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Structure and mechanisms of action of the estrogen receptor (ER). (A) The evolutionarily conserved domains of several nuclear receptors, including ER, AR (androgen receptor), PR (progesterone receptor), GR (glucocorticoid receptor), VDR (vitamin D receptor), RAR (retinoid acid receptor) and TR (thyroid receptor). Domains involved in DNA and ligand binding, as well as in dimerization, ligand-independent transactivation function (AF1) and ligand-dependent transactivation function (AF2) are shown. The number of amino acids for each domain is presented. The approximate molecular weight of each nuclear receptor is also indicated on the right side; (B) estradiol (E2) mediates multiple phenotypic changes in cells by binding to its receptor. E2 enter the cell through the lipid membranes and binds ER in the cytoplasm or the nucleus. ER mediates E2 effects through diverse transcriptional mechanisms. In the nucleus, the activated ER forms a dimer to tightly fix DNA directly at the ERE sites or indirectly at Sp1 or Ap1 sites. The activated ER is then able to recruit cofactors and RNA polymerase II (pol. II), which allows the transcription of target genes (ER genomic action). Furthermore, ERs can use rapid non-genomic action through the activation of intracellular kinases related or not to the growth factor signaling.
Source publication
In mammals, the effects of estrogen are mainly mediated by two different estrogen receptors, ERα and ERβ. These proteins are members of the nuclear receptor family, characterized by distinct structural and functional domains, and participate in the regulation of different biological processes, including cell growth, survival and differentiation. Th...
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Selective agonism of the estrogen receptor (ER) subtypes, ERα and ERβ, has historically been difficult to achieve due to the high degree of ligand-binding domain structural similarity. Multiple efforts have focused on the use of classical organic scaffolds to model 17β-estradiol geometry in the design of ERβ selective agonists, with several proceed...
Estrogen receptor (ER) is a member of the nuclear receptor superfamily whose members share conserved domain structures, including a DNA-binding domain (DBD) and ligand-binding domain (LBD). Estrogenic chemicals work as ligands for activation or repression of ER-mediated transcriptional activity derived from two transactivation domains: AF-1 and AF-...
Citations
... Phytochemical compounds found in plants that offer numerous benefits to humans. Non-steroidal estrogen from plant products with estrogenic activity is known as phytoestrogen (Lecomte et al., 2017). Flavonoids serve as a primary group of phytoestrogens with agonistic properties (Kiyama, 2023). ...
... Flavonoids serve as a primary group of phytoestrogens with agonistic properties (Kiyama, 2023). Their estrogenic effects are mediated by two distinct ER (ERα and ERβ), which can regulate various biological activities such as cell growth and differentiation (Lecomte et al., 2017). Flavonoids influence cell proliferation through various mechanisms, including interaction with hormonal signaling pathways and binding to ER (Vachetta et al., 2022). ...
This study aims to determine how the effect of flavonoid phaleria macrocarpa fruit extract on the endometrial thickness of Mus musculus which is used as an experimental animal with a menopause model. This study employed a randomized post-test-only control group design on 32 female mice. Ovariectomy simulated menopause, followed by treatment with flavonoid from Phaleria macrocarpa fruit extract. Post-observariectomized, follicle-stimulating hormone levels indicated menopausal status. Hematoxylin-Eosin methods assessed endometrial thickness. The result indicated reduced endometrial thinning in the positive control group (K+). Conversely, the treatment group (P1-P4) exhibited increased endometrial thickness post-flavonoid extract administration. Ovariectomized-induced estrogen decline resulted in reduced endometrial thinning, mimicking menopausal conditions. Statistically, flavonoid extract administration increased endometrial thickness in ovariectomized-induced menopausal mice, with optimal effect observed at 7.5 mg/mice/day for 14 days. The preferred intervention dose for altering endometrial thickness in menopausal conditions was identified as P1 (3.75 mg/mice/day). In conclusion, a flavonoid from Phaleria macrocarpa fruit extract mitigates endometrial thinning in the menopausal mice model. For implication in menopausal women, clinical trials need to be conducted to evaluate the dosage of these flavonoids for their potential as a natural SERM (Selective Estrogen Receptor Modulator) before clinical application in managing endometrial health. Additionally, research on molecular effects particularly regarding ER (Estrogen Receptors) in the endometrial organ, is needed to confirm their phytoestrogenic effect.
... Recent research showed that phytoestrogens, such as flavonoids and stilbenes, have a biphasic effect on cell proliferation, increasing it at low doses while inhibiting growth at high doses. Genistein and daidzein, known phytoestrogens, for example, promote the growth of ER-positive carcinomas at low concentrations and inhibit their growth by inducing apoptosis at high concentrations [30][31][32][33][34]. Therefore, in the case of ER-positive breast cancers, biphasic effects are observed due to interactions of phytoestrogens with ER-subtypes and the recruitment of cofactors that regulate gene expression and promote or prevent the progression of breast cancer cells [35]. The T47D cell line showed a significant increase in proliferation when treated with female M. pomifera extract and pomiferin, a phytoestrogen, compared to MCF-7 cells. ...
Globally, breast cancer is a significant cause of mortality. Recent research focused on identifying compounds regulating the transient receptor potential vanilloid 1 (TRPV1) ion channel activity for the possibility of developing cancer therapeutics. In this study, the antiproliferative properties and mechanisms of action through TRPV1 of Maclura pomifera, a dioecious tree native to the south-central USA, have been investigated. Male and female extracts of spring branch tissues and leaves (500 µg/mL) significantly reduced the viability of MCF-7 and T47D cells by 75–80%. M. pomifera extracts induced apoptosis by triggering intracellular calcium overload via TRPV1. Blocking TRPV1 with the capsazepine antagonist and pretreating cells with the BAPTA-AM chelator boosted cell viability, revealing that M. pomifera phytochemicals activate TRPV1. Both male and female M. pomifera extracts initiated apoptosis through multiple pathways, the mitochondrial, ERK-induced, and endoplasmic reticulum-stress-mediated apoptotic pathways, demonstrated by the expression of activated caspase 3, caspase 9, caspase 8, FADD, FAS, ATF4, and CHOP, the overexpression of phosphorylated PERK and ERK proteins, and the reduction of BCL-2 levels. In addition, AKT and pAKT protein expressions were reduced in female M. pomifera-treated cells, revealing that female plant extract also inhibits PI3K/Akt signaling pathways. These results suggest that phytochemicals in M. pomifera extracts could be promising for developing breast cancer therapeutics.
... In colon cancer, loss of WNT expression occurs due to hypermethylation of the promoter or hyperactivation of the signalling pathway. It can be concluded that genistein may have a chemopreventive effect in the development of CRC due to its action on the WNT pathway [6]. ...
Familial adenomatous polyposis (FAP) is a rare disease characterized by the development of adenomatous polyps in the colon and rectum already in adolescence. If left untreated, patients develop colorectal cancer (CRC) with a 100% probability. To date, the gold standard of FAP management is surgery, which is associated with morbidity and mortality. A chemopreventive agent capable of delaying, preventing and reversing the development of CRC has been sought. Several classes of drugs have been used but to date no chemopreventive drug has been found for the management of this disease. In recent years, the importance of estrogen receptors in FAP and CRC, particularly the β subtype, has emerged. Indeed, the expression of the latter is strongly reduced in adenomatous polyps and CRC and is inversely correlated with the aggressiveness of the disease. Since phytoestrogens have a high affinity for this receptor, they have been suggested for use as chemopreventive agents in FAP and CRC. A combination of phytoestrogens and insoluble fibres has proved particularly effective. In this review, the various mechanisms of action of phytoestrogens were analyzed and the effectiveness of using phytoestrogens as an effective chemopreventive strategy was discussed.
... Apart from the well-known commercial or synthetic antiestrogens, many compounds extracted from plants, so called phytoestrogens, have also shown the inhibition of estrogenic effects [126]. Therefore, phytoestrogens can also be involved in the prevention and treatment of hormone-dependent cancers by acting directly or indirectly on ERs. ...
Head and neck squamous cell carcinoma (HNSCC) is the most common histological form of head and neck tumors (HNTs), which originate from the epithelium of the lips and oral cavity, pharynx, larynx, salivary glands, nasal cavity, and sinuses. The main risk factors include consumption of tobacco in all forms and alcohol, as well as infections with high-risk human papillomaviruses or the Epstein–Barr virus. Regardless of the etiological agent, the risk of developing different types of HNTs is from two to more than six times higher in males than in females. The reason for such disparities probably lies in a combination of both biological and psychosocial factors. Therefore, it is hypothesized that exposure to female sex hormones, primarily estrogen, provides women with protection against the formation and metastasis of HNTs. In this review, we synthesized available knowledge on the role of estrogen and estrogen receptors (ERs) in the development and progression of HNTs, with special emphasis on membrane ERs, which are much less studied. We can summarize that in addition to epidemiologic studies unequivocally pointing to the protective effect of estrogen in women, an increased expression of both nuclear ERs, ERα, and ERβ, and membrane ERs, ERα36, GPER1, and NaV1.2, was present in different types of HNSCC, for which anti-estrogens could be used as an effective therapeutic approach.
... The isoflavones binding to the estrogen receptors (ERs) leads to the direct binding of ERs to the estrogen-responsive-element (ERE) of the target gene, and then activates the transcription. Isoflavones-ERs complex may also act as a transcription factor that interacts with other transcription factors to activate the other nuclear receptor-mediated transcription, such as vitamin D receptor (VDR) [4][5][6][7][8]. ...
... In addition, isoflavones exhibit considerable antioxidant activity by increasing antioxidant enzyme activity, reducing oxidative stress, and preventing low-density lipoprotein cholesterol oxidation [1,5]. Furthermore, isoflavones activate mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3kinase (PI3K) signaling pathways to regulate the target genes [7,10,11]. These broad spectrums of isoflavone action may affect physiological conditions of human health, especially during development. ...
Soybean is a source of protein, fibers, and phytochemical isoflavones which are considered to have numerous health benefits for children and adulthood. On the other hand, isoflavones are widely known as phytoestrogens that exert their action via the estrogen signaling pathway. With this regard, isoflavones are also considered as endocrine-disrupting chemicals. Endogenous estrogen plays a crucial role in brain development through binding to estrogen receptors (ERs) or G protein-coupled estrogen receptors 1 (GPER1) and regulates morphogenesis, migration, functional maturation, and intracellular metabolism of neurons and glial cells. Soy isoflavones can also bind to ERs, GPER1, and, furthermore, other receptors to modulate their action. Therefore, soy isoflavone consumption may affect brain development during the pre-and post-natal periods. This review summarizes the current knowledge on the mechanisms of isoflavone action, particularly in the early stages of brain development by introducing representative human, and animal models, and in vitro studies, and discusses their beneficial and adverse impact on neurobehavior. As a conclusion, the soy product consumption during the pre-and post-natal periods under proper range of dose showed beneficial effects in neurobehavior development, including improvement of anxiety, aggression, hyperactive behavior, and cognition, whereas their adverse effect by taking higher doses cannot be excluded. We also present novel research lines to further assess the effect of soy isoflavone administration during brain development.
... The binding can either mimic estrogen (estrogenic effect) or block estrogen from binding (antiestrogenic effect). They may also influence the body's production of natural estrogen, either by modulating the activity of enzymes involved in estrogen metabolism or by affecting the overall hormonal balance [159,165]. ...
... estrogenic effect). They may also influence the body's production of natural estrogen, either by modulating the activity of enzymes involved in estrogen metabolism or by affecting the overall hormonal balance [159,165]. ...
... The effect of phytoestrogens on endometriosis; based on[159][160][161]165,166]. ...
Endometriosis is a chronic, hormone-dependent disease characterized by the presence of endometrial tissue in ectopic locations. Since the treatment options for this disease are still limited, and the cure rate is unsatisfactory, the search for ways to treat symptoms and modify the course of the disease is of key importance in improving the quality of life of patients with endometriosis. So far, the literature has shown that nutrition can influence endometriosis through hormonal modification and altering the inflammatory or oxidative response. Since the importance of nutrition in this disease is still a subject of scientific research, we aimed to summarize the current knowledge on the role of dietary modifications in endometriosis. Our review showed that nutrients with anti-inflammatory and antioxidant properties, including most vitamins and several trace elements, may influence the pathogenesis of endometriosis and can be considered as the nutrients preventing the development of endometriosis. However, despite the many discoveries described in this review, further interdisciplinary research on this topic seems to be extremely important, as in the future, it may result in the development of personalized therapies supporting the treatment of endometriosis.
... 10 Enterolignans can inhibit estrogen-dependent cancers, such as breast cancer. 11 In addition, enterolignans can reduce the risk of developing prostate and colon cancer. 12 Podophyllotoxin (PTOX) is an important lignan that induces apoptosis in cancer cells. ...
Background
Herbal medicines are the preferred anticancer agents due to their lower cytotoxic effects on healthy cells. Plant lignans play an important role in treating various diseases, especially cancer. The present study aimed to evaluate the effect of podophyllotoxin, pinoresinol, and lariciresinol on cellular toxicity and inducing apoptosis in fibroblasts, HEK-293, and SkBr3 cell lines.
Methods
An in vitro study was conducted from 2017 to 2019 at the Faculty of Biological Sciences, Tarbiat Modares University (Tehran, Iran). The cell lines were treated for 24 and 48 hours with different concentrations of lignans. Cell viability and apoptosis were examined using MTT and flow cytometry, respectively. Expression levels of cell cycle and apoptosis regulator genes were determined using quantitative real-time polymerase chain reaction. Data were analyzed using a two-way analysis of variance followed by Tukey’s HSD test. P<0.05 was considered statistically significant.
Results
Podophyllotoxin significantly increased apoptosis in fibroblast cells compared to pinoresinol and lariciresinol (P<0.001). The percentage of cell viability of fibroblast cells treated for 48 hours with pinoresinol, lariciresinol, and podophyllotoxin was reduced by 49%, 47%, and 36%, respectively. Treatment with pinoresinol and lariciresinol significantly overexpressed pro-apoptotic genes and underexpressed anti-apoptotic genes in SkBr3 cells (P<0.001). SkBr3 cells treated with lariciresinol significantly reduced gene expression (P<0.001).
Conclusion
Pinoresinol and lariciresinol can potentially be used as new therapeutic agents for the treatment of breast cancer.
... However, not all phytoestrogens are associated with health benefits, and some are known to cause hormone disruption. One example includes the soy phytoestrogen metabolite, daidzein, which completely inhibits the activity of estrogen receptors [87]. ...
... Daily intake of soybeans causes accumulation and influences various biological processes in the body (Zaheer & Humayoun Akhtar, 2017;Pabich & Materska, 2019;Kim, 2021). The estrogenic activity of isoflavones affects all systems in the body, including the male reproductive system (Vitale et al., 2013;Lecomte et al., 2017;Sleiman et al., 2021). ...
Isoflavones are active compounds in soybean seeds with a chemical structure resembling 17 β-estradiol and are able to bind to estrogen receptors on Leydig cells. The chemical structure and physiological activity of isoflavones are similar to estrogen. This research was conducted to evaluate changes in the structure of testicular seminiferous tubule tissue and spermatozoa morphology. Male Balb/c mice, 9 weeks old, 20–25 g, 24 mice, grouped into 4 treatments: 6 mice in control group (P0), 6 mice given 0.369 g/kg soy flour (P1), 6 mice given 0.369 g/kg soy flour 0.74 g/kg (P2), 6 mice given soybean flour 1.47 g/kg (P3) treatment for 36 days. Surgery and removal of testicular organs were carried out on the 37th day, and HE staining and preparation of spermatozoa smears were made. Data analysis parameters are changes in the structure of the testicular seminiferous tubule tissue and testicular germ cells (spermatogonia, primary spermatocytes, secondary spermatocytes, spermatids, and spermatozoa). Spermatozoa abnormalities include the head, neck, and tail. The results showed that the administration of soy flour caused the widening of the testicular tubule lumen; no spermatozoa were found in the tubule lumen. Spermatozoa abnormalities in treatment P1 was 18%, P2 was 29%, and P3 was 38%.
... Further, biochanin-A is a chief phytoconstituent of the red clover plant, which is well known for alleviating menopause symptoms through its oestrogenic and antioxidant properties (Romm et al., 2010;Raheja et al., 2018). Patients with prostate and breast malignancies have proven to show a defensive effect from an isoflavone-rich diet with evidence to various epidemiological studies and the mechanism behind such an action is by isoflavone and oestrogen receptor binding resulting in osteoprotective actions (Messina and Hilakivi-Clarke, 2009;Shu et al., 2009;Lecomte et al., 2017). Common dietary mixtures have gained consideration because of their synergistic impacts with several anticancer drugs seen in different kinds of malignancy. ...
This review was aimed at summarizing the cellular and molecular mechanisms behind the various pharmacological actions of biochanin-A. Many studies have been reported claiming its application in cancers, metabolic disorders, airway hyperresponsiveness, cardiac disorders, neurological disorders, etc. With regard to hormone-dependent cancers like breast, prostate, and other malignancies like pancreatic, colon, lung, osteosarcoma, glioma that has limited treatment options, biochanin-A revealed agreeable results in arresting cancer development. Biochanin-A has also shown therapeutic benefits when administered for neurological disorders, diabetes, hyperlipidaemia, and other chronic diseases/disorders. Isoflavones are considered phenomenal due to their high efficiency in modifying the physiological functions of the human body. Biochanin-A is one among the prominent isoflavones found in soy (glycine max), red clover (Trifolium pratense), and alfalfa sprouts, etc., with proven potency in modulating vital cellular mechanisms in various diseases. It has been popular for ages among menopausal women in controlling symptoms. In view of the multi-targeted functions of biochanin-A, it is essential to summarize it's mechanism of action in various disorders. The safety and efficacy of biochanin-A needs to be established in clinical trials involving human subjects. Biochanin-A might be able to modify various systems of the human body like the cardiovascular system, CNS, respiratory system, etc. It has shown a remarkable effect on hormonal cancers and other cancers. Many types of research on biochanin-A, particularly in breast, lung, colon, prostate, and pancreatic cancers, have shown a positive impact. Through modulating oxidative stress, SIRT-1 expression, PPAR gamma receptors, and other multiple mechanisms biochanin-A produces anti-diabetic action. The diverse molecular mechanistic pathways involved in the pharmacological ability of biochanin-A indicate that it is a very promising molecule and can play a major impact in modifying several physiological functions.
