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The Role of Estrogen Receptors in Health and Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 59775

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Dr. Farzad Pakdel

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Research Institute in Health, Environment and Occupation (Irset), Inserm U1085, Transcription, Environment and Cancer Group, University of Rennes 1, 35000 Rennes, France
Interests: estrogen receptor; gene expression; transcription mechanisms; endocrine disrupter chemicals; breast cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Estrogens and estrogen receptors (ERs) control a diversity of biological and physiological processes, including the growth, development, and metabolism of reproductive and non-reproductive tissues. They are also tightly associated with several human pathologies, such as breast and ovarian cancers, osteoporosis, and coronary or neurodegenerative diseases. Over the past three decades following the discovery of the nuclear ER-alpha, ER-beta, and the membrane receptor designated as the G protein-coupled estrogen receptor (GPER), multiple mechanisms of action have been identified. These mechanisms implicate either genomic actions through direct binding to specific DNA sequences, or non-genomic actions by modulating intracellular kinases cascades. The comprehension of the mechanisms underlining ER-mediated effects in the physiopathological processes is the main goal of this Special Issue. Notably, how do ERs control transcription and epigenetic regulations, and interact with intracellular kinases, coregulators of transcription, growth factors, and cellular signaling pathways to regulate cell fate, such as proliferation, differentiation, and apoptosis? What is the role of ligands, including environmental estrogens, in modulating the genomic and non-genomic activity of ERs? What are the consequence of ER mutations or the dysregulation of ER-target genes’ profiling in cancer?

In order to provide a comprehensive overview of the molecular mechanisms of ERs, researchers are invited to submit original research, comprehensive reviews, and short communications for this Special Issue of the International Journal of Molecular Sciences, titled the "The Role of Estrogen Receptors in Health and Disease", which will cover a selection of topics, highlighting the key roles of ERs in physiopatholohy.

Dr. Farzad Pakdel
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Estrogens and estrogen receptors
Cancer
Cell signaling
Selective estrogen receptor modulators
Ligand and cofactor interactions
Transcription and epigenetics regulation
Endocrine disrupter chemicals

Related Special Issue

The Role of Estrogen Receptors in Health and Disease 2.0 in International Journal of Molecular Sciences (4 articles)

Published Papers (14 papers)

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Editorial

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3 pages, 195 KiB

Open AccessEditorial

The Role of Estrogen Receptors in Health and Disease

by Farzad Pakdel

Int. J. Mol. Sci. 2023, 24(14), 11354; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241411354 - 12 Jul 2023

Viewed by 707

Abstract

Many biological and physiological events, including growth, development, and metabolism of reproductive and non-reproductive tissues in men and women, are regulated by estrogens and estrogen receptors (ERs) [...] Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

Research

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17 pages, 5155 KiB

Open AccessArticle

Early Inactivation of Membrane Estrogen Receptor Alpha (ERα) Recapitulates the Endothelial Dysfunction of Aged Mouse Resistance Arteries

by Julie Favre, Emilie Vessieres, Anne-Laure Guihot, Linda Grimaud, Coralyne Proux, Laurent Loufrani, Françoise Lenfant, Coralie Fontaine, Jean-François Arnal and Daniel Henrion

Int. J. Mol. Sci. 2022, 23(5), 2862; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052862 - 05 Mar 2022

Cited by 5 | Viewed by 2183

Abstract

Flow-mediated dilation (FMD) of resistance arteries is essential for tissue perfusion but it decreases with ageing. As estrogen receptor alpha (Erα encoded by Esr1), and more precisely membrane ERα, plays an important role in FMD in young mice in a ligand-independent fashion, we evaluated its influence on this arteriolar function in ageing. We first confirmed that in young (6-month-old) mice, FMD of mesenteric resistance arteries was reduced in Esr1−/− (lacking ERα) and C451A-ERα (lacking membrane ERα). In old (24-month-old) mice, FMD was reduced in WT mice compared to young mice, whereas it was not further decreased in Esr1−/− and C451A-ERα mice. Markers of oxidative stress were similarly increased in old WT and C451A-ERα mice. Reduction in oxidative stress with superoxide dismutase plus catalase or Mito-tempo, which reduces mitochondrial superoxide restored FMD to a normal control level in young C451A-ERα mice as well as in old WT mice and old C451A-ERα mice. Estradiol-mediated dilation was absent in old WT mice. We conclude that oxidative stress is a key event in the decline of FMD, and that an early defect in membrane ERα recapitulates phenotypically and functionally ageing of these resistance arteries. The loss of this function could take part in vascular ageing. Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

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17 pages, 6491 KiB

Open AccessArticle

Berberine Inhibits MDA-MB-231 Cells as an Agonist of G Protein-Coupled Estrogen Receptor 1

by Miaomiao Qi, Xiang Liu, Ying Zhou, Haoyu Wang, Ying Zhao, Jing Ren and Jin Xiang

Int. J. Mol. Sci. 2021, 22(21), 11466; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111466 - 24 Oct 2021

Cited by 3 | Viewed by 2256

Abstract

G protein-coupled estrogen receptor 1 (GPER1) is a potential therapeutic target for treating triple-negative breast cancers (TNBC). However, modulators for GPER1 that can be used to treat TNBC have not appeared. Berberine (BBR) is a bioactive isoquinoline alkaloid with high oral safety. In recent years, BBR has shown an inhibitory effect on TNBC tumors such as MDA-MB-231, but the molecular target remains unclear, which hinders related clinical research. Our work proved that BBR is a modulator of GPER1 that can inhibit cell viability, migration, and autophagy of MDA-MB-231 cells. The inhibitory effect of BBR on MDA-MB-231 cells has a dependence on estrogen levels. Although BBR promoted the proteasome, which is a major factor in the degradation of GPER1, it could still induce the protein level of GPER1. Correspondingly, the transcription of cellular communication network factor 2 (CCN2) was promoted. BBR could bind to GPER1 directly and change the secondary structure of GPER1, as in the case of 17β-estradiol (E2). In addition, BBR induced not only a high degree of co-localization of GPER1 and microtubule-associated protein 1 light chain 3 (MAP1LC3), but also the accumulation of sequestosome 1 (SQSTM1/p62) by the inhibition of the nuclear translocation of the nuclear factor-kappa B (NF-κB) subunit (RELA/p65), which indicates NF-κB inhibition and anti-cancer effects. This result proved that the promotional effect of BBR on the GPER1/NF-κB pathway was closely related to its inhibitory effect on autophagy, which may serve as a new mechanism by which to explain the inhibitory effect of BBR on MDA-MB-231 cells and expand our understanding of the function of both BBR and GPER1. Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

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20 pages, 7166 KiB

Open AccessArticle

HPTE-Induced Embryonic Thymocyte Death and Alteration of Differentiation Is Not Rescued by ERα or GPER Inhibition but Is Exacerbated by Concurrent TCR Signaling

by Eddie Avellaneda, Atalie Lim, Sara Moeller, Jacqueline Marquez, Priscilla Escalante Cobb, Cristina Zambrano, Aaditya Patel, Victoria Sanchez, K. Godde and Christine Broussard

Int. J. Mol. Sci. 2021, 22(18), 10138; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810138 - 20 Sep 2021

Cited by 1 | Viewed by 1957

Abstract

Organochlorine pesticides, such as DDT, methoxychlor, and their metabolites, have been characterized as endocrine disrupting chemicals (EDCs); suggesting that their modes of action involve interaction with or abrogation of endogenous endocrine function. This study examined whether embryonic thymocyte death and alteration of differentiation induced by the primary metabolite of methoxychlor, HPTE, rely upon estrogen receptor binding and concurrent T cell receptor signaling. Estrogen receptor inhibition of ERα or GPER did not rescue embryonic thymocyte death induced by HPTE or the model estrogen diethylstilbestrol (DES). Moreover, adverse effects induced by HPTE or DES were worsened by concurrent TCR and CD2 differentiation signaling, compared with EDC exposure post-signaling. Together, these data suggest that HPTE- and DES-induced adverse effects on embryonic thymocytes do not rely solely on ER alpha or GPER but may require both. These results also provide evidence of a potential collaborative signaling mechanism between TCR and estrogen receptors to mediate adverse effects on embryonic thymocytes, as well as highlight a window of sensitivity that modulates EDC exposure severity. Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

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14 pages, 1068 KiB

Open AccessArticle

Voluntary Wheel Running Partially Compensates for the Effects of Global Estrogen Receptor-α Knockout on Cortical Bone in Young Male Mice

by Rebecca K. Dirkes, Nathan C. Winn, Thomas J. Jurrissen, Dennis B. Lubahn, Victoria J. Vieira-Potter, Jaume Padilla and Pamela S. Hinton

Int. J. Mol. Sci. 2021, 22(4), 1734; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041734 - 09 Feb 2021

Cited by 9 | Viewed by 2282

Abstract

Estrogen receptor-α knockout (ERKO) in female, but not male, mice results in an impaired osteogenic response to exercise, but the mechanisms behind this ability in males are unknown. We explored the main and interactive effects of ERKO and exercise on cortical geometry, trabecular microarchitecture, biomechanical strength, and sclerostin expression in male mice. At 12 weeks of age, male C57BL/6J ERKO and WT animals were randomized into two groups: exercise treatment (EX) and sedentary (SED) controls, until 22 weeks of age. Cortical geometry and trabecular microarchitecture were measured via μCT; biomechanical strength was assessed via three-point bending; sclerostin expression was measured via immunohistochemistry. Two-way ANOVA was used to assess sclerostin expression and trabecular microarchitecture; two-way ANCOVA with body weight was used to assess cortical geometry and biomechanical strength. ERKO positively impacted trabecular microarchitecture, and exercise had little effect on these outcomes. ERKO significantly impaired cortical geometry, but exercise was able to partially reverse these negative alterations. EX increased cortical thickness regardless of genotype. There were no effects of genotype or exercise on sclerostin expression. In conclusion, male ERKO mice retain the ability to build bone in response to exercise, but altering sclerostin expression is not one of the mechanisms involved. Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

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17 pages, 2614 KiB

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ESR1 ChIP-Seq Identifies Distinct Ligand-Free ESR1 Genomic Binding Sites in Human Hepatocytes and Liver Tissue

by Joseph M. Collins, Zhiguang Huo and Danxin Wang

Int. J. Mol. Sci. 2021, 22(3), 1461; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031461 - 02 Feb 2021

Cited by 8 | Viewed by 2894

Abstract

The estrogen receptor alpha (ESR1) is an important gene transcriptional regulator, known to mediate the effects of estrogen. Canonically, ESR1 is activated by its ligand estrogen. However, the role of unliganded ESR1 in transcriptional regulation has been gaining attention. We have recently shown that ligand-free ESR1 is a key regulator of several cytochrome P450 (CYP) genes in the liver, however ligand-free ESR1 has not been characterized genome-wide in the human liver. To address this, ESR1 ChIP-Seq was conducted in human liver samples and in hepatocytes with or without 17beta-estradiol (E2) treatment. We identified both ligand-dependent and ligand-independent binding sites throughout the genome. These two ESR1 binding categories showed different genomic localization, pathway enrichment, and cofactor colocalization, indicating different ESR1 regulatory function depending on ligand availability. By analyzing existing ESR1 data from additional human cell lines, we uncovered a potential ligand-independent ESR1 activity, namely its co-enrichment with the zinc finger protein 143 (ZNF143). Furthermore, we identified ESR1 binding sites near many gene loci related to drug therapy, including the CYPs. Overall, this study shows distinct ligand-free and ligand-bound ESR1 chromatin binding profiles in the liver and suggests the potential broad influence of ESR1 in drug metabolism and drug therapy. Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

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15 pages, 2880 KiB

Open AccessArticle

Estrogen Receptor Signaling Pathways Involved in Invasion and Colony Formation of Androgen-Independent Prostate Cancer Cells PC-3

by Ana Paola G. Lombardi, Renan P. Cavalheiro, Catarina S. Porto and Carolina M. Vicente

Int. J. Mol. Sci. 2021, 22(3), 1153; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031153 - 25 Jan 2021

Cited by 13 | Viewed by 2960

Abstract

Castration-resistant prostate cancer (CRPC) is an advanced and androgen-independent form of prostate cancer. Recent studies of rapid actions mediated by estrogen in the prostate and its relationship with CRPC are emerging. We have previously shown that estrogen receptor (ER) promotes migration and invasion of the androgen-independent prostate cancer cells PC-3, but the signaling pathways involved in these events remain to be elucidated. Therefore, this study aimed to analyze the role of ERα and ERβ in the activation of SRC, and the involvement of SRC and PI3K/AKT on invasion and colony formation of the PC-3 cells. Our results showed that the activation of ERα (using ERα-selective agonist PPT) and ERβ (using ERβ-selective agonist DPN) increased phosphorylation of SRC in PC-3 cells. In the presence of the selective inhibitor for SRC-family kinases PP2, the effects of DPN and PPT on transmigration and soft agar colony formation assays were decreased. Furthermore, SRC is involved in the expression of the non-phosphorylated β-catenin. Finally, using PI3K specific inhibitor Wortmannin and AKT inhibitor MK2206, we showed that PI3K/AKT are also required for invasion and colony formation of PC-3 cells simulated by ER. This study provides novel insights into molecular mechanisms of ER in PC-3 cells by demonstrating that ER, located outside the cell nucleus, activates rapid responses molecules, including SRC and PI3K/AKT, which enhance the tumorigenic potential of prostate cancer cells, increasing cell proliferation, migration, invasion, and tumor formation. Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

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19 pages, 6465 KiB

Open AccessArticle

G Protein-Coupled Estrogen Receptor Mediates Cell Proliferation through the cAMP/PKA/CREB Pathway in Murine Bone Marrow Mesenchymal Stem Cells

by Shu-Chun Chuang, Chung-Hwan Chen, Ya-Shuan Chou, Mei-Ling Ho and Je-Ken Chang

Int. J. Mol. Sci. 2020, 21(18), 6490; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186490 - 05 Sep 2020

Cited by 30 | Viewed by 4058

Abstract

Estrogen is an important hormone to regulate skeletal physiology via estrogen receptors. The traditional estrogen receptors are ascribed to two nuclear estrogen receptors (ERs), ERα and ERβ. Moreover, G protein-coupled estrogen receptor-1 (GPER-1) was reported as a membrane receptor for estrogen in recent years. However, whether GPER-1 regulated osteogenic cell biology on skeletal system is still unclear. GPER-1 is expressed in growth plate abundantly before puberty but decreased abruptly since the very late stage of puberty in humans. It indicates GPER-1 might play an important role in skeletal growth regulation. GPER-1 expression has been confirmed in osteoblasts, osteocytes and chondrocytes, but its expression in mesenchymal stem cells (MSCs) has not been confirmed. In this study, we hypothesized that GPER-1 is expressed in bone MSCs (BMSC) and enhances BMSC proliferation. The cultured tibiae of neonatal rat and murine BMSCs were tested in our study. GPER-1-specific agonist (G-1) and antagonist (G-15), and GPER-1 siRNA (siGPER-1) were used to evaluate the downstream signaling pathway and cell proliferation. Our results revealed BrdU-positive cell counts were higher in cultured tibiae in the G-1 group. The G-1 also enhanced the cell viability and proliferation, whereas G-15 and siGPER-1 reduced these activities. The cAMP and phosphorylation of CREB were enhanced by G-1 but inhibited by G-15. We further demonstrated that GPER-1 mediates BMSC proliferation via the cAMP/PKA/p-CREB pathway and subsequently upregulates cell cycle regulators, cyclin D1/cyclin-dependent kinase (CDK) 6 and cyclin E1/CDK2 complex. The present study is the first to report that GPER-1 mediates BMSC proliferation. This finding indicates that GPER-1 mediated signaling positively regulates BMSC proliferation and may provide novel insights into addressing estrogen-mediated bone development. Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

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Review

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Estradiol Signaling at the Heart of Folliculogenesis: Its Potential Deregulation in Human Ovarian Pathologies

by Stéphanie Chauvin, Joëlle Cohen-Tannoudji and Céline J. Guigon

Int. J. Mol. Sci. 2022, 23(1), 512; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010512 - 03 Jan 2022

Cited by 27 | Viewed by 2941

Abstract

Estradiol (E2) is a major hormone controlling women fertility, in particular folliculogenesis. This steroid, which is locally produced by granulosa cells (GC) within ovarian follicles, controls the development and selection of dominant preovulatory follicles. E2 effects rely on a complex set of nuclear and extra-nuclear signal transduction pathways principally triggered by its nuclear receptors, ERα and ERβ. These transcription factors are differentially expressed within follicles, with ERβ being the predominant ER in GC. Several ERβ splice isoforms have been identified and display specific structural features, which greatly complicates the nature of ERβ-mediated E2 signaling. This review aims at providing a concise overview of the main actions of E2 during follicular growth, maturation, and selection in human. It also describes the current understanding of the various roles of ERβ splice isoforms, especially their influence on cell fate. We finally discuss how E2 signaling deregulation could participate in two ovarian pathogeneses characterized by either a follicular arrest, as in polycystic ovary syndrome, or an excess of GC survival and proliferation, leading to granulosa cell tumors. This review emphasizes the need for further research to better understand the molecular basis of E2 signaling throughout folliculogenesis and to improve the efficiency of ovarian-related disease therapies. Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

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16 pages, 1220 KiB

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A Closer Look at Estrogen Receptor Mutations in Breast Cancer and Their Implications for Estrogen and Antiestrogen Responses

by Léa Clusan, Pascale Le Goff, Gilles Flouriot and Farzad Pakdel

Int. J. Mol. Sci. 2021, 22(2), 756; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020756 - 13 Jan 2021

Cited by 24 | Viewed by 6916

Abstract

Breast cancer (BC) is the most common cancer among women worldwide. More than 70% of BC cases express estrogen receptor alpha (ERα), a central transcription factor that stimulates the proliferation of breast cancer cells, usually in the presence of estrogen. While most cases of ER-positive BC initially respond to antiestrogen therapies, a high percentage of cases develop resistance to treatment over time. The recent discovery of mutated forms of ERα that result in constitutively active forms of the receptor in the metastatic-resistance stage of BC has provided a strong rationale for the development of new antiestrogens. These molecules targeting clinically relevant ERα mutants and a combination with other pharmacological inhibitors of specific pathways may constitute alternative treatments to improve clinical practice in the fight against metastatic-resistant ER-positive BC. In this review, we summarize the latest advances regarding the particular involvement of point mutations of ERα in endocrine resistance. We also discuss the involvement of synonymous ERα mutations with respect to co-translational folding of the receptor and ribosome biogenesis in breast carcinogenesis. Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

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20 pages, 848 KiB

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Estrogen Receptors: Therapeutic Perspectives for the Treatment of Cardiac Dysfunction after Myocardial Infarction

by Jaqueline S. da Silva, Tadeu L. Montagnoli, Bruna S. Rocha, Matheus L. C. A. Tacco, Sophia C. P. Marinho and Gisele Zapata-Sudo

Int. J. Mol. Sci. 2021, 22(2), 525; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020525 - 07 Jan 2021

Cited by 25 | Viewed by 4337

Abstract

Estrogen receptors (ER) mediate functions beyond their endocrine roles, as modulation of cardiovascular, renal, and immune systems through anti-inflammatory and anti-apoptotic effects, preventing necrosis of cardiomyocytes and endothelial cells, and attenuating cardiac hypertrophy. Estradiol (E2) prevents cardiac dysfunction, increases nitric oxide synthesis, and reduces the proliferation of vascular cells, yielding protective effects, regardless of gender. Such actions are mediated by ER (ER-alpha (ERα), ER-beta (ERβ), or G protein-coupled ER (GPER)) through genomic or non-genomic pathways, which regulate cardiovascular function and prevent tissue remodeling. Despite the extensive knowledge on the cardioprotective effects of estrogen, clinical studies conducted on myocardial infarction (MI) and cardiovascular diseases still include favorable and unfavorable profiles. The purpose of this review is to provide up-to-date information regarding molecular, preclinical, and clinical aspects of cardiovascular E2 effects and ER modulation as a potential therapeutic target for the treatment of MI-induced cardiac dysfunction. Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

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21 pages, 770 KiB

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The Role of Estrogen Receptors and Their Signaling across Psychiatric Disorders

by Wu Jeong Hwang, Tae Young Lee, Nahrie Suk Kim and Jun Soo Kwon

Int. J. Mol. Sci. 2021, 22(1), 373; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010373 - 31 Dec 2020

Cited by 78 | Viewed by 15114

Abstract

Increasing evidence suggests estrogen and estrogen signaling pathway disturbances across psychiatric disorders. Estrogens are not only crucial in sexual maturation and reproduction but are also highly involved in a wide range of brain functions, such as cognition, memory, neurodevelopment, and neuroplasticity. To add more, the recent findings of its neuroprotective and anti-inflammatory effects have grown interested in investigating its potential therapeutic use to psychiatric disorders. In this review, we analyze the emerging literature on estrogen receptors and psychiatric disorders in cellular, preclinical, and clinical studies. Specifically, we discuss the contribution of estrogen receptor and estrogen signaling to cognition and neuroprotection via mediating multiple neural systems, such as dopaminergic, serotonergic, and glutamatergic systems. Then, we assess their disruptions and their potential implications for pathophysiologies in psychiatric disorders. Further, in this review, current treatment strategies involving estrogen and estrogen signaling are evaluated to suggest a future direction in identifying novel treatment strategies in psychiatric disorders. Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

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23 pages, 1879 KiB

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Astrocytoma: A Hormone-Sensitive Tumor?

by Alex Hirtz, Fabien Rech, Hélène Dubois-Pot-Schneider and Hélène Dumond

Int. J. Mol. Sci. 2020, 21(23), 9114; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239114 - 30 Nov 2020

Cited by 37 | Viewed by 6082

Abstract

Astrocytomas and, in particular, their most severe form, glioblastoma, are the most aggressive primary brain tumors and those with the poorest vital prognosis. Standard treatment only slightly improves patient survival. Therefore, new therapies are needed. Very few risk factors have been clearly identified but many epidemiological studies have reported a higher incidence in men than women with a sex ratio of 1:4. Based on these observations, it has been proposed that the neurosteroids and especially the estrogens found in higher concentrations in women’s brains could, in part, explain this difference. Estrogens can bind to nuclear or membrane receptors and potentially stimulate many different interconnected signaling pathways. The study of these receptors is even more complex since many isoforms are produced from each estrogen receptor encoding gene through alternative promoter usage or splicing, with each of them potentially having a specific role in the cell. The purpose of this review is to discuss recent data supporting the involvement of steroids during gliomagenesis and to focus on the potential neuroprotective role as well as the mechanisms of action of estrogens in gliomas. Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

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31 pages, 684 KiB

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Application of Various Molecular Modelling Methods in the Study of Estrogens and Xenoestrogens

by Anna Helena Mazurek, Łukasz Szeleszczuk, Thomas Simonson and Dariusz Maciej Pisklak

Int. J. Mol. Sci. 2020, 21(17), 6411; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176411 - 03 Sep 2020

Cited by 6 | Viewed by 3696

Abstract

In this review, applications of various molecular modelling methods in the study of estrogens and xenoestrogens are summarized. Selected biomolecules that are the most commonly chosen as molecular modelling objects in this field are presented. In most of the reviewed works, ligand docking using solely force field methods was performed, employing various molecular targets involved in metabolism and action of estrogens. Other molecular modelling methods such as molecular dynamics and combined quantum mechanics with molecular mechanics have also been successfully used to predict the properties of estrogens and xenoestrogens. Among published works, a great number also focused on the application of different types of quantitative structure–activity relationship (QSAR) analyses to examine estrogen’s structures and activities. Although the interactions between estrogens and xenoestrogens with various proteins are the most commonly studied, other aspects such as penetration of estrogens through lipid bilayers or their ability to adsorb on different materials are also explored using theoretical calculations. Apart from molecular mechanics and statistical methods, quantum mechanics calculations are also employed in the studies of estrogens and xenoestrogens. Their applications include computation of spectroscopic properties, both vibrational and Nuclear Magnetic Resonance (NMR), and also in quantum molecular dynamics simulations and crystal structure prediction. The main aim of this review is to present the great potential and versatility of various molecular modelling methods in the studies on estrogens and xenoestrogens. Full article

(This article belongs to the Special Issue The Role of Estrogen Receptors in Health and Disease)

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