title: Polyenylpyrrole derivatives inhibit NLRP3 inflammasome activation and inflammatory mediator expression by reducing reactive oxygen species production and mitogen-activated protein kinase activation.
abstract: Two polyenylpyrroles from a soil ascomycete Gymnoascus reessii were previously identified as hit compounds in screening for cytotoxicity against lung cancer cells. These compounds and various analogs, which have been previously synthesized and tested for anti-lung cancer cell activity, were tested for anti-inflammatory activity. After preliminary screening for cytotoxicity for RAW 264.7 murine macrophage cells, the non-toxic compounds were tested for anti-inflammatory activity using lipopolysaccharide (LPS)-activated RAW 264.7 cells. Compounds 1h, 1i, and 1n reduced LPS-induced nitric oxide (NO) production, with respective ED50 values of 15 ± 2, 16 ± 2, and 17 ± 2 µM. They also reduced expression of inducible NO synthase and interleukin-6 (IL-6) without affecting cyclooxygenase-2 expression. Compound 1h also reduced secretion of IL-6 and tumor necrosis factor-α by LPS-activated J774A.1 murine macrophage cells, primary mice peritoneal macrophages, and JAWSII murine bone marrow-derived dendritic cells and reduced NLRP3 inflammasome-mediated interleukin-1β (IL-1β) secretion by LPS + adenosine triphosphate-activated J774A.1 and JAWSII cells. The underlying mechanisms for the anti-inflammatory activity of compound 1h were found to be a decrease in LPS-induced reactive oxygen species (ROS) production, mitogen-activated protein kinase phosphorylation, and NF-κB activation and a decrease in ATP-induced ROS production and PKC-α phosphorylation. These results provide promising insights into the anti-inflammatory activity of these conjugated polyenes and a molecular rationale for future therapeutic intervention in inflammation-related diseases. They also show how compound 1h regulates inflammation and suggest it may be a new source for the development of anti-inflammatory agents to ameliorate inflammation- and NLRP3 inflammasome-related diseases.
authors.affiliation: Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan.
authors.forename: Kuo-Feng
authors.initials: KF
authors.lastname: Hua
authors.forename: Ju-Ching
authors.initials: JC
authors.lastname: Chou
authors.forename: Yulin
authors.initials: Y
authors.lastname: Lam
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Tasi
authors.forename: Ann
authors.initials: A
authors.lastname: Chen
authors.forename: Shuk-Man
authors.initials: SM
authors.lastname: Ka
authors.forename: Zhanxiong
authors.initials: Z
authors.lastname: Fang
authors.forename: May-Lan
authors.initials: ML
authors.lastname: Liu
authors.forename: Feng-Ling
authors.initials: FL
authors.lastname: Yang
authors.forename: Yu-Liang
authors.initials: YL
authors.lastname: Yang
authors.forename: Yi-Chich
authors.initials: YC
authors.lastname: Chiu
authors.forename: Shih-Hsiung
authors.initials: SH
authors.lastname: Wu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000378:metabolism; D011753:Pyrones / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D058847:Inflammasomes; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011753:Pyrones; D011758:Pyrroles; D017382:Reactive Oxygen Species; C514631:auxarconjugatin A; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D051571:Protein Kinase C-alpha; D020928:Mitogen-Activated Protein Kinases