, Inhibits Inflammatory Responses via Inhibition of Src, Syk, and TAK1 Kinase Activities.
10.4062/biomolther.2016.027
- Author:
Sungjae YANG
1
;
Yong KIM
;
Deok JEONG
;
Jun Ho KIM
;
Sunggyu KIM
;
Young Jin SON
;
Byong Chul YOO
;
Eun Jeong JEONG
;
Tae Woong KIM
;
In Sook HAN LEE
;
Jae Youl CHO
Author Information
1. Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea. jaecho@skku.edu
- Publication Type:Original Article
- Keywords:
Pyrrole;
Chalcone;
Anti-inflammatory activity;
Macrophages;
NF-κB
- MeSH:
Chalcone*;
Genes, Reporter;
HEK293 Cells;
Luciferases;
Macrophages;
Necrosis;
Nitric Oxide;
Nitric Oxide Synthase;
Phosphotransferases*;
RNA, Messenger;
Transcription Factor AP-1
- From:Biomolecules & Therapeutics
2016;24(6):595-603
- CountryRepublic of Korea
- Language:English
-
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 β-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-κB 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-α (TNF-α) 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-κB-mediated luciferase activity dose-dependently diminished. Additionally, it was confirmed that PPP dampens the upstream signaling cascade of NF-κB 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.
