Diet habits and nutrition quality significantly impact health and disease. Here is delve into the intricate relationship between diet habits, nutrition quality, and their direct impact on health and homeostasis. Focusing on (-)-Epicatechin, a natural flavanol found in various foods like green tea and cocoa, known for its positive effects on cardiovascular health and diabetes prevention. The investigation encompasses the absorption, metabolism, and distribution of (-)-Epicatechin in the human body, revealing a diverse array of metabolites in the circulatory system. Notably, (-)-Epicatechin demonstrates an ability to activate nitric oxide synthase (eNOS) through the G protein-coupled estrogen receptor (GPER). While the precise role of GPER and its interaction with classical estrogen receptors (ERs) remains under scrutiny, the study employs computational methods, including density functional theory, molecular docking, and molecular dynamics simulations, to assess the physicochemical properties and binding affinities of key (-)-Epicatechin metabolites with GPER. DFT analysis revealed distinct physicochemical properties among metabolites, influencing their reactivity and stability. Rigid and flexible molecular docking demonstrated varying binding affinities, with some metabolites surpassing (-)-Epicatechin. Molecular dynamics simulations highlighted potential binding pose variations, while MMGBSA analysis provided insights into the energetics of GPER-metabolite interactions. The outcomes elucidate distinct interactions, providing insights into potential molecular mechanisms underlying the effects of (-)-Epicatechin across varied biological contexts.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global public health and economic burden worldwide in the past few decades. Epidemiological studies have shown that MASLD is a multisystem disease that is associated not only with liver-related complications but also with an increased risk of developing extrahepatic cancers. MASLD is a sexually dimorphic disease with sex hormones playing an important role in the development and progression of MASLD, especially by the levels and ratios of circulating estrogens and androgens. MASLD is associated with hormone-sensitive cancers including breast and gynecological cancer. The risk of breast and gynecological cancer is elevated in individuals with MASLD driven by shared metabolic risk factors including obesity and insulin resistance. Multiple potential mechanisms underline these associations including metabolic dysfunction, gut dysbiosis, chronic inflammation and dysregulated release of hepatokines. However, the effect of hormone therapy including hormone replacement therapy and anti-estrogen treatment on MASLD and female-specific cancers remains debatable at this time. This synopsis will review the associations between MASLD and breast and gynecological cancer, their underlying mechanisms, implications of hormonal therapies, and their future directions.

Tamoxifen is a cornerstone in the treatment of estrogen receptor (ER)-positive breast cancer, yet resistance to this therapy remains a significant clinical challenge. In most cases, the resistance phenotype is not caused by loss or mutation of the ER, but by changes in multiple proliferative and survival pathways. The mitogen-activated protein kinase (MAPK) signaling pathways regulate various cellular processes such as cell growth, proliferation, and apoptosis. This review provides a comprehensive analysis of molecular mechanisms that sustain MAPK activation and promote tamoxifen resistance. We evaluated molecular factors that promote the survival of tamoxifen-resistant cells through the regulation of MAPK signaling, including growth factors, RNA-binding proteins, non-genomic ER variants, and microRNAs. Mitochondrial dynamics and their regulation by MAPK highlight novel adaptive mechanisms employed by resistant cells to survive. Furthermore, MAPK-mediated phosphorylation of ERα enhances resistance through ligand-independent activation and sustained cellular proliferation. MAPK and parallel oncogenic pathways, including PI3K/AKT and receptor tyrosine kinases (EGFR, IGF-1R, and FGFR), function synergistically to enhance signaling redundancy and compensatory survival mechanisms. Therapeutic interventions targeting MAPK signaling-ranging from small-molecule inhibitors to RNA-based therapies-offer promising avenues for overcoming tamoxifen resistance.

Temporal lobe epilepsy (TLE) is the most common type of refractory epilepsy, characterized by highly synchronized abnormal neuronal discharge. The insula cortex (IC) serves as a key "node" in the TLE transmission network, and the anterior insula (AI) is a critical gatekeeper to executive control; however, the pathological changes of the IC/AI have been overlooked. GPER1 is a G protein coupled estrogen receptor anchored by PSD95 to the plasma membrane of dendritic spine (DS), participating in the regulation of DS plasticity. We found that Gper1 deletion rats exhibited increased susceptibility to epilepsy, but it remains unclear whether and how GPER1 regulates alterations in DS plasticity in the IC after TLE induction. Here, we observed that the interaction between GPER1 and PSD95 diminished at TLE induction 7 d, the dendrite complexity and DS density were altered in the AI. While, activating of GPER1 ameliorated the neuronal damage and loss in the AI of TLE rats, decreased dendrite complexity and increased DS density，enhanced the interaction between GPER1 and PSD95, then mitigated the inhibition of Rock2 and its downstream targets, cofilin and the imbalance of F/G-actin, which was induced by the over-activation of CAMKII and RhoA. Thus, improved the emotion and cognitive dysfunction of TLE rats. Our results offer compelling evidence for elucidating the mechanism of abnormal changes in insular synaptic plasticity following TLE and the selection of therapeutic targets.

Histological evidence suggests that the estrous cycle exerts a powerful influence on CA1 neurons in the mammalian hippocampus. Decades have passed since this landmark observation, yet how the estrous cycle shapes dendritic spine dynamics and hippocampal spatial coding in vivo remains a mystery. Here, we used a custom hippocampal microperiscope and two-photon calcium imaging to track CA1 pyramidal neurons in female mice across multiple cycles. Estrous cycle stage had a potent effect on spine dynamics, with spine density peaking during proestrus when estradiol levels are highest. These morphological changes coincided with greater somatodendritic coupling and increased infiltration of back-propagating action potentials into the apical dendrite. Finally, tracking CA1 response properties during navigation revealed greater place field stability during proestrus, evident at both the single-cell and population levels. These findings demonstrate that the estrous cycle drives large-scale structural and functional plasticity in hippocampal neurons essential for learning and memory.

Ferroptosis represents a significant target for mitigating myocardial ischemia-reperfusion (I/R) injury. Existing literature indicates that estrogen (17β-estradiol, E2) can alleviate such injuries through various pathways. However, the specific mechanisms by which E2 may confer protection against myocardial I/R injury through the inhibition of ferroptosis remain to be fully elucidated. This study employed a mouse model of left anterior descending coronary artery ligation to investigate the protective effects of E2 on myocardial I/R injury, with a particular focus on its inhibitory effects on ferroptosis and PHLDA3 in both hypoxia-reoxygenation (H/R) and I/R models. A bioinformatics analysis was conducted to evaluate the impact of estrogen receptor GPER knockout on PHLDA3 expression and ferroptosis. Loss-of-function approaches were employed to elucidate the role of PHLDA3 in ferroptosis during myocardial I/R injury. Our findings demonstrate that E2 can ameliorate myocardial I/R injury, primarily by inhibiting ferroptosis. Notably, PHLDA3 expression levels were significantly elevated during ischemia-reperfusion events; however, E2 was observed to suppress this expression. Bioinformatics analysis indicated that PHLDA3 levels increased following GPER knockdown, and the inhibitory effect of E2 on PHLDA3 expression could be partially reversed by GPER inhibitors (G15) in animal models. Furthermore, the suppression of PHLDA3 reduced ferroptosis and mitigated the severity of myocardial I/R injury. Utilizing mass spectrometry and co-immunoprecipitation methodologies, we have elucidated a potential mechanism in which PHLDA3 directly binds to and interacts with proteins involved in the process of ferroptosis. Our findings demonstrate that E2 effectively suppresses ferroptosis and mitigates myocardial I/R injury by downregulating PHLDA3 expression through the activation of the GPER receptor.

The estrogen receptor (ER) is a nuclear receptor and one of the most extensively researched targets in the study of endocrine-disrupting chemicals (EDCs). Many biosensors and bioassays for estrogenic EDCs use the ligand-binding domain of human ERα (LBD-hERα) as a biological recognition element. However, the LBD-hERα is poorly stable and difficult to produce as a functional LBD-hERα in the E. coli expression system. In this study, we efficiently expressed the functional LBD-hERα tagged with the cyan fluorescent protein, mTurquoise2 (LBD-hERα-mTq2) by the addition of ethanol (3 %) to E. coli suspension during protein expression (> 40 times more compared to without ethanol). We found that ethanol not only promoted the proper folding of LBD-hERα-mTq2, but also prevented the proteolysis of poorly folded recombinant proteins. We established a FRET-based binding assay between a fluorescent estrogen, coumestrol, and the LBD-hERα-mTq2, in which the formation of the complex exhibits a significant degree of FRET. A subsequent competitive binding assay with diethylstilbestrol demonstrates that our system successfully functions as a simple and reliable bioassay to detect estrogenic EDCs.

Environmental estrogens (EEs), as typical endocrine-disrupting chemicals (EDCs), can bind to classic estrogen receptors (ERs) to induce genomic effects, as well as to G protein-coupled estrogen receptor (GPER) located on the membrane, thereby inducing downstream nongenomic effects rapidly. However, due to the relatively scarce ligand data, receptor-based or ligand-based screening models for GPER are challenging. Inspired by functional similarity between GPER and ER, this study constructs a deep transfer learning model named GPNET to predict potential GPER-binding ligands by using three-dimensional (3D) molecular surface electrostatic potential point clouds (SepPC) as input. The model retains a part of molecular structural knowledge learned from the ER ligands and then trains the remaining parameters of the model using the GPER ligands, ultimately obtaining the GPNET model, which effectively predicts the binding activity of compounds with GPER. GPNET outperforms From Scratch (nontransfer) model on the small data set, achieving the area under the receiver operating characteristic (ROC) curve (AUCROC) of 0.898 on the validation set and 0.863 on the test set, respectively. Furthermore, by visualizing the critical points and extracting the features from activation points of active ligands, the study provides a more in-depth interpretation of the molecular mechanism of two bisphenol A (BPA) alternatives binding to GPER.

Neurodegenerative disorders such as Alzheimer's disease and macular degeneration represent major sources of human suffering, yet factors influencing disease severity remain poorly understood. Sex has been implicated as one modifying factor. Here, we show that female sex is a risk factor for worsened outcomes in a model of retinal degeneration and that this susceptibility is caused by the presence of female-specific sex hormones. The adverse effect of female sex hormones was specific to diseased retinal neurons, and depletion of these hormones ameliorated this phenotypic effect, while reintroduction worsened rates of disease in females. Transcriptional analysis of retinas showed significant differences between genes involved in pyroptosis, inflammatory responses, and endoplasmic reticulum stress-induced apoptosis between males and females with retinal degeneration. These findings provide crucial insights into the pathogenesis of neurodegenerative diseases and how sex hormones can affect disease severity. These findings have far-reaching implications for clinical trial design and the use of hormonal therapy in females with certain neurodegenerative disorders.

Breast cancer is one of the most significant causes of mortality among women and the second most prevalent cancer worldwide. Estrogen receptor (ER)-positive breast cancers are the most common molecular subtype of breast cancer, comprising about 70% of breast carcinoma diagnoses worldwide. Endocrine therapy is the foremost strategy for the treatment of ER-positive breast cancer. In the United States, the Food and Drug Administration (FDA) has approved endocrine therapies for ER-positive breast cancers that include selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators/degraders (SERDs) and aromatase inhibitors (AIs). The approved SERMS, tamoxifen, toremifene and raloxifene, are the gold-standard treatments. The only FDA-approved SERD available for treating ER and hormone-positive breast cancers is fulvestrant, and various generations of AIs, including exemestane, letrozole, and anastrozole, have also received FDA approval. Herein, we review the major FDA-approved SERMs and SERDs for treating ER-positive breast cancer, focusing on their mechanisms of action. We also explore molecular events that contribute to the resistance of these drugs to endocrine therapies and combinational strategies with drugs such as cyclin-dependant kinases 4/6 (CDK4/6) inhibitors in clinical trials to combat endocrine drug resistance.

G-1, a G protein-coupled estrogen receptor (GPER)-specific agonist, exhibits anticancer potential in breast cancer cells. This study aims to explore the molecular basis of apoptosis induced by G-1 in MCF-7 and MDA-MB-231 breast cancer cells. Here, we found that G-1 induced cytotoxicity and GPER-dependent apoptosis with PARP cleavage and mitochondrial membrane potential (MMP) loss, as well as nuclear condensation. Fluorescence resonance energy transfer (FRET) analysis in living cells indicated that G-1 effectively disrupted the interaction between large tumor suppressor 1/2 (LATS1/2) and Yes-associated protein (YAP). Furthermore, G-1 reduced YAP phosphorylation levels and promoted its nuclear accumulation. Notably, knockdown of YAP attenuated G-1-induced apoptosis, highlighting the crucial role of YAP in this process. Additionally, FRET analysis revealed that G-1 enhanced the binding of YAP to p73, leading to an increase in Bcl-2-associated X protein (Bax) expression and an induction of apoptosis. In summary, our findings demonstrate that G-1 induces apoptosis through the GPER/YAP/p73-mediated pathway.

Cardiovascular disease (CVD), such as hypertension and coronary artery disease, involves pathological changes in vascular signaling, function, and structure. Vascular signaling is regulated by multiple intrinsic and extrinsic factors that influence endothelial cells, vascular smooth muscle, and extracellular matrix. Vascular function is also influenced by environmental factors including diet, exercise, and stress, as well as genetic background, sex differences, and age. CVD is more common in adult men and postmenopausal women than in premenopausal women. Specifically, women during menopausal transition, with declining ovarian function and production of estrogen (E2) and progesterone, show marked increase in the incidence of CVD and associated vascular dysfunction. Mechanistic research suggests that E2 and E2 receptor signaling have beneficial effects on vascular function including vasodilation, decreased blood pressure, and cardiovascular protection. Also, the tangible benefits of E2 supplementation in improving menopausal symptoms have prompted clinical trials of menopausal hormone therapy (MHT) in CVD, but the results have been inconsistent. The inadequate benefits of MHT in CVD could be attributed to the E2 type, dose, formulation, route, timing, and duration as well as menopausal changes in E2/E2 receptor vascular signaling. Other factors that could affect the responsiveness to MHT are the integrated hormonal milieu including gonadotropins, progesterone, and testosterone, vascular health status, preexisting cardiovascular conditions, and menopause-related dysfunction in the renal, gastrointestinal, endocrine, immune, and nervous systems. Further analysis of these factors should enhance our understanding of menopause-related changes in vascular signaling by sex hormones and provide better guidance for management of CVD in postmenopausal women. SIGNIFICANCE STATEMENT: Cardiovascular disease is more common in adult men and postmenopausal women than premenopausal women. Earlier observations of vascular benefits of menopausal hormone therapy did not materialize in randomized clinical trials. Further examination of the cardiovascular effects of sex hormones in different formulations and regimens, and the menopausal changes in vascular signaling would help to adjust the menopausal hormone therapy protocols in order to enhance their effectiveness in reducing the risk and the management of cardiovascular disease in postmenopausal women.

The bladder and prostate originate from the urogenital sinus. However, bladder cancer (BC) is usually classified as an immune "hot" tumor, whereas prostate cancer (PCa) is deemed as an immune "cold" tumor according to the tumor microenvironment (TME) and clinical outcomes. To investigate the immune differences between BC and PCa, studies are compared focusing on immune regulation mediated by sex hormones and receptors to identify key genes and pathways responsible for the immune differences. From a developmental perspective, it is shown that PCa and BC activate genes and pathways similar to those in the developmental stage. During prostate development, the differential expression and function of the androgen receptor (AR) across cell types may contribute to its dual role in promoting and inhibiting immunity in different cells. Androgen deprivation therapy affects AR function in different cells within the TME, influencing immune cell infiltration and antitumor function. Additionally, estrogenα and estrogenβ exert contrasting effects in PCa and BC, which may hold the potential for modifying the "cold" and "hot" tumor phenotypes. Future research should target key genes and pathways involved in bladder development to clarify the immune regulatory similarities and differences between BC and PCa.

Progression of Prostatic Intra-epithelial Neoplasia (PIN) to Prostate Cancer (PCa) is characterized by a long latency period. This presents several opportunities for intervention. G-Protein coupled Estrogen Receptor 1 (GPER1) has emerged as an attractive target in the field of oncology. Existing data suggest that GPER1 activation inhibits PCa growth. However, the potential of GPER1 as a target for PCa chemoprevention remains unexplored. Analysis of publicly available datasets revealed a significant reduction in the prostatic GPER1 expression in the advanced PCa cases, compared to non-cancerous prostates. This was corroborated by our investigations of human primary PCa samples and the TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mouse model. The frequency of GPER1-positive cells and the expression of GPER1 were significantly higher in the TRAMP prostates presenting High-Grade PIN (HGPIN), compared to control prostates. However, this pattern reversed as HGPIN progressed to PCa. Activation with G1 (an agonist of GPER1) at the HGPIN stage prevented the progression of HGPIN to PCa in TRAMP mice. This effect was abrogated by co-administration of G1 with G15 (an antagonist of GPER1). In vitro activation with G1 inhibited proliferation in LNCaP, PC3, and RWPE-1 cell lines. On the other hand, GPER1-silencing led to a significant increase in in-vitro migration, invasion, and epithelial to mesenchymal transition through miR200a-ZEB2-E-Cadherin loop and by dysregulating the expression of metastasis-associated genes. These observations collectively suggest that GPER1 has a protective role in the context of PCa. Human studies are warranted to assess the potential of GPER1 as a target for PCa chemoprevention.

Biased signaling refers to the phenomenon where a ligand selectively activates specific downstream pathways of G protein-coupled receptors (GPCRs), such as the G protein-mediated pathway or the β-arrestin-mediated pathway. This mechanism can be influenced by receptor bias, ligand bias, system bias and spatial bias, all of which are shaped by the receptor's conformational distinctions and kinetics. Since GPCRs are the largest class of drug targets, signaling bias garnered significant attention for its potential to enhance therapeutic efficacy while minimizing side effects. Despite intensive investigation, a major challenge lies in translating in vitro ligand efficacy into in vivo biological responses due to the dynamic and multifaceted nature of the in vivo environment. This review delves into the current understanding of GPCR-biased signaling, examining the role of structural bias at the molecular level, the impact of kinetic context on system and observational bias, and the challenges of applying these insights in drug development. It further explores future directions for advancing biased signaling applications, offering valuable perspectives on how to bridge the gap between in vitro studies and in vivo therapeutic design, ultimately accelerating the development of viable, biased therapeutics.

Triple-positive breast cancer (TPBC), a unique subtype of luminal breast cancer, is characterized by concurrent positivity for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Owing to the crosstalk between the ER and HER2 signaling pathways, the standard of care and drug resistance of this particular subtype are difficult challenges. Recent research and clinical trials have indicated a shift in the treatment paradigm for TPBC from single-target therapies to multi-pathway, multitarget strategies aiming to comprehensively modulate intricate signaling networks, thereby overcoming resistance and enhancing therapeutic outcomes. Among multiple strategies, triple-drug therapy has emerged as a promising treatment modality, demonstrating potential efficacy in patients with TPBC. Moving forward, there is a critical need to perform in-depth analyses of specific mechanisms of cancer pathogenesis and metastasis, decipher the complex interactions between different genes or proteins, and identify concrete molecular targets, thus paving the way for the development of tailored therapeutic strategies to combat TPBC effectively.

Cardiovascular diseases (CVDs) are among the leading causes of death globally and pose a significant threat to public health. Factors such as prolonged high cholesterol levels, diabetes, smoking, unhealthy diet, and genetic predisposition could contribute to the occurrence and development of CVDs. Common CVDs include hypertension (HTN), atherosclerosis (AS), myocardial infarction (MI), myocardial ischemia-reperfusion injury (MIRI), heart failure (HF) and arrhythmia. Estrogen is recognized for its cardiovascular protective effects, resulting in lower incidence and mortality rates of CVDs in premenopausal women compared to men. The G protein-coupled estrogen receptor (GPER), a G protein-coupled receptor with a seven-transmembrane structure, exhibits unique structural characteristics and widespread tissue distribution. GPER activates intracellular signaling pathways through its interaction with G proteins, mediating estrogen's biological effects and participating in the regulation of cardiovascular function, metabolic balance, and nervous system. Although recent research has highlighted the significant role of GPER in the cardiovascular system, its specific mechanisms remain unclear. Therefore, this review summarizes the latest research on GPER in CVDs, including its fundamental characteristics, physiological functions in the cardiovascular system, and its roles and potential therapeutic applications in common CVDs such as HTN, AS, MI, MIRI, HF and arrhythmia. Exploring GPER's positive effects on cardiovascular health will provide new strategies and research directions for the treatment of CVDs.

G protein-coupled receptors (GPCRs), the largest family of membrane receptors in the mammalian genomes, regulate almost all known physiological processes by transducing numerous extracellular stimuli including almost two-thirds of endogenous hormones and neurotransmitters. The traditional view held that GPCR signaling occurs exclusively at the cell surface, where the receptors bind with the ligands and undergo conformational changes to recruit and activate heterotrimeric G proteins. However, with the application of advanced biochemical and biophysical techniques, this conventional model is challenged by the elucidation of spatiotemporal GPCR activation with the evidence that receptors can signal from subcellular compartments to exhibit various molecular and cellular responses with physiological and pathophysiological relevance. Thus, this 'location bias' of GPCR signaling has become another layer of complexity of GPCR signal transduction. In this review, we generally introduce the development of the concept of compartmentalized GPCR signaling and comprehensively summarize the receptors reported to be localized on the membranes of different intracellular organelles. We review the physiological functions of these compartmentalized GPCRs with emphasis on some well-characterized prototypical hormone/neurotransmitter-binding receptors, including β2-adrenergic receptor, opioid receptors, parathyroid hormone type 1 receptor, thyroid-stimulating hormone receptor, cannabinoid receptor type 1, and metabotropic glutamate receptor 5, as examples. In addition, the therapeutic implications of compartmentalized GPCR signaling by introducing lipophilic or hydrophilic ligands for intracellular targeting, lipid conjugation anchor drugs, and strategy to modulate receptor internalization/resensitization, are highlighted and open new avenues in GPCR pharmacology and therapeutics.

The G protein-coupled estrogen receptor (GPER) plays a crucial role in various biological processes, but its regulation of oocyte meiosis remains unclear. In this study, we generated a Gper1 knockout in growing oocytes using Zp3-Cre, revealing that GPER is essential for oocyte maturation and embryo development. RNA-seq analysis indicated that GPER deficiency significantly altered the oocyte transcriptome and disrupted mRNA translation. Immunoprecipitation mass spectrometry revealed that GPER directly interacts with HSP90 and modulates the ERK1/2 and PI3K-AKT signaling pathways, which are vital for enhancing maternal mRNA translation and developmental potential. We also found that cumulus cell-derived GPER-positive vesicles and delivered to oocytes through a RAB11A-dependent pathway. RAB11A facilitates GPER recycling, preventing its degradation in late endosomes and promoting its plasma membrane localization. Moreover, epidermal growth factor (EGF) improves GPER expression in cumulus cells by upregulating RAB11A, thereby enhancing the exocytosis of recycling vesicles. Knockdown of Rab11a severely reduced GPER-positive vesicles in oocytes, impairing spindle morphogenesis and meiosis. Our findings highlight the critical role of somatic cell signals in regulating maternal mRNA translation and oocyte quality for embryonic development.

Metabolic syndrome (MetS) and its constituent comorbidities, along with mineral imbalances, pose a significant health burden in the Qatari population. Although Magnesium (Mg) and Calcium (Ca) have been individually linked to MetS, the impact of the calcium-to-magnesium ratio (Ca: Mg) on MetS remains unclear, especially in the adult population of Qatar. In this study, we aim to investigate the association between the total serum concentrations of Ca, Mg and Ca: Mg ratio with the outcome of MetS.

This comprehensive cross-sectional study included data on 9693 participants collected by Qatar Biobank (QBB). The serum levels of Mg and Ca, in addition to recorded metabolic parameters for the study participants, were used in the analyses. The presence of MetS was deemed as our primary outcome and its components as secondary outcomes. Logistic regression models were run to examine these associations.

MetS was present in more than 19% of the population. The mean serum Mg was higher in the non-MetS group 0.83 ± 0.06 mmol/L compared to the MetS group 0.81 ± 0.08 mmol/L. Conversely, the mean serum Ca and Ca: Mg ratio were higher in the MetS group (2.33 ± 0.09 mmol/L, 2.92 ± 0.36 mmol/L) compared to the non-MetS group (2.30 ± 0.08 mmol/L, 2.77 ± 0.23 mmol/L) respectively. In the context of MetS, we observed a negative dose-response relationship between Mg quartiles and MetS. In contrast, we found a positive association between Ca as well as Ca: Mg ratio and MetS.

G Protein-Coupled Estrogen Receptor 1 (GPER-1) is a membrane estrogen receptor that has emerged as a key player in breast cancer development and progression. In addition to its direct influence on estrogen signaling, a crucial interaction between GPER-1 and the hypothalamic-pituitary-gonadal (HPG) axis has been evidenced. The novel and complex relationship between GPER-1 and HPG implies a hormonal regulation with important homeostatic effects on general organ development and reproductive tissues, but also on the pathophysiology of cancer, especially breast cancer. Recent research points to a great versatility of GPER-1, interacting with classical estrogen receptors and with signaling pathways related to inflammation. Importantly, through its activation by environmental and synthetic estrogens, GPER-1 is associated with hormone therapy resistance in breast cancer. These findings open new perspectives in the understanding of breast tumor development and raise the possibility of future applications in the design of more personalized and effective therapeutic approaches.

What is the hormone receptor profile of adenomyosis lesions in comparison to correctly located endometrium?

Adenomyosis lesions exhibit increased oestrogen receptor (ER) expression compared to the eutopic endometrium; there are conflicting results regarding progesterone receptor (PR) expression and a lack of studies on androgen receptor (AR) expression.

Adenomyosis lesions express hormone receptors indicating an influence from ovarian steroid hormones. However, hormone treatments are often ineffective in controlling adenomyosis symptoms, which suggests alternate hormonal responses and, potentially, a distinct hormone receptor expression profile within adenomyosis lesions compared to the eutopic endometrium.

This systematic review with a thematic analysis retrieved studies from the PubMed, Ovid Medline, Embase, Scopus, and Cochrane Library databases, and searches were conducted from inception through to May 2024. Human studies were included and identified using a combination of exploded MeSH terms ('adenomyosis') and free-text search terms ('oestrogen receptor', 'progesterone receptor', 'androgen receptor', 'hormone receptor').

This review was reported in accordance with the PRISMA guidelines. All studies reporting original data concerning hormone receptors in adenomyosis lesions compared to eutopic endometrium in adenomyosis were included. Studies that did not report original data or provide a review of the field were excluded. Bias analysis was completed for each study using the Newcastle-Ottawa scoring system.

There were 1905 studies identified, which were screened to include 12 studies that met the eligibility criteria, including 11 proteomic studies and one transcriptional study, with a total of 555 individual participants. ER expression was consistently increased in adenomyosis lesions compared to the eutopic endometrium, specifically in the secretory phase. When endometrial subregion was considered, this difference was specific to the endometrial functionalis only. When different isoforms were considered, this increase in ER expression was specific to ERα rather than ERβ. There were conflicting results on PR expression, with most studies showing no significant difference or reduced levels in adenomyosis lesions compared to the eutopic endometrium. There is a paucity of data on AR expression in adenomyosis lesions, with only one study of small sample size included.

A high risk of bias arose from studies grouping endometrial samples across different menstrual cycle phases for analysis. The coexistence of gynecological conditions like endometriosis may also confound the hormone receptor profile of the eutopic endometrium. Most studies employing immunostaining did not comment on region-specific differences in the endometrium. Given the well-documented cyclical variations in hormone receptor expression within the endometrium, the need for more attention to region-specific differences represents a notable limitation in the current body of literature.

The systematic review highlights oestrogen dominance through elevated ERα levels in adenomyosis lesions, which agrees with the literature suggesting local hyper-oestrogenism in adenomyosis lesions. Heterogeneity in menstrual cycle timing and lack of endometrial region specificity prevent conclusions on progesterone resistance within adenomyosis lesions in this study. Future investigations should minimize the bias through well-defined cohorts, leading to robust exploration of hormone receptor profiles in adenomyosis lesions to identify therapeutic targets and deepen our understanding of adenomyosis pathogenesis.

This work was supported by Wellbeing of Women Research Project grants RG1073 and RG2137 (D.K.H.), a Wellbeing of Women Entry-Level Scholarship ELS706 and a Medical Research Council grant MR/V007238/1 (A.M. and D.K.H.), as well as the University of Liverpool (L.T.). There are no conflicts of interest.

The review protocol was published in the PROSPERO Register of Systematic Reviews on 27 September 2023, registration number CRD4202346.

Allergies are closely associated with sex-related hormonal variations that influence immune function, leading to distinct symptom profiles. Similar sex-based differences are observed in other immune disorders, such as autoimmune diseases. In allergies, women exhibit a higher prevalence of atopic conditions, such as allergic asthma and eczema, in comparison to men. However, age-related changes play a significant role because men have a higher incidence of allergies until puberty, and then comes a switch ratio of prevalence and severity in women. Investigations into the mechanisms of how the hormones influence the development of these diseases are crucial to understanding the molecular, cellular, and pathological aspects. Sex hormones control the reproductive system and have several immuno-modulatory effects affecting immune cells, including T and B cell development, antibody production, lymphoid organ size, and lymphocyte death. Moreover, studies have suggested that female sex hormones amplify memory immune responses, which may lead to an excessive immune response impacting the pathogenesis, airway hyperresponsiveness, inflammation of airways, and mucus production of allergic diseases. The evidence suggests that estrogens enhance immune humoral responses, autoimmunity, mast cell reactivity, and delayed IV allergic reactions, while androgens, progesterone, and glucocorticoids suppress them. This review explores the relationship between sex hormones and allergies, including epidemiological data, experimental findings, and insights from animal models. We discuss the general properties of these hormones, their effects on allergic processes, and clinical observations and therapeutic results. Finally, we describe hypersensitivity reactions to these hormones.

Endometriosis is a gynecologic condition characterized by the growth of endometrium-like stroma and glandular elements outside of the uterine cavity. The involvement of hormonal dysregulation, specifically estrogen, is well established in the initiation, progression, and maintenance of the condition. Evidence also highlights the association between endometriosis and altered immune states. The human endometrium is a highly dynamic tissue that undergoes frequent remodeling in response to hormonal regulation during the menstrual cycle. Similarly, endometriosis shares this propensity, compounded by unclear pathogenic mechanisms, presenting unique challenges in defining its etiology and pathology. Here, we provide a lens to understand the interplay between estrogen and innate and adaptive immune systems throughout the menstrual cycle in the pathogenesis of endometriosis. Estrogen is closely linked to many altered inflammatory and immunomodulatory states, affecting both tissue-resident and circulatory immune cells. This review summarizes estrogenic interactions with specific myeloid and lymphoid cells, highlighting their implications in the progression of endometriosis.

Sex-related differences characterize multiple sclerosis, an autoimmune, inflammatory and neurodegenerative disease displaying higher incidence in females as well as discrepancies in susceptibility and progression. Besides clinical specificities, molecular and cellular differences related to sex hormones were progressively uncovered improving our understanding of the mechanisms involved in this disabling disease. The most recent findings may give rise to the identification of novel therapeutic perspectives that could meet the urgent need for a treatment preventing the transition from the recurrent- to the progressive form of the disease. The present review is an update of our current knowledge about progestagens, androgens and estrogens in the context of CNS demyelination including their synthesis, the impact of their dysregulation, the preclinical and clinical data presently available, the main molecular dimorphisms related to these hormones and their age-related changes and relationship with failure of spontaneous remyelination, likely impacting the inexorable progression of multiple sclerosis towards irreversible disabilities.

Breast cancer (BC) is the most frequent female neoplasm worldwide. Its establishment and development have been related to inflammatory cytokine expression. Steroid hormones such as estradiol (E2) can regulate proinflammatory cytokine secretion through interaction with its nuclear receptors. However, little is known regarding the activation of its membrane estrogen receptor (GPER1) and the inflammatory cytokine environment in BC. We have studied the synthesis and biological effects of molecules analogs to E2 for hormone replacement therapy (HRT), such as pentolame. Nevertheless, its interaction with GPER1 and the modulation of inflammatory cytokines in different BC types has been barely studied and deserves deeper investigation. In this research, the role of GPER1 in the proliferation and modulation of inflammatory cytokines involved in carcinogenesis and metastatic processes in different BC cell lines was assessed by binding to various compounds. To achieve this goal, the presence of GPER1 was identified in different BC cell lines. Subsequently, cell proliferation after exposure to E2, pentolame and GPER1 agonist, G1, was subsequently determined alone or in combination with the GPER1 antagonist, G15. Finally, the pro-inflammatory cytokine secretion derived from the supernatants of BC cells exposed to the previous treatments was also assessed. Interestingly, GPER1 activation or inhibition has significant effects on the cytokine regulation associated with invasion in BC. Notably, pentolame did not induce cell proliferation or increase the proinflammatory cytokine expression compared to E2 in BC cell lines. In addition, pentolame did not induce the presence of the cell adhesion molecule PECAM-1. In contrast, E2 treatment weakly induced the expression of PECAM-1 in MCF-7 and HCC1937 cells, and G1 treatment showed this effect only in MCF-7 cells. The results suggest that GPER1 might be a significant inflammatory modulator with angiogenic-related effects in BC cells. In addition, pentolame might represent an HRT alternative in patients with BC predisposition.

G-protein-coupled receptors (GPCRs) are the largest family of cell receptors. They mediate the effects of a multitude of endogenous and exogenous cues, are deeply involved in human physiology and disease, and are major pharmacological targets. Whereas GPCRs were long thought to signal exclusively at the plasma membrane, research over the past 15 years has revealed that they also signal via classical G-protein-mediated pathways on membranes of intracellular organelles such as endosomes and the Golgi complex. This review provides an overview of recent advances and emerging concepts related to endomembrane GPCR signaling, as well as ongoing research aimed at a better understanding of its mechanisms, physiological relevance, and potential therapeutic applications.

To date five members of estrogen receptors (ESRs) have been reported. They are grouped into two classes, the nuclear estrogen receptors are members of the nuclear receptor family which found at nuclear, cytoplasm and plasma membrane, and the membrane estrogen receptors, such as G protein-coupled estrogen receptor 1, ESR-X and Gq-coupled membrane estrogen receptor. The structure and function of estrogen receptors, and interaction between ESR and coregulators were reviewed. In canonical pathway ESRs can translocate to the nucleus, bind to the target gene promotor with or without estrogen responsive element and regulate transcription, mediating the genomic effects of estrogen. Coactivators and corepressors are recruited to activate or inhibit transcription by activated ESRs. Many coactivators and corepressors are recruited to activate or inhibit ESR mediated gene transcription via different mechanisms. ESRs also indirectly bind to the promoter via interaction with other transcription factors, tethering the transcription factors. ESRs can be phosphorylated by several kinases such as p38, extracellular-signal-regulated kinase, and activated protein kinase B, and which activates transcription without ligand binding. Non-genomic estrogen action can be manifested by the increases of cytoplasmic NO and Ca2+ through the activation of membrane ESRs. In female, ESRs signaling is crucial for folliculogenesis, oocyte growth, ovulation, oviduct and uterus. In male, ESRs signaling modulates libido, erectile function, leydig cell steroidogenesis, sertoli cell's function, and epididymal fluid homeostatsis, supporting spermatogenesis and sperm maturation. The abnormal ESRs signaling is believed to be closely related to reproductive diseases and cancer.

Melanoma is the most aggressive and deadly form of skin cancer that arises from the transformation of melanocytes, the pigment producing cells of the skin. In the year 2024 there will be approximately 10,000 new cases of melanoma diagnosed and approximately 8,000 deaths attributed to melanoma in the United States. In this study we treated a group of male and female transgenic mice that spontaneously develop metastatic melanoma, TGS, with a G-protein-coupled estrogen receptor agonist LNS8801 to assess the efficacy on disease progression. A second group of male and female TGS mice was also exposed to UVB irradiation to mimic exposure to sunlight. Over the course of the 32-week experiment, visible images were taken by the small animal imaging IVIS system to track tumor progression, and blood and tissue samples were collected for molecular analyses. Results showed that sex-biased effects were observed in the efficacy of LNS8801 and that LNS8801 shows a UV-protective influence in both male and female TGS mice.

We aim to investigate whether chemical inhibition of NRF2 transcriptional activity (TA) influences distal colon contractions, particularly in an age-dependent manner in females, and whether it impacts oestrogen receptor signalling in female mice. This study was performed on 3 and 6-month-old female mice treated with ML385 (30 mg/kg) or a vehicle for 7 days (i.p.). The colon functionality was verified with a colon bead expulsion test; serum samples were collected for oestradiol levels, and colon samples were stored for various histological analyses. The results show that the seven-day treatment of ML385 significantly downregulated TA (p < 0.05) and impacted its contractility. Additionally, young females treated with ML385 exhibited an increase in goblet cell number and significantly increased ERα, but not ERβ, especially in older mice. It is worth noting that the basal level of the membrane oestrogen receptor GPR30 was higher in older mice within the epithelial layer, and ML385 treatment led to a downregulation of GPR30 in 6-month-old mice. In summary, ML385 decreases NRF2 TA in the colon and impacts its contractility and goblet cell numbers. Additionally, NRF2 TA influences the expression of oestrogen receptors in the colons of female mice.

Pulmonary arterial hypertension (PAH) is a fatal lung disease characterized by progressive pulmonary vascular remodeling. The initial cause of pulmonary vascular remodeling is the dysfunction of pulmonary arterial endothelial cells (PAECs), manifested by changes in the categorization of cell subtypes, endothelial programmed cell death, such as apoptosis, necroptosis, pyroptosis, ferroptosis, et al., overproliferation, senescence, metabolic reprogramming, endothelial-to-mesenchymal transition, mechanosensitivity, and regulation ability of peripheral cells. Therefore, it is essential to explore the mechanism of endothelial dysfunction in the context of PAH. This review aims to provide a comprehensive understanding of the molecular mechanisms underlying endothelial dysfunction in PAH. We highlight the developmental process of PAECs and changes in PAH and summarise the latest classification of endothelial dysfunction. Our review could offer valuable insights into potential novel EC-specific targets for preventing and treating PAH.

The conventional way steroid hormones work through receptors inside cells is widely acknowledged. There are unanswered questions about what happens to the hormone in the end and why there isn't always a strong connection between how much tissue takes up and its biological effects through receptor binding. Steroid hormones can also have non-traditional effects that happen quickly but don't involve entering the cell. Several possible mechanisms for these non-traditional actions include (a) changes in membrane fluidity, (b) steroid hormones acting on receptors on the outer surface of cells, (c) steroid hormones regulating GABAA receptors on cell membranes, and (d) activation of steroid receptors by factors like EGF, IGF-1, and dopamine. Data also suggests that steroid hormones may be inserted into DNA through receptors, acting as transcription factors. These proposed new mechanisms of action should not be seen as challenging the conventional mechanism. Instead, they contribute to a more comprehensive understanding of how hormones work, allowing for rapid, short-term, and prolonged effects to meet the body's physiological needs.

Sex hormones and their related receptors have been reported to impact the development and progression of tumors. However, their influence on the composition and function of the tumor microenvironment is not well understood. We aimed to investigate the influence of sex disparities on the proliferation and accumulation of macrophages, one of the major components of the tumor microenvironment, in hepatocellular carcinoma (HCC).

Immunohistochemistry was applied to assess the density of immune cells in HCC tissues. The role of sex hormone related signaling in macrophage proliferation was determined by immunofluorescence and flow cytometry. The underlying regulatory mechanisms were examined with both in vitro experiments and murine HCC models.

We found higher levels of macrophage proliferation and density in tumor tissues from male patients compared to females. The expression of G protein-coupled estrogen receptor 1 (GPER1), a non-classical estrogen receptor, was significantly decreased in proliferating macrophages, and was inversely correlated with macrophage proliferation in HCC tumors. Activation of GPER1 signaling with a selective agonist G-1 suppressed macrophage proliferation by downregulating the MEK/ERK pathway. Additionally, G-1 treatment reduced PD-L1 expression on macrophages and delayed tumor growth in mice. Moreover, patients with a higher percentage of GPER1+ macrophages exhibited longer overall survival and recurrence-free survival compared to those with a lower level.

These findings reveal a novel role of GPER1 signaling in regulating macrophage proliferation and function in HCC tumors and may offer a potential strategy for designing therapies based on understanding sex-related disparities of patients.

G protein-coupled receptors (GPCRs) have historically been associated with signalling events driven from the plasma membrane. More recently, signalling from endosomes has been recognized as a feature of internalizing receptors. However, there was little consideration given to the notion that GPCRs can be targeted to distinct subcellular locations that did not involve an initial trafficking to the cell surface. Here, we focus on the evidence for and the potential impact of GPCR signalling specifically initiated from the nuclear membrane. We also discuss the possibilities for selectively targeting this and other internal pools of receptors as novel venues for drug discovery.

HeLa cell transfection with plasmid DNA (pDNA) is widely used to materialize biologicals and as a preclinical test of nucleic acid-based vaccine efficacy. We sought to genetically encode mammalian transfection sensor (Trensor) circuits and test their utility in HeLa cells for detecting molecules and methods for their propensity to influence transfection. We intended these Trensor circuits to be triggered if their host cell was treated with polyplexed pDNA or certain small-molecule modulators of transfection. We prioritized three promoters, implicated by others in feedback responses as cells import and process foreign material and stably integrated each into the genomes of three different cell lines, each upstream of a green fluorescent protein (GFP) open reading frame within a transgene. All three Trensor circuits showed an increase in their GFP expression when their host HeLa cells were incubated with pDNA and the degraded polyamidoamine dendrimer reagent, SuperFect. We next experimentally demonstrated the modulation of PEI-mediated HeLa cell transient transfection by four different small molecules, with Trichostatin A (TSA) showing the greatest propensity to boost transgene expression. The Trensor circuit based on the TRA2B promoter (Trensor-T) was triggered by incubation with TSA alone and not the other three small molecules. These data suggest that mammalian reporter circuits could enable low-cost, high-throughput screening to identify novel transfection methods and reagents without the need to perform actual transfections requiring costly plasmids or expensive fluorescent labels.

Estrogens and HPV are necessary for cervical cancer (CC) development. The levels of the G protein-coupled estrogen receptor (GPER) increase as CC progresses, and HPV oncoproteins promote GPER expression. The role of this receptor is controversial due to its anti- and pro-tumor effects. This study aimed to determine the effect of GPER activation, using its agonist G-1, on the transcriptome, cell migration, and invasion in SiHa cells and non-tumorigenic keratinocytes transduced with the HPV16 E6 or E7 oncogenes.

Transcriptome analysis was performed to identify G-1-enriched pathways in SiHa cells. We evaluated cell migration, invasion, and the expression of associated proteins in SiHa, HaCaT-16E6, and HaCaT-16E7 cells using various assays.

Transcriptome analysis revealed pathways associated with proliferation/apoptosis (TNF-α signaling, UV radiation response, mitotic spindle formation, G2/M cell cycle, UPR, and IL-6/JAK/STAT), cellular metabolism (oxidative phosphorylation), and cell migration (angiogenesis, EMT, and TGF-α signaling) in SiHa cells. Key differentially expressed genes included PTGS2 (pro/antitumor), FOSL1, TNFRSF9, IL1B, DIO2, and PHLDA1 (antitumor), along with under-expressed genes with pro-tumor effects that may inhibit proliferation. Additionally, DKK1 overexpression suggested inhibition of cell migration. G-1 increased vimentin expression in SiHa cells and reduced it in HaCaT-16E6 and HaCaT-16E7 cells. However, G-1 did not affect α-SMA expression or cell migration in any of the cell lines but increased invasion in HaCaT-16E7 cells.

GPER is a promising prognostic marker due to its ability to activate apoptosis and inhibit proliferation without promoting migration/invasion in CC cells. G-1 could potentially be a tool in the treatment of this neoplasia.

Estrogen drives the growth of some cancers, such as breast cancer, via estrogen receptor alpha (ERα). Estrogen also activates ERβ, but whether ERβ is expressed and has a role in different cancers is debated. The use of nonspecific antibodies has contributed to the confusion, and this review delves into ERβ's controversial role in cancer and focuses on tumor expression that can be supported by non-antibody-dependent assays. We discuss its expression at the transcript level and focus on its potential role in lymphoma, granulosa cell tumors, testicular, and adrenal cancers, emphasizing recent findings and the complexities that necessitate further research.

This work examined the potential benefit of curcumin in breast cancer patients as a supplementary drug in ER-positive cancers. The results indicated that in the MCF-7 human breast cancer cell line, E2 and curcumin decreased cell proliferation and the colony-forming capacity and down-regulated protein expression as well as important molecules associated with cell proliferation, such as PCNA and estrogen receptor alpha; genes associated with the epithelial-mesenchymal transition, such as β-catenin, Vimentin, and E-cadherin; and molecules associated with apoptosis. Clinical studies in bioinformatics have indicated a positive correlation between ESR1 and either CCND1 or BCL2 gene expression in all breast cancer patients. Thus, curcumin could become a potential natural adjuvant treatment for patients with estrogen receptor alpha-positive breast cancer and those with resistance or a poor response to endocrine therapy since the reactivation of estrogen receptor alpha is inevitable.

Estrogen is a group of hormones that collaborate with the nervous system to impact the overall well-being of all genders. It influences many processes, including those occurring in the central nervous system, affecting learning and memory, and playing roles in neurodegenerative diseases and mental disorders. The hormone's action is mediated by specific receptors. Significant roles of classical estrogen receptors, ERα and ERβ, in various diseases were known since many years, but after identifying a structurally and locationally distinct receptor, the G protein-coupled estrogen receptor (GPER), its role in human physiology and pathophysiology was investigated. This review compiles GPER-related information, highlighting its impact on homeostasis and diseases, while putting special attention on functions and dysfunctions of this receptor in neurobiology and biobehavioral processes. Understanding the receptor modulation possibilities is essential for therapy, as disruptions in receptors can lead to diseases or disorders, irrespective of correct estrogen levels. We conclude that studies on the GPER receptor have the potential to develop therapies that regulate estrogen and positively impact human health.

Estrogen and related receptors have been shown to have a significant impact on human development, reproduction, metabolism and immune regulation and to play a critical role in tumor development and treatment. Traditionally, the nuclear estrogen receptors (nERs) ERα and ERβ have been thought to be involved in mediating the estrogenic effects. However, our group and others have previously demonstrated that the G protein-coupled estrogen receptor (GPER) is the third independent ER, and estrogen signaling mediated by GPER is known to play an important role in normal physiology and a variety of abnormal diseases. Interestingly, recent studies have progressively revealed GPER involvement in the maintenance of the normal immune system, abnormal immune diseases, and inflammatory lesions, which may be of significant clinical value primarily in the immunotherapy of tumors. In this article, we review current advances in GPER-related immunomodulators and provide a theoretical basis and potential clinical targets to ameliorate immune-related diseases and immunotherapy for tumors.