A novel synthetic small molecule DMFO targets Nrf2 in modulating proinflammatory/antioxidant mediators to ameliorate inflammation

Geetha Mathew, Arpeeta Sharma, Raelene J. Pickering, Carlos J. Rosado, Jeremie Lemarie, Jayesh Mudgal, Magith Thambi, Sarine Sebastian, Karin A. Jandeleit-Dahm, Judy B. de Haan, Mazhuvancherry K. Unnikrishnan

Research output: Contribution to journalArticle

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Abstract

Inflammation 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 TNFα levels. Mechanistic studies revealed that DMFO reduced proinflammatory genes (IL1β, TNFα, 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.

Original languageEnglish
Pages (from-to)1140-1157
Number of pages18
JournalFree Radical Research
Volume52
Issue number10
DOIs
Publication statusPublished - 03-10-2018

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Macrophages
Antioxidants
Inflammation
Heme Oxygenase (Decyclizing)
Molecules
Diclofenac
Mast Cells
Lipopolysaccharides
Assays
Reactive Oxygen Species
Anti-Inflammatory Agents
Genes
p-Methoxy-N-methylphenethylamine
Freund's Adjuvant
Carrageenan
Edema
Scavenging
Ovalbumin
Pathogens
Infiltration

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Mathew, Geetha ; Sharma, Arpeeta ; Pickering, Raelene J. ; Rosado, Carlos J. ; Lemarie, Jeremie ; Mudgal, Jayesh ; Thambi, Magith ; Sebastian, Sarine ; Jandeleit-Dahm, Karin A. ; de Haan, Judy B. ; Unnikrishnan, Mazhuvancherry K. / A novel synthetic small molecule DMFO targets Nrf2 in modulating proinflammatory/antioxidant mediators to ameliorate inflammation. In: Free Radical Research. 2018 ; Vol. 52, No. 10. pp. 1140-1157.
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abstract = "Inflammation 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 TNFα levels. Mechanistic studies revealed that DMFO reduced proinflammatory genes (IL1β, TNFα, 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.",
author = "Geetha Mathew and Arpeeta Sharma and Pickering, {Raelene J.} and Rosado, {Carlos J.} and Jeremie Lemarie and Jayesh Mudgal and Magith Thambi and Sarine Sebastian and Jandeleit-Dahm, {Karin A.} and {de Haan}, {Judy B.} and Unnikrishnan, {Mazhuvancherry K.}",
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Mathew, G, Sharma, A, Pickering, RJ, Rosado, CJ, Lemarie, J, Mudgal, J, Thambi, M, Sebastian, S, Jandeleit-Dahm, KA, de Haan, JB & Unnikrishnan, MK 2018, 'A novel synthetic small molecule DMFO targets Nrf2 in modulating proinflammatory/antioxidant mediators to ameliorate inflammation', Free Radical Research, vol. 52, no. 10, pp. 1140-1157. https://doi.org/10.1080/10715762.2018.1533636

A novel synthetic small molecule DMFO targets Nrf2 in modulating proinflammatory/antioxidant mediators to ameliorate inflammation. / Mathew, Geetha; Sharma, Arpeeta; Pickering, Raelene J.; Rosado, Carlos J.; Lemarie, Jeremie; Mudgal, Jayesh; Thambi, Magith; Sebastian, Sarine; Jandeleit-Dahm, Karin A.; de Haan, Judy B.; Unnikrishnan, Mazhuvancherry K.

In: Free Radical Research, Vol. 52, No. 10, 03.10.2018, p. 1140-1157.

Research output: Contribution to journalArticle

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AU - Mathew, Geetha

AU - Sharma, Arpeeta

AU - Pickering, Raelene J.

AU - Rosado, Carlos J.

AU - Lemarie, Jeremie

AU - Mudgal, Jayesh

AU - Thambi, Magith

AU - Sebastian, Sarine

AU - Jandeleit-Dahm, Karin A.

AU - de Haan, Judy B.

AU - Unnikrishnan, Mazhuvancherry K.

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N2 - Inflammation 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 TNFα levels. Mechanistic studies revealed that DMFO reduced proinflammatory genes (IL1β, TNFα, 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.

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