Fumarates for Alcoholic Liver Disease

摘要 酒精性肝病(ALD)仍然是主要的致命性肝病，其主要原因是 用于移植。目前还没有有效的治疗方法。富马酸二甲酯(DMF) 富马酸(MMF)前体药物，是FDA证实的治疗神经退行性疾病的药物，并已 我们开发了一部小说 携带优化药代动力学的模拟分子富马酸烟酰胺(NMF) 人物。我们的初步数据显示，NMF显著改善了小鼠酒精性肝损伤。 小鼠，优于DMF。 最近有报道称，它可以拯救小鼠的酒精性肝损伤。 我们认为，NMF通过三条途径获得保护： NRF2驱动的抗氧化反应，Hca2介导的抗炎反应，以及 线粒体诱导。在本研究中，我们将评估其预防和治疗效果。 在ALD小鼠模型上，将NMF与单独诱导NRF2的药物RTA408进行比较。我们会 也可以通过对Nrf2、Hca2和线粒体功能的研究来识别机制信号。 这项研究可能会导致新的治疗方式和翻译研究的发展 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.