Search Results (301)

The abnormal growth of smooth muscle cells (SMCs) contributes to the vascular remodeling associated with coronary artery disease, a leading cause of death in women. Estradiol (E2) mediates cardiovascular protective actions, in part, by inhibiting the abnormal growth (proliferation and migration) of SMCs through various mechanism. Since microRNAs (miRNAs) play a major role in regulating cell growth and vascular remodeling, we hypothesize that miRNAs may mediate the protective actions of E2. Following preliminary leads from E2-regulated miRNAs, we found that platelet-derived growth factor (PDGF)-BB-induced miR-193a in SMCs is downregulated by E2 via estrogen receptor (ER)α, but not the ERβ or G-protein-coupled estrogen receptor (GPER). Importantly, miR-193a is actively involved in regulating SMC functions. The ectopic expression of miR-193a induced vascular SMC proliferation and migration, while its suppression with antimir abrogated PDGF-BB-induced growth, effects that were similar to E2. Importantly, the restoration of miR-193a abrogated the anti-mitogenic actions of E2 on PDGF-BB-induced growth, suggesting a key role of miR-193a in mediating the growth inhibitory actions of E2 in vascular SMCs. E2-abrogated PDGF-BB, but not miR-193a, induced SMC growth, suggesting that E2 blocks the PDGF-BB-induced miR-193a formation to mediate its anti-mitogenic actions. Interestingly, the PDGF-BB-induced miR-193a formation in SMCs was also abrogated by 2-methoxyestradiol (2ME), an endogenous E2 metabolite that inhibits SMC growth via an ER-independent mechanism. Furthermore, we found that miR-193a induces SMC growth by activating the phosphatidylinositol 3-kinases (PI3K)/Akt signaling pathway and promoting the G1 to S phase progression of the cell cycle, by inducing Cyclin D1, Cyclin Dependent Kinase 4 (CDK4), Cyclin E, and proliferating-cell-nuclear-antigen (PCNA) expression and Retinoblastoma-protein (RB) phosphorylation. Importantly, in mice, treatment with miR-193a antimir, but not its control, prevented cuff-induced vascular remodeling and significantly reducing the vessel-wall-to-lumen ratio in animal models. Taken together, our findings provide the first evidence that miR-193a promotes SMC proliferation and migration and may play a key role in PDGF-BB-induced vascular remodeling/occlusion. Importantly, E2 prevents PDGF-BB-induced SMC growth by downregulating miR-193a formation in SMCs. Since, miR-193a antimir prevents SMC growth as well as cuff-induced vascular remodeling, it may represent a promising therapeutic molecule against cardiovascular disease. Full article

Long-chain fatty acids (LCFAs) have emerged as important regulators of cancer metabolism, but their impact on hormone receptor expression in breast cancer (BCA) remains poorly understood. In this study, we investigated the effects of five LCFAs—linoleic acid (LA), oleic acid (OA), elaidic acid (EA), palmitic acid (PA), and α-linolenic acid (LNA)—on two BCA cell lines: luminal-type MCF7 and triple-negative MDA-MB-231 (MB231). All LCFAs suppressed cell viability and mitochondrial function in a dose-dependent manner, accompanied by decreased membrane potential, increased reactive oxygen species production, and a metabolic shift. Notably, OA reduced both mRNA and nuclear protein levels of estrogen receptor alpha (ERα) in MCF7 cells, leading to impaired responses to estradiol and tamoxifen. In contrast, PA induced nuclear ERα expression in MB231 cells, although ER signaling remained inactive. MicroRNA profiling revealed that OA upregulated ER-suppressive miR-22 and miR-221 in MCF7, while PA increased miR-34a in MB231, contributing to ERα induction. These findings suggest that specific LCFAs modulate ER expression through epigenetic and post-transcriptional mechanisms, altering hormonal responsiveness in BCA. Our results offer new insights into how dietary lipids may influence therapeutic efficacy and tumor behavior by regulating nuclear receptor signaling. Full article

Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. In addition to its two major pathological hallmarks, extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), recent evidence highlights the critical roles of mitochondrial dysfunction and neuroinflammation in disease progression. Aβ impairs mitochondrial function, which, in part, can subsequently trigger inflammatory cascades, creating a vicious cycle of neuronal damage. Estrogen receptors (ERs) are widely expressed throughout the brain, and the sex hormone 17β-estradiol (E2) exerts neuroprotection through both anti-inflammatory and mitochondrial mechanisms. While E2 exhibits neuroprotective properties, its mechanisms against Aβ toxicity remain incompletely understood. In this study, we investigated the neuroprotective effects of E2 against Aβ-induced mitochondrial dysfunction and neuroinflammation in primary cortical neurons, with a particular focus on the role of AMP-activated protein kinase (AMPK). We found that E2 treatment significantly increased phosphorylated AMPK and upregulated the expression of mitochondrial biogenesis regulator peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α), leading to improved mitochondrial respiration. In contrast, Aβ suppressed AMPK and PGC-1α signaling, impaired mitochondrial function, activated the pro-inflammatory nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and reduced neuronal viability. E2 pretreatment also rescued Aβ-induced mitochondrial dysfunction, suppressed NF-κB activation, and, importantly, prevented the decline in neuronal viability. However, the pharmacological inhibition of AMPK using Compound C (CC) abolished these protective effects, resulting in mitochondrial collapse, elevated inflammation, and cell death, highlighting AMPK’s critical role in mediating E2’s actions. Interestingly, while NF-κB inhibition using BAY 11-7082 partially restored mitochondrial respiration, it failed to prevent Aβ-induced cytotoxicity, suggesting that E2’s full neuroprotective effects rely on broader AMPK-dependent mechanisms beyond NF-κB suppression alone. Together, these findings establish AMPK as a key mediator of E2’s protective effects against Aβ-driven mitochondrial dysfunction and neuroinflammation, providing new insights into estrogen-based therapeutic strategies for AD. Full article

Pleomorphic invasive lobular carcinoma (PILC or PLC) is a malignant breast tumor considered a rare variant of invasive lobular carcinoma in women, characterized morphologically by marked nuclear pleomorphism, with cells resembling plasmacytoid, histiocytoid, or apocrine cells. One of its defining features is the loss of E-cadherin expression. Considering the biological similarities between species and the limited data available for female dogs, this study aimed to characterize PLC in canines, with an emphasis on its histopathological and immunophenotypic features and its potential applicability as a comparative model. Histopathological analysis of PLC was performed alongside immunohistochemical evaluation using HER2, estrogen receptors (ER), progesterone receptors (PR), E-cadherin, and Ki-67 (cell proliferation indexing) markers. All canine PLCs tested positive for PR, with the majority being negative for ER, and all were negative for HER2 and E-cadherin. In contrast, in women, all cases were positive for ER, most were positive for PR, and all were negative for HER2. The Luminal B molecular subtype was the most frequent in dogs, whereas Luminal A and Luminal B subtypes showed equal prevalence in women. These findings reveal shared and distinct immunophenotypic features between species. The similarities and differences observed emphasize the relevance of the canine model for comparative oncology. Furthermore, the use of spontaneous tumors in immunocompetent dogs in this study strengthens the translational potential of the findings, thereby reinforcing the use of the canine model in breast cancer research and supporting its role within the One Medicine concept. Full article

Background: Premenstrual syndrome is characterized by emotional changes, including anxiety and depression symptoms, which may be treated with anxiolytic and antidepressant drugs, as well as estrogen therapy. However, steroidal estrogen therapy is contraindicated for patients with a potential risk of developing estrogen-dependent cancers through interactions with estrogen receptor α (ERα). Alternatively, genistein produces estrogenic effects in animals and humans at dietary dosages that act on the nuclear and membrane ERα, estrogen receptor β (ERβ), and the G-protein-coupled estrogen receptor (GPER). These receptors are likely involved in the anxiety symptoms observed in premenstrual disorders. The objective of this study was to evaluate the effects of genistein and 17β-estradiol on anxiety-like behavior and the plasma concentrations of estradiol and progesterone throughout the ovarian cycle of Wistar rats. Methods: The effect of the administration of 0.09 mg/kg of genistein or 17β-estradiol was evaluated using the elevated plus maze (EPM) test, locomotor activity test (LAT), and light/dark box (LDB) test, as well as by assessing the plasma concentrations of estradiol and progesterone, while considering the ovarian cycle phases. Results: Higher levels of anxiety-like behavior were detected in the metestrus–diestrus phase compared to the proestrus–estrus phase, which was associated with low concentrations of estradiol. Genistein, similarly to 17β-estradiol, significantly reduced anxiety-like behaviors in the EPM and LDB; however, 17β-estradiol, but not genistein, significantly increased the plasma estradiol concentration. No significant changes were found in locomotor activity or the plasma progesterone concentrations due to the treatments. Conclusions: These findings suggest that genistein may be useful in the development of alternative therapies to reduce the anxiety associated with low steroid hormone concentrations, which occur in premenstrual syndrome. Genistein could be an alternative to steroidal estrogen therapy to avoid potential side effects due to estradiol or antidepressant treatments, although it still requires medical care. Full article

Background/Objectives: Gelsolin (GSN) is an actin-binding protein that helps maintain neuronal structure and shape, regulates neuronal growth, and apoptosis. Our previous work demonstrated that GSN associated with estrogen receptor beta (ERβ1) in the brains of female rats, but this association was lost in advanced age. GSN was also required for ERβ1-mediated transcriptional repression at activator protein-1 (AP-1) motifs upstream of a minimal gene promoter. However, the consequences of the loss of GSN:ERβ1 protein interaction on ERβ1 nuclear translocation and transcriptional repression at AP-1 sites located within complex endogenous gene promoters remained unclear. Methods: We used immunofluorescent super resolution microscopy and luciferase reporter assays to test the hypothesis that GSN facilitates ERβ1 nuclear translocation and transcriptional repression of two genes relevant for Alzheimer Disease: APP (amyloid-beta precursor protein) and ITPKB (inositol-1,4,5-trisphosphate 3-kinase B). Results: Our results revealed the novel finding that GSN is required for ERβ1 ligand-independent nuclear translocation in neuronal cells. Moreover, we show that GSN increased APP and ITPKB promoter activity, which was repressed by ERβ1. Conclusions: Together, these data revealed the importance of the cytoskeletal protein, GSN, in regulating intracellular trafficking of nuclear receptors and demonstrate the first evidence of ERβ1 directly regulating two genes that are implicated in the progression of AD. Full article

Estrogen-related receptors (ERRs) are important transcription factors within the nuclear receptor family that regulate cellular energy storage and consumption by binding to estrogen-related receptor response elements (ERREs) on gene promoters. While ERRs’ role in vertebrates is well-studied, their molecular mechanisms in insect metabolism and development remain unclear. This study systematically summarizes the functions of ERRs in insects, focusing on silkworms by analyzing gene functions and comparing databases. ERRE-like elements were identified in the 2000 bp upstream promoter regions of 69 metabolism-related silkworm genes. Furthermore, electrophoretic mobility shift assays (EMSAs) revealed that ERREs within the promoters of 15 genes related to sugar, fat, and protein metabolism specifically bind to ERR. Notably, an ERRE in the promoter of the trehalose transporter 1 gene (BmTret1), crucial for trehalose homeostasis in insect hemolymph, exhibited significantly enhanced activity in ERR-overexpressing cells. These findings suggest that ERR is a potential regulatory factor in silkworm metabolism and refine its metabolic regulatory network. This study highlights the broader and more critical role of ERR in insects than that previously recognized, contributing to a deeper understanding of insect metabolism and its potential applications in related fields. Full article

Background and Objectives: Osteoporosis is a common chronic condition after menopause that increases the risk of fractures. In South Korea, the prevalence of osteoporosis among adults aged 50 and older is 22.4%, with 94.4% of treated patients being women, highlighting its significant impact on postmenopausal health. In this study, we examine the sales trends of osteoporosis medications in Korea from 2018 to 2023 to understand current usage patterns and market dynamics. Materials and Methods: This study is a retrospective analysis based on pre-recorded sales data from Intercontinental Marketing Services (IMS). Data covering a five-year period (2018–2023) were analyzed to examine the sales trends of osteoporosis medications, including bisphosphonates, selective estrogen receptor modulators (SERMs), parathyroid hormone analogs, denosumab, romosozumab, and others. Romosozumab, approved in November 2019, was included in the analysis. Given the nature of this study, no direct patient data or clinical interventions were involved. Results: The total market size for osteoporosis medications in South Korea reached USD 285.42 million in 2023, reflecting a 15.3% increase from 2022. Bisphosphonates, previously the dominant therapy, experienced an 11% decline in market share over five years. Meanwhile, denosumab, a receptor activator of the nuclear factor-κB ligand inhibitor, showed a remarkable growth rate of 957.6% from 2018 to 2023, surpassing bisphosphonates in their market share. Romosozumab, a newly introduced anabolic agent, accounted for 7.4% of the market, with sales increasing by 59% in 2023. Conclusions: This analysis revealed major shifts in treatment preferences, with newer drugs like denosumab and romosozumab gaining prominence over traditional bisphosphonates. These trends highlight the increasing clinical adoption of anabolic agents for high-risk patients and the impact of expanded reimbursement policies on osteoporosis management. Given the increasing use of advanced therapies, it is essential to monitor treatment access, patient adherence, and long-term clinical outcomes. Understanding these sales trends can aid healthcare professionals and policymakers in optimizing osteoporosis treatment strategies and ensuring better patient care. Full article

Background/Objectives: Breast cancer is the most prevalent cancer in adult women. Currently, new therapies and protein determinations with prognostic value are under development. Fascin (encoded by the FSCN1 gene) is an actin-binding protein that is critical for the development of cytoplasmic projections that are essential for tumor invasion. DNA topoisomerase 2-alpha (TOP2A) is a nuclear protein crucial for ATP-dependent breakage, passage, and rejoining of double-stranded DNA and cell division. Both proteins are associated with higher proliferation rates and worse prognosis in breast cancer and together can provide comprehensive information on prognosis and treatment response. Methods: We simultaneously assessed fascin expression and TOP2A/CEP17 DNA copy number ratios in various histological and molecular subtypes. Additionally, these markers were analyzed along with previously established diagnostic markers and other relevant clinical data. Results: Our series included 265 patients, four of whom were male, and all of which were diagnosed with breast carcinoma. Of the 265 patients initially included, sufficient material for analysis was available for 175 cases, as some samples were excluded because of insufficient tissue quantity, poor preservation, or lack of hybridization in certain assays. Immunohistochemical (IHC) expression of fascin, both in its aggregated form and by category, showed no association with the TOP2A gene alteration ratio. Fascin expression was significantly associated with histological subtype (p < 0.001), molecular subtype (p < 0.001), hormone receptor (HR) (p < 0.001), BCL2 (p = 0.003), Ki67 (p = 0.002), and histological grade (p < 0.001). TOP2A was significantly associated with molecular subtype (p = 0.041), Ki67 (p = 0.048), and histological grade (p = 0.033). In our study, molecular subtype (p = 0.037) emerged as an independent variable for the complete histological response to neoadjuvant treatment. Multivariate analysis linked pathological stage (p = 0.002) and estrogen receptor (ER) expression (p = 0.004) to overall survival (OS) and disease-free survival (DFS). Conclusions: No statistical relationship was evident between fascin expression (IHC) and the TOP2A copy ratio. The results of this study suggested that the mechanisms of increased cell proliferation associated with alterations in fascin and TOP2A are independent. Full article

Sex steroids and the neurotrophin brain-derived neurotrophic factor (BDNF) participate in neural tissue formation, phenotypic differentiation, and neuroplasticity. These processes are essential for the health and maintenance of the central nervous system. Aim: The aim of our review is to elucidate the interaction mechanisms between BDNF and sex steroids in neuronal function. Method: A series of searches were performed using Mesh terms for androgen/receptors, estrogen/receptors, and BDNF/receptors, and a collection of the scientific data available on PubMed up to February 2025 about mechanical interactions between BDNF and sex steroids was included in this literature review. Discussion: This review discussed the influence of sex steroids on the formation and/or maintenance of neural circuits via different mechanisms, including the regulation of BDNF expression and signaling. Estrogens exert a time- and region-specific effect on BDNF synthesis. The nuclear estrogen receptor can directly regulate BDNF expression, independently of the presence of estrogen, in neuronal cells, whereas progesterone and testosterone upregulate BDNF expression via their specific nuclear receptors. In addition, testosterone has a positive effect on BDNF release by glial cells, which lack androgen receptors. Full article

Medicinal plants and natural compounds have been considered alternative therapeutic options for counteracting postmenopausal disorders thanks to their different concomitant effects, including antioxidant and anti-inflammatory properties and the regulation of hormone activity. It is important to highlight that the efficacy of medicinal plants and natural compounds increases when used in combination, thus making the development of herbal formulations rational. Therefore, the present study aimed to evaluate the phytochemical and pharmacological properties of an innovative formulation consisting of resveratrol and water extracts from Equisetum arvense, Crateagus curvisepala, Vitex agnus-castus, and Glycine max. The phenolic composition and radical scavenger properties were evaluated using chromatographic and colorimetric (ABTS) methods, whilst the limits of biocompatibility were assessed through allelopathy, the Artemia salina (brine shrimp) lethality test, and Daphnia magna cardiotoxicity assay. The protective effects were evaluated on C2C12 cell lines exposed to the pro-oxidant stimulus, which consisted of hydrogen peroxide. The gene expression of estrogen 1 (ESR1, also known as ERα) and prolactin (PRLR) receptors, interleukin 6 (IL-6), tumor necrosis factor α (TNFα), and receptor activator of nuclear factor kappa-Β ligand (RANKL) was measured. The results of the phytochemical analysis showed that the main phytochemicals were hydroxycinnamic and phenolic acids, in particular coumaric acid (7.53 µg/mL) and rosmarinic acid (6.91 µg/mL), respectively. This could explain the radical scavenger effect observed from the 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay. According to the ecotoxicological models’ results, the formulation was revealed to be non-toxic, with a LC₅₀ value > 1 mg/mL. Therefore, a biocompatible concentration range (200–1000 µg/mL) was used in C2C12 cells, where the formulation blunted the hydrogen peroxide-induced upregulation of TNFα, IL-6, RANKL, ESR1, and PRLR. Overall, the results of this study corroborate the use of the formulation for facing the oxidative stress and inflammation, which forms the basis of the osteoclastogenic process. Full article

Background/Objectives: In 2022, approximately 2.3 million women were diagnosed with breast cancer worldwide, resulting in 670,000 deaths, which accounted for 6.9% of all cancer-related deaths. In the United States, 1 in 8 women will be diagnosed with breast cancer during their lifetime. It was estimated that 2024 would identify about 310,720 women and 2800 men diagnosed with invasive breast cancer. The future global burden of breast cancer is projected to rise to over 3 million new cases and 1 million deaths by 2040. Approximately 20% of breast cancer diagnoses are triple-negative breast cancer (TNBC), a type of cancer that lacks receptors for estrogen (ER-negative), progesterone (PR-negative), and human epidermal growth factor receptor 2 (HER2/neu-negative). Consequently, TNBC does not respond to hormonal or targeted therapies, making it challenging to treat due to its rapid growth, metastasis, and high recurrence rate within the first three years of therapy. Alternative chemotherapies are needed to address this problem. A pharmacological dose of vitamin C (high-dose VC) has been identified as a potential treatment for some cancer cells. The present study aimed to evaluate whether VC has a therapeutic effect on TNBC, using MDA-MB-231 cells as the model. Additionally, VC’s effects were trialed on other cancer cells such as MCF7 and on non-cancerous kidney HEK 293 and lung CCL205 cells. Methods: The MTT assay, Hoechst 33342 staining, nuclear-ID red/green staining, Rhodamine 123 staining, and Western blot analysis were employed to test the hypothesis that a pharmacological dose of VC can kill TNBC cells. Results: The upregulation of Apaf-1 and caspases -7, -8, and -9, the inhibition of matrix metalloproteinases (MMP-2 and MMP-9), a reduction in cell cycle protein expression, and the enhancement of tumor suppressor proteins such as p53 and p21 indicate that a pharmacological dose of VC has promising anti-cancer properties in the treatment of breast cancers. Conclusions: Pharmacological dose of VC exerts significant anti-cancer effects in MDA-MB-231 cells by promoting apoptosis, inhibiting metastasis, disrupting cell cycle progression, and enhancing tumor suppressor activity. Full article

Breast cancer (BC) is the most common cancer in women, and a higher level of prolactin-induced protein (PIP) is associated with better responses to adjuvant chemotherapy. The signal transducer and activator of transcription 5 (STAT5) is a potential regulator of the PIP gene. Prolactin (PRL) and its receptor (PRLR) activate JAK2/STAT5 signaling in BC, which is modulated by inhibitors like suppressors of cytokine signaling (SOCS) proteins and protein inhibitors of activated STAT (PIAS). Using real-time PCR and immunohistochemistry, we studied the relationship between PIP and STAT5 inhibitors in BC. Our findings indicated that PIP and STAT5 levels decrease with a higher tumor grade, size, and tumor/nodes/metastasis (TNM) clinical stage, while nuclear PIAS3 levels increase with tumor progression. Both STAT inhibitors are linked to estrogen and progesterone receptor status. Notably, STAT5 correlates positively with PIP, SOCS3, and PIAS3, suggesting that it may be a favorable prognostic factor. Among the STAT inhibitors, only nuclear PIAS3 expression correlates with PIP. In vitro studies indicated that silencing PIAS3 in T47D cells does not affect PIP expression or sensitivity to doxorubicin (DOX), but T47D control cells with a higher PIP expression are more sensitive to DOX, highlighting the need for further investigation into these mechanisms. Full article

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate a broad array of biological processes, including inflammation, lipid metabolism, cell proliferation, and apoptosis. Among the diverse family of NRs, peroxisome proliferator-activated receptors (PPARs), estrogen receptor (ER), liver X receptor (LXR), farnesoid X receptor (FXR), retinoid X receptor (RXR), and aryl hydrocarbon receptor (AhR) have garnered significant attention for their roles in neurodegenerative diseases, particularly Alzheimer’s disease (AD). NRs influence the pathophysiology of AD through mechanisms such as modulation of amyloid-beta (Aβ) deposition, regulation of inflammatory pathways, and improvement of neuronal function. However, the dual role of NRs in AD progression, where some receptors may exacerbate the disease while others offer therapeutic potential, presents a critical challenge for their application in AD treatment. This review explores the functional diversity of NRs, highlighting their involvement in AD-related processes and discussing the therapeutic prospects of NR-targeting strategies. Furthermore, the key challenges, including the necessity for the precise identification of beneficial NRs, detailed structural analysis through molecular dynamics simulations, and further investigation of NR mechanisms in AD, such as tau pathology and autophagy, are also discussed. Collectively, continued research is essential to clarify the role of NRs in AD, ultimately facilitating their potential use in the diagnosis, prevention, and treatment of AD. Full article

Evidence indicates a bidirectional link between depressive symptoms and neuroinflammation. This study evaluated chronic cannabidiol (CBD) treatment effects in male and female rats subjected to the unpredictable chronic mild stress (UCMS) model of depression. We analyzed the gene expression related to neuroinflammation, cannabinoid signaling, estrogen receptors, and specific microRNAs in the ventromedial prefrontal cortex (vmPFC), CA1, and ventral subiculum (VS). UCMS influenced immobility in a sex-specific manner, increasing it in males and decreasing it in females, effects that were reversed by CBD. CBD also normalized the UCMS-induced upregulation of tumor necrosis factor α (TNF-α) in the CA1 and VS in males. In both sexes, UCMS induced the upregulation of the nuclear factor kappa B subunit 1 (NF-κB1) gene in the VS, which was unaffected by CBD. Additionally, CBD reversed CB1 downregulation in the VS of males but not in the vmPFC of either sex. In males, CBD restored the UCMS-induced downregulation of VS estrogen receptor genes ERα and ERβ. UCMS also altered miR-146a-5p expression, downregulating it in females (VS) and upregulating it in males (CA1), with no CBD effect. These findings highlight the sex-specific mechanisms of CBD’s antidepressant effect, with hippocampal neuroinflammatory and estrogenic pathways playing a key role in males. Full article