Phytotherapy for Endometriosis

摘要/摘要 子宫内膜异位症是育龄妇女的一种炎症性妇科疾病。两大症状 慢性盆腔疼痛和不孕症，深刻影响生殖健康和生活质量。支持- 子宫内膜异位病变的炎性微环境、子宫内膜和腹膜是 子宫内膜异位症的特征，导致慢性盆腔疼痛和不孕。新出现的证据表明 子宫内膜异位症的盆腔疼痛是内脏炎症和神经病理性疼痛的结合。长期的 目的是了解子宫内膜异位症的分子和细胞发病机制，并识别非类固醇 子宫内膜异位症的治疗。金缕梅是一种古老的药用植物，已被用来治疗炎症。 精神障碍、神经疾病/障碍、神经病理性和炎症性疼痛以及癌症。范围广泛的 睡莲的治疗作用是通过其活性的类固醇内酯和非铁蛋白-A发挥作用的。然而， 还没有研究探讨睡莲/维他林-A在子宫内膜异位症中的作用。建议适时 需要假说驱动的新的临床前研究集中在Withaferin-A的治疗效果上 子宫内膜异位症。最重要的假设：Withaferin-A的治疗抑制了肿瘤的生长和存活 子宫内膜异位症病变，改善盆腔疼痛，恢复子宫内膜微环境，支持生育。 目的：探讨维非他林-A对子宫内膜异位症的治疗作用 病变，(Ii)腹膜腔的促炎状态，子宫内膜异位症病变，以及疼痛-脑区，(Iii)促炎症 子宫内膜炎性和激素微环境；(Iv)上皮和间质细胞特异性基因 子宫内膜异位病变和子宫内膜的征象，(V)上行和下行疼痛通路和 中枢敏感化及其潜在的分子和细胞机制，以及(Vi)骨盆痛阈值和 自发性疼痛。特异性Aim-1将决定联合用药对子宫内膜异位症病变的治疗效果 和子宫内膜。特异性Aim-2将决定Withaferin-A对中枢性疼痛的疗效 子宫内膜异位症的发病机制。实验方法包括临床前同种异体移植小鼠模型。 子宫内膜异位症，RNA-Seq，脑神经元电生理学，上行和下行疼痛通路，疼痛 行为，活体生物成像，荧光显微镜，和流式细胞术。创新和影响：新的 所获得的信息应该填补关于Withaferin-A治疗效果的知识空白(I) 盆腔疼痛的机制、疼痛脑区的基因表达特征及其与慢性盆腔疼痛的关系 子宫内膜异位症中的盆腔疼痛；(Ii)子宫内膜异位症中上皮和间质细胞特异性基因表达特征 子宫内膜异位病变及其与子宫内膜异位病变生长和存活的关系；(Iii)上皮 子宫内膜间质细胞特异性基因表达特征及其与不孕症的关系。(四) 这一新的结果将为将Withaferin-A用作非 激素和非阿片类药物治疗子宫内膜异位症患者的盆腔疼痛和不孕症。

ABSTRACT/SUMMARY Endometriosis is an inflammatory gynecological disease of reproductive-age women. The two major symptoms are chronic pelvic pain and infertility, which profoundly affect reproductive health and life quality. The pro- inflammatory microenvironment of the endometriotic lesions, endometrium, and the peritoneal cavity are the hallmarks of endometriosis, which leads to chronic pelvic pain and infertility. Emerging evidence suggests that pelvic pain in endometriosis is a combination of visceral inflammatory and neuropathic pain. The long-term goals are to understand the molecular and cellular pathogenesis of endometriosis and identify non-steroidal therapy for endometriosis. Withania somnifera, an ancient medicinal plant, has been used to treat inflammatory disorders, neurological diseases/disorders, neuropathic and inflammatory pain, and cancers. A wide range of therapeutic effects of Withania somnifera is exerted through its active steroidal lactone Withaferin-A. However, no studies have investigated the role of Withania somnifera/Withaferin-A in endometriosis. The proposed timely needed hypothesis-driven novel preclinical research is focused on the therapeutic effects of Withaferin-A in endometriosis. Overarching Hypothesis: Treatment of Withaferin-A suppresses the growth and survival of endometriotic lesions, ameliorates pelvic pain, and restores the endometrial microenvironment to support fertility. Objectives: Determine the therapeutic effects of Withaferin-A on (i) growth and survival of the endometriotic lesions, (ii) pro-inflammatory state of the peritoneal cavity, endometriotic lesions, and pain-brain areas, (iii) pro- inflammatory and hormonal microenvironment of the endometrium, (iv) epithelial and stromal cell-specific gene signatures in the endometriotic lesions and endometrium, (v) ascending and descending pain pathway and central sensitization and the underlying molecular and cellular mechanisms, and (vi) pelvic pain threshold and spontaneous pain. Specific Aim-1 will determine the therapeutic effects of Withaferin-A on endometriotic lesions and endometrium. Specific Aim-2 will determine the therapeutic effects of Withaferin-A on central pain mechanisms in endometriosis. The experimental approaches include the preclinical allograft mouse model of endometriosis, RNA-Seq, electrophysiology of brain neurons, ascending and descending pain pathways, pain behavior, in vivo bioimaging, fluorescence microscopy, and flow cytometry. Innovation and Impact: The new information obtained should fill the gap in the knowledge on therapeutic effects of Withaferin-A in (i) central mechanisms of pelvic pain, gene expression signatures in the pain-brain areas, and their association with chronic pelvic pain in endometriosis; (ii) epithelial and stromal cell-specific gene expression signatures in the endometriotic lesions and their association with growth and survival of endometriotic lesions; and (iii) epithelial and stromal cell-specific gene expression signatures in the endometrium and their association with infertility. (iv) The novel results will establish a molecular therapeutic and preclinical basis to use Withaferin-A as a non- steroidal and non-opioid therapy to treat pelvic pain and infertility in women with endometriosis.