Mechanisms of Silymarin Hepatoprotection

水飞蓟素的保肝机制

• 批准号: 8195766
• 负责人: STEPHEN J. POLYAK
• 金额: $ 47.03万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195766
• 关键词: Address; Adverse drug effect; Affinity; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Antiviral Agents; Asteraceae; Binding; Bioinformatics; Biological Assay; Biological Factors; Biological Markers; Biotin; Botanicals; Cell Line; Cells; Chemicals; Chemistry; Chronic; Chronic Hepatitis; Clinical Research; Clinical Trials; Complementary and alternative medicine; Complex; Data; Data Set; Disease; Disease Progression; Exogenous Factors; Funding; Gene Expression; Gene Expression Regulation; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Individual; Inflammation; Injury; Lead; Ligands; Liver; Liver diseases; Malignant Neoplasms; Measures; Medicine; Methods; Milk Thistle; Milk thistle extract; Molecular; Molecular Target; National Center for Complementary and Alternative Medicine; North Carolina; Oxidative Stress; Patients; Physiological; Prevention; Property; Proteomics; Research; Research Project Grants; Seeds; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Pathway Gene; Silymarin; Specificity; Staging; Systems Biology; Testing; Therapeutic; Transcription factor genes; Transduction Gene; Treatment Efficacy; Universities; Viral Load result; Virus; Washington; anti-hepatitis C; base; cellular targeting; global health; hepatoma cell; improved; isosilybin; novel; prevent; response; silibinin; taxifolin

DESCRIPTION (provided by applicant): Silymarin, an extract of milk thistle seeds, prevents liver injury and disease progression in many animal models. Recent clinical studies indicate that silymarin also reduces hepatitis C viral load and progression of hepatitis C liver disease in humans. If we are to understand and exploit the full value of this natural product, we must understand how silymarin protects the liver, which has not been clearly elucidated. In our NCCAM-funded R21, we discovered that silymarin blocks hepatitis C virus (HCV) infection and have since defined the stages of the HCV lifecycle that are blocked by silymarin. We have isolated and evaluated the 8 major components of silymarin in hepatoprotection assays that measure antiviral, antioxidant, and anti-inflammatory functions. This proposal will use two parallel approaches to discover the mechanisms of action of silymarin. Specifically, we will identify the physiological target(s) of silymarin components that confer hepatoprotection in the forms of antiviral, antioxidant, and anti-inflammatory activities. Our hypothesis is that silymarin components interact with mammalian biomolecules in a specific and productive manner to cause changes in signal transduction and gene expression in a cell to protect the liver. We will address the hypothesis in two specific aims that will 1) identify transcriptional changes using microarrays of liver cell lines and primary hepatocyte cultures treated with silymarin and silymarin-derived pure compounds, 2) identify and validate cellular targets of silymarin compounds using chemical proteomics. By examining silymarin-induced gene regulation and elucidating cellular targets of silymarin, this application is intentionally responsive to RFA-AT-11-001. At the end of the funding period, we anticipate that we will know the cellular targets of silymarin and how silymarin causes changes in a cell at a systems biology level, thereby providing the first detailed explanation of how silymarin protects the liver. The novel data emanating from this research project are expected to pave the way for identification of biomarkers of silymarin treatment and efficacy, as well as guiding refinements in silymarin- based natural product treatments for liver disease. PUBLIC HEALTH RELEVANCE: Silymarin, an extract of milk thistle seeds, has been used in a variety of therapeutic applications that take advantage of its hepatoprotective properties, including prevention of HCV infection, inflammation, and oxidative stress. The physiological cellular target(s) and mechanism(s) of action of the component silymarin compounds are currently not known, and this proposal describes methods to identify these targets and mechanisms. We will then use this information to improve natural product-based treatments for liver disease, which is global health problem.

描述（由申请人提供）：水飞蓟素是水飞蓟种子的提取物，可在许多动物模型中预防肝损伤和疾病进展。最近的临床研究表明，水飞蓟素还可以减少人类丙型肝炎病毒载量和丙型肝炎肝病的进展。如果我们要了解和利用这种天然产品的全部价值，我们必须了解水飞蓟素如何保护肝脏，而这一点尚未明确阐明。在 NCCAM 资助的 R21 中，我们发现水飞蓟素可以阻断丙型肝炎病毒 (HCV) 感染，并确定了水飞蓟素阻断的 HCV 生命周期阶段。我们在抗病毒、抗氧化和抗炎功能的保肝测定中分离并评估了水飞蓟素的 8 种主要成分。该提案将使用两种并行的方法来发现水飞蓟素的作用机制。具体来说，我们将确定水飞蓟素成分的生理目标，这些成分以抗病毒、抗氧化和抗炎活性的形式赋予肝脏保护作用。我们的假设是，水飞蓟素成分以特定且有效的方式与哺乳动物生物分子相互作用，引起细胞内信号转导和基因表达的变化，从而保护肝脏。我们将通过两个具体目标来解决这一假设：1）使用经水飞蓟素和水飞蓟素衍生的纯化合物处理的肝细胞系和原代肝细胞培养物的微阵列来识别转录变化，2）使用化学蛋白质组学来识别和验证水飞蓟素化合物的细胞靶标。通过检查水飞蓟素诱导的基因调控并阐明水飞蓟素的细胞靶标，该应用有意响应 RFA-AT-11-001。在资助期结束时，我们预计我们将了解水飞蓟素的细胞靶点以及水飞蓟素如何在系统生物学水平上引起细胞变化，从而首次详细解释水飞蓟素如何保护肝脏。该研究项目产生的新数据预计将为鉴定水飞蓟素治疗和功效的生物标志物铺平道路，并指导改进基于水飞蓟素的天然产品治疗肝病的方法。 公共健康相关性：水飞蓟素是一种水飞蓟种子提取物，利用其保肝特性，已被用于多种治疗应用，包括预防丙型肝炎病毒感染、炎症和氧化应激。目前，水飞蓟素化合物的生理细胞靶点和作用机制尚不清楚，本提案描述了识别这些靶点和机制的方法。然后，我们将利用这些信息来改进基于天然产品的肝病治疗方法，肝病是全球健康问题。