title: Development and mechanism investigation of a new piperlongumine derivative as a potent anti-inflammatory agent.
abstract: Inflammation, especially chronic inflammation, is directly involvement in the pathogenesis of many diseases including cancer. An effective approach for managing inflammation is to employ chemicals to block activation of nuclear factor-κB (NF-κB), a key regulator for inflammatory processes. Piperlongumine (piplartine, PL), an electrophilic molecule isolated from Piper longum L., possesses excellent anti-cancer and anti-inflammatory properties. In this study, a new PL analogue (PL-0N) was designed by replacing nitrogen atom of lactam in PL with carbon atom to increase its electrophilicity and thus anti-inflammatory activity. It was found that PL-0N is more potent than the parent compound in suppressing lipopolysaccharide (LPS)-induced secretion of nitric oxide and prostaglandin E2 as well as expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW264.7 macrophages. Mechanistic investigation implies that PL-0N exerts anti-inflammatory activity through inhibition of LPS-induced NF-κB transduction pathway, down-regulation of LPS-induced MAPKs activation and impairment of proteasomal activity, but also enhancement of LPS-induced autophagy; the inhibition of NF-κB by PL-0N is achieved at various stages by: (i) preventing phosphorylation of IKKα/β, (ii) stabilizing the suppressor protein IκBα, (iii) interfering with the nuclear translocation of NF-κB, and (iv) inhibiting the DNA-binding of NF-κB. These data indicate that nitrogen-atom-lacking pattern is a successful strategy to improve anti-inflammatory property of PL, and that the novel molecule, PL-0N may be served as a promising lead for developing natural product-directed anti-inflammatory agents.
authors: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000, Gansu, China.
authors: Lan-Di
authors: LD
authors: Sun
authors: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000, Gansu, China.
authors: Fu
authors: F
authors: Wang
authors: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000, Gansu, China.
authors: Fang
authors: F
authors: Dai
authors: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000, Gansu, China.
authors: Yi-Hua
authors: YH
authors: Wang
authors: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000, Gansu, China.
authors: Dong
authors: D
authors: Lin
authors: State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Street S., Lanzhou 730000, Gansu, China. Electronic address: bozhou@lzu.edu.cn.
authors: Bo
authors: B
authors: Zhou
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004148:Dioxolanes / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D010881:Piperidones
chemical_list: D000893:Anti-Inflammatory Agents; D051546:Cyclooxygenase 2; D004148:Dioxolanes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; C498077:piperlongumine; D010881:Piperidones
keywords: Autophagy; Inflammation; MAPK; Mechanism; NF-κB; Piperlongumine; Piperlongumine (PubChem CID: 637858)