Mechanisms of Silymarin Hepatoprotection

水飞蓟素的保肝机制

• 批准号: 8305463
• 负责人: STEPHEN J. POLYAK
• 金额: $ 55.28万
• 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/8305463
• 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.

描述(申请人提供)：水飞蓟素，一种牛奶蓟种子的提取物，在许多动物模型中防止肝脏损伤和疾病进展。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。如果我们要理解和开发这种天然产品的全部价值，我们必须了解水飞蓟素是如何保护肝脏的，这一点还没有明确阐明。在我们由NCCAM资助的R21中，我们发现水飞蓟素可以阻止丙型肝炎病毒(丙型肝炎病毒)的感染，并定义了被水飞蓟素阻止的丙型肝炎病毒生命周期的各个阶段。在衡量抗病毒、抗氧化和抗炎功能的保肝试验中，我们分离并评估了水飞蓟素的8种主要成分。这项提议将使用两种平行的方法来发现水飞蓟素的作用机制。具体地说，我们将确定水飞蓟素成分的生理靶点(S)，这些成分具有抗病毒、抗氧化和抗炎活性的保肝作用。我们的假设是水飞蓟素成分与哺乳动物生物分子以一种特定和多产的方式相互作用，导致细胞中信号转导和基因表达的变化，从而保护肝脏。我们将在两个特定目标中解决这一假设：1)使用水飞蓟素和水飞蓟素衍生纯化合物处理的肝细胞系和原代肝细胞培养物微阵列确定转录变化；2)使用化学蛋白质组学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和阐明水飞蓟素的细胞靶点，这一应用有意地响应RFA-AT-11-001。在资助期结束时，我们预计我们将知道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。这一研究项目产生的新数据有望为水飞蓟素治疗和疗效的生物标记物的鉴定铺平道路，并指导水飞蓟素天然产物治疗肝病的改进。