Synergistic Nutraceutical Effects of DLPC and SAMe

DLPC 和 SAMe 的协同保健作用

• 批准号: 7024566
• 负责人: CHARLES S LIEBER
• 金额: $ 27.82万
• 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/7024566
• 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（由申请人提供）：我们的长期目标是开发有效的肝硬化预防和治疗。它的营养后果之一是减少了必需营养物质向其活性形式的酶促转化，包括蛋氨酸向S-腺苷硫氨酸的有缺陷激活（相同），并损失了许多蛋氨酸的重要功能。由于最佳[细胞功能]也需要膜的完整性，因此这种缺陷仅部分响应相同的补充，这些膜受到对其磷脂酰胆碱（PC）基础结构的自由基攻击而受到伤害。这可以通过用二氨基磷脂酰胆碱（DLPC）（DLPC）（一种高度可生物利用的PC）来克服这一点，但也需要相同，因为它是PC通过磷脂酰氨基胺的甲基化而在PC中重新生成的至关重要的共同因素。氧化应激和肝损伤的主要原因是细胞色素P4502E1（CYP2E1）当乙醇（在酒精性肝病中），脂质（肥胖）和酮（糖尿病中）诱导时。可用的CYP2E1抑制剂对临床使用过于毒性，除了最近发现以抑制CYP2E1的DLPC。我们的直接目的是使用啮齿动物的酗酒和非酒精性脂肪性肝炎以及CCI4诱导的肝硬化的啮齿动物模型来测试相同 + DLPC的协同作用。将在体内研究相同和DLPC之间有益相互作用的机制，并在培养的啮齿动物肝星状细胞，库普弗夫尔细胞和巨噬细胞中进行体外研究，重点是保留生理学抗氧化剂谷胱甘肽，磷脂酰胺甲基甲基甲基甲基甲基生物酶的恢复，并在磷酸氧化粘液钉中的恢复，该甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基甲基化酶的活性及其属性？激活，脂质过氧化和致病性细胞因子TNF-？，TGF-？1，IL-1？和IL-6。通过降低的星状细胞激活，增强的胶原酶活性并降低了瘦素的产生，可以实现纤维化的降低。总而言之，将测试相同和DLPC的两个无害和肝保护营养的营养素，以实验性肝损伤的关键方式进行测试，包括非酒精性和酒精性脂肪性肝炎和CCI4 cci4诱导的cirrhosis，从而诱导CIRRHOSIS，从而提供必要的criftional nutifiention，并在临床上进行临床验证，并在临床上进行临床验证，并在临床上进行了临床，并在临床上进行了临床范围，并将其用于治疗肝硬化，这是死亡率目前尚无有效治疗的常见原因。