Synergistic Nutraceutical Effects of DLPC and SAMe

描述(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变。其营养后果之一是必需营养物质的酶转化减少到其活性形式，包括蛋氨酸被缺陷地激活为S-腺苷蛋氨酸(Same)，失去了蛋氨酸的许多重要功能。这一缺陷对相同的补充剂只有部分反应，因为最佳的[细胞功能]还需要膜的完整性，膜受到自由基对其磷脂酰胆碱(PC)基础设施的攻击而受到损害。这可以通过用高生物利用度的磷脂酰磷脂酰胆碱(DLPC)补充磷脂来克服，但同样也是必需的，因为它是通过磷脂酰乙醇胺甲基化再生PC的关键辅助因素。乙醇(在酒精性肝病中)、脂类(在肥胖中)和酮(在糖尿病中)诱导时，细胞色素P4502E1(CYP2E1)是氧化应激和肝脏损伤的主要原因。现有的CYP2E1抑制剂毒性太大，不适合临床使用，除了最近发现的DLPC抑制CYP2E1。我们的直接目标是使用肝硬化前期酒精性和非酒精性脂肪性肝炎以及CCI4诱导的肝硬变的啮齿动物模型，测试相同的DLPC给药的协同效应。在体内和体外培养的大鼠肝星状细胞、枯否细胞和巨噬细胞中，将研究其与DLPC的有益相互作用的机制，重点是保存生理抗氧化的谷胱甘肽，恢复磷脂酰乙醇胺甲基转移酶的活性，减轻氧化应激和由此导致的核因子-βB的激活，以及脂质过氧化和致病细胞因子肿瘤坏死因子-β、转化生长因子-β、白介素1-β的升高。和IL-6。减少纤维化可能是通过减少星状细胞的激活、增强胶原酶活性和降低瘦素的产生来实现的。总之，SAME和DLPC这两种无毒和保护肝脏的营养制剂的协同效应将针对实验性肝损伤的关键模式进行测试，包括非酒精性和酒精性脂肪性肝炎以及CCI4诱导的肝硬变，从而提供临床前数据，以最终在临床试验中验证这种营养制剂组合在预防和治疗肝硬变方面的有效性。肝硬变是目前尚无有效治疗方法的常见死亡原因。

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.