title: Pyrrole-Derivative of Chalcone, (E)-3-Phenyl-1-(2-Pyrrolyl)-2-Propenone, Inhibits Inflammatory Responses via Inhibition of Src, Syk, and TAK1 Kinase Activities.
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.
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Sungjae
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Yong
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Deok
authors.initials: D
authors.lastname: Jeong
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Jun Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Research and Business Foundation, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Sunggyu
authors.initials: S
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Sunchon National University, Suncheon 57922, Republic of Korea.
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Son
authors.affiliation: Colorectal Cancer Branch, Research Institute, National Cancer Center, Gyeonggi 10408, Republic of Korea.
authors.forename: Byong Chul
authors.initials: BC
authors.lastname: Yoo
authors.affiliation: Department of Science Education, Kangwon National University, Chuncheon 24341, Republic of Korea.
authors.forename: Eun Jeong
authors.initials: EJ
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry, Kangwon National University, Chuncheon 24341, Republic of Korea.
authors.forename: Tae Woong
authors.initials: TW
authors.lastname: Kim
authors.affiliation: Department of Science Education, Kangwon National University, Chuncheon 24341, Republic of Korea.
authors.forename: In-Sook Han
authors.initials: IH
authors.lastname: Lee
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Jae Youl
authors.initials: JY
authors.lastname: Cho
keywords: Anti-inflammatory activity; Chalcone; Macrophages; NF-κB; Pyrrole