Search Results (58)

Background/Objectives: Breast cancer was the leading cause of malignant tumors among women in 2022. About two-thirds of breast cancer cases are hormone-receptor-positive. In these patients, aromatase inhibitors are a mainstay of treatment, but associated musculoskeletal symptoms can negatively affect patient compliance. Aromatase-inhibitor-induced carpal tunnel syndrome represents one of the main causes of aromatase inhibitor discontinuation, with a non-compliance rate of up to 67%, potentially leading to increased cancer mortality. This study investigates estrogen receptor expression in aromatase-inhibitor-induced carpal tunnel syndrome tissues, in order to better define its etiopathogenesis and derive preventive or therapeutic measures that can improve aromatase inhibitor patient compliance. To our knowledge, there is no study on this subject in the literature. Methods: Between 2023 and 2024, we recruited 14 patients at the Jewish Hospital of Rome, including seven patients with aromatase-inhibitor-induced carpal tunnel syndrome (study group) and seven with postmenopausal idiopathic carpal tunnel syndrome (control group). Each patient was evaluated based on a clinical visit, a questionnaire, instrumental exams, and serum hormone dosages and were treated with open carpal tunnel release surgery, during which transverse carpal ligament and flexor tenosynovium samples were collected. For immunohistochemical experiments, sections were treated with anti-estrogen receptor α and anti-estrogen receptor β antibodies. Results: The immunohistochemical features in the study and control groups were similar, demonstrating that tissues affected by aromatase-inhibitor-induced carpal tunnel syndrome are targets of direct estrogen action and that estrogen deprivation is correlated with disease etiogenesis. Surgery was effective in patient treatment. Conclusions: Aromatase-inhibitor-induced carpal tunnel syndrome represents a newly defined form of the disease. This syndrome represents one of the main causes of aromatase inhibitor discontinuation, due to its negative impact on the patient’s quality of life. The identification by clinicians of aromatase inhibitor use as a possible risk factor for carpal tunnel syndrome development is of essential importance, as early diagnosis and prompt management can improve patient compliance and overall breast cancer treatment outcomes. Full article

Aim of the study: Traditional Chinese herbs have a unique therapeutic effect on stroke and numerous successful clinical cases. However, these clinical cases are highly dispersed, creating challenges for translational research. This study employs a new paradigm to identify treatment patterns and the active compound interactions contained within these clinical cases, with experimental validation after target screening. Methods and Materials: Stroke-related targets were identified through GEO, DisGeNET, and Genecards. Active ingredients were extracted from BATMAN-TCM 2.0. All herbs and diseases were confirmed by the Pharmacopoeia of the People’s Republic of China (2020 edition) and Medical Subject Heading (MeSH). All networks in this study were constructed by Cytoscape, and data analysis was done by Python. All formulations and herbs were retrieved from the literature review. For the molecular docking process, Autodock was applied as the docking platform, and all the protein structures were downloaded from PDB. For experimental validation after target screening, HT22 cells were incubated with glucose-free DMEM and placed in an anaerobic chamber for 2 h. Subsequently, HT22 cells were reoxygenated for 24 h. Estrogen Receptor 1 (ESR1) protein levels were measured in vitro. Results: seven materials, including Angelicae Sinensis Radix, Pheretima, Chuanxiong Rhizoma, Persicae Semen, Astragali Radix, Carthami Flos, and Radix Paeoniae Rubra, were identified as the core herbs for the treatment of stroke. The targets of the stroke mechanism were screened, and the herbs-compound-target network was constructed. Among them, paeoniflorin (PF) was identified as the core active compound, and its interaction with ESR1 was verified by molecular docking as the key interaction for the treatment of stroke. In vitro experiments showed that PF inhibited cell apoptosis under hypoxia by increasing the expression of ESR1 compared with the oxygen-glucose deprivation-reperfusion (OGD/R) model group. Western showed that PF (100 μM, 200 μM) can significantly increase the decreased ESR1 protein level caused by the OGD/R model. Conclusions: seven key herbs were screened. Further bioinformatics and network pharmacology studies suggested that PF is expected to become a new active compound for the treatment of stroke. In vitro validation further demonstrated that PF enhanced neuronal survival and ESR1 expression under ischemic conditions, supporting its therapeutic candidacy. Full article

Background: Standard treatment for patients with early-stage estrogen receptor-positive (ER+) breast cancer often includes sequential adjuvant radiation and endocrine therapies. Unfortunately, ~1/3 of patients eventually experience disease recurrence, partly due to residual disease in the form of drug-tolerant persister cancer cells. The anti-cancer efficacy of radiation therapy is partly attributable to the production of oxyradicals that damage biomolecules. We previously showed that endocrine therapy increases mitochondrial content in ER+ breast cancer cells; we postulated that this may also increase oxidative stress. Methods: Herein, we tested the efficacy of concurrent endocrine and radiation therapies, including both conventional (CDR) and ultra-high dose rate (UHDR) radiation. Results: We found that estrogen deprivation and radiation inhibit cell growth, induce apoptosis, and force cells into an oxidatively stressed state. DNA damage was almost exclusive to cells treated with the combination of endocrine and radiation therapy. Radiation slowed tumor growth in two xenograft models, and combination with estrogen deprivation prolonged the time to regrowth in ZR75-1 tumors. Conclusions: These findings indicate that simultaneous treatment with endocrine and radiation therapies can be advantageous, warranting further evaluation to identify tumor features predictive of response to individual and combination treatments. Full article

Sleep deprivation is a prevalent issue that disrupts the circadian rhythm of estrogen, particularly estradiol, thereby significantly affecting women’s skin health and appearance. These disruptions can impair skin barrier functionality and decrease dermal collagen synthesis. In this study, our results demonstrate that topical taurine supplementation promotes the expression of tight junction (TJ)-related proteins and enhances collagen production, effectively restoring skin homeostasis in sleep-deprived female mice. Mechanistically, taurine upregulates the expression of TMEM38B, a gene encoding the TRIC-B trimeric cation channel, resulting in increased intracellular calcium ion levels. This, in turn, promotes the upregulation of TJ-related proteins, such as ZO-1, occludin, and claudin-11 in epidermal cells, while also enhancing the expression of type III collagen in fibroblasts, thus restoring skin homeostasis. These findings suggest that taurine may serve as an alternative to estradiol, effectively improving skin homeostasis disrupted by sleep deprivation while mitigating the potential risks associated with exogenous estrogen supplementation. Collectively, these results provide preliminary insights into the protective mechanisms of taurine against sleep deprivation-induced skin impairments and establish a foundation for its potential application in treating skin conditions related to estrogen imbalances, such as skin aging in menopausal women. Full article

Perinatal asphyxia (PA) is a clinical condition characterized by oxygen supply suspension before, during, or immediately after birth, and it is an important risk factor for neurodevelopmental damage. Its estimated 1/1000 live births incidence in developed countries rises to 5–10-fold in developing countries. Schizophrenia, cerebral palsy, mental retardation, epilepsy, blindness, and others are among the highly disabling chronic pathologies associated with PA. However, so far, there is no effective therapy to neutralize or reduce PA-induced harm. Selective regulators of estrogen activity in tissues and selective estrogen receptor modulators like raloxifene have shown neuroprotective activity in different pathological scenarios. Their effect on PA is yet unknown. The purpose of this paper is to examine whether raloxifene showed neuroprotection in an oxygen–glucose deprivation/reoxygenation astrocyte cell model. To study this issue, T98G cells in culture were treated with a glucose-free DMEM medium and incubated at 37 °C in a hypoxia chamber with 1% O₂ for 3, 6, 12, and 24 h. Cultures were supplemented with raloxifene 10, and 100 nM during both glucose and oxygen deprivation and reoxygenation periods. Raloxifene 100 nM and 10 nM improved cell survival—65.34% and 70.56%, respectively, compared with the control cell groups. Mitochondrial membrane potential was preserved by 58.9% 10 nM raloxifene and 81.57% 100 nM raloxifene cotreatment. Raloxifene co-treatment reduced superoxide production by 72.72% and peroxide production by 57%. Mitochondrial mass was preserved by 47.4%, 75.5%, and 89% in T98G cells exposed to 6-h oxygen–glucose deprivation followed by 3, 6, and 9 h of reoxygenation, respectively. Therefore, raloxifene improved cell survival and mitochondrial membrane potential and reduced lipid peroxidation and reactive oxygen species (ROS) production, suggesting a direct effect on mitochondria. In this study, raloxifene protected oxygen–glucose-deprived astrocyte cells, used to mimic hypoxic–ischemic brain injury. Two examiners performed the qualitative assessment in a double-blind fashion. Full article

This review focuses on the pivotal roles of nuclear receptors (NRs) in driving endocrine resistance in prostate and breast cancers. In prostate cancer (PCa), androgen receptor (AR) amplification, mutations, and altered coactivator interactions sustain tumor growth under androgen deprivation therapy (ADT), leading to castration-resistant prostate cancer (CRPC). Orphan NRs like RORβ, TLX, and COUP-TFII further contribute to CRPC by regulating stemness and therapeutic resistance mechanisms. In breast cancer, NRs, including estrogen receptor alpha (ERα), androgen receptor (AR), glucocorticoid receptor (GR), and liver receptor homolog-1 (LRH-1), modulate estrogen signaling pathways and alternative survival mechanisms like PI3K/AKT/mTOR and NFκB, promoting resistance to endocrine therapies such as tamoxifen. Understanding these NR-mediated mechanisms is critical for developing targeted therapies to overcome endocrine resistance and improve patient outcomes in hormone-dependent cancers. Full article

Background: The co-treatment of androgen deprivation therapy (ADT) for advanced prostate cancer (PCa) with the fetal estrogen estetrol (E4) may further inhibit endocrine PCa tumor stimulators. We previously reported the suppression of follicle-stimulating hormone (FSH), total and free testosterone, and prostate-specific antigen by ADT+E4. Here, we provide more detailed data on FSH suppression by E4 and present new findings on the effect of ADT+E4 on insulin-like growth factor-1 (IGF-1). Methods: A Phase II, double-blind, randomized, placebo-controlled study (the PCombi study) was conducted in advanced PCa patients treated with ADT. The study assessed the effect of E4 co-treatment with LHRH agonist ADT on tumor stimulators, including FSH and IGF-1. Patients starting ADT were randomized 2:1 to receive either 40 mg E4 (n = 41) or placebo (n = 21) for 24 weeks. Non-parametric analyses were performed on the per-protocol population (PP) and individual changes were visualized. Results: The PP included 57 patients (37 ADT+E4; 20 ADT+placebo). ADT+E4 almost completely suppressed FSH in all patients (98% versus 37%; p < 0.0001). IGF-1 levels decreased by 41% with ADT+E4 versus an increase of 10% with ADT+placebo (p < 0.0001). Conclusions: The almost complete suppression of the tumor stimulator FSH using ADT plus E4 observed in all individual patients in this study, along with the augmented suppression of IGF-1 versus an increase by ADT only, may be clinically relevant and suggest the enhanced anti-cancer treatment efficacy of E4 in addition to the previously reported additional suppression of total and free T and PSA. Full article

Osteoporosis is a bone-debilitating disease, demonstrating a higher prevalence in post-menopausal women due to estrogen deprivation. One of the main mechanisms underlying menopause-related bone loss is oxidative stress. S-allylmercapto-N-acetylcysteine (ASSNAC) is a nuclear factor erythroid 2-related factor 2 (Nrf2) activator and cysteine supplier, previously shown to have anti-oxidation protective effects in cultured cells and animal models. Here, we studied the therapeutic potential of ASSNAC with and without Alendronate in ovariectomized (OVX) female mice. The experimental outcome included (i) femur and L3 lumbar vertebra morphometry via Micro-Computed Tomography (μCT); (ii) bone remodeling (formation vs. resorption); and (iii) oxidative stress markers in bone marrow (BM) cells. Four weeks after OVX, there was a significant bone loss that remained evident after 8 weeks, as demonstrated via µCT in the femur (cortical and trabecular bone compartments) and vertebra (trabecular bone). ASSNAC at a dose of 50 mg/Kg/day prevented bone loss after the four-week treatment but had no significant effect after 8 weeks, while ASSNAC at a dose of 20 mg/Kg/day significantly protected against bone loss after 8 weeks of treatment. Alendronate prevented ovariectomy-induced bone loss, and combining it with ASSNAC further augmented this effect. OVX mice demonstrated high serum levels of both C-terminal cross-linked telopeptides of type I collagen (CTX) (bone resorption) and procollagen I N-terminal propeptide (P1NP) (bone formation) after 2 weeks, and these returned to control levels after 8 weeks. Alendronate, ASSNAC and their combination decreased CTX and increased P1NP. Alendronate induced oxidative stress as reflected by decreased glutathione and increased malondialdehyde (MDA) levels, and combining it with ASSNAC partially attenuated these changes. These results portray the therapeutic potential of ASSNAC for the management of post-menopausal osteoporosis. Furthermore, ASSNAC ameliorates the Alendronate-associated oxidative stress, suggesting its potential to prevent Alendronate side effects as well as improve its bone-protective effect. Full article

Background: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity. Methods: All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan–Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS). Results: Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8–6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively. Conclusion: Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients. Full article

Perimenopausal depression, occurring shortly before or after menopause, is characterized by symptoms such as emotional depression, anxiety, and stress, often accompanied by endocrine dysfunction, particularly hypogonadism and senescence. Current treatments for perimenopausal depression primarily provide symptomatic relief but often come with undesirable side effects. The development of agents targeting the specific pathologies of perimenopausal depression has been relatively slow. The erratic fluctuations in estrogen and progesterone levels during the perimenopausal stage expose women to the risk of developing perimenopausal-associated depression. These hormonal changes trigger the production of proinflammatory mediators and induce oxidative stress, leading to progressive neuronal damage. This review serves as a comprehensive overview of the underlying mechanisms contributing to perimenopausal depression. It aims to shed light on the complex relationship between perimenopausal hormones, neurotransmitters, brain-derived neurotrophic factors, chronic inflammation, oxidative stress, and perimenopausal depression. By summarizing the intricate interplay between hormonal fluctuations, neurotransmitter activity, brain-derived neurotrophic factors, chronic inflammation, oxidative stress, and perimenopausal depression, this review aims to stimulate further research in this field. The hope is that an increased understanding of these mechanisms will pave the way for the development of more effective therapeutic targets, ultimately reducing the risk of depression during the menopausal stage for the betterment of psychological wellbeing. Full article

Aging in women is accompanied by a dramatic change in circulating sex steroid hormones. Specifically, the primary circulating estrogen, 17β-estradiol (E₂), is nearly undetectable in post-menopausal women. This decline is associated with a variety of cognitive and mood disorders, yet hormone replacement therapy is only effective within a narrow window of time surrounding the menopausal transition. Our previous work identified microRNAs as a potential molecular substrate underlying the change in E₂ efficacy associated with menopause in advanced age. Specifically, we showed that E₂ regulated a small subset of mature miRNAs in the aging female brain. In this study, we hypothesized that E₂ regulates the stability of mature miRNAs by altering their subcellular localization and their association with argonaute proteins. We also tested the hypothesis that the RNA binding protein, hnRNP A1, was an important regulator of mature miR-9-5p expression in neuronal cells. Our results demonstrated that E₂ treatment affected miRNA subcellular localization and its association with argonaute proteins differently, depending on the length of time following E₂ deprivation (i.e., ovariectomy). We also provide strong evidence that hnRNP A1 regulates the transcription of pri-miR-9 and likely plays a posttranscriptional role in mature miR-9-5p turnover. Taken together, these data have important implications for considering the optimal timing for hormone replacement therapy, which might be less dependent on age and more related to how long treatment is delayed following menopause. Full article

The castration of stallions is traditionally performed after puberty, at around the age of 2 years old. No studies have focused on the effects of early castration on osteoarticular metabolism. Thus, we aimed to compare early castration (3 days after birth) with traditional castration (18 months of age) in horses. Testosterone and estradiol levels were monitored from birth to 33 months in both groups. We quantified the levels of biomarkers of cartilage and bone anabolism (CPII and N-MID) and catabolism (CTX-I and CTX-II), as well as of osteoarthritis (HA and COMP) and inflammation (IL-6 and PGE₂). We observed a lack of parallelism between testosterone and estradiol synthesis after birth and during puberty in both groups. The extra-gonadal synthesis of steroids was observed around the 28-month mark, regardless of the castration age. We found the expression of estrogen receptor (ESR1) in cartilage and bone, whereas androgen receptor (AR) expression appeared to be restricted to bone. Nevertheless, with respect to osteoarticular metabolism, steroid hormone deprivation resulting from early castration had no discernable impact on the levels of biomarkers related to bone and cartilage metabolism, nor on those associated with OA and inflammation. Consequently, our research demonstrated that early castration does not disrupt bone and cartilage homeostasis. Full article

A collection of metabolic disorders and neurodegenerative diseases linked to oxidative stress and neuroinflammation frequently affect postmenopausal women or estrogen deprivation. Recent research has focused on alternative therapies that can enhance these women’s quality of life. This study set out to investigate the effects of physical exercise (EX) and intermittent fasting (IF) on oxidants/antioxidants, inflammatory cytokines, neurotransmitters, and brain-derived neurotrophic factor (BDNF) in the cortex of rats. Additionally, it sought to assess the response to oxidative stress and neuroinflammation in the brains of rats following ovariectomy (OVX) and the potential mechanisms of these interventions. Fifty female rats were divided into one of the following groups 30 days after bilateral OVX: Control, OVX, OVX + EX, OVX + IF, and OVX + EX + IF groups. The rats in the Control and OVX groups continued their normal activities and had unrestricted access to food and water, but the rats in the OVX + EX and OVX + EX + IF groups had a 4-week treadmill training program, and the rats in the OXV + IF and OVX + EX + IF groups fasted for 13 h each day. The rats were killed, the cerebral cortex was taken, tissue homogenates were created, and various parameters were estimated using these homogenates. The results show that ovariectomized rats had decreased levels of neurotransmitters (DA, NE, and SE), acetylcholinesterase, brain GSH (glutathione), SOD (superoxide dismutase), catalase, GPx (glutathione peroxidase), and TAC (total antioxidant capacity), as well as elevated levels of proinflammatory cytokines and mediators (TNF-α, IL-1β, Cox-2). While ovariectomy-induced declines in neurotransmitters, enzymatic and nonenzymatic molecules, neuroinflammation, and oxidative brain damage were considerably mitigated and prevented by treadmill exercise and intermittent fasting, BDNF was significantly increased. These results suggest that ovariectomy can impair rat neuronal function and regular treadmill exercise and intermittent fasting seem to protect against ovariectomy-induced neuronal impairment through the inhibition of oxidative stress and neuroinflammation and increased BDNF levels in the brain cortex. However, combining regular exercise and intermittent fasting did not provide additional benefits compared to either treatment alone. Full article

To identify effective treatment modalities for breast cancer with acquired resistance, we first compared the responsiveness of estrogen receptor-positive breast cancer MCF-7 cells and long-term estrogen-deprived (LTED) cells (a cell model of endocrine therapy-resistant breast cancer) derived from MCF-7 cells to G-1 and 2-methoxyestradiol (2-MeO-E2), which are microtubule-destabilizing agents and agonists of the G protein-coupled estrogen receptor 1 (GPER1). The expression of GPER1 in LTED cells was low (~0.44-fold), and LTED cells displayed approximately 1.5-fold faster proliferation than MCF-7 cells. Although G-1 induced comparable antiproliferative effects on both MCF-7 and LTED cells (IC₅₀ values of >10 µM), 2-MeO-E2 exerted antiproliferative effects selective for LTED cells with an IC₅₀ value of 0.93 μM (vs. 6.79 μM for MCF-7 cells) and induced G2/M cell cycle arrest. Moreover, we detected higher amounts of β-tubulin proteins in LTED cells than in MCF-7 cells. Among the β-tubulin (TUBB) isotype genes, the highest expression of TUBB2B (~3.2-fold) was detected in LTED cells compared to that in MCF-7 cells. Additionally, siTUBB2B restores 2-MeO-E2-mediated inhibition of LTED cell proliferation. Other microtubule-targeting agents, i.e., paclitaxel, nocodazole, and colchicine, were not selective for LTED cells. Therefore, 2-MeO-E2 can be an antiproliferative agent to suppress LTED cell proliferation. Full article

Triple-negative breast cancer (TNBC) is usually the most malignant and aggressive mammary epithelial tumor characterized by the lack of expression for estrogen receptors and progesterone receptors, and the absence of epidermal growth factor receptor (HER)2 amplification. Corresponding to 15–20% of all breast cancers and well-known by its poor clinical outcome, this negative receptor expression deprives TNBC from targeted therapy and makes its management therapeutically challenging. Type 2 diabetes mellitus (T2DM) is the most common ageing metabolic disorder due to insulin deficiency or resistance resulting in hyperglycemia, hyperinsulinemia, and hyperlipidemia. Due to metabolic and hormonal imbalances, there are many interplays between both chronic disorders leading to increased risk of breast cancer, especially TNBC, diagnosed in T2DM patients. The purpose of this review is to provide up-to-date information related to epidemiology and clinicopathological features, risk factors, diagnosis, biomarkers, and current therapy/clinical trials for TNBC patients with T2DM compared to non-diabetic counterparts. Thus, in-depth investigation of the diabetic complications on TNBC onset, development, and progression and the discovery of biomarkers would improve TNBC management through early diagnosis, tailoring therapy for a better outcome of T2DM patients diagnosed with TNBC. Full article