Dexamethasone and Fumaric Acid Ester Conjugate Synergistically Inhibits Inflammation and NF-κB in Macrophages.
Dexamethasone and Fumaric Acid Ester Conjugate Synergistically Inhibits Inflammation and NF-κB in Macrophages.
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DOI：
10.1021/acs.bioconjchem.1c00200
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发表时间：
2021-08-18
影响因子：
4.7
通讯作者：
Ainslie, Kristy M.
中科院分区：
文献类型：
--
作者：
Genito, Christopher J.;Eckshtain-Levi, Meital;Piedra-Quintero, Zayda L.;Krovi, Sai Archana;Kroboth, Abriana;Stiepel, Rebeca T.;Guerau-de-Arellano, Mireia;Bachelder, Eric M.;Ainslie, Kristy M.
巨噬细胞介导的炎症驱动自身免疫性和慢性炎症性疾病。用消炎药治疗是减少炎症的有效策略；然而，高浓度的这些药物会产生免疫抑制和其他严重的副作用。抗炎剂的协同组合可以通过减少药物用量来减轻剂量。评估多种抗炎药联合使用对巨噬细胞炎症的协同抑制作用。在地塞米松（DXM）和富马酸酯（如富马酸单甲基（MMF））之间观察到最有效的协同作用。此外，发现该组合协同抑制炎症核因子κB （NF-κB）转录因子活性。确定了最佳协同比为1:1，并在此摩尔比下进行了ddxm和MMF的酯化反应。在小鼠和人巨噬细胞中，ddxm - mmf偶联物对炎症的抑制作用优于未偶联物。在治疗人供体单核细胞源性巨噬细胞时，DXM与MMF合用可显著抑制NF-κB下游炎症基因表达，总体效果优于单用。此外，DXM-MMF偶联物显著抑制NOD-、LRR-和pyrin结构域蛋白3 （NLRP3）炎症小体相关基因的表达。ddxm - mmf偶联物在人巨噬细胞中的有效抗炎活性表明它可能有益于自身免疫性和炎症性疾病的治疗。
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.
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影响因子：
4.7
作者：
Hahn, Bevra H.;McMahon, Maureen A.;Wilkinson, Alan;Wallace, W. Dean;Daikh, David I.;Fitzgerald, John D.;Karpouzas, George A.;Merrill, Joan T.;Wallace, Daniel J.;Yazdany, Jinoos;Ramsey-Goldman, Rosalind;Singh, Karandeep;Khalighi, Mazdak;Choi, Soo-In;Gogia, Maneesh;Kafaja, Suzanne;Kamgar, Mohammad;Lau, Christine;Martin, William J.;Parikh, Sefali;Peng, Justin;Rastogi, Anjay;Chen, Weiling;Grossman, Jennifer M.
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影响因子：
3.6
作者：
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作者：
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通讯作者：
De Bosscher, Karolien
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影响因子：
15
作者：
Huang, Ping;Wang, Dali;Yan, Deyue
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影响因子：
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作者：
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