Synergistic Nutraceutical Effects of DLPC and SAMe

DLPC 和 SAMe 的协同保健作用

• 批准号: 6770613
• 负责人: CHARLES S LIEBER
• 金额: $ 28.49万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6770613
• 关键词: Kupffer' s cell; S adenosylmethionine; alcoholic hepatitis; alternative medicine; biotherapeutic agent; carbon tetrachloride; combination chemotherapy; disease /disorder; drug interactions; enzyme activity; enzyme linked immunosorbent assay; fatty liver; glutathione; laboratory rat; liver cells; liver cirrhosis; liver disorder; macrophage; methyltransferase; necrosis; nuclear factor kappa beta; oxidative stress; pharmacokinetics; phosphatidylcholines; phosphatidylethanolamines

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.

描述（申请人提供）：我们的长期目标是开发有效的肝硬化预防和治疗方法。其营养后果之一是必需营养物质向活性形式的酶促转化减少，包括蛋氨酸到s-腺苷蛋氨酸（SAMe）的缺陷激活，以及蛋氨酸许多重要功能的丧失。这种缺陷只对SAMe补充有部分反应，因为最佳的[细胞功能]也需要膜的完整性，而膜会被自由基对磷脂酰胆碱（PC）基础结构的攻击所损伤。这可以通过dilinoleoyl磷脂酰胆碱（DLPC）补充磷脂来克服，DLPC是一种高度生物利用的磷脂，但SAMe也是必需的，因为它是通过磷脂酰乙醇胺甲基化再生磷脂的关键辅助因子。氧化应激和肝损伤的主要原因是细胞色素P4502E1 (CYP2E1)，当乙醇（酒精性肝病）、脂质（肥胖）和酮类（糖尿病）诱导时。除了最近发现的抑制CYP2E1的DLPC外，现有的CYP2E1抑制剂毒性太大，不能用于临床。我们的直接目标是通过使用肝硬化前酒精性和非酒精性脂肪性肝炎以及cci4诱导的肝硬化啮齿动物模型，测试SAMe + DLPC的协同作用。在体外和体内研究SAMe和DLPC在培养的啮齿动物肝星状细胞、Kupffer细胞和巨噬细胞中有益相互作用的机制，重点研究生理性抗氧化剂谷胱甘肽的保存，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，脂质过氧化和致病性细胞因子TNF-？TGF - ?1, il - 1 ?和il - 6。纤维化的减少可能通过星状细胞活化的减少、胶原酶活性的增强和瘦素产生的降低来实现。综上所述，SAMe和DLPC这两种无害且保护肝脏的营养保健品的协同作用将被测试，以对抗主要的实验性肝损伤，包括非酒精性和酒精性脂肪性肝炎以及CCI4诱导的肝硬化，从而提供临床前数据，最终在临床试验中验证这种营养保健品组合在预防和治疗肝硬化方面的有效性。一种常见的死亡原因，目前尚无有效的治疗方法。