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Nobiletin exhibits protective potential on inflammation and inhibits the activation of transcription factors nuclear factor-κB (NF-κB). However, its effects on the progression of endometriosis remain unsettled. The present study aimed to explore the in vivo alleviation of nobiletin on endometriosis and its mechanism of action. The mouse model of endometriosis was established and administered with nobiletin. The ectopic lesion size was measured and the hotplate test was performed to assess the amelioration of nobiletin on endometriosis. The expression of proliferation and angiogenesis relevant genes including proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), and E-cadherin was measured by immunostaining and the mRNA expression of proinflammatory mediators including interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, matrix metalloproteinases (MMP)-1, and MMP-3 was measured by RT-PCR. The change of NF-κB activity in endometriotic cells was evaluated by Western blotting and confirmed by luciferase assay. Administration of nobiletin significantly reduced lesions size and pain in endometriosis mice. Nobiletin significantly altered the expression of PCNA, VEGF, and E-cadherin in ectopic endometrium, as well as the levels of IL-6, IL-1β, TNF-α, MMP-1, and MMP-3. Nobiletin also showed remarkably impairment on the activation of NF-κB in promoting endometriotic cells, likely targeting on the activity of IκB kinases (IKKs). The present study provides the first evidence that nobiletin exerts protection on endometriosis via inhibition the activation of NF-κB, specifically on the activity of IκB kinases., (© 2018 The Author(s).)

Recent evidence points to a possible role for hypoxia-inducible factor (HIF)-1 in the pathogenesis and development of endometriosis. The objectives of this study were to investigate the critical role of HIF-1 in endometriosis and the effect of the HIF-1 inhibitor echinomycin on human ectopic endometriotic stromal cells (eESCs). Ectopic endometriotic tissues were obtained from 20 patients, who received an operation for ovarian endometriomas. We examined vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1 (SDF-1) production, HIF-1 expression, cell proliferation and apoptosis of eESCs. Cobalt chloride (CoCl2) significantly induced expression of HIF-1α protein and VEGF production in a time-dependent manner in eESCs, but reduced SDF-1 production. VEGF production was significantly suppressed by treatment of 100 nM echinomycin without causing cell toxicity, but 0.1-10 nM echinomycin or 100 nM progestin had no significant effect. SDF-1 production was not affected by echinomycin treatment at any dose. Echinomycin inhibited cell proliferation and induced apoptotic cell death of the eESCs, and significantly inhibited expression of the anti-apoptotic proteins Bcl-2 and Bcl-xL. Echinomycin inhibits VEGF production and induces apoptosis of eESCs by suppression of Bcl-2 and Bcl-xL. These findings suggest the unique therapeutic potential for echinomycin as an inhibitor of HIF-1 activation for endometriosis treatment.

Ethnopharmacological Relevance: Ferulic acid (FA), ligustrazine (LZ) and tetrahydropalmatine (THP) are separately isolated from Chinese Angelica, Szechwan Lovage Rhizome and Rhizoma in the Jiawei-Foshou-San formula, a popular traditional Chinese medicine for irregular menses. It has been reported that the combination use of FA+LZ+THP has similar effect on endometriosis, but the underlying mechanisms are unclear. This study was to investigate the combination effects and mechanisms of FA+LZ+THP on endometriosis rats., Materials and Methods: Fifty endometriosis rats were intragastricly treated with FA+LZ+THP for 4 wk. The volume of ectopic endometrial tissue was measured to evaluate the effects. Then the changes in hypothalamic-pituitary-ovarian axis and ERE pathway were indicated by the levels of E2, GnRH, FSH and LH, and the expressions of ER, HSP90 and COX-2, respectively. In addition, peritoneal macrophages of each rat were cultured in vitro and treated with (FA+LZ+THP)-medicated serum for 24h. The proliferation and phagocytosis abilities, the levels of IL-1β and TNF-α, and the expression of IκBα were then measured for the changes of peritoneal macrophage activities., Results: Combination use of FA+LZ+THP diminished the volume of the ectopic endometrial tissues (P<0.05 or P<0.01). It also decreased the E2 level, suppressed the expression of GnRH, FSH and LH, and decreased the protein expression of ER, HSP90 and COX-2 (all P<0.05 or P<0.01). The phagocytosis ability of peritoneal macrophage was enhanced by (FA+LZ+THP)-medicated serum (P<0.05) with no change of proliferation (P>0.05). Moreover, IL-1β and TNF-α were downregulated (both P<0.05 or P<0.01) and IκBα was upregulated by the (FA+LZ+THP)-medicated serum (P<0.01)., Conclusions: The combination use of FA, LZ and THP could inhibit the growth of ectopic endometrial tissue in endometriosis rats. It might be related to the down-regulation of hypothalamic-pituitary-ovarian axis, the amelioration in ERE pathway and the improvement of peritoneal macrophage activities., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Context: Decidualization of the endometrium involves the morphological and biochemical reprogramming of the estrogen-primed proliferative endometrial stromal compartment under the continuing influence of progesterone., Objectives: The aim of this study was to evaluate the involvement of the extracellular matrix contractility of eutopic and ectopic endometrial stromal cells during the tissue remodeling processes associated with decidualization., Design: The effect of decidualization on the contractile profile of the endometriotic cyst stromal cells and eutopic endometrial stromal cells with or without endometriosis in the three-dimensional collagen gel culture was investigated using laser scanning microscopy, collagen gel contraction assays, and Western blot analysis., Results: Decidualized ectopic and eutopic endometrial stromal cells in the three-dimensional collagen gel culture mimicked the morphology of decidual tissue in vivo. In vitro decidualization inhibited the contractility of these eutopic and ectopic endometrial stromal cells. Down-regulation of integrin alpha1beta1 and alpha2beta1 expression, suppression of Ras homology A (Rho A), Rho-associated coiled-coil-forming protein kinase (ROCK)-I and ROCK-II expression, inhibition of the differentiation into the myofibroblastic phenotype, and induction of differentiation into epithelioid decidual phenotype were observed in these cells during decidualization., Conclusions: It is suggested that the attenuation of eutopic endometrial stromal cell-mediated contractility by decidualization is a novel and integral mechanism of the physiological endometrial tissue remodeling process during menstrual cycles. Although ectopic endometrial stromal cells have enhanced contractile profile, decidualization can attenuate the contractility of these cells. These findings may be one of the action mechanisms by which oral contraceptives and progestins ameliorate endometriosis.