Fumarates for Alcoholic Liver Disease

摘要 酒精性肝病（ALD）仍然是主要的致命肝脏疾病， 进行移植目前还没有有效的治疗方法。富马酸二甲酯（DMF）， 富马酸酯（MMF）前药是FDA证明的用于神经退行性疾病的疗法， 我们已经开发出一种新颖 类似分子富马酸烟酰胺（NMF），具有优化的药代动力学 字符.我们的初步数据表明，NMF显著改善酒精性肝损伤， 对小鼠的作用优于DMF，且上级。 最近有报道称，它可以挽救小鼠的酒精性肝损伤。 我们提出NMF通过三种途径增强其保护作用： Nrf2驱动的抗氧化反应，Hca2介导的抗炎反应，以及 线粒体诱导在这项研究中，我们将评估预防和治疗效果， 使用ALD小鼠模型，与单独诱导Nrf2的药物RTA 408比较NMF。我们将 还通过关注Nrf2、Hca2和线粒体功能来鉴定机制信号传导。 这项研究可能会导致新的治疗方式和转化研究的发展 在未来

Abstract Alcoholic liver disease (ALD) remains the leading lethal liver condition, and the primary reason for transplantation. There is still no effective therapy. Dimethyl fumarate (DMF), a monomethyl fumarate (MMF) prodrug, is an FDA proved therapy for neural degenerative diseases and has We have developed a novel analogue molecule nicotinamide fumarate (NMF) that carries optimized pharmacokinetic characters. Our preliminary data show that NMF significantly ameliorates alcoholic liver injury in mice, and is superior to DMF. been recently reported to rescue alcoholic liver injury in mice. We propose that NMF elicits its protection via three pathways: Nrf2-driven anti-oxidative reaction, Hca2-mediated anti-inflammatory response, and mitochondrial induction. In this study, we will evaluate the preventive and therapeutic efficacy of NMF comparing with RTA408 a drug solely inducing Nrf2, using mouse models of ALD. We will also identify the mechanistic signaling by focusing on Nrf2, Hca2 and mitochondrial functions. The study may lead to the development of new therapeutic modalities and translational studies in the future.