The anti-implantation effects of high oestradiol (E2) concentrations could be mediated by E2 metabolites. Herein, we examined whether 2-methoxyoestradiol (2ME) impairs embryo implantation via its target protein F-spondin. Mice on Day 3 of pregnancy were treated with E2 concomitantly with the cathecol-O-methyl transferase inhibitor OR486 and the number of implanted embryos was recorded 5 days later. The effect of 2ME or 4-methoxyoestradiol (4ME) on embryo implantation was also investigated. Plasma and uterine levels of 2ME were measured 0.5, 1 or 3h after E2 treatment while the mRNA for spondin 1 (Spon1) and F-spondin were determined in the uterus 3, 6, 12 or 24h after 2ME treatment. Finally, the effect of a neutralising F-spondin antibody on the anti-implantation effect of 2ME was explored. OR486 blocked the anti-implantation effect of E2; 2ME, but not 4ME, affected embryo implantation. The 2ME concentration was increased after 0.5 and 1h in plasma and 3h in uterine fluid following E2 treatment. 2ME increased levels of Spon1 at 12 and 24h although F-spondin was increased at 12h. F-spondin antibody blocked the effect of 2ME on embryo implantation. We conclude that 2ME impairs mouse embryo implantation via activation of F-spondin in the uterus.
The estrogen metabolite 2-methoxyestradiol (2ME) is a promissory anticancer drug mainly because of its pro-apoptotic properties in cancer cells. However, the therapeutic use of 2ME has been hampered due to its low solubility and bioavailability. Thus, it is necessary to find new ways of administration for 2ME. Zeolites are inorganic aluminosilicates with a porous structure and are considered good adsorbents and sieves in the pharmaceutical field. Here, mordenite-type zeolite nanoparticles were loaded with 2ME to assess its efficiency as a delivery system for prostate cancer treatment. The 2ME-loaded zeolite nanoparticles showed an irregular morphology with a mean hydrodynamic diameter of 250.9 ± 11.4 nm, polydispersity index of 0.36 ± 0.04, and a net negative surface charge of −34 ± 1.73 meV. Spectroscopy with UV-vis and Attenuated Total Reflectance Infrared Fourier-Transform was used to elucidate the interaction between the 2ME molecules and the zeolite framework showing the formation of a 2ME-zeolite conjugate in the nanocomposite. The studies of adsorption and liberation determined that zeolite nanoparticles incorporated 40% of 2ME while the liberation of 2ME reached 90% at pH 7.4 after 7 days. The 2ME-loaded zeolite nanoparticles also decreased the viability and increased the mRNA of the 2ME-target gene F-spondin, encoded by SPON1, in the human prostate cancer cell line LNCaP. Finally, the 2ME-loaded nanoparticles also decreased the viability of primary cultures from mouse prostate cancer. These results show the development of 2ME-loaded zeolite nanoparticles with physicochemical and biological properties compatible with anticancer activity on the human prostate and highlight that zeolite nanoparticles can be a good carrier system for 2ME.
During embryo implantation, endometrial angiogenesis is regulated by signals originating from the endometrium itself and the developing embryo. It has been suggested that hCG may play a pro-angiogenic role; therefore, we sought to understand its regulatory role in blood vessel formation in human endometrium using in vivo and in vitro models. In the in vivo model, we screened 16 angiogenesis-related transcripts in the endometrium upon intrauterine administration of hCG. Oocyte donors were recruited and during their controlled ovarian stimulation cycle received a single dose of hCG or vehicle on the day of oocyte pick up during a cycle of ovarian stimulation. One hour before obtaining an endometrial sample, women received an intrauterine administration of vehicle or hCG (500, 1500 and 5000 IU). Transcript and protein analysis showed that MMP-3 and VEGF increased whereas TIMP-1 decreased. The in vitro analysis studied the angiogenic potential of conditioned medium (CM) from primary cultures of human endometrial stromal cells (ESC) stimulated with hCG. Using a two- and three-dimensional in vitro angiogenesis assays, our results indicate that CM from ESC almost completely inhibits the capillary-like structure formation in endothelial cells, overriding the pro-angiogenic effect of hCG; and this inhibition due to secreted factors present in CM specifically reduced the migration potential of endothelial cells. In conclusion, the endometrial stromal milieu seems to modulate the direct pro-angiogenic effects of hCG on endothelial cells during embryo implantation.
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