Estrogen Receptor-Selective Herbs for Menopause Symptoms

雌激素受体选择性草药治疗更年期症状

• 批准号: 7113637
• 负责人: DALE C LEITMAN
• 金额: $ 35.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7113637
• 关键词: alternative medicine; athymic mouse; biotherapeutic agent; breast neoplasms; cell proliferation; chromatin immunoprecipitation; clinical research; clinical trials; estrogen receptors; estrogens; high performance liquid chromatography; hot flash; human subject; mass spectrometry; medicinal plants; menopause; neoplastic cell; osteoporosis; patient oriented research; polymerase chain reaction; sign /symptom; transfection

DESCRIPTION (provided by applicant): Our long-term objective is to identify safe and effective natural agents to prevent menopausal symptoms and osteoporosis. Currently, there are 36 million postmenopausal women in the USA, and this number is projected to soar to 50 million by the year 2020. Menopause is characterized by severe estrogen deficiency, which leads to hot flushes, vaginal dryness, mood swings and osteoporosis. Although these conditions have been effectively treated with hormone replacement therapy (HILT) for the past 50 years, recent clinical trials have found that HRT is associated with increased risk of breast cancer, cardiovascular disease and dementia. The failure of HRT to live up to expectations has left the rapidly expanding menopausal population without a good alternative that prevents both hot flushes and osteoporosis. Thus, there is a tremendous need to discover more selective and safer estrogens. Many women seek alternatives to HRT, particularly estrogens derived from plants, known as phytoestrogens. Interest in phytoestrogens has been fueled by observational studies showing a lower incidence of menopausal symptoms, osteoporosis, cardiovascular disease and breast cancer in Asian women who consume soy and herbal products. Unfortunately, little scientific data exists to show that they are effective at preventing menopausal symptoms and osteoporosis. Based on our studies showing that estrogen receptor (ER) alpha mediates breast cancer cell proliferation and ERBeta inhibits proliferation and breast tumor formation in mouse xenografts, we are using molecular biology techniques to identify herbs that exhibit selective estrogenic activity for ERBbeta. We hypothesize that ERBeta-selective estrogens will be safer than estrogens found in current HRT regimens that interact non-selectively with ERalpha and ERBeta, and will be effective at reducing hot flushes and osteoporosis. To discover ERbeta-selective herbs, we screened 67 Chinese herbs using transient transfection assays with luciferase reporters in the presence of ERalpha or ERBeta Seven herbs selectively regulated transcription with ERli Some of these herbs also recruited the coregulator, GRIP1 to ERBeta, and were very weak at causing the proliferation of MCF-7 breast cancer cells. The goals of this proposal are to: (1) employ molecular biology techniques to determine how herbs are ER-selective and if the herbs retain ER-selectivity in vivo. (2) identify active compounds in herbs responsible for ER-selectivity. (3) identify which class of ER-selective herbs are most effective at reducing the frequency and severity of hot flushes. Identifying ER-selective herbs could lead to the discovery of novel agents that retain the beneficial effects on bone and menopausal symptoms, but lack the cancer promoting properties of estrogens in current HRT on the breast and endometrium.

描述（由申请人提供）：我们的长期目标是确定安全有效的天然药物，以防止绝经症状和骨质疏松症。目前，美国有3600万绝经后妇女，到2020年，这一数字预计将飙升至5000万。更年期的特征是严重的雌激素缺乏症，这会导致热水冲洗，阴道干燥，情绪波动和骨质疏松症。尽管这些疾病在过去的50年中已通过激素替代疗法（HILT）有效治疗，但最近的临床试验发现，HRT与乳腺癌，心血管疾病和痴呆症的风险增加有关。 HRT无法实现期望的未能使更年期人口的迅速扩大，而没有良好的替代方法可以防止热潮和骨质疏松症。因此，需要发现更多选择性和更安全的雌激素。许多妇女寻求替代HRT的替代品，尤其是源自植物的雌激素，称为植物雌激素。观察性研究激发了对植物雌激素的兴趣，表明在食用大豆和草药产品的亚洲女性中，绝经症状，骨质疏松症，心血管疾病和乳腺癌的发病率较低。不幸的是，很少有科学数据表明它们有效预防更年期症状和骨质疏松症。基于我们的研究表明，雌激素受体（ER）α介导乳腺癌细胞的增殖和ERBETA抑制了小鼠异种移植物中的增殖和乳腺肿瘤的形成，我们使用分子生物学技术来识别ERBBETA表现出选择性雌激活活性的草药。我们假设Erbe​​ta选择性雌激素将比与Eralpha和Erbeta非选择性相互作用的当前HRT方案中发现的雌激素更安全，并且可以有效地减少热水冲洗和骨质疏松症。 To discover ERbeta-selective herbs, we screened 67 Chinese herbs using transient transfection assays with luciferase reporters in the presence of ERalpha or ERBeta Seven herbs selectively regulated transcription with ERli Some of these herbs also recruited the coregulator, GRIP1 to ERBeta, and were very weak at causing the proliferation of MCF-7 breast cancer cells.该提案的目标是：（1）采用分子生物学技术来确定草药是er选择性的，以及药草是否在体内保留ER - 选择性。 （2）确定负责ER选择性的草药中的活性化合物。 （3）确定哪种ER选择性草药最有效地降低了潮热的频率和严重程度。识别ER选择性草药可能会导致发现新型药物，这些药物保留了对骨骼和绝经症状的有益作用，但缺乏促进乳腺癌特性的癌症，目前HRT在乳房和子宫内膜上都缺乏癌症。

项目成果

Estrogen receptor beta-selective agonists stimulate calcium oscillations in human and mouse embryonic stem cell-derived neurons.

• DOI: 10.1371/journal.pone.0011791
• 发表时间: 2010-07-27
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zhang L;Blackman BE;Schonemann MD;Zogovic-Kapsalis T;Pan X;Tagliaferri M;Harris HA;Cohen I;Pera RA;Mellon SH;Weiner RI;Leitman DC
• 通讯作者: Leitman DC

Regulation of specific target genes and biological responses by estrogen receptor subtype agonists.

• DOI: 10.1016/j.coph.2010.09.009
• 发表时间: 2010-12
• 期刊: CURRENT OPINION IN PHARMACOLOGY
• 影响因子: 4
• 作者: Leitman, Dale C.;Paruthiyil, Sreenivasan;Vivar, Omar I.;Saunier, Elise F.;Herber, Candice B.;Cohen, Isaac;Tagliaferri, Mary;Speed, Terence P.
• 通讯作者: Speed, Terence P.

Drug and cell type-specific regulation of genes with different classes of estrogen receptor beta-selective agonists.

• DOI: 10.1371/journal.pone.0006271
• 发表时间: 2009-07-17
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Paruthiyil S;Cvoro A;Zhao X;Wu Z;Sui Y;Staub RE;Baggett S;Herber CB;Griffin C;Tagliaferri M;Harris HA;Cohen I;Bjeldanes LF;Speed TP;Schaufele F;Leitman DC
• 通讯作者: Leitman DC