MECHANISMS OF ACTION IN MENOPAUSE

更年期的作用机制

• 批准号: 6954972
• 负责人: Judy L Bolton
• 金额: $ 20.45万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6954972
• 关键词: alternative medicine; antioxidants; bioassay; biological models; chemoprevention; chromatography; depression; dietary supplements; drug screening /evaluation; emotions; female; hormone regulation /control mechanism; hot flash; laboratory rat; medicinal plants; menopause; nutrition related tag; pharmacokinetics; phytoestrogens; plant extracts; serotonin; serotonin receptor; women' s health

The major objective of Project by Bolton continues to be to provide in vitro bioassay support for the discovery of the active components for the major dietary supplements for the relief of menopausal symptoms. To achieve this objective several in vitro cell based and animal assays have been developed in order to investigate the mechanism of action of these dietary supplements. Specifically, we are interested in botanicals with estrogenic activity such as hops (Humulus lupulus), kudzu (Pueraria lobata), and kwao keur (Pueraria mirifica). In addition, we have discovered an alternative serotonergic mechanism for the relief of menopausal symptoms which could be important for black cohosh (Cimicifuga racemosa), dong quai (Angelica sinensis), and valerian (Valeriana officinalis). The hypothesis to be addressed is whether select plant extracts contain potent estrogenic and/or serotonergic compounds useful for the relief of menopausal symptoms as well as other beneficial properties of estrogens such as antioxidant/chemopreventive effects. The following specific aims are proposed: 1. To evaluate the hormonal activity of plant extracts and active compounds. We have already screened a number of plant extracts and pure compounds for estrogenic effects and investigated their mechanism of action using a variety of in vitro assays including competitive ER binding assays, induction of estrogen sensitive genes, and ERE-luciferase assays. In addition, we have tested several of these extracts for hormonal activity in vivo using the ovariectomized rat model. We have also incorporated two new screening assays including the estrogen receptor coactivator assay and an assay to measure ERE and AP-1 DNA binding capacity. 2. To evaluate the serotonergic activity of plant extracts and active compounds. We plan to further fractionate black cohosh (aim 3) in order to determine the active compounds as well as test other promising plants using established serotonergic assays (competitive binding to serotonin receptors, elevation in cyclic AMP activity, and SSRI assays), addition, we plan to further test the hypothesis that the 5-HT7 receptor is involved in thermoregulation (i.e. hot flashes) whereas the 5-HT1A and 5-HT5A receptors are likely responsible for depression and mood. Animal models will be incorporated including the hot flash model and the forced swim test (mood). 3. To evaluate the chemoprevention/antioxidant properties of plant extracts and active compounds. During the previous granting period, we have developed a variety of antioxidant/chemoprevention assays including scavenging of stable free radicals, inhibition of DNA damage induced by the quinone menadione using the comet assay, and induction of quinone reductase. In this aim, extracts of the above mentioned botanical dietary supplements will be fractionated and activity will be determined using the antioxidant/chemoprevention assays. The completion of these aims will determine which specific botanicals have health benefits for relief of menopausal symptoms and determine their mechanism of action.

博尔顿（Bolton）项目的主要目标是为了发现主要饮食补充剂的活性成分，以减轻更年期症状。为了实现这一目标，已经开发了几种基于体外细胞的基于体外细胞和动物测定 补品。具体而言，我们对具有雌激素活性的植物性感兴趣，例如啤酒花（Humulus lupulus），kudzu（pueraria lobata）和Kwao Keur（pueraria mirifica）。此外，我们还发现了一种替代性血清素能机制，可缓解绝经症状，这对于黑色同岛（Cimicifuga racemosa），dong Quai（Angelica sinensis）和Valerian（Valeriana officinalis）可能很重要。要解决的假设是，精选的植物提取物是否含有有效的雌激素和/或血清素能化合物，可用于缓解绝经症状以及雌激素的其他有益特性，例如抗氧化剂/化学抗性作用。提出了以下特定目的：1。评估植物提取物和活性化合物的激素活性。我们已经筛选了 植物提取物的数量和纯化合物用于雌激素作用，并使用各种体外测定法研究了其作用机理，包括竞争性的ER结合测定，诱导雌激素敏感基因和ERE-LUCIFERASE分析。此外，我们使用卵巢切除大鼠模型在体内测试了其中一些提取物的激素活性。我们还结合了两个新的筛选测定法，包括雌激素受体共激活因子测定法和测量ERE和AP-1 DNA结合能力的测定。 2。评估植物提取物和活性化合物的血清素能活性。我们计划进一步分割黑色co（AIM 3），以确定活性化合物以及使用已建立的血清素能测定法（与5-羟色胺受体的竞争结合，环状AMP活性升高和SSRI分析的升高），并补充的其他有希望的植物，我们补充，我们，我们计划进一步测试 假设5-HT7受体参与了温度调节（即热闪光），而5-HT1A和5-HT5A受体可能导致抑郁症和情绪。动物模型将合并，包括热闪光模型和强制游泳测试（情绪）。 3。评估植物提取物和活性化合物的化学预防/抗氧化特性。在上一个授予期间，我们开发了各种抗氧化剂/化学预防测定法，包括清除稳定的自由基，使用彗星测定法抑制喹酮甲酮造成的DNA损伤以及诱导醌还原酶。在此目的中，将对上述植物饮食补充剂的提取物进行分级，并使用抗氧化剂/化学预防测定法确定活性。这些目标的完成将确定哪些特定的植物有健康 缓解更年期症状的好处并确定其作用机理。