DLPC Treatment of Alcoholic and Non-Alcoholic Fibrosis

超出所提供的空间。过度肝纤维化导致终末期肝硬化，发病率和死亡率高。目前尚无有效的治疗方法。本研究的目的是建立二烯油基磷脂酰胆碱（DLPC）作为一种有效、安全、化学上明确的治疗剂，阐明其作用方式并规范其正确使用。我们之前观察到，从大豆中提取的聚乙烯磷脂酰胆碱（PPC）可以完全预防非人类灵长类动物酒精诱导的肝硬化。DLPC是PPC的主要磷脂种类，我们之前的一些体外和目前的体内研究表明它是PPC的活性成分。我们现在计划扩展这些实验，包括在体外研究DLPC对Kupffer细胞氧化应激的影响，可能涉及细胞因子作为这些细胞、肝细胞和星状细胞之间的介质。此外，经济和足够纯净的DLPC现在已经可以使用，使我们能够进行体内实验，以确定PPC在脂肪变性和纤维化方面的有益作用是否可以用DLPC复制。本文还将探讨其预防细胞凋亡的机制。此外，我们将评估DLPC是否可以逆转由CCH或异源白蛋白在大鼠或酒精在我们的狒狒模型中产生的预先存在的纤维化。目前，PPC治疗使用的速率限制因素之一是剂量（每天3片3.3克）。从理论上讲，如果DLPC被证实是活性化合物，它可以被给予更高的剂量，至少是PPC的两倍。因此，我们将测试更高剂量的DLPC是否能达到比PPC更大的肝纤维化作用。我们还将尝试通过将DLPC与无毒的活化氨基酸s -腺苷合乙硫氨酸结合来提高其效果，因为这两种化合物的作用不同，但相互依赖，有效防御乙醇引起的氧化应激所需的步骤，也用于维持细胞膜的正常结构和功能。如果提议的方法成功，它可能提供所需的临床前研究，以计划一项多中心安慰剂对照临床试验，以确定SAMe + DLPC联合预防酒精性肝病及其治疗在男性中的有效性。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. Excess liver fibrosis leads to end-stage cirrhosis with high morbidity and mortality. Presently, no effective treatment is available. The objectives of the proposed research are to establish dilinoleoylphosphatidylcholine (DLPC) as an effective, safe, and chemically defined therapeutic agent, clarify its mode of action and codify its proper use. We previously observed that polyenylphosphatidylcholine (PPC) extracted from soybeans fully prevents alcohol-induced cirrhosis in non-human primates. DLPC is the main phospholipid species of PPC and some of our prior hi vitro and current in vivo studies suggest that it is its active component. We now plan to extend these experiments, including in vitro studies of the effect of DLPC on oxidative stress in Kupffer cells, with possible involvement of cytokines as mediators between these cells, hepatocytes and stellate cells. Furthermore, economical and sufficiently pure DLPC has now become available to allow us to carry out experiments in vivo to determine whether the beneficial effects of PPC in terms of steatosis and fibrosis can be reproduced with DLPC. The mechanisms of the prevention of apoptosis will also be investigated. In addition, we will assess whether DLPC can reverse preexisting fibrosis, either produced by CCH or heterologous albumin in the rat or by alcohol in our baboon model. Currently one of the rate limiting factors of the therapeutic use of PPC is the dose (3 daily 3.3 gm tablets). Theoretically, if DLPC is confirmed to be the active compound, it could be given at a much higher dose, at least twice that of PPC. Therefore, we will test whether an effect on liver fibrosis greater than that of PPC could be achieved with a higher dose of DLPC. We will also attempt to boost the effect of DLPC by combining it with the non-toxic activated ammo-acid S-adenosyhnethionine, since both compounds act on different, but interdependent, steps required for an effective defense against the oxidative stress caused by ethanol and also for the maintenance of the normal structure and function of cellular membranes. If the proposed approach is successful, it may provide the preclinical studies needed to plan a multicenter, placebo controlled clinical trial to define the effectiveness of the SAMe + DLPC combination for the prevention of alcoholic liver disease and its treatment in man. PERFORMANCE SITE ========================================Section End===========================================