title: 1,3-Diphenylpropenone ameliorates TNBS-induced rat colitis through suppression of NF-κB activation and IL-8 induction.
abstract: In the present study, we examined whether newly synthesized phenylpropenone derivatives, by inhibiting NF-κB activity, would inhibit IL-8 expression, inflammation and abnormal angiogenesis, resulting in amelioration of disease conditions. The phenylpropenone derivatives inhibited NF-κB transcriptional activity, which correlated with their suppressive activity against TNF-α-induced adhesion of U937 human monocytic cells to HT-29 human colonic epithelial cells, an in vitro model of IBD. Among the derivatives, 1,3-diphenylpropenone (DPhP) was most efficacious, and it significantly suppressed TNF-α-induced production of IL-8 which is a proinflammatory and proangiogenic cytokine. The anti-inflammatory activity of DPhP was also confirmed in the trinitrobenzene sulfonic acid (TNBS)-induced rat colitis model. DPhP was protective against the TNBS-induced inflammatory responses, which included weight loss, increased myeloperoxidase activity and mucosal damage. In the colon tissue, DPhP inhibited TNBS-induced NF-κB nuclear translocation, IL-8 and TNF-α expressions, and abnormal angiogenesis. In addition, DPhP also suppressed IL-8-induced angiogenesis, which was revealed by an in vivo assay using chick chorioallantoic membrane. Furthermore, the level of IL-6, a pleiotropic cytokine which is implicated in the pathogenesis of IBD and colitis-associated cancer, was suppressed by DPhP in rat colon tissue and serum. In conclusion, the results suggest that DPhP is a potential dual-acting IBD drug candidate targeting both inflammation and abnormal angiogenesis, possibly through the NF-κB and IL-8 signaling pathway.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, South Korea.
authors.forename: Su-Young
authors.initials: SY
authors.lastname: Park
authors.forename: Sae Kwang
authors.initials: SK
authors.lastname: Ku
authors.forename: Eung Seok
authors.initials: ES
authors.lastname: Lee
authors.forename: Jung-Ae
authors.initials: JA
authors.lastname: Kim
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000494:pharmacology*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000276:immunology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014302:Trinitrobenzenesulfonic Acid; D020298:U937 Cells
chemical_list: D047188:Chalcones; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D012313:RNA; D014302:Trinitrobenzenesulfonic Acid