6b,11b-Dihydroxy-6b,11b-dihydro-7H-indeno[1,2-b]naphtho[2,1-d]furan-7-one (DHFO), a small molecule targeting NF-κB, demonstrates therapeutic potential in immunopathogenic chronic inflammatory conditions
| Autor: | Geetha Mathew, Ega Durgashivaprasad, Neetinkumar D. Reddy, Anija Jacob, Mazhuvancherry Kesavan Unnikrishnan |
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| Rok vydání: | 2012 |
| Předmět: |
Serum
Lipopolysaccharide Immunology Freund's Adjuvant Anti-Inflammatory Agents Arthritis Inflammation Pharmacology Naphthalenes Immunoglobulin E Carrageenan Nitric Oxide Histamine Release Cell Line chemistry.chemical_compound Mice medicine Hypersensitivity Immunology and Allergy Animals Edema p-Methoxy-N-methylphenethylamine Antigens Rats Wistar Furans Peroxidase Sheep biology Chemistry Interleukin-6 Degranulation NF-kappa B Mast cell medicine.disease Rats medicine.anatomical_structure Indenes Freund's adjuvant Cyclooxygenase 2 Myeloperoxidase biology.protein medicine.symptom Reactive Oxygen Species |
| Zdroj: | International immunopharmacology. 15(1) |
| ISSN: | 1878-1705 |
| Popis: | 6b,11b-Dihydroxy-6b,11b-dihydro-7H-indeno[1,2-b]naphtho[2,1-d]furan-7-one (DHFO), an easily synthesisable, orally bioavailable and relatively non-toxic small molecule synthesised in our lab, was previously reported to possess anti-oxidant, 5-lipoxygenase inhibitory, anti-inflammatory and peripheral analgesic activities. The present work deals with exploration of DHFO's efficacy in immunopathogenic chronic inflammatory conditions - arthritis and allergy. In carrageenan-induced inflammatory air pouch, which resembles the arthritic synovium, DHFO effectively reduced inflammatory redness and swelling and neutrophil infiltration. In complete Freund's adjuvant-induced arthritis, DHFO significantly decreased paw oedema and nitrite levels with efficacy comparable to diclofenac. DHFO inhibited neutrophil activation (observed as decreased myeloperoxidase levels), in both the in vivo models of inflammation. Interestingly, DHFO did not ulcerate the gastrointestinal tract, while diclofenac was observed to be extremely ulcerogenic. In antigen-induced active and passive anaphylaxis (allergy) models, DHFO dose-dependently prevented mesenteric mast cell (MC) degranulation with efficacy comparable to ketotifen. DHFO also inhibited compound 48/80 (C48/80)-induced paw oedema and peritoneal MC degranulation. DHFO stabilised p815 murine MCs stimulated by C48/80 and calcium ionophore-A23187, indicating an action downstream of calcium mobilisation. DHFO's anti-allergic mechanism could be two-pronged involving (1) inhibition of IgE production and/or (2) MC stabilisation. DHFO inhibited lipopolysaccharide (LPS)-induced pro-inflammatory mediator release (ROS, NO, IL-6 levels) and COX2 expression in RAW264.7 murine macrophages. Protein expression studies confirmed DHFO's ability to reduce nuclear levels of NF-κB in LPS-stimulated macrophages. Thus, DHFO is a promising non-ulcerogenic synthetic small molecule lead for immunopathogenic chronic inflammatory conditions. |
| Databáze: | OpenAIRE |
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