雌激素受体与抑郁症的相关性研究进展

雌激素主要通过雌激素受体发挥抗抑郁作用。目前研究较多的是雌激素受体 α（ERα）、雌激素受体 β （ERβ）和 G蛋白偶联雌激素受体（GPER）。三者在雌激素的抗抑郁作用中发挥不同的效应,其中 GPER可能与雌激 素的快速抗抑郁作用有关。深入了解雌激素受体的不同效应对于寻找治疗抑郁症的新靶点,充分发挥雌激素的抗 抑郁作用,最大程度减少其不良反应具有重要意义。     

Two novel GPER agonists induce gene expression changes and growth effects in cancer cells

Although the action of estrogens has been traditionally explained by the binding to and transactivation of the nuclear estrogen receptor (ER)α and ERβ, recently the G protein-coupled receptor GPR30/GPER has been involved in the rapid estrogen signaling. We investigated the ability of two original molecules, which were named GPER-L1 and GPERL2, to bind to and activate the GPER transduction pathway in cancer cells. Competition assays, docking simulations, transfection experiments, real-time PCR, immunoblotting, gene silencing technology and growth assays were performed to ascertain the selective action of GPER-L1 and GPER-L2 in activating the GPER-mediated signaling. Both compounds, which did not show any ability to bind to and activate the classical ERs, were able to bind to GPER and to trigger the rapid activation of the GPER/EGFR/ERK transduction pathway which led to the up-regulation of GPER-target genes. Notably, GPER-L1 and GPER-L2 induced the proliferation of SkBr3 breast and Ishikawa endometrial cancer cells at nM concentrations through GPER, hence providing further evidence on their capability to elicit relevant biological responses mediated by GPER. The identification and characterization of these novel compounds as selective GPER agonists represent a valuable tool to further dissect the pharmacology of this novel estrogen receptor and to better differentiate the specific functions elicited by each estrogen receptor subtype in cancer cells.     

雌激素的血管作用：快速作用,新的机制和治疗潜力

Although estrogen-dependent effects on the vasculature were first observed more than a century ago, many of the mechanisms by which estrogens interact with the vascular wall have been identified only in the past 15 years. Estrogens bind to vascular estrogen receptors (ER), including the ER alpha, the novel ER beta as well as to membrane-bound receptors. Estrogens have direct effects in human coronary and internal mammary arteries by inducing rapid, endothelium-independent relaxation, enhancement of endothelial function and inhibition of vasoconstriction by vasoactive agonists. Furthermore, estrogens contribute to vascular homeostasis through modulation of gene expression, changes in membrane potentials, as well as expression and function of receptors. In addition, estrogens interfere with the activity of vasoactive peptides and vascular enzymes and act as natural antioxidants. Some of these effects have also been observed for phyto-estrogens, which are important dietary components in Asian countries. In the vasculature, the sum of these actions of estrogens results in vasodilatation and inhibition of vascular cell growth. Accordingly, estrogens have been shown to improve vascular function of animals and humans and to inhibit the response to injury after balloon angioplasty and the progression of atherosclerosis. Prospective clinical studies are ongoing to determine whether replacement therapy with estrogen or derivatives provides an alternative to lower cardiovascular mortality in postmenopausal women.     

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

G protein-coupled receptors (GPCRs) are cell surface proteins mainly involved in signal transmission; however, they play a role also in several pathophysiological conditions. Chemically heterogeneous molecules like peptides, hormones, lipids, and neurotransmitters activate second messengers and induce several biological responses by binding to these seven transmembrane receptors, which are coupled to heterotrimeric G proteins. Recently, additional molecular mechanisms have been involved in GPCR-mediated signaling, leading to an intricate network of transduction pathways. In this regard, it should be mentioned that diverse GPCR family members contribute to the adaptive cell responses to low oxygen tension, which is a distinguishing feature of several illnesses like neoplastic and cardiovascular diseases. For instance, the G protein estrogen receptor, namely G protein estrogen receptor (GPER)/GPR30, has been shown to contribute to relevant biological effects induced by hypoxia via the hypoxia-inducible factor (HIF)-1α in diverse cell contexts, including cancer. Likewise, GPER has been found to modulate the biological outcome of hypoxic/ischemic stress in both cardiovascular and central nervous systems. Here, we describe the role exerted by GPCR-mediated signaling in low oxygen conditions, discussing, in particular, the involvement of GPER by a hypoxic microenvironment.     

Estrogen receptor ligands: a patent review update

Introduction: The role of estrogens is mostly mediated by two nuclear receptors (ERα and ERβ) and a membrane-associated G-protein (GPR30 or GPER), and it is not limited to reproduction, but it extends to the skeletal, cardiovascular and central nervous systems. Various pathologies such as cancer, inflammatory, neurodegenerative and metabolic diseases are often associated with dysfunctions of the estrogenic system. Therapeutic interventions by agents that affect the estrogenic signaling pathway might be useful in the treatment of many dissimilar diseases.

Areas covered: The massive chemodiversity of ER ligands, limited to patented small molecules, is herein reviewed. The reported compounds are classified on the basis of their chemical structures. Non-steroidal derivatives, which mostly consist of diphenolic compounds, are further segregated into chemical classes based on their central scaffold.

Expert opinion: Estrogens have been used for almost a century and their earlier applications have concerned interventions in the female reproductive functions, as well as the treatment of some estrogen-dependent cancers and osteoporosis. Since the discovery of ERβ in 1996, the patent literature has started to pay a progressively increasing attention to this newer receptor subtype, which holds promise as a target for new indications, most of which still need to be clinically validated.     

MF101: a multi-component botanical selective estrogen receptor beta modulator for the treatment of menopausal vasomotor symptoms

INTRODUCTION: The Women's Health Initiative Estrogen Plus Progestin clinical trial demonstrated the risks exceeded the benefits which have led to a decline in menopausal hormone therapy (MHT) by greater than 50%. MHT use was initiated long before there was a significant understanding of the molecular mechanisms of estrogens. It has become clear that the problem with the current estrogens in MHT is they act non-selectively as an agonist in all tissues that contain estrogen receptors. MF101 is an oral, botanically derived extract that was designed to selectively regulate estrogen receptor beta (ERβ) because the increased risk of breast and endometrial cancer is due to the activation of estrogen receptor alpha (ERα) by estrogens. Preclinical and clinical data support a role for selective ERβ agonists, such as MF101, for vasomotor symptoms without increasing cancer risks. AREAS COVERED: The review covers the biological, pharmacological and clinical advantages of MF101, and the unique ability of MF101 to selectively target the ERβ pathway for the treatment of hot flashes (HF). EXPERT OPINION: Preclinical and clinical studies indicate that MF101, a selective estrogen receptor beta agonist, represents a new class of drugs that is safe and effective for treating HF and nighttime awakenings.     

Estrogen receptor beta in cancer: an attractive target for therapy

While it is well documented that the mitogenic actions of estrogens are critical in the development and progression of human breast and some gynecologic cancers, only latest data demonstrate a crucial involvement of estrogen-signaling in the carcinogenesis of non-classical estrogen target tissues, as colon, prostate, lung, skin, and brain. Only recently it has also been found out that the biological effects of estrogens are mediated by two distinct estrogen receptors (ERs), ERα and ERβ, and that their relative levels in a given cell are important determinants of response to estradiol and selective estrogen receptor modulators. Indeed, although ERα and ERβ have similar structure, they produce different effects, and there is currently increasing evidence that, for some tumors, an imbalanced ERβ expression might play a pivotal role in tumor development and progression. However, the prognostic value, the potential significance in predicting response to endocrine therapy, and, eventually, the utility of ERβ as a therapeutic target need to be assessed in large-scale and prospective clinical studies. This review examines the experimental and clinical evidences for a role of ERβ in carcinogenesis of classical and nonclassical estrogen target tissues. If anomalies of ERβ expression could be demonstrated to represent a critical step in the development and progression of some types of cancers, its re-expression by genetic engineering, as well as the use of targeted ERβ therapies would constitute new important therapeutic approaches.     

Estrogenic Endocrine-Disrupting Chemicals: Molecular Mechanisms of Actions on Putative Human Diseases

Endocrine-disrupting chemicals (EDC), including phthalates, bisphenol A (BPA), phytoestrogens such as genistein and daidzein, dichlorodiphenyltrichloroethane (DDT), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are associated with a variety of adverse health effects in organisms or progeny by altering the endocrine system. Environmental estrogens, including BPA, phthalates, and phytoestrogens, are the most extensively studied and are considered to mimic the actions of endogenous estrogen, 17β-estradiol (E2). Diverse modes of action of estrogen and estrogen receptors (ERα and ERβ) have been described, but the mode of action of estrogenic EDC is postulated to be more complex and needs to be more clearly elucidated. This review examines the adverse effects of estrogenic EDC on male or female reproductive systems and molecular mechanisms underlying EDC effects that modulate ER-mediated signaling. Mechanisms of action for estrogenic EDC may involve both ER-dependent and ER-independent pathways. Recent findings from systems toxicology of examining estrogenic EDC are also discussed.     

Aberrant ligand-induced activation of G protein-coupled estrogen receptor 1 (GPER) results in developmental malformations during vertebrate embryogenesis

G protein-coupled estrogen receptor 1 (GPER) is a G protein-coupled receptor (GPCR) unrelated to nuclear estrogen receptors but strongly activated by 17β-estradiol in both mammals and fish. To date, the distribution and functional characterization of GPER within reproductive and nonreproductive vertebrate organs have been restricted to juvenile and adult animals. In contrast, virtually nothing is known about the spatiotemporal distribution and function of GPER during vertebrate embryogenesis. Using zebrafish as an animal model, we investigated the potential functional role and expression of GPER during embryogenesis. Based on real-time PCR and whole-mount in situ hybridization, gper was expressed as early as 1 h postfertilization (hpf) and exhibited strong stage-dependent expression patterns during embryogenesis. At 26 and 38 hpf, gper mRNA was broadly distributed throughout the body, whereas from 50 to 98 hpf, gper expression was increasingly localized to the heart, brain, neuromasts, craniofacial region, and somite boundaries of developing zebrafish. Continuous exposure to a selective GPER agonist (G-1)-but not continuous exposure to a selective GPER antagonist (G-15)-from 5 to 96 hpf, or within three developmental windows ranging from 10 to 72 hpf, resulted in adverse concentration-dependent effects on survival, gross morphology, and somite formation within the trunk of developing zebrafish embryos. Importantly, based on co-exposure studies, G-15 blocked severe G-1-induced developmental toxicity, suggesting that G-1 toxicity is mediated via aberrant activation of GPER. Overall, our findings suggest that xenobiotic-induced GPER activation represents a potentially novel and understudied mechanism of toxicity for environmentally relevant chemicals that affect vertebrate embryogenesis.     

Selective estrogen receptor-beta (SERM-beta) compounds modulate raphe nuclei tryptophan hydroxylase-1 (TPH-1) mRNA expression and cause antidepressant-like effects in the forced swim test

Estrogen acts through two molecularly distinct receptors termed estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) which bind estradiol with similar affinities and mediate the effects of estrogen throughout the body. ERα plays a major role in reproductive physiology and behavior, and mediates classic estrogen signaling in such tissues as the uterus, mammary gland, and skeleton. ERβ, however, modulates estrogen signaling in the ovary, the immune system, prostate, gastrointestinal tract, and hypothalamus, and there is some evidence that ERβ can regulate ERα activity. Moreover, ERβ knockout studies and receptor distribution analyses in the CNS suggest that this receptor may play a role in the modulation of mood and cognition. In recent years several ERβ-specific compounds (selective estrogen receptor beta modulators; SERM-beta) have become available, and research suggests potential utility of these compounds in menopausal symptom relief, breast cancer prevention, diseases that have an inflammatory component, osteoporosis, cardiovascular disease, and inflammatory bowel disease, as well as modulation of mood, and anxiety. Here we demonstrate an antidepressant-like effect obtained using two SERM-beta compounds, SERM-beta1 and SERM-beta2. These compounds exhibit full agonist activity at ERβ in a cell based estrogen response element (ERE) transactivation assay. SERM-beta1 and 2 are non-proliferative with respect to breast as determined using the MCF-7 breast cancer cell-based assay and non-proliferative in the uterus as determined by assessing the effects of SERM-beta compounds on immature rat uterine weight and murine uterine weight. In vivo SERM-beta1 and 2 are brain penetrant and display dose dependent efficacy in the murine dorsal raphe assays for induction of tryptophan hydroxylase mRNA and progesterone receptor protein. These compounds show activity in the murine forced swim test and promote hippocampal neurogenesis acutely in rats. Taken together these data suggest that ERβ may play an important role in modulating mood and the ERβ specific compounds described herein will be useful tools for probing the utility of an ERβ agonist for treating neuroendocrine-related mood disturbance and menopausal symptoms.     

Insights from the structure of estrogen receptor into the evolution of estrogens: implications for endocrine disruption

In the last decade, there has been important progress in understanding the origins and evolution of receptors for adrenal steroids (aldosterone, cortisol) and sex steroids (estradiol, progesterone, testosterone) due to the sequencing of genomes from animals that are at key sites in vertebrate evolution. Although the estrogen receptor [ER] appears to be the ancestral vertebrate steroid receptor and estradiol [E2] is the physiological ligand for vertebrate ERs, the identity of the ancestral ligand(s) for the ER remains unknown. Here, using an analysis of crystal structures of human ERα with E2 and other chemicals and 3D models of human ERα with 27-hydroxycholesterol and 5-androsten-3β,17β-diol, I propose that one or more Δ5 steroids were the ancestral ligands for the ER, with E2 evolving later as the canonical estrogen. The evidence that chemicals with a β-hydroxy at C3 in a saturated A ring can act as estrogens and the conformational flexibility of the vertebrate ER can explain the diversity of synthetic chemicals that disrupt estrogen responses by binding to vertebrate ERs.     

Estrogens and SERMs in coronary heart disease

Estrogen combines beneficial and harmful actions by affecting many intracellular pathways in a large number of target organs related to the cardiovascular system. In observational studies and large outcome trials, an improvement of serum lipid profile and reduction of cardiovascular event rate were reported, whereas thrombembolic complications and stroke rate increased. Recognition of the diversity and tissue selectivity of estrogen's effects prompted the development of selective estrogen receptor modulators (SERMs), which were subsequently used to dissect the different mechanisms of action. SERMs are estrogen receptor (ER) ligands that exert partial agonist or antagonist actions on the ER in a tissue-, pathway- or isoform-specific manner. As ER ligands, they trigger a large variety of effects, including extranuclear ER actions, which can be further modulated by coactivators, corepressors and potential novel estrogen-binding proteins/receptors. Thus, SERMs can display tissue- or pathway-specific effects, or a combination of these. Pharmacological and clinical data are available for the classical SERM prototypes raloxifene and tamoxifene, as well as for new SERMs in different stages of development, isotype-specific agonists and pathway-selective ligands. These compounds exert many different effects, including vasodilatation in coronary arteries, altered responses to ischemic damage, hypertrophy of the myocardium, and improvement in serum cholesterol and lipid profile. The development of future SERMs will focus on different indications, including hormone therapy or cardiovascular disease. However, they all should antagonize estrogen action in female reproductive organs, yet protect from bone loss and not interfere with the beneficial effects of estrogen in the brain.