Dexamethasone and Fumaric Acid Ester Conjugate Synergistically Inhibits Inflammation and NF-κB in Macrophages
| Autor: | Zayda L Piedra-Quintero, Mireia Guerau-de-Arellano, Abriana Kroboth, Meital Eckshtain-Levi, Rebeca T Stiepel, Sai Archana Krovi, Kristy M. Ainslie, Christopher J Genito, Eric M. Bachelder |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Fumaric acid
Anti-Inflammatory Agents Biomedical Engineering Pharmaceutical Science Bioengineering Inflammation 02 engineering and technology Nod Pharmacology Nitric Oxide 01 natural sciences Dexamethasone Mice chemistry.chemical_compound Fumarates medicine Animals Humans Macrophage Transcription factor 010405 organic chemistry Macrophages Organic Chemistry NF-kappa B Drug Synergism NF-κB 021001 nanoscience & nanotechnology 0104 chemical sciences RAW 264.7 Cells Gene Expression Regulation chemistry Cytokines medicine.symptom 0210 nano-technology Biotechnology Conjugate medicine.drug |
| Zdroj: | Bioconjugate Chemistry. 32:1629-1640 |
| ISSN: | 1520-4812 1043-1802 |
| DOI: | 10.1021/acs.bioconjchem.1c00200 |
| Popis: | Macrophage-mediated inflammation drives autoimmune and chronic inflammatory diseases. Treatment with anti-inflammatory agents can be an effective strategy to reduce this inflammation; however, high concentrations of these agents can have immune-dampening and other serious side effects. Synergistic combination of anti-inflammatory agents can mitigate dosing by requiring less drug. Multiple anti-inflammatory agents were evaluated in combination for synergistic inhibition of macrophage inflammation. The most potent synergy was observed between dexamethasone (DXM) and fumaric acid esters (e.g., monomethyl fumarate (MMF)). Furthermore, this combination was found to synergistically inhibit inflammatory nuclear factor κB (NF-κB) transcription factor activity. The optimal ratio for synergy was determined to be 1:1, and DXM and MMF were conjugated by esterification at this molar ratio. The DXM-MMF conjugate displayed improved inhibition of inflammation over the unconjugated combination in both murine and human macrophages. In the treatment of human donor monocyte-derived macrophages, the combination of DXM and MMF significantly inhibited inflammatory gene expression downstream of NF-κB and overall performed better than either agent alone. Further, the DXM-MMF conjugate significantly inhibited expression of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome-associated genes. The potent anti-inflammatory activity of the DXM-MMF conjugate in human macrophages indicates that it may have benefits in the treatment of autoimmune and inflammatory diseases. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|