title: The In Vitro and In Vivo Anti-Inflammatory Effects of a Phthalimide PPAR-γ Agonist.
abstract: Previously, the authors found that 4-hydroxy-2-(4-hydroxyphenethyl) isoindoline-1,3-dione (PD1) (a phthalimide analogue) bound to and activated peroxisome proliferator-activated receptor-γ (PPAR-γ). Since PPAR-γ suppresses inflammatory responses, the present study was undertaken to investigate the anti-inflammatory effects ofPD1. In lipopolysaccharide (LPS)-stimulated murine RAW264.7 macrophages,PD1suppressed the inductions of pro-inflammatory factors, including inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase 2 (COX-2), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Concomitantly,PD1enhanced the expressions of anti-inflammatory factors, such as arginase-1 and interleukin-10 (IL-10), and suppressed LPS-evoked nuclear factor kappa B (NF-κB) p65 subunit phosphorylation in macrophages. In addition, PPAR-γ activated byPD1was intensively translocated to the nucleus. These observations suggest that the anti-inflammatory mechanism ofPD1involves inhibition of the NF-κB pathway. In a subsequent in vivo animal experiment conducted using a carrageenan-induced acute inflammatory rat paw edema model, intraperitoneal injection ofPD1significantly reduced paw swelling. Histological analysis of rat paw tissue sections revealed less infiltration of immune cells inPD1-pretreated animals. These findings suggest thatPD1be viewed as a lead compound for the development of novel anti-inflammatory therapeutics.
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Korea. sumingzhi0310@gmail.com.
authors.forename: Mingzhi
authors.initials: M
authors.lastname: Su
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Korea. caojiafu1985@163.com.
authors.forename: Jiafu
authors.initials: J
authors.lastname: Cao
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Korea. jellyohuang@gmail.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Korea. ls691392008@sina.com.
authors.forename: Sen
authors.initials: S
authors.lastname: Liu
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Korea. imds@pusan.ac.kr.
authors.forename: Dong Soon
authors.initials: DS
authors.lastname: Im
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Korea. jinwook@pusa.ac.kr.
authors.forename: Jin-Wook
authors.initials: JW
authors.lastname: Yoo
authors.affiliation: College of Pharmacy, Pusan National University, Busan 609-735, Korea. jhjung@pusan.ac.kr.
authors.forename: Jee H
authors.initials: JH
authors.lastname: Jung
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D010797:Phthalimides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D047495:PPAR gamma; D010797:Phthalimides; C037431:phthalimide
keywords: NF-κB pathway; PPAR-γ agonist; RAW264.7 macrophage; anti-inflammatory effect; cytokines; paw edema; phthalimide analogue