Phytotherapy for Endometriosis

摘要/总结 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严重影响生殖健康和生活质量。亲- 炎症微环境的子宫内膜病变，和腹膜腔是 子宫内膜异位症的标志，导致慢性盆腔疼痛和不孕症。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性疼痛的组合。长期 目的是了解子宫内膜异位症的分子和细胞发病机制， 子宫内膜异位症的治疗睡莲是一种古老的药用植物， 在一些实施方案中，所述药物组合物包括但不限于神经系统疾病/病症、神经性和炎性疼痛以及癌症。广泛的 催眠睡茄的治疗作用是通过其活性甾体内酯Withaferin-A发挥的。然而，在这方面， 没有研究调查睡茄/Withaferin-A在子宫内膜异位症中的作用。建议及时 需要的假设驱动的新的临床前研究集中在Withaferin-A的治疗作用， 子宫内膜异位症总体假设：Withaferin-A的治疗抑制了 子宫内膜增生性病变，改善盆腔疼痛，并恢复子宫内膜微环境，以支持生育。 目的：确定Withaferin-A对（i）肿瘤生长和存活的治疗作用。 病变，（ii）腹膜腔的促炎状态，炎性病变和疼痛脑区，（iii）促炎状态， 子宫内膜的炎症和激素微环境，（iv）上皮和基质细胞特异性基因 （v）上行和下行疼痛通路，以及 中枢致敏和潜在的分子和细胞机制，和（vi）骨盆疼痛阈值， 自发性疼痛。特异性目的-1将确定Withaferin-A对肿瘤病变的治疗效果 和子宫内膜特异性目标-2将确定Withaferin-A对中枢性疼痛的治疗效果 子宫内膜异位症的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、体内生物成像、荧光显微术和流式细胞术。创新与影响：新 所获得的信息应填补关于Withaferin-A在以下方面的治疗作用的知识的差距：（i）中枢神经系统 骨盆疼痛的机制，疼痛脑区的基因表达特征，以及它们与慢性疼痛的关系。 子宫内膜异位症的盆腔疼痛;（ii）子宫内膜异位症中上皮细胞和基质细胞特异性基因表达特征 增生性病变及其与增生性病变的生长和存活的相关性;以及（iii）上皮 和子宫内膜中基质细胞特异性基因表达特征及其与不孕症的关系。（四） 新的结果将建立一个分子治疗和临床前基础，使用Withaferin-A作为非药物， 类固醇和非阿片类药物治疗子宫内膜异位症妇女盆腔疼痛和不孕症。

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.