title: Inhibition of inflammatory mediators contributes to the anti-inflammatory activity of KYKZL-1 via MAPK and NF-κB pathway.
abstract: KYKZL-1, a newly synthesized compound with COX/5-LOX dual inhibition, was subjected to the anti-inflammatory activity test focusing on its modulation of inflammatory mediators as well as intracellular MAPK and NF-κB signaling pathways. In acute ear edema model, pretreatment with KYKZL-1 (p.o.) dose-dependently inhibited the xylene-induced ear edema in mice with a higher inhibition than diclofenac. In a three-day TPA-induced inflammation, KYKZL-1 also showed significant anti-inflammatory activity with inhibition ranging between 20% and 64%. In gastric lesion test, KYKZL-1 elicited markedly fewer stomach lesions with a low index of ulcer as compared to diclofenac in rats. In further studies, KYKZL-1 was found to significantly inhibit the production of NO, PGE2, LTB4 in LPS challenged RAW264.7, which is parallel to its attenuation of the expression of iNOS, COX-2, 5-LOX mRNAs or proteins and inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB. Taken together, our data indicate that KYKZL-1 comprises dual inhibition of COX and 5-LOX and exerts an obvious anti-inflammatory activity with an enhanced gastric safety profile via simultaneous inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-κB.
authors.affiliation: Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, China; Department of Pharmacology, University of Michigan, Ann Arbor, USA.
authors.forename: Guang-Lin
authors.initials: GL
authors.lastname: Xu
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Du
authors.forename: Jing
authors.initials: J
authors.lastname: Cheng
authors.forename: Lin
authors.initials: L
authors.lastname: Huan
authors.forename: Shi-Cui
authors.initials: SC
authors.lastname: Chen
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Wei
authors.forename: Zhu-Nan
authors.initials: ZN
authors.lastname: Gong
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.forename: Ting
authors.initials: T
authors.lastname: Qiu
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Ting
authors.initials: T
authors.lastname: Sun
authors.forename: Gui-Zhen
authors.initials: GZ
authors.lastname: Ao
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D015153:Blotting, Western; D002460:Cell Line; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D007202:Indicators and Reagents; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D007975:Leukotriene B4 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D010666:Phenylpropionates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology; D014992:Xylenes / Q000633:toxicity
chemical_list: D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D018836:Inflammation Mediators; C584310:KYKZL-1 compound; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; D010666:Phenylpropionates; D013267:Stilbenes; D014992:Xylenes; D007975:Leukotriene B4; D009569:Nitric Oxide; D015232:Dinoprostone
keywords: COX; Inflammation; Inflammatory mediators; LOX; NSAIDs