Search Results (1,986)

The menstrual cycle represents a dynamic infradian rhythm characterized by coordinated fluctuations in ovarian steroids that extend beyond reproductive function and influence systemic metabolism. This narrative review synthesizes current evidence on how menstrual cycle phase modulates energy balance, macronutrient metabolism, micronutrient handling, and responses to dietary bioactive compounds. Across phases, small-to-moderate but consistent differences emerge in energy intake, resting energy expenditure, substrate utilization, and protein turnover, with a tendency toward increased energy intake and lipid oxidation during the mid-luteal phase compared with the early follicular and peri-ovulatory phases. Emerging metabolomics data further reveal coordinated cyclical variation in amino acids, B vitamins, and lipid species, suggesting temporally sensitive windows in which low energy availability or micronutrient insufficiency may more readily impair performance, recovery, or symptom burden. Importantly, menstrual cycle-related metabolic variability reflects not only estradiol and progesterone oscillations but also integrated adaptations across the hypothalamic–pituitary–adrenal axis, autonomic nervous system, immune signaling, and gut microbiota. These interconnected systems contribute to inter- and intra-individual heterogeneity in metabolic phenotype. From a clinical and applied perspective, the evidence supports “cycle-aware” but non-dogmatic nutritional strategies, particularly in contexts of metabolic dysfunction, high training loads, or reproductive disorders. Future research should systematically verify cycle phase, incorporate multi-system biomarkers, and adopt sex-specific analytical frameworks to improve translational relevance. Recognizing the menstrual cycle as a biologically meaningful metabolic variable may enhance precision nutrition, exercise prescription, and metabolic risk assessment in women. Full article

Progesterone receptor (PR) regulates gene expression through recruiting coregulators and general transcription factors by activation functions AF1 and AF2. AF1 localizes to the non-conserved and disordered N-terminal domain and is believed to facilitate tissue- and gene-specific activity. Our previous proteomic analysis identified three key residues (K464, K481 and R492) in AF1 that are monomethylated. Methylation mimic mutations KKR → FFF created hypoactive PR, whereas the KKR → QQQ mutation generated hyperactive PR in gene reporter assays. The current study used these mutants to determine the roles of AF1 in PR regulation of cellular activities and global gene regulation in breast cancer cells MCF-7. AF1-FFF mutation attenuated PR regulation of cell proliferation and apoptosis in response to progestin, whereas AF1-QQQ mutation enhanced these effects. AF1-FFF mutation attenuated gene regulation by progestin in ~60% of PR target genes, including genes involved in cell proliferation, hypoxia and TNFα signaling. However, the AF1-FFF mutation had little effect on ligand-independent gene regulation, suggesting distinct mechanisms of gene regulation by liganded and unliganded PR. Intriguingly, impaired activity of methylation mimic mutant PRB-FFF is associated with greater chromatin binding in ChIP-Seq analysis, corresponding to a stronger association between PRB-FFF and Steroid Receptor Coactivator-1 (SRC-1), a member of the p160 family of nuclear receptor coactivators, as was previously reported. In conclusion, PR AF1 is important for the core activities of liganded PR in regulating ~half of target genes and cell proliferation. AF1 monomethylation may modulate PR-chromatin interactions through stronger association with coregulators, thereby decelerating chromatin binding kinetics. This is supported by PRODIGY’s prediction of higher binding affinities of monomethylated AF1 and methylation mimic mutant with SRC-1. Full article

Intracranial meningiomas (ICMs) are the most common primary adult brain tumor. They are more frequent in women, respond to female hormones, are associated with breast cancer and are often progesterone receptor-positive (PR+), consistent with hormonal sensitivity. Yet <20% are weakly estrogen receptor-positive (ER+). This work reviews the literature to investigate this paucity of ER by first testing if Dexamethasone (Dex), which has been used since 1984 to reduce peritumoral brain edema, is suppressing ER. Ligand-binding assays after 1984 have shown a significant decrease in any and supra-threshold (>10 fmol/mg) ER+ from 68.5% and 39.6% to 25.5% and 12%, respectively (both p < 0.0001). This was confirmed as Dex-related in 93 patients with known Dex exposure (p = 0.0075). Immunohistochemical tests after 1984 have shown that 16% (95%CI 8.4–24.4) of ICMs have rare ER+ cells unrelated to PR and pS2 expression, consistent with Dex inhibition of ER transcription activity. Dex suppression of ER may be compounded by lower endogenous ER concentrations in ICMs compared to breast cancer. The difference in intra-tumoral estrogen concentration is proposed as a potential cause for lower ER in ICM. Replacement of Dex and more sensitive ER assays are needed to determine the role of hormones in the causation and treatment of ER+ ICM. Full article

Background: Zearalenone (ZEA) is a potent estrogenic mycotoxin that adversely affects the female reproductive system, causing hormonal imbalance, uterine enlargement, structural changes in the reproductive tract, and reduced fertility. This study evaluated the protective effects of melittin-loaded chitosan nanoparticles (MEL-NPs) against ZEA-induced ovarian toxicity in female rats. Methods: Forty-eight adult female Wistar rats (180–200 g) were divided into four groups: Control, ZEA, ZEA + MEL, and ZEA + MEL-NPs. ZEA (2.7 mg/kg b.w.) was administered orally twice weekly for two weeks. MEL and MEL-NPs (40 μg/kg b.w.) were given orally three times weekly for one month. Serum biochemical parameters were measured, and ovarian tissues were examined grossly and histopathologically. qRT-PCR was performed to assess mRNA expression of inflammatory markers (TNF-α, IL-6, IL-1β), apoptotic marker (Caspase-3), and steroidogenic enzyme (CYP19A1). Results: ZEA exposure induced significant ovarian toxicity, evidenced by increased TNF-α, IL-6, IL-1β, LH, FSH, CA-125, and Caspase-3, along with decreased progesterone, antioxidant capacity, and CYP19A1 expression. Histopathology revealed ovarian atrophy, follicular degeneration, and fibrosis. Treatment with MEL-NPs markedly reversed these alterations, normalizing cytokine and hormonal profiles, restoring CYP19A1 expression, and improving ovarian morphology. MEL-NPs demonstrated superior protective effects compared to free MEL. Conclusions: MEL-NPs effectively ameliorate ZEA-induced ovarian toxicity by restoring hormonal balance, enhancing antioxidant defense, and reducing inflammation and apoptosis. These findings suggest that MEL-NPs could be a promising therapeutic strategy for preventing mycotoxin-induced ovarian dysfunction. Full article

Background/Objectives: Bone is the most common organ affected by distant metastasis in advanced breast cancer, and the development of skeletal-related events (SREs) often leads to significant deterioration in patients’ quality of life and survival outcomes. In this study, we aimed to explore the risk factors associated with bone metastasis in breast cancer and to develop a predictive nomogram for identifying high-risk patients, which may facilitate timely preventive interventions and improve clinical prognosis. Methods: A retrospective analysis was conducted on 672 patients with breast cancer who underwent surgery at the Fourth Hospital of Hebei Medical University (Shijiazhuang, China) between 2013 and 2023; this cohort served as the training set. Clinical and pathological characteristics potentially influencing bone metastasis—including age, menopausal status, histological grade, affected side, maximum tumor diameter, lymph node staging, TNM staging, ER status, PR status, HER-2 status, Ki-67, molecular subtypes, vascular tumor thrombus, nerve infiltration and visceral metastasis—were collected. The median follow-up time was 42 months. Patients were stratified into two cohorts based on whether postoperative bone metastasis occurred, with groups matched according to Tumor–Node–Metastasis (TNM) stage. Univariate and multivariate logistic regression models were applied to identify independent factors associated with breast cancer bone metastasis, and a nomogram prediction model was constructed using the variables retained in the final analysis. For external validation, data from 2814 patients with breast cancer who underwent surgery between 2013 and 2021 were extracted from the U.S. Surveillance, Epidemiology, and End Results database. Results: The multivariate logistic regression analysis revealed that histological grade (p = 0.002), progesterone receptor (PR) negativity (p = 0.001), human epidermal growth factor receptor 2 (HER-2) negativity (p = 0.002) and visceral metastasis (p < 0.001) were identified as independent predictors of bone metastasis in breast cancer. A nomogram predictive model was established using these four factors. The area under the receiver operating characteristic curve was 0.720 (95% confidence interval (CI): 0.6797–0.7607) for the training cohort and 0.701 (95% CI: 0.6813–0.7205) for the external validation cohort. Decision curve analysis further confirmed the clinical applicability of the model. Conclusions: The present study confirms that histological grade, PR status, HER-2 status and visceral metastasis are independent factors associated with bone metastasis in breast cancer. The constructed nomogram may effectively predict breast cancer-related bone metastasis and could serve as a practical tool for clinical decision-making. Full article

Polycystic ovary syndrome (PCOS) is associated with impaired ovarian steroidogenesis and ovulation, which necessitates the development of effective ovulation inducers for PCOS. The aim of the study was to evaluate the effects of allosteric luteinizing hormone receptor agonist TP03 and human chorionic gonadotropin (hCG) on ovarian steroidogenesis, as well as ovulation in prepubertal female rats with dehydroepiandrosterone(DHEA)-induced PCOS. Taking into account differences in progesterone levels, cohorts with high (PCOS(H)) and low (PCOS(L)) progesterone were formed and treated with Follimag and Cetrotide. After 48 h, TP03 (25 mg/kg) or hCG (25 IU/rat) were injected, and hormone levels, gene expression, and ovarian morphology were assessed. The PCOS(H)-cohort exhibited irregular estrous cycles, ovarian cysts, and increased ovarian mass and estradiol levels, but the number of corpora lutea (CL) was maintained. In the PCOS(L)-cohort, ovarian weight was increased, and Star, Cyp11a1, and Adamts1 gene expression as well as the CL number were decreased. In both cohorts, TP03 and hCG increased progesterone levels and the expression of steroidogenesis (Star, Cyp11a1) and ovulation (Cox2, Adamts1, Egr1) genes, as well as inducing CL formation. Thus, TP03, like hCG, stimulates steroidogenesis and ovulation in PCOS-rats with different progesterone levels, which provides the first evidence of the effectiveness of allosteric LHR agonists as ovulation triggers in PCOS. Full article

Triple-negative breast cancer (TNBC) represents 10–20% of breast cancers and is characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, leaving cytotoxic chemotherapy as the main systemic treatment. However, rapid development of resistance, via drug efflux, enhanced DNA repair, apoptosis evasion, epithelial-to-mesenchymal transition, and tumor microenvironment protection, limit long-term efficacy. Small interfering RNA (siRNA) therapeutics can silence key resistance drivers, but their clinical potential is hindered by instability, poor biodistribution, and off-target effects. Nanocarrier-based delivery systems offer solutions by protecting siRNA, enhancing tumor accumulation, enabling targeted intracellular release, and permitting co-delivery with chemotherapeutics for synergistic effects. We conducted a narrative review in PubMed from database inception to August 2025. The included studies demonstrated that lipid, polymeric, inorganic, and hybrid nanocarriers can achieve efficient target knockdown, reverse drug resistance mechanisms, and significantly enhance antitumor responses in resistant TNBC models. Several platforms also reduced metastatic spread and improved survival in vivo. While preclinical results are compelling, clinical translation remains limited by incomplete safety profiling and heterogeneity in delivery efficiency. This review synthesizes mechanistic insights and delivery innovations, outlining a roadmap for translating siRNA-loaded nanocarriers into effective therapies for chemoresistant TNBC. Full article

Background/Objectives: EndoPredict is a second-generation prognostic assay for estrogen-receptor-positive, HER2-negative breast cancer that integrates molecular and clinical parameters for risk stratification. Multiple studies have reported its clinical utility, while differences in the proportion of patients classified as high- or low-risk have been observed across cohorts. This study aimed to characterize clinical, pathological, and demographic factors associated with these differences. Methods: We conducted a descriptive review of 17 published studies and analyzed a single-institution cohort of 140 patients. Associations between clinicopathological variables and high-risk classification were assessed, including tumor size, lymph node status, histological grade, Ki-67 expression, and reproductive and demographic factors. Differences in inclusion criteria and cohort characteristics were also examined. Results: Tumor size and lymph node involvement emerged as primary determinants of high-risk classification. A high histological grade and Ki-67 levels above 25% were significantly associated with high-risk status (p < 0.001). Conversely, age, age at menarche, menopausal status, Body Mass Index, progesterone receptor expression, molecular subtype, and histological type showed no significant association. A higher number of pregnancies correlated with a lower frequency of high-risk classification (p < 0.01). Heterogeneity in risk distribution across studies was largely attributable to differences in tumor size, nodal involvement, and histological grade. Additional variability was associated with inclusion criteria, sample selection, and regional demographic characteristics. Conclusions: Variability in EndoPredict risk classification reflects both tumor biological features and population-specific factors. These findings emphasize the importance of interpreting genomic risk scores within their clinical and demographic context and support the comparison of risk distributions across heterogeneous patient cohorts. Full article

Background/Objectives: This article employs both in vivo and in vitro experiments. Methods: The core targets and key pathways of Paeoniflorin were predicted using a PPI network analysis, GO analysis, and KEGG analysis. Subsequently, molecular docking analysis and molecular simulation dynamics were performed on the core effector. In vitro experiments employed a UVB-irradiated B16F10 cell model. The effects of Paeoniflorin on melanin content and tyrosinase activity were evaluated. Apoptosis and inflammatory cytokine levels were also assessed in vitro. In vivo experiments used a model combining progesterone injection with UV irradiation. Histopathological skin changes and melanin granule distribution were examined using HE staining. Skin melanin content, tyrosinase activity, and expression levels of related proteins were measured. Additionally, ELISA assays measured serum IL-6 and TNF-α inflammatory cytokines in mice. Results: Rese screening identified 69 targets involved in Paeoniflorin’s effects on melanogenesis, including TNF-α, IL-6, TP53, MAPK3, HIF1A and BCL2. Molecular docking and molecular dynamics simulations indicate that Paeoniflorin exhibits strong affinity for tumor necrosis factor-α. In in vitro experiments, Paeoniflorin significantly reduced UVB-induced melanin content and tyrosinase activity in B16F10 cells. It also promoted melanocyte apoptosis and a dose-dependent decrease in IL-6 and TNF-α levels. In vivo, Paeoniflorin significantly reduced epidermal and dermal thickness and inhibited inflammatory infiltration. It decreased melanin granules, melanin content, tyrosinase activity, and IL-6 and TNF-α levels in mouse skin tissue. Conclusions: This research indicates that Paeoniflorin can significantly suppress UVB-induced cellular inflammatory responses by inhibiting the TNF signaling pathway, thereby reducing hyperpigmentation. Full article

Polyphenols represent the largest and most diverse class of dietary antioxidants. Epidemiological evidence linking specific (poly)phenol classes, such as flavonoids and lignans, to breast cancer (BC) risk remains limited and largely inconclusive in prospective studies. The aim of this study is to examine the association between the intake of total (poly)phenols—and its classes and subclasses—and BC risk—overall and by subtypes (estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2))—in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The EPIC cohort includes 257,960 adult women from seven European countries. During a mean follow-up of 14 years, there were 10,722 incident overall BC cases. Associations were computed using Cox regression models adjusted for potential confounders. No significant associations were found between total (poly)phenol intake and overall BC risk (HR_{Q5 vs. Q1} = 1.02; 95% CI: 0.95–1.11). In addition, null associations were mostly found between classes and subclasses of (poly)phenols and BC subtypes. After stratifying by menopausal status, no significant associations were observed. In conclusion, this study found no evidence of associations between the intake of any class or subclass of (poly)phenols and BC risk in the European population. Full article

The peri-implantation window is a tightly regulated temporal phase during which the human endometrium undergoes coordinated molecular remodeling to establish receptivity. MicroRNAs (miRNAs) contribute to implantation-related processes; however, whether dynamic endometrial regulatory signals are functionally reflected in circulation within a defined temporal framework remains unclear. We hypothesized that although individual miRNA identities differ between endometrial tissue and plasma, temporally regulated miRNAs in both compartments may exhibit overlap at the level of enriched biological pathways during the peri-implantation window. To test this hypothesis, we performed time-resolved small RNA sequencing on paired endometrial and plasma samples collected from 62 participants across progesterone exposure days P+3 to P+7 in hormonally controlled cycles. Temporal modeling identified 27 dynamic miRNAs in endometrial tissue and 17 in plasma (FDR < 0.05). Despite limited overlap at the individual miRNA level, functional enrichment analysis revealed recurrent overlap in apoptosis-, cell cycle-, aging-, inflammatory-, and metabolic-related pathways across compartments. Four miRNAs exhibited concordant directional temporal trends between tissue and plasma with moderate correlation coefficients. These findings suggest that dynamic miRNA-associated enrichment patterns during the peri-implantation window may exhibit pathway-level overlap despite divergence in specific molecular identities. This temporally aligned integrative framework provides a pathway-centric perspective for interpreting cross-compartment miRNA-associated temporal patterns and supports a hypothesis-generating systems-level view of human implantation biology. Full article

Background and objectives: Early biomarkers that can reliably predict treatment outcomes during CDK4/6 inhibitor therapy remain an unmet clinical need in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (MBC). Metabolic changes on ^18F-FDG PET/CT may precede radiologic response and provide insight into tumor biology and early treatment resistance. Methods: This two-center retrospective study included 203 patients with HR+/HER2− MBC who received first-line CDK4/6 inhibitors (ribociclib or palbociclib) plus endocrine therapy between 2018 and 2024. Baseline and interim ^18F-FDG PET/CT scans performed after 2–4 cycles were evaluated. Early metabolic response was defined as a ≥30% reduction in SUVmax on the most metabolically active lesion, consistent with PERCIST 1.0. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and multivariable Cox models. ROC analysis assessed the discriminative performance of ΔSUVmax for predicting disease progression. Results: Among 203 patients, 153 (75.4%) achieved a ≥30% SUVmax reduction. Responders had significantly longer PFS (median 44.4 vs. 4.8 months; p < 0.001) and OS (median not reached vs. 32.0 months; p < 0.001). Metabolic response remained independently associated with improved PFS (HR 0.24; 95% CI 0.15–0.37; p < 0.001) and OS (HR 0.37; 95% CI 0.20–0.67; p = 0.001) after adjustment for tumor grade, endocrine resistance, and visceral disease involvement. Non-responders demonstrated more aggressive baseline features, including higher rates of liver (34.0% vs. 15.0%) and brain metastasis (10.0% vs. 1.3%), as well as lower progesterone receptor expression (median 30% vs. 60%). Conclusions: Early metabolic response assessed by SUV-max on interim ^18F-FDG PET/CT is independently associated with substantially improved PFS and OS in HR+/HER2− MBC receiving treatment with CDK4/6 inhibitors. Although the predictive accuracy of ΔSUVmax alone was modest, the strong survival gradient suggests meaningful prognostic value. Prospective studies with standardized imaging time points and comprehensive metabolic metrics are warranted to define the role of PET-guided treatment adaptation: Full article

Timely and accurate detection of sow oestrus is crucial for enhancing reproductive efficiency and reducing non-productive days (NPDs) in large-scale pig farms. However, traditional manual observation is labour-intensive and subjective, while cloud-based deep learning solutions face challenges such as high latency and privacy risks when applied in intensive housing environments. This study developed an edge-intelligent monitoring system that integrates deep temporal modelling with sound source localisation technology. A three-stage hierarchical screening strategy was utilised to select and deploy a lightweight Stacked-LSTM model on the resource-constrained ESP32-S3 hardware platform. This model was trained and calibrated using a high-quality acoustic dataset validated against serum reproductive hormones, specifically follicle-stimulating hormone (FSH), luteinising hormone (LH), and progesterone ($P_4$). Experimental results demonstrate that the optimised model achieved a classification accuracy of 96.17%, with an inference latency of only 41 ms, thereby fully satisfying the stringent real-time monitoring requirements while maintaining a minimal memory footprint. Furthermore, the system integrates a localisation algorithm based on Generalised Cross-Correlation with Phase Transform (GCC-PHAT). Through spatial geometric modelling, the system successfully implements the functional mapping of vocalisation events to individual gestation stalls (Stall IDs). Laboratory pressure tests validated the robustness and low-cost deployment advantages of the “edge recognition–cloud synchronization” architecture, providing a reliable technical framework for the precision management of smart livestock farming. Full article

Cutaneous metastases are an uncommon but clinically relevant manifestation of breast cancer (BC), often indicating advanced disease and biological progression. Temporal heterogeneity between primary tumors and metastatic lesions, particularly involving hormone receptors (HRs) and HER2 status, may influence prognosis and treatment decisions. We retrospectively analyzed BC patients with cutaneous metastases diagnosed at a tertiary care center between 2015 and 2024. Clinical data, histopathological features, and immunohistochemical profiles of estrogen receptor (ER), progesterone receptor (PgR), and HER2 were evaluated in paired primary tumors and cutaneous metastatic lesions under uniform pre-analytic and analytic conditions. Receptor discordance and survival outcomes were assessed. Among 660 patients with metastatic BC, 28 (4.2%) developed cutaneous metastases. Median age at diagnosis was 63 years, with chest wall as the most frequent site of skin involvement. HR-positive/HER2-negative tumors were predominant, while triple-negative breast cancer accounted for 19.4% of cases and was associated with a shorter disease course and earlier cutaneous metastatic spread. Receptor discordance occurred in 18.2% for ER, 36.4% for PgR and 41.4% for HER2, mainly involving transitions to or from HER2-low status. After skin involvement, prognosis remained poor. Cutaneous BC metastases show marked receptor heterogeneity, reflecting dynamic tumor evolution. These findings support re-biopsy and biomarker reassessment to guide personalized treatment in metastatic BC. Full article

Normal pregnancy is associated with uterine and vascular remodeling by matrix metalloproteinases (MMPs) to facilitate placental blood flow and uterine expansion for the growing fetus. Increases in MMP-2 and MMP-9 in response to estrogen and progesterone promote placentation, uteroplacental vascularization and fetal growth during healthy pregnancy, but are altered in preeclampsia (PE). PE is characterized by hypertension in pregnancy (HTN-Preg) and fetal growth restriction (FGR). Predisposing genetic, demographic and environmental factors alter uteroplacental MMPs, immune response and integrins leading to apoptosis of invasive trophoblasts, inadequate spiral arteries remodeling, and reduced uteroplacental perfusion pressure (RUPP). Ensuing placental ischemia causes imbalance between anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and pro-angiogenic placental growth factor (PlGF) and promotes the release of tumor necrosis factor-α (TNF-α), hypoxia-inducible factor, reactive oxygen species, and angiotensin AT₁ receptor agonistic autoantibodies. Systemically, these bioactive factors target vascular endothelial cells, smooth muscle cells, and extracellular matrix, causing endothelial dysfunction, vasoconstriction, inadequate vascular remodeling, and HTN-Preg, while locally they diminish uteroplacental remodeling and cause FGR. In support, animal models of HTN-Preg induced by RUPP or infusion of sFlt-1 or TNF-α show decreases in vascular MMP-2, MMP-9 and vasodilation, increases in MMP-1, MMP-7 and vasoconstriction, collagen accumulation, and arterial stiffness. Also, decreases in uterine MMP-2 and MMP-9 could impede uterine expansion and lead to preterm birth. Conversely, PlGF and TNF-α antagonist reversed MMPs imbalance and collagen accumulation, and improved vascular function, blood pressure, and pup weight in HTN-Preg models. Persistent postpartum changes in MMPs could affect maternal hemorrhage, future pregnancies, and HTN, and cause fetal programming of cardiovascular and metabolic diseases. Understanding the aberrant uteroplacental and vascular signaling and remodeling by MMPs could help design new biomarkers and remedies for PE. Targeting bioactive factors and rectifying MMP imbalance could improve vascular and uteroplacental remodeling, and manage HTN-Preg, FGR and PE. Full article