Abstract：
BACKGROUND: Leonurus japonicus Houtt (L. japonicus, Chinese motherwort), known as Yi Mu Cao which means \"good for women\", has long been widely used in China and other Asian countries to alleviate gynecological disorders, often characterized by estrogen dysregulation. It has been used for the treatment of polycystic ovary syndrome (PCOS), a common endocrine disorder in women but the underlying mechanism remains unknown.
OBJECTIVE: The present study was designed to investigate the effect and mechanism of flavonoid luteolin and its analog luteolin-7-methylether contained in L. japonicus on aromatase, a rate-limiting enzyme that catalyzes the conversion of androgens to estrogens and a drug target to induce ovulation in PCOS patients.
METHODS: Estrogen biosynthesis in human ovarian granulosa cells was examined using ELISA. Western blots were used to explore the signaling pathways in the regulation of aromatase expression. Transcriptomic analysis was conducted to elucidate the potential mechanisms of action of compounds. Finally, animal models were used to assess the therapeutic potential of these compounds in PCOS.
RESULTS: Luteolin potently inhibited estrogen biosynthesis in human ovarian granulosa cells stimulated by follicle-stimulating hormone. This effect was achieved by decreasing cAMP response element-binding protein (CREB)-mediated expression of aromatase. Mechanistically, luteolin and luteolin-7-methylether targeted tumor progression locus 2 (TPL2) to suppress mitogen-activated protein kinase 3/6 (MKK3/6)-p38 MAPK-CREB pathway signaling. Transcriptional analysis showed that these compounds regulated the expression of different genes, with the MAPK signaling pathway being the most significantly affected. Furthermore, luteolin and luteolin-7-methylether effectively alleviated the symptoms of PCOS in mice.
CONCLUSIONS: This study demonstrates a previously unrecognized role of TPL2 in estrogen biosynthesis and suggests that luteolin and luteolin-7-methylether have potential as novel therapeutic agents for the treatment of PCOS. The results provide a foundation for further development of these compounds as effective and safe therapies for women with PCOS.
OBJECTIVE: The present study was designed to investigate the effect and mechanism of flavonoid luteolin and its analog luteolin-7-methylether contained in L. japonicus on aromatase, a rate-limiting enzyme that catalyzes the conversion of androgens to estrogens and a drug target to induce ovulation in PCOS patients.
METHODS: Estrogen biosynthesis in human ovarian granulosa cells was examined using ELISA. Western blots were used to explore the signaling pathways in the regulation of aromatase expression. Transcriptomic analysis was conducted to elucidate the potential mechanisms of action of compounds. Finally, animal models were used to assess the therapeutic potential of these compounds in PCOS.
RESULTS: Luteolin potently inhibited estrogen biosynthesis in human ovarian granulosa cells stimulated by follicle-stimulating hormone. This effect was achieved by decreasing cAMP response element-binding protein (CREB)-mediated expression of aromatase. Mechanistically, luteolin and luteolin-7-methylether targeted tumor progression locus 2 (TPL2) to suppress mitogen-activated protein kinase 3/6 (MKK3/6)-p38 MAPK-CREB pathway signaling. Transcriptional analysis showed that these compounds regulated the expression of different genes, with the MAPK signaling pathway being the most significantly affected. Furthermore, luteolin and luteolin-7-methylether effectively alleviated the symptoms of PCOS in mice.
CONCLUSIONS: This study demonstrates a previously unrecognized role of TPL2 in estrogen biosynthesis and suggests that luteolin and luteolin-7-methylether have potential as novel therapeutic agents for the treatment of PCOS. The results provide a foundation for further development of these compounds as effective and safe therapies for women with PCOS.
摘要：
背景：益母草（L.日本,中国益母草），被称为“伊木草”，意思是“对妇女有好处”，长期以来在中国和其他亚洲国家广泛用于缓解妇科疾病，通常以雌激素失调为特征。它已被用于治疗多囊卵巢综合征（PCOS），这是女性常见的内分泌紊乱，但其潜在机制尚不清楚。
目的：本研究旨在研究日本血吸虫中黄酮类木犀草素及其类似物7-甲基醚对芳香化酶的作用及其机制。一种催化雄激素转化为雌激素的限速酶，也是PCOS患者诱导排卵的药物靶标。
方法：使用ELISA检测人卵巢颗粒细胞中雌激素的生物合成。蛋白质印迹法用于探索芳香化酶表达调控中的信号通路。进行转录组学分析以阐明化合物的潜在作用机制。最后,动物模型用于评估这些化合物在PCOS中的治疗潜力。
结果：木犀草素有效抑制人卵巢颗粒细胞受促卵泡激素刺激的雌激素生物合成。这种作用是通过降低cAMP反应元件结合蛋白（CREB）介导的芳香酶表达来实现的。机械上,Lutolin和Lutolin-7-甲基醚靶向肿瘤进展基因座2（TPL2）以抑制丝裂原活化蛋白激酶激酶3/6（MKK3/6）-p38MAPK-CREB通路信号传导。转录分析表明,这些化合物调控不同基因的表达,MAPK信号通路受影响最大。此外，木犀草素和木犀草素-7-甲基醚可有效缓解PCOS小鼠的症状。
结论：这项研究证明了TPL2在雌激素生物合成中的作用，并表明木犀草素和木犀草素-7-甲基醚具有作为治疗PCOS的新型治疗剂的潜力。该结果为进一步开发这些化合物作为PCOS女性的有效和安全疗法提供了基础。
目的：本研究旨在研究日本血吸虫中黄酮类木犀草素及其类似物7-甲基醚对芳香化酶的作用及其机制。一种催化雄激素转化为雌激素的限速酶，也是PCOS患者诱导排卵的药物靶标。
方法：使用ELISA检测人卵巢颗粒细胞中雌激素的生物合成。蛋白质印迹法用于探索芳香化酶表达调控中的信号通路。进行转录组学分析以阐明化合物的潜在作用机制。最后,动物模型用于评估这些化合物在PCOS中的治疗潜力。
结果：木犀草素有效抑制人卵巢颗粒细胞受促卵泡激素刺激的雌激素生物合成。这种作用是通过降低cAMP反应元件结合蛋白（CREB）介导的芳香酶表达来实现的。机械上,Lutolin和Lutolin-7-甲基醚靶向肿瘤进展基因座2（TPL2）以抑制丝裂原活化蛋白激酶激酶3/6（MKK3/6）-p38MAPK-CREB通路信号传导。转录分析表明,这些化合物调控不同基因的表达,MAPK信号通路受影响最大。此外，木犀草素和木犀草素-7-甲基醚可有效缓解PCOS小鼠的症状。
结论：这项研究证明了TPL2在雌激素生物合成中的作用，并表明木犀草素和木犀草素-7-甲基醚具有作为治疗PCOS的新型治疗剂的潜力。该结果为进一步开发这些化合物作为PCOS女性的有效和安全疗法提供了基础。
