Please use this identifier to cite or link to this item: https://hdl.handle.net/1/1773
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dc.contributor.authorMathew, Geetha-
dc.contributor.otherSharma, A.-
dc.contributor.otherPickering, R.J.-
dc.contributor.otherRosado, C.J.-
dc.contributor.otherLemarie, J.-
dc.contributor.otherMudgal, J.-
dc.contributor.otherThambi, M.-
dc.contributor.otherSebastian, S.-
dc.contributor.otherJandeleit-Dahm, K.A.-
dc.contributor.otherde Haan, J.B.-
dc.contributor.otherUnnikrishnan, M.K.-
dc.date.accessioned2020-05-19T02:00:26Z-
dc.date.available2020-05-19T02:00:26Z-
dc.date.issued2018-10-
dc.identifier.citation52(10):1140-1157en
dc.identifier.issn1029-2470en
dc.identifier.urihttps://elibrary.cclhd.health.nsw.gov.au/cclhdjspui/handle/1/1773-
dc.description.abstractInflammation is a protective immune response against invading pathogens, however, dysregulated inflammation is detrimental. As the complex inflammatory response involves multiple mediators, including the involvement of reactive oxygen species, concomitantly targeting proinflammatory and antioxidant check-points may be a more rational strategy. We report the synthesis and anti-inflammatory/antioxidant activity of a novel indanedione derivative DMFO. DMFO scavenged reactive oxygen species (ROS) in in-vitro radical scavenging assays and in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. In acute models of inflammation (carrageenan-induced inflammation in rat paw and air pouch), DMFO effectively reduced paw oedema and leucocyte infiltration with an activity comparable to diclofenac. DMFO stabilised mast cells (MCs) in in-vitro A23187 and compound 48/80-induced assays. Additionally, DMFO stabilised MCs in an antigen (ovalbumin)-induced MC degranulation model in-vivo, without affecting serum IgE levels. In a model of chronic immune-mediated inflammation, Freund's adjuvant-induced arthritis, DMFO reduced arthritic score and contralateral paw oedema, and increased the pain threshold with an efficacy comparable to diclofenac but without being ulcerogenic. Additionally, DMFO significantly reduced serum TNFalpha levels. Mechanistic studies revealed that DMFO reduced proinflammatory genes (IL1beta, TNFalpha, IL6) and protein levels (COX2, MCP1), with a concurrent increase in antioxidant genes (NQO1, haem oxygenase 1 (HO-1), Glo1, Nrf2) and protein (HO-1) in LPS-stimulated macrophages. Importantly, the anti-inflammatory/antioxidant effect on gene expression was absent in primary macrophages isolated from Nrf2 KO mice suggesting an Nrf2-targeted activity, which was subsequently confirmed using siRNA transfection studies in RAW macrophages. Therefore, DMFO is a novel, orally-active, safe (even at 2 g/kg p.o.), a small molecule which targets Nrf2 in ameliorating inflammation.en
dc.description.sponsorshipPharmacyen
dc.subjectDrug Therapyen
dc.titleA novel synthetic small molecule DMFO targets Nrf2 in modulating proinflammatory/antioxidant mediators to ameliorate inflammationen
dc.typeJournal Articleen
dc.identifier.doi10.1080/10715762.2018.1533636en
dc.description.pubmedurihttps://www.ncbi.nlm.nih.gov/pubmed/30422019en
dc.description.affiliatesCentral Coast Local Health Districten
dc.description.affiliatesGosford Hospitalen
dc.identifier.journaltitleFree radical researchen
dc.originaltypeTexten
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.fulltextNo Fulltext-
item.grantfulltextnone-
item.openairetypeJournal Article-
item.cerifentitytypePublications-
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