Acquired resistance to endocrine therapy poses a major limitation in the treatment of estrogen receptor (ER)-positive breast cancer (BC). Somatic mutations of the ESR1 gene, which encodes ERα, are one of the key resistance mechanisms. However, the effect of mutations and especially double mutations on the binding of novel drugs remains insufficiently understood. To evaluate the effect of the mutations at the molecular level, a comprehensive computational approach was employed, including molecular docking, binding free energy calculations (MM-GBSA), and molecular dynamics simulations. A comparative analysis revealed opposite effects of ESR1 mutations on affinities of various selective ER degraders (SERDs). Vepdegestrant and fulvestrant were found to bind far less efficiently with ERα mutants and especially double mutants (e.g., Y537C/D538G) than with the native ERα. In contrast, the SERD ZB716 demonstrated the same or even better binding with most mutants. A potential structural cause of its resilience to mutations was identified via a comprehensive analysis, which included the evaluation of individual amino acid residue mobility through root-mean-square fluctuation (RMSF) calculations and an assessment of intermolecular hydrogen bond stability. ZB716 was shown to maintain a stable hydrogen bond with Glu353, and the bond was preserved in the ERα mutants. A lower stability of this key interaction was observed with fulvestrant. The findings elucidate the molecular mechanism of ESR1 mutation-driven resistance and support the promise of ZB716 as a compound capable of overcoming resistance conferred by a subset of the most common somatic ESR1 mutations in BC patients. The results justify the targeted design of new SERDs aimed at interacting with ERα mutants and outline an avenue of further research in the field of personalized therapy for ER+ BC.

The loss of ovarian hormones in postmenopause influences cognition, emotion and energy homeostasis, processes integrated by the hippocampus. The mechanisms by which estradiol influences this area have not been fully understood. The present study aimed at investigating the effects of estradiol on the rat hippocampus proteome of ovariectomy-induced menopause either followed by estradiol replacement or not. Eighteen 3-month-old female Wistar rats were either ovariectomized or sham operated and fed with standard chow for 3 months. A subgroup of ovariectomized rats received estradiol replacement. The hippocampi were processed using data independent acquisition MS-based proteomics and differentially expressed proteins were submitted to bioinformatics analysis for a pathway-based functional understanding of the estradiol effects. Proteomic analysis revealed that 49 hippocampal proteins were modulated by ovariectomy and estradiol replacement. Functional analysis of the differentially expressed proteins revealed the enrichment of terms related to energy metabolism (comprising glycolysis/gluconeogenesis, pyruvate metabolism, oxidative phosphorylation, and response to oxidative stress) and neuron projection (comprising cytoskeleton organization, regulation of vesicle-mediated transport, and modulation of chemical synaptic transmission). The present dataset indicates that, at the hippocampus, estradiol affects mitochondrial dynamics, lipid metabolism and intracellular trafficking machinery and influences dendritic and synaptic transmission and brain plasticity. Some alterations observed in proteins have not yet been described in the hippocampus in the context of menopause and estradiol replacement. These data provide new insights into the mechanisms involved with menopause effects and may help future studies related to drug development for the prevention and treatment of postmenopause associated symptoms.

Alzheimer's disease (AD) represents a devastating neurodegenerative disorder globally. It is clinically characterized by cognitive dysfunction, predominantly learning and memory impairments, and is closely associated with cholinergic system damage. Osthol (OST), a bioactive compound with well-documented neuroprotective properties, has been shown to enhance learning and memory functions. However, the precise molecular mechanisms underlying its therapeutic effects on AD-related cognitive impairment remain unclear. This study elucidates the critical interplay between estrogen-cholinergic system imbalance and AD progression across distinct temporal windows in female AD models. By focusing on this sex-specific regulatory axis, we aimed to address a key gap in understanding AD pathogenesis and OST's targeted efficacy. We employed age-stratified 3×Tg-AD mice as an experimental model and utilized comprehensive behavioral paradigms to assess learning and memory functions. An age-dependent gradient of cognitive impairment, accompanied by varying degrees of neuropathological damage, was observed in 3×Tg AD mice across different age groups. OST significantly improved learning and memory performance in 3×Tg AD mice of all age groups. Western blotting, ELISA, and immunofluorescence staining indicated that OST treatment effectively alleviated damage to the estrogen-cholinergic-NGF axis through multiple synergistic mechanisms: upregulation of Acetylcholine (ACh), Choline acetyltransferase (ChAT), Tyrosine kinase-A (TrkA), and Nerve growth factor (NGF) expression; downregulation of Acetylcholinesterase (AChE) activity; and increased expression of Estradiol (E2), Estrogen receptor-α (ERα), and Estrogen receptor-β (ERβ). In addition, OST improved synaptic plasticity (Postsynaptic density protein-95 (PSD95), Synuclein (SYN), and Brain-derived neurotrophic factor (BDNF)), inhibited neuronal apoptosis (B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (BAX)), and enhanced neurotransmitter signaling cascades (γ-aminobutyric acid (GABA), Glutamic acid (Glu), Epinephrine (E), and ACh). These findings provide new insights into the mechanisms of AD and support OST as a promising candidate for targeted AD therapy.

While GnRH induces the preovulatory LH surge, PGF2α triggers luteolysis and uterine contraction. Therefore, Lecirelin-Cloprostenol combination given at the end of the TAI protocol may improve fertility in cows. Eight studies evaluated a novel Lecirelin-Cloprostenol (GPG) fixed-dose combination for ovulation and fertility in Nelore cattle subjected to timed artificial insemination (TAI) protocols. Initial experiments (Exp. 1, n = 28) showed GPG and GnRH induced earlier ovulation than PGF. In Exp. 2 (n = 25) and Exp. 4 (n = 17), the GPG protocol reduced the dispersion of ovulation timing compared to GnRH alone (Bartlett's test, P < 0.05). In Exp. 3, the GPG group had lower intrafollicular estradiol (P = 0.04) and higher PTGS2 gene expression (P = 0.05) compared to the GnRH group. Fertility outcomes varied: GPG tended (P = 0.1) to increase pregnancy per artificial insemination (P/AI) in postpartum cows (Exp. 5, n = 326) and improved ovulation rates when estradiol cypionate (EC) was used (Exp. 6, n = 17). While a large field study (Exp. 7, n = 948) showed no overall P/AI difference when the GPG treatment was given following estradiol cypionate. Finally, GPG and GnRH had similar P/AI (P = 0.3) in non-estrus cows (Exp. 8, n = 1692) compared to GnRH. In conclusion, GPG upregulated PTGS2 expression and decreased intrafollicular E2 concentrations in the ovulatory follicle relative to GnRH, providing a mechanistic basis for the improved ovulatory synchrony observed in GPG-treated cows. While the GPG formulation consistently reduced the dispersion of ovulation timing across experiments, effects on P/AI were marginal in the present study.

This study was conducted to systematically elucidate the molecular regulatory mechanisms underlying egg production traits in indigenous chickens. Using a self-bred White-feathered Green-shelled (WG) chicken line as the research subject, high-yield and low-yield individuals were selected based on egg numbers at 43 weeks (EN43). Hypothalamus, pituitary, and ovarian tissues were collected from these individuals for targeted metabolomics profiling and transcriptome sequencing. The results showed a significant difference in EN43 between the two groups (P < 0.05). Targeted metabolomics of ovarian tissue detected a total of 17 steroid hormones, among which pregnenolone, progesterone, and 17β-estradiol were identified as differentially expressed steroid hormones (DESHs) between the two groups. Differential expression analysis of transcriptomes identified 666, 149, and 69 differentially expressed genes (DEGs) in the hypothalamus, pituitary, and ovary, respectively. Functional enrichment analysis revealed that hypothalamic DEGs were primarily involved in transcriptional regulation, neuropeptide signaling, and neurodevelopmental processes. Pituitary DEGs were mainly enriched in synaptic plasticity, calcium ion binding, and neurotransmitter transport, while ovarian DEGs were predominantly associated with signal transduction, calcium signaling regulation, and the cGMP signaling pathway. A molecular regulatory network (MRN) was constructed based on DEGs and DESHs. Through modular analysis, four key regulatory modules were identified, involving neuroendocrine regulation, neurotransmitter transport, steroid hormone synthesis, and transcriptional/developmental regulation. Combined with comprehensive network topology scoring, 25 potential candidate genes were identified, including POMC, NPY, CRH, SLC18A2, CD36, EGF, and WNT3A. In conclusion, this study integrated multi-omics data to reveal the molecular mechanisms of the HPO axis regulating egg production traits from a multi-tissue and multi-level perspective, providing a theoretical foundation for molecular breeding in indigenous poultry.

Recent evidence suggests that use of menopausal estrogen-only therapy in patients who have undergone hysterectomy reduces breast cancer risk among patients at population risk for breast cancer as well as in those with pathogenic high-risk BRCA variants. A meta-analysis of 10 randomized trials of estrogen therapy compared with placebo among 14,282 participants at population risk noted that 3.6% those randomized to estrogen alone were diagnosed with breast cancer, compared with 4.7% of those randomized to placebo (relative risk 0.77; 95% CI, 0.65-0.91, P=.002). A matched prospective cohort study of 676 patients with BRCA mutations and intact breasts who used menopausal hormone therapy (MHT) found that the estimated 15-year cumulative incidence of breast cancer with estrogen alone compared with no MHT was 24.3%, compared with 47.3% in the matched nonusers of MHT (P<.0001). This evidence underscores the need for more data that specifically assess the effect of estradiol therapy among patients who have undergone hysterectomy. Until such data are available, counseling patients at risk for breast cancer who have completed childbearing and are planning surgery for benign gynecologic conditions should involve shared decision-making that addresses the future risk of breast and endometrial cancers, cardiovascular disease, as well as the morbidity associated with hysterectomy. When appropriate, such counseling should also describe the availability of uterine-sparing alternatives.

Estrogenic hormones are potent endocrine-disrupting contaminants that are inefficiently removed by conventional wastewater treatment processes. Herein, we evaluate a family of isoreticular amino-acid-derived metal-organic frameworks (MOFs), including multivariate variants, for the simultaneous capture of estrone (E1), 17β-estradiol (E2), estriol (E3), and 17α-ethinylestradiol (EE2) from water. Using a solid-phase extraction configuration, a leucine-based oxamidato MOF emerges as a highly efficient sorbent, achieving >90%-95% removal of all four hormones within 30 s in a single loading step, representing one of the fastest simultaneous estrogen capture systems reported to date under SPE conditions. This material exhibits exceptional regenerability, enabling near-quantitative desorption under mild conditions with minimal solvent consumption (1 mL methanol), and stable performance over at least ten reuse cycles. Notably, comparable capture efficiencies are maintained in real river-water samples, demonstrating robustness toward complex aqueous matrices. The crystal structure of a host-guest aggregate confirms estrogen encapsulation within the flexible framework, providing direct structural insight into the origin of the high capture efficiency. These results identify amino-acid-based MOFs as a highly competitive platform for rapid, regenerable, and selective estrogen capture, combining excellent performance with valuable structural insight into host-guest interactions.