美国食品药品监督管理局批准的赋形剂N,N-二甲基乙酰胺在体外和体内模型中减轻炎症性肠病

J. Koya, Tong Shen, Geming Lu, Alex G. Gauthier, L. Mantell, C. Ashby, S. Reznik
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引用次数: 1

摘要

炎症性肠病(IBD)影响着全球近700万人,并且发病率正在上升。虽然IBD的确切发病机制尚不清楚,但炎性细胞因子和趋化因子的产生起着核心作用。我们之前发现,N,N-二甲基乙酰胺(DMA)是一种广泛使用的无毒药物赋形剂,在体外抑制细胞因子和趋化因子的分泌,并在体内预防炎症诱导的早产。使用夹心酶联免疫吸附试验(ELISAs),我们测试DMA是否减弱LPS或TNFa刺激的人类肠上皮细胞和人类单核细胞的细胞因子和趋化因子分泌,以及RAW 264.7细胞的HMGB1释放。为了验证DMA在IBD体外和体内模型中的作用机制是抑制NF-kB途径的假设,我们使用蛋白质印迹来跟踪在不存在或存在DMA的情况下THP-1人单核细胞中核因子κB(NF-kB)抑制分子IκBα(IkBa)的水平。最后,我们用右旋糖酐硫酸钠(DSS)在C57Bl/6小鼠中诱导结肠炎,然后测试每天以2.1 g/kg/天的剂量腹腔注射DMA是否能减轻结肠炎的临床和组织病理学症状。DMA减弱了人肠上皮细胞和人单核细胞的细胞因子和趋化因子释放以及RAW 264.7细胞的HMGB1释放。重要的是,DMA阻止了THP-1细胞中IkBa的降解,从而提示了DMA作用的一种机制。最后,我们在这里首次表明,DMA减轻了DSS诱导的结肠炎的临床和组织学特征。基于这些数据,DMA应在临床前和临床试验中进一步探索其作为IBD新型药物治疗的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
FDA-Approved Excipient N,N-Dimethylacetamide Attenuates Inflammatory Bowel Disease in In-Vitro and In-Vivo Models
Inflammatory bowel disease (IBD) affects almost 7 million people worldwide and is increasing in incidence. While the precise pathogenesis of IBD remains unknown, the production of inflammatory cytokines and chemokines play a central role. We have previously found that N,N-dimethylacetamide (DMA), a widely used non-toxic drug excipient, suppresses cytokine and chemokine secretion in vitro and prevents inflammation-induced preterm birth in vivo. Using sandwich enzyme-linked immunosorbent assays (ELISAs), we tested whether DMA attenuates cytokine and chemokine secretion from LPS- or TNFa-stimulated human intestinal epithelial cells and human monocytes and HMGB1 release from RAW 264.7 cells. To test our hypothesis that the mechanism of DMA’s effects in in-vitro and in-vivo models of IBD is inhibition of the NF-kB pathway, we used western blotting to track levels of the nuclear factor kappa B (NF-kB) inhibitory molecule I kappa B alpha (IkBa) in THP-1 human monocytes in the absence or presence of DMA. Finally, we induced colitis in C57Bl/6 mice with dextran sodium sulfate (DSS) and then tested whether daily i.p injections of DMA at 2.1 g/kg/day attenuates clinical and histopathologic signs of colitis. DMA attenuated cytokine and chemokine release from human intestinal epithelial cells and human monocytes and HMGB1 release from RAW 264.7 cells. Importantly, DMA prevented degradation of IkBa in THP-1 cells, thereby suggesting one mechanism for DMA’s effects. Finally, we show here, for the first time, that DMA attenuates clinical and histologic features of DSS-induced colitis. Based on these data, DMA should be further explored in preclinical and clinical trials for its potential as novel drug therapy for IBD.
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