estrogen regulation
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2022 ◽  
Vol 12 (2) ◽  
pp. 352-357
Author(s):  
Xiaofang Kang ◽  
Hongcheng Zhu

Hormone support (estrogen and progesterone) is a key factor in decidualization and embryo implantation. Elevated levels of estrogen lead to luteal phase defects through Neuropilin 1, a membranecytoskeleton junction protein. This study aimed to explore the effect of BMSCs on endometrial stromal cells (ESCs) in adenomyosis. ESCs obtained from patients with adenomyosis were cocultured with BMSCs in the absence of presence of Neuropilin 1 inhibitor followed by analysis of expression of decidualization-related genes by RT-qPCR and western blot, cell viability by MTT assay, cell invasion and migration by Transwell assay, oxidative stress factors by ROS kit. Treatment with Neuropilin 1 inhibitor significantly decreased ESC proliferation and invasion, blocked epithelialmesenchymal transition (EMT) process, and restrained decidualization with a downregulation of decidualization-related genes. Furthermore, inhibition of Neuropilin 1 exerted effects through estrogen regulation. However, co-culture with BMSCs restored ESC activity by promoting Neuropilin expression and enhanced intrauterine ESC decidualization. In conclusion, Neuropilin 1 inhibitor restrains decidualization through estrogen regulation which can be abrogated by estrogen receptor antagonists. BMSCs restore the damaged ESC decidualization through increasing Neuropilin 1 expression, which provides new insights into the adverse effect of Neuropilin 1 on human ESCs, suggesting that BMSC is a potential therapeutic drug candidate for adenomyosis.


Author(s):  
Hemangini A. Dhaibar ◽  
Natalie G. Carroll ◽  
Shripa Amatya ◽  
Lilly Kamberov ◽  
Pranshu Khanna ◽  
...  

Background Stress has emerged as an important risk factor for heart disease in women. Stress levels have been shown to correlate with delayed recovery and increased mortality after a myocardial infarction. Therefore, we sought to investigate if the observed sex‐specific effects of stress in myocardial infarction may be partly attributed to genomic interactions between the female sex hormones, estrogen (E2), and the primary stress hormones glucocorticoids. Methods and Results Genomewide studies show that glucocorticoids inhibit estrogen‐mediated regulation of genes with established roles in cardiomyocyte homeostasis. These include 5‐HT2BR (cardiac serotonin receptor 2B), the expression of which is critical to prevent cardiomyocyte death in the adult heart. Using siRNA, gene expression, and chromatin immunoprecipitation assays, we found that 5‐HT2BR is a primary target of the glucocorticoid receptor and the estrogen receptor α at the level of transcription. The glucocorticoid receptor blocks the recruitment of estrogen receptor α to the promoter of the 5‐HT2BR gene, which may contribute to the adverse effects of stress in the heart of premenopausal women. Using immunoblotting, TUNEL (terminal deoxynucleotidal transferase–mediated biotin–deoxyuridine triphosphate nick‐end labeling), and flow cytometry, we demonstrate that estrogen decreases cardiomyocyte death by a mechanism relying on 5‐HT2BR expression. In vitro and in vivo experiments show that glucocorticoids inhibit estrogen cardioprotection in response to hypoxia/reoxygenation injury and exacerbate the size of the infarct areas in myocardial infarction. Conclusions These results established a novel mechanism underlying the deleterious effects of stress on female cardiac health in the setting of ischemia/reperfusion.


Author(s):  
Claudie Pinteur ◽  
Benoit Julien ◽  
Nathalie Véga ◽  
Hubert Vidal ◽  
Danielle Naville ◽  
...  

Postmenopausal women represent a vulnerable population towards endocrine disruptors due to hormonal deficit. We previously demonstrated that chronic exposure of ovariectomized C57Bl6/J mice fed a high-fat, high-sucrose diet to a low-dose mixture of chemicals with one dioxin, one polychlorobiphenyl, one phthalate, and bisphenol A triggered metabolic alterations in the liver but the intestine was not explored. Yet, the gastrointestinal tract is the main route by which pollutants enter the body. In the present study, we investigated the metabolic consequences of ovarian withdrawal and E2 replacement on the various gut segments along with investigating the impact of the mixture of pollutants. We showed that genes encoding estrogen receptors (Esr1, Gper1 not Esr2), xenobiotic processing genes (e.g., Cyp3a11, Cyp2b10), and genes related to gut homeostasis in the jejunum (e.g., Cd36, Got2, Mmp7) and to bile acid biosynthesis in the gut (e.g., Fgf15, Slc10a2) and liver (e.g., Abcb11, Slc10a1) were under estrogen regulation. Exposure to pollutants mimicked some of the effects of E2 replacement, particularly in the ileum (e.g., Esr1, Nr1c1) suggesting that the mixture had estrogen-mimetic activities. The present findings have important implications for the understanding of estrogen-dependent metabolic alterations with regards to situations of loss of estrogens as observed after menopause.


2021 ◽  
Vol 12 ◽  
Author(s):  
Katherine M. Livingstone ◽  
Mun Hua Tan ◽  
Gavin Abbott ◽  
Rachel L. Duckham ◽  
Larry Croft ◽  
...  

Body composition (fat, skeletal muscle and bone mass) is an important determinant of overall health and risk of endocrine disorders such as type 2 diabetes and osteoporosis. Although diet and physical activity are strongly implicated, body composition is also heritable. We conducted a discovery genome-wide association study on 31 phenotypes from the three-compartment body composition model (fat, lean and bone mass) in a set of 4 386 individuals (n = 2 109 males, n = 2 294 females) from the UK Biobank pilot imaging enhancement program that underwent a dual energy X-ray absorptiometry (DXA) scan for assessment of body composition and genetic screening. From 6 137 607 imputed single nucleotide polymorphisms (SNPs) we identified 17 body composition loci (P<5.0 x 10-8). GWAS from the combined dataset identified four statistically significant SNPs (rs7592270, rs145972737, rs13212044, rs77772562). In sex-stratified GWAS, 10 male specific SNPs across all traits were identified and five female specific SNPs. Of the 17 SNPs, six were in or close to a gene where there was a plausible functional connection. Three SNPs (rs7592270, rs77772562 and rs7552312) were correlated with obesity phenotypes, one SNP (rs2236705) with lean phenotypes and two with bone mass phenotypes (rs112098641 and rs113380185). These results highlight candidate genes and biological pathways related to body composition, including glucose metabolism and estrogen regulation, that are of interest to replicate in future studies.


Endocrinology ◽  
2021 ◽  
Author(s):  
Shannon B Z Stephens ◽  
Alexander S Kauffman

Abstract In females, ovarian estradiol (E2) exerts both negative and positive feedback regulation on the neural circuits governing reproductive hormone secretion, but the cellular and molecular mechanisms underlying this remain poorly understood. In rodents, ERα-expressing kisspeptin neurons in the hypothalamic anteroventral periventricular region (AVPV) are prime candidates to mediate E2 positive feedback induction of preovulatory GnRH and LH surges. E2 stimulates AVPV Kiss1 expression, but the full extent of estrogen effects in these neurons is unknown; whether E2 stimulates or inhibits other genes in AVPV Kiss1 cells has not been determined. Indeed, understanding of the function(s) of AVPV kisspeptin cells is limited, in part, by minimal knowledge of their overall molecular phenotype, as only a few genes are currently known to be co-expressed in AVPV Kiss1 cells. To provide a more detailed profiling of co-expressed genes in AVPV Kiss1 cells, including receptors and other signaling factors, and test how these genes respond to E2, we selectively isolated actively-translated mRNAs from AVPV Kiss1 cells of female mice and performed RNA-Seq. This identified >13,000 mRNAs co-expressed in AVPV Kiss1 cells, including multiple receptor and ligand transcripts positively or negatively regulated by E2. We also performed RNAscope to validate high co-expression of several transcripts identified by RNA-Seq, including Pdyn (prodynorphin), Penk (proenkephalin), Vgf (VGF), and Cartpt (CART), in female AVPV Kiss1 cells. Given the important role of AVPV kisspeptin cells in positive feedback, E2 effects on identified genes may relate to the LH surge mechanism and/or other physiological processes involving these AVPV kisspeptin cells.


2021 ◽  
Vol Volume 14 ◽  
pp. 931-940
Author(s):  
Xiushuai Shang ◽  
Liaoran Zhang ◽  
Rilong Jin ◽  
Hu Yang ◽  
Hairong Tao
Keyword(s):  

Author(s):  
Anna Ianza ◽  
Marianna Sirico ◽  
Ottavia Bernocchi ◽  
Daniele Generali

Over the last two decades, many studies have demonstrated that the insulin-like growth factor-1 (IGF-1) is involved in a number of patho-physiological processes, as well as in the development of different types of solid tumors, including breast cancer (BC). Preclinical and clinical data showed that IGF-1 receptor (R) is overexpressed and hyper-phosphorylated in several subtypes of BCs. The central implications of this pathway in tumor cell proliferation and metastasis make it an important therapeutic target. Moreover, the IGF-1 axis has shown strong interconnection with estrogen regulation and endocrine therapy, suggesting a possible solution to anti-estrogen resistance. IGF-1R might also interfere with other pivotal therapeutic strategies, such as anti HER2 treatments and mTOR inhibitors; several clinical trials are ongoing evaluating the role of IGF-1R inhibition in modulating resistance mechanisms to target therapies. Our aim is to offer an overview of the most recent and significant field of application of IGF-1 inhibitors and relevant therapeutic strategies, weighing their possible future impact on clinical practice.


Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 99
Author(s):  
Karen Cristina Rego Gregorio ◽  
Caroline Pancera Laurindo ◽  
Ubiratan Fabres Machado

Impaired circulating estrogen levels have been related to impaired glycemic homeostasis and diabetes mellitus (DM), both in females and males. However, for the last twenty years, the relationship between estrogen, glycemic homeostasis and the mechanisms involved has remained unclear. The characterization of estrogen receptors 1 and 2 (ESR1 and ESR2) and of insulin-sensitive glucose transporter type 4 (GLUT4) finally offered a great opportunity to shed some light on estrogen regulation of glycemic homeostasis. In this manuscript, we review the relationship between estrogen and DM, focusing on glycemic homeostasis, estrogen, ESR1/ESR2 and GLUT4. We review glycemic homeostasis and GLUT4 expression (muscle and adipose tissues) in Esr1−/− and Esr2−/− transgenic mice. We specifically address estradiol-induced and ESR1/ESR2-mediated regulation of the solute carrier family 2 member 4 (Slc2a4) gene, examining ESR1/ESR2-mediated genomic mechanisms that regulate Slc2a4 transcription, especially those occurring in cooperation with other transcription factors. In addition, we address the estradiol-induced translocation of ESR1 and GLUT4 to the plasma membrane. Studies make it clear that ESR1-mediated effects are beneficial, whereas ESR2-mediated effects are detrimental to glycemic homeostasis. Thus, imbalance of the ESR1/ESR2 ratio may have important consequences in metabolism, highlighting that ESR2 hyperactivity assumes a diabetogenic role.


Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2931 ◽  
Author(s):  
Madeleine T. Shackleford ◽  
Deviyani M. Rao ◽  
Evelyn K. Bordeaux ◽  
Hannah M. Hicks ◽  
Christina G. Towers ◽  
...  

Invasive lobular carcinoma of the breast (ILC) is strongly estrogen-driven and represents a unique context for estrogen receptor (ER) signaling. In ILC, ER controls the expression of the Wnt ligand WNT4, which is critical for endocrine response and anti-estrogen resistance. However, signaling mediated by WNT4 is cell type- and tissue-specific, and has not been explored in ILC. We utilized reverse phase protein array (RPPA) to characterize ER and WNT4-driven signaling in ILC cells and identified that WNT4 mediates downstream mTOR signaling via phosphorylation of S6 Kinase. Additionally, ER and WNT4 control levels of MCL-1, which is associated with regulation of mitochondrial function. In this context, WNT4 knockdown led to decreased ATP production and increased mitochondrial fragmentation. WNT4 regulation of both mTOR signaling and MCL-1 were also observed in anti-estrogen resistant models of ILC. We identified that high WNT4 expression is associated with similar mTOR pathway activation in ILC and serous ovarian cancer tumors, suggesting that WNT4 signaling is active in multiple tumor types. The identified downstream pathways offer insight into WNT4 signaling and represent potential targets to overcome anti-estrogen resistance for patients with ILC.


2020 ◽  
Vol 34 (9) ◽  
pp. 12768-12784
Author(s):  
Carlotta Boscaro ◽  
Marcello Carotti ◽  
Mattia Albiero ◽  
Annalisa Trenti ◽  
Gian Paolo Fadini ◽  
...  

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