Synergistic Nutraceutical Effects of DLPC and SAMe

描述（由申请人提供）：我们的长期目标是开发有效的预防和治疗肝硬化。其营养后果之一是必需营养素向其活性形式的酶促转化减少，包括甲硫氨酸向s-腺苷甲硫氨酸（SAMe）的缺陷性活化，以及甲硫氨酸的许多重要功能的丧失。这种缺陷仅部分地响应于SAMe补充，因为最佳[细胞功能]还需要膜的完整性，膜被自由基攻击其磷脂酰胆碱（PC）基础结构而损伤。这可以通过用二亚油酰磷脂酰胆碱（DLPC）（一种高度生物利用度的PC）补充磷脂来克服，但也需要SAMe，因为它是通过磷脂酰乙醇胺甲基化再生PC的关键辅因子。氧化应激和肝损伤的主要原因是细胞色素P4502E1（CYP2E1），由乙醇（酒精性肝病）、脂质（肥胖症）和酮（糖尿病）诱导。除了最近发现的抑制CYP2E1的DLPC外，现有的CYP2E1抑制剂对于临床使用来说毒性太大。我们的直接目的是使用胰腺炎前酒精性和非酒精性脂肪性肝炎以及CCl 4诱导的肝硬化的啮齿动物模型来测试施用SAMe + DLPC的协同效应。SAMe和DLPC之间的有益相互作用的机制将在体内和体外培养的啮齿动物肝星状细胞，枯否细胞和巨噬细胞中进行研究，重点是生理抗氧化谷胱甘肽的保存，磷脂酰乙醇胺甲基转移酶活性的恢复，氧化应激的衰减和由此产生的NF-？B活化，脂质过氧化和致病细胞因子TNF-？升高，TGF-？1、IL-1？和il-6减少纤维化可以通过减少星状细胞活化、增强胶原酶活性和降低瘦素产生来实现。总之，将针对实验性肝损伤的关键模式（包括非酒精性和酒精性脂肪性肝炎和CCl 4诱导的肝硬化）测试SAMe和DLPC（两种无害的保肝营养品）的协同作用，从而提供最终在临床试验中验证这种营养品组合在预防和治疗肝硬化中的有效性所需的临床前数据。这是一种常见的死亡原因，目前还没有有效的治疗方法。

DESCRIPTION (provided by applicant): Our long-term objective is to develop effective prevention and therapy for liver cirrhosis. One of its nutritional consequences is decreased enzymatic transformation of essential nutrients to their active form, including defective activation of methionine to s-adenosylmethionine (SAMe), with loss of many of methionine's vital functions. This deficiency responds only partially to SAMe supplementation because optimal [cellular function] also requires integrity of the membranes, which are injured by free radical attack on their phosphatidylcholine (PC) infrastructure. This can be overcome through phospholipid replenishment with dilinoleoylphosphatidylcholine (DLPC), a highly bioavailable PC, but SAMe is also required because it is a crucial co-factor in the regeneration of PC through methylation of phosphatidylethanolamine. A major cause of oxidative stress and liver injury is cytochrome P4502E1 (CYP2E1) when induced by either ethanol (in alcoholic liver disease), lipids (in obesity) and ketones (in diabetes). Available CYP2E1 inhibitors are too toxic for clinical use, except for DLPC recently discovered to inhibit CYP2E1. Our immediate aim is to test the synergistic effects of the administration of SAMe + DLPC, using rodent models of precirrhotic alcoholic and nonalcoholic steatohepatitis and CCI4-induced cirrhosis. Mechanisms of the beneficial interaction between SAMe and DLPC will be studied in vivo and also in vitro in cultured rodent hepatic stellate cells, Kupffer cells and macrophages, with focus on the preservation of the physiologic anti-oxidant glutathione, the restoration of phosphatidylethanolamine methyltransferase activity, the attenuation of oxidative stress and the resulting NF-?B activation, with lipid peroxidation and rise in the pathogenic cytokines TNF-?, TGF-?1, IL-1? and IL-6. Decreased fibrosis may be achieved through diminished stellate cell activation, enhanced collagenase activity and lowered leptin production. In summary, the synergistic effects of SAMe and DLPC, two innocuous and hepatoprotective nutraceuticals, will be tested against key modalities of experimental liver injury, including non-alcoholic and alcoholic steatohepatitis and CCI4 induced cirrhosis, thereby providing preclinical data needed to ultimately verify, in a clinical trial, the effectiveness of this nutraceutical combination in the prevention and treatment of liver cirrhosis, a common cause of mortality for which effective therapy is presently not available.