Transcriptome study of receptive endometrium in overweight and obese women shows important expression differences in immune response and inflammatory pathways in women who do not conceive

Obesity and being overweight are growing worldwide health problems that also affect women of reproductive age. They impair women’s fertility and are associated with lower IVF success rates. The mechanism by which increased body weight disrupts fertility has not yet been established. One possibility is that it affects the process of embryo implantation on the endometrial level. The purpose of our study was to determine the differences in enriched biological pathways in the endometrium of overweight and obese women undergoing IVF procedures. For this purpose, 14 patients (5 pregnant, 9 non-pregnant) were included in the study. Endometrial samples were obtained during the window of implantation and RNA sequencing was performed. There were no differences in general patient’s and IVF cycle characteristics between pregnant and non-pregnant women. In the endometrial samples of women who did not conceive, pathways related to the immune response, inflammation, and reactive oxygen species production were over-expressed. Our findings show that the reason for implantation failure in overweight and obese women could lie in the excessive immune and inflammatory response at the endometrial level.

PINK1 deficiency impairs osteoblast differentiation through aberrant mitochondrial homeostasis

Background PTEN-induced kinase 1 (PINK1) is a serine/threonine-protein kinase in mitochondria that is critical for mitochondrial quality control. PINK1 triggers mitophagy, a selective autophagy of mitochondria, and is involved in mitochondrial regeneration. Although increments of mitochondrial biogenesis and activity are known to be crucial during differentiation, data regarding the specific role of PINK1 in osteogenic maturation and bone remodeling are limited. Methods We adopted an ovariectomy model in female wildtype and Pink1−/− mice. Ovariectomized mice were analyzed using micro-CT, H&E staining, Masson’s trichrome staining. RT-PCR, western blot, immunofluorescence, alkaline phosphatase, and alizarin red staining were performed to assess the expression of PINK1 and osteogenic markers in silencing of PINK1 MC3T3-E1 cells. Clinical relevance of PINK1 expression levels was determined via qRT-PCR analysis in normal and osteoporosis patients. Results A significant decrease in bone mass and collagen deposition was observed in the femurs of Pink1−/− mice after ovariectomy. Ex vivo, differentiation of osteoblasts was inhibited upon Pink1 downregulation, accompanied by impaired mitochondrial homeostasis, increased mitochondrial reactive oxygen species production, and defects in mitochondrial calcium handling. Furthermore, PINK1 expression was reduced in bones from patients with osteoporosis, which supports the practical role of PINK1 in human bone disease. Conclusions In this study, we demonstrated that activation of PINK1 is a requisite in osteoblasts during differentiation, which is related to mitochondrial quality control and low reactive oxygen species production. Enhancing PINK1 activity might be a possible treatment target in bone diseases as it can promote a healthy pool of functional mitochondria in osteoblasts.

2-Methoxyestradiol Ameliorates Angiotensin II–Induced Hypertension by Inhibiting Cytosolic Phospholipase A 2 α Activity in Female Mice

We tested the hypothesis that CYP1B1 (cytochrome P450 1B1)-17β-estradiol metabolite 2-methoxyestradiol protects against Ang II (angiotensin II)–induced hypertension by inhibiting group IV cPLA 2 α (cytosolic phospholipase A 2 α) activity and production of prohypertensive eicosanoids in female mice. Ang II (700 ng/kg per minute, SC) increased mean arterial blood pressure (BP), systolic and diastolic BP measured by radiotelemetry, renal fibrosis, and reactive oxygen species production in wild-type mice ( cPLA 2 α +/+ /Cyp1b1 +/+ ) that were enhanced by ovariectomy and abolished in intact and ovariectomized -cPLA 2 α −/− /Cyp1b1 +/+ mice. Ang II–induced increase in SBP measured by tail-cuff, renal fibrosis, reactive oxygen species production, and cPLA 2 α activity measured by its phosphorylation in the kidney, and urinary excretion of prostaglandin E 2 and thromboxane A 2 metabolites were enhanced in ovariectomized- cPLA 2 α +/+ /Cyp1b1 +/+ and intact cPLA 2 α +/+ /Cyp1b1 −/− mice. 2-Methoxyestradiol and arachidonic acid metabolism inhibitor 5,8,11,14-eicosatetraynoic acid attenuated the Ang II–induced increase in SBP, renal fibrosis, reactive oxygen species production, and urinary excretion of prostaglandin E 2 , and thromboxane A 2 metabolites in ovariectomized- cPLA 2 α +/+ /Cyp1b1 +/+ and intact cPLA 2 α +/+ /Cyp1b1 −/− mice. Antagonists of prostaglandin E 2 and thromboxane A 2 receptors EP1 and EP3 and TP, respectively, inhibited Ang II–induced increases in SBP and reactive oxygen species production and renal fibrosis in ovariectomized- cPLA 2 α +/+ /Cyp1b1 +/+ and intact cPLA 2 α +/+ /Cyp1b1 −/− mice. These data suggest that CYP1B1-generated metabolite 2-methoxyestradiol mitigates Ang II–induced hypertension and renal fibrosis by inhibiting cPLA 2 α activity, reducing prostaglandin E 2 , and thromboxane A 2 production and stimulating EP1 and EP3 and TP receptors, respectively. Thus, 2-methoxyestradiol and the drugs that selectively block EP1 and EP3 and TP receptors could be useful in treating hypertension and its pathogenesis in females.