Search Results (4,292)

Lignans are plant-derived biphenolic compounds with multiple hydroxyl groups, which, upon ingestion, are metabolized by gut microbiota into enterolignans—enterolactone and enterodiol. These mammalian metabolites exhibit structural similarity to estradiol, enabling lignans to modulate hormonal balance and exert estrogen-like effects. A growing body of evidence highlights their broad spectrum of health-promoting properties, including antioxidant, anti-inflammatory, and hormone-regulating effects. Lignans have shown potential in alleviating menopausal symptoms, preventing estrogen-dependent cancers, and mitigating conditions such as cardiovascular disease, diabetes, and metabolic syndrome. Additionally, their antimicrobial activity against bacteria, fungi, and viruses is being increasingly recognized. This review provides a comprehensive and up-to-date synthesis of current knowledge. It uniquely integrates the latest insights into lignan biosynthesis, gut microbiota-mediated metabolism, and clinically relevant outcomes. Importantly, this review incorporates recent findings from prospective cohort studies and meta-analyses and sheds light on emerging therapeutic applications, including antifungal activity—an area rarely covered in earlier literature. By presenting a holistic perspective, this review advances our understanding of lignans as multifaceted compounds with significant potential in preventive and therapeutic health strategies. Full article

Background/Objectives: Estrogen deficiency-related menopause is associated with various physical and psychological symptoms. Although hormone replacement therapy (HRT) effectively alleviates these symptoms, its long-term use is associated with several side effects such as an increased risk of breast cancer and cardiovascular disease. Consequently, there is a growing interest in some plant-derived phytoestrogens that are considered safer alternatives to estrogen. Recent studies on Scrophularia buergeriana confirmed their anti-inflammatory and antioxidant properties; however, their effects on menopausal health remain unclear. Therefore, the aim of this study was to investigate the estrogen-like effects of S. buergeriana root (SB-R) extract, a potential phytoestrogen. Methods: Briefly, the MCF-7 cell line, a widely used in vitro model for assessing estrogen-like activity, was treated with SB-R extract and 17β-estradiol (E2; positive control) in the presence or absence of ICI 182,780 (Fulvestrant), an estrogen receptor antagonist. An E-screen assay and flow cytometry were performed to assess the effects of the treatments on cell proliferation and the cell cycle, respectively. Additionally, Western blotting and immunofluorescence assays were performed to elucidate the potential mechanisms underlying the estrogen-like effects of SB-R. Result: Treatment with SB-R extract promoted MCF-7 cell proliferation in a manner similar to E2. However, ICI 182,780 co-treatment inhibited the SB-R extract-induced increase in MCF-7 cell proliferation. Additionally, SB-R extract promoted cell cycle progression by increasing the proportion of cells in the S and G2/M phases. Moreover, Western blotting and immunofluorescence assays showed that SB-R extract increased the expression of estrogen receptor alpha (ERα). Furthermore, SB-R treatment activated downstream signaling pathways by enhancing AKT and ERK phosphorylation and upregulated the expression of cell cycle regulators, including cyclin D1, cyclin dependent kinase 4 (CDK4), cyclin E1, and cyclin dependent kinase 2 (CDK2). Conclusions: SB-R exhibits estrogen-like activity by activating ERα-mediated AKT and ERK pathways and thereby increasing the expression of proteins involved in cell cycle regulation. This makes it a promising phytoestrogen candidate and a safer alternative to conventional hormonal therapy for alleviating menopausal symptoms. Full article

Estrogens have been widely shown to induce cell proliferation in breast cancer (BC) cells. Recently, we have described their involvement in the induction of epithelial–mesenchymal transition (EMT), migration, and invasion. The aim of this work is to review the molecular mechanisms by which estradiol (E₂) activates different signaling pathways, both genomic and non-genomic, through binding to different estrogen receptors (ERs), depending on the phosphorylated amino acid (Ser-118 or Tyr-537). The relevance of the present work lies in the molecular details of c-Src kinase activation by the membrane estrogen receptor (mER) and its effects on the early and late phases of EMT. This process initiates a loss of cell adhesion, leading to migration, which culminates in metastasis of cancer cells to distant tissues. Understanding how estrogens induce metastasis will facilitate the development of better strategies to counteract the lethality of BC. Finally, the quantification of Snail may serve as a molecular marker in the early stages of tumor progression, as well as the use of drugs against c-Src and ERs, as they may be therapeutic targets. Full article

Dehydroepiandrosterone (DHEA) and its sulfate ester form DHEAS, are multifunctional steroid hormones primarily produced in the adrenal cortex, with additional synthesis in peripheral tissues. DHEA/DHEAS serve as precursors to sex steroids and exhibit neuroprotective, anti-inflammatory, and immune-modulating effects. DHEA levels decline significantly with age, a phenomenon termed “adrenopause,” prompting interest in supplementation to mitigate age-related symptoms. Particularly in postmenopausal women, DHEA has shown potential benefits in treating genitourinary syndrome of menopause (GSM), including improved vaginal health, lubrication, and sexual function. While intravaginal DHEA appears effective and safer than systemic estrogen therapy, especially for women with estrogen sensitivity, results remain mixed for oral administration. DHEA and DHEAS exhibit diverse neuroactive properties through modulation of GABA-A, NMDA, and sigma-1 receptors. These neurosteroids contribute to neuroprotection, synaptic plasticity, and mood regulation. Altered DHEA/DHEAS levels have been implicated in neurodegenerative disorders and depression, with emerging evidence supporting their potential therapeutic value. In addition, DHEA plays a multifaceted role in aging-related physiological changes. It supports muscle anabolism, bone density maintenance, cardiovascular protection, and immune regulation. Though supplementation shows potential benefits, especially in conjunction with resistance training, results remain discrepant. Current evidence has revealed that the therapeutic effects of DHEA supplementation are inconsistent in different human systems among different studies. The diversity of results is mainly due to heterogeneous receptor distribution, various action pathways, and distinct tissue responses in different systems. Further research is needed to define its efficacy and dosage across various systems. Full article

Background: Endometriosis is a chronic, estrogen-dependent inflammatory and immunological disease, with chronic pain being its predominant clinical manifestation. This condition significantly impairs quality of life and is frequently associated with depressive and anxiety symptoms, further exacerbating social and occupational dysfunction in affected women. The aim of this study was to assess the relationship between chronic pain in patients with endometriosis and the severity of depressive symptoms. Methods: A retrospective analysis was conducted on the medical records of 60 women of reproductive age treated at the Tomaszewski Medical Center in Białystok between 2023 and 2024. Pain intensity was evaluated using the Visual Analogue Scale (VAS) and the McGill Pain Questionnaire, while depressive symptoms were assessed with the Beck Depression Inventory (BDI). Results: Statistical analyses included the Student t-test, Wilcoxon signed-rank test, chi-square test, and Shapiro–Wilk test, with significance set at p < 0.05. Pain intensity was significantly higher during menstruation (M = 7.23) compared to non-menstrual phases of the cycle (M = 4.55; p < 0.001). Accompanying symptoms included sleep disturbances, reduced activity, and gastrointestinal complaints. Depressive symptoms were also more severe during menstruation (M = 30.12) than during the rest of the cycle (M = 22.15; p < 0.001). A significant association between pain severity and depressive symptoms was observed during menstruation (χ²(4) = 12.89; p = 0.012), but not outside this phase. Conclusions: (1) Pain in endometriosis is chronic and cyclic in nature. (2) Depressive symptoms are common but may be masked by nonspecific somatic complaints. (3) Pain intensity strongly correlates with the severity of depressive disorders, particularly during menstruation. (4) The coexistence of depression significantly impairs patient functioning. (5) Effective management of endometriosis should integrate gynecological treatment with psychological support and psychiatric care when necessary. Full article

Background: Theophylline, which is biologically important and found in tea, coffee, and cocoa beans, can be synthesized chemically or by direct extraction and concentration from natural sources. Theophylline derivatives have garnered attention in recent years for their potential therapeutic effects on Mycobacterium tuberculosis, antihistaminic, anti-inflammatory, and anticancer. Also, trifluoromethyl (CF₃) group has also been widely used in drug and agrochemical design. Methods: In this study, a series of new theophylline derivatives containing substituted trifluoromethyl and trifluoromethoxy groups were synthesized. The structures of these new compounds were confirmed by NMR, FT-IR, and elemental analyses. Additionally, the anticancer activities of the molecules were analyzed against VEGFR-2, CYP P450, and estrogen receptor by molecular docking method. Furthermore, in vitro biological effects of the compounds were comprehensively evaluated in cancer (A549 and HeLa) and normal (BEAS-2B) cells. Cell viability was assessed by MTT assay, and selectivity index (SI) values were calculated to determine tumor-specific toxicity. Results: N(7)-substituted theophyllines were prepared by the reaction of 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (theophylline) and trifluoromethyl substituted benzyl halide compounds. The synthesized N(7)-substituted theophyllines were obtained as white powder in high yield. The structure of synthesized compounds was confirmed by various spectroscopic techniques such as ¹H, ¹³C, ¹⁹F NMR, and FT-IR spectroscopy, and elemental analysis. The highest interaction was recorded as −5.69 kcal/mol for 3-CF₃ substituted against VEGFR-2 structure while the best binding affinity was determined for 4-OCF₃ substituted with −6.69 kcal/mol against Human Cytochrome P450 with in silico analysis. The in vitro anticancer activities of the molecules were also evaluated against A549 and HeLa cells, and displayed considerably higher cytotoxicity with 2-CF₃, 3-CF_3, and 4-CF₃ substituted molecules in Hela and A549 cell line. To elucidate the molecular mechanism, apoptosis-related gene expression changes were analyzed by RT-qPCR in A549 and HeLa cells treated with compound 2-CF₃. Significant upregulation of pro-apoptotic markers and downregulation of anti-apoptotic genes were observed. Consistently, ELISA-based quantification confirmed increased protein levels of Caspase-3, BAX, and Cytochrome C, and decreased BCL-2, validating the apoptotic mechanism at the protein level. Also, the antibacterial and antibiofilm activity details of the molecules were evaluated against DNA Gyrase, and SarA crystal structures by molecular docking method. The highest interaction was recorded as −5.56 kcal/mol for 2-CF₃ substituted with H-bonds with Asn46, Val71, Asp73, and Thr165 against DNA Gyrase crystal structure while 3-CF₃ substituted has the best binding affinity against SarA. The in vitro antimicrobial effects of the molecules were also evaluated. Conclusions: The synthesized molecules may provide insight into the development of potential therapeutic agents to the increasing antimicrobial resistance and biofilm-forming capacity of microorganisms. Additionally, compound 2-CF₃ substituted exhibited promising and selective anticancer activity through apoptosis induction, supported by gene and protein level evidence. Full article

Lead (Pb) is a naturally occurring metal that is environmentally ubiquitous due to industrial activities, such as mining, smelting, and fossil fuel combustion. Exposure to Pb adversely affects the central nervous system, gastrointestinal tract, lungs, liver, bones, and cardiovascular system, leading to a multitude of negative health impacts, such as anemia and neurological disorders. While significant research has focused on the effects of Pb on the nervous and immune systems, Pb’s impact as a reproductive endocrine disruptor remains largely understudied. The first objective of this review was to collate the current literature regarding the effects of Pb on the reproductive system of aquatic species (primarily fish) and agricultural livestock to highlight the ecological significance and impacts on animal health. Literature supports the hypothesis that exposure to Pb can impede reproductive processes by affecting hormone levels, reproductive organ development, and fertility. A second objective of this review was to elucidate putative mechanisms underlying Pb as a reproductive endocrine disruptor using molecular data and computational approaches. Based on transcriptomics data, Pb is hypothesized to perturb key pathways important for hypothalamic–pituitary–gonadal axis functions, such as circadian regulation and estrogen receptor signaling. Given the widespread environmental presence of Pb, understanding these mechanisms is essential for improving risk assessments and protecting animal reproductive health. Full article

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-related deaths, with notable sex-specific differences in its incidence, diagnosis, and outcomes. Our previous work identified casein kinase 2 alpha (CK2α) as being capable of impairing DNA mismatch repair (MMR) via phosphorylation of MLH1, thereby increasing the tumor mutational burden. This study aimed to investigate sex-specific differences in CK2α protein expression in CRC. Methods: Immunohistochemical (IHC) analysis was performed on 161 CRC tumors and adjacent normal tissues to quantify the CK2α protein levels. A multi-cohort meta-analysis of proteomic and clinical data was conducted to validate our findings and assess the correlations with age, sex, and relevant signaling pathways. Results: Female CRC patients exhibited significantly higher CK2α expression than male patients, which was confirmed in two independent cohorts. Additionally, CK2α expression was positively correlated with age in female but not male patients. Cross-cohort correlation analyses linked CK2α levels with key proteins involved in estrogen receptor signaling and aging, including DEAD-box helicase 5 (DDX5), histone deacetylase 1 (HDAC1), proliferating cell nuclear antigen (PCNA), prohibitin-2 (PHB2), H/ACA ribonucleoprotein complex subunit 2 (NHP2), and dual-specificity mitogen-activated protein kinase kinase 3 (MAP2K3). Conclusions: CK2α is significantly overexpressed in the tumor tissue of female CRC patients and shows a strong age-related correlation. These findings suggest a sex- and age-specific regulatory mechanism potentially influenced by estrogen signaling or menopause. Such dimorphisms underscore the need for sex-specific strategies in CRC biomarker development and therapy. Full article

The aim of this study was to investigate the metabolites in Aspergillus subramanianii 1901NT-1.40.2 extract using UPLC-MS, isolate and elucidate the structure of individual compounds, and study the antimicrobial and cytotoxic activities of the isolated compounds. The structures of two previously unreported ergostane triterpenoid aspersubrin A (1) and pyrazine alkaloid ochramide E (2) were established using NMR and HR ESI-MS. The absolute configuration of 1 was determined using quantum chemical calculations. Moreover, the known polyketides sclerolide (3) and sclerin (4); the indolediterpene alkaloid 10,23-dihydro-24,25-dehydroaflavinine (5); the bis-indolyl benzenoid alkaloids kumbicin D (6), asterriquinol D dimethyl ether (7), petromurin C (8); and the cyclopentenedione asterredione (9) were isolated. The effects of compounds 3-9 on the growth and biofilm formation of the yeast-like fungus Candida albicans and the bacteria Staphylococcus aureus and Escherichia coli were investigated. Compounds 5 and 6 inhibited C. albicans growth and biofilm formation at an IC₅₀ of 7–10 µM. Moreover, the effects of compounds 3-9 on non-cancerous H9c2 cardiomyocytes, HaCaT keratinocytes, MCF-10A breast epithelial cells, and breast cancer MCF-7 and MDA-MB-231 cells were also investigated. Compound 8 (10 µM) significantly decreased the viability of MCF-7 cells, inhibited colony formation, and arrested cell cycle progression and proliferation in monolayer culture. Moreover, 8 significantly decreased the area of MCF-7 3D spheroids by approximately 30%. A competitive test with 4-hydroxytamoxyfen and molecular docking showed that estrogen receptors (ERβ more than ERα) were involved in the anticancer effect of petromurin C (8). Full article

Microplastics (MPs) are a growing environmental concern due to their ability to adsorb hazardous chemicals, such as estrogens, and be ingested by marine organisms. This study focuses on low-density polyethylene (LDPE), a polymer widely used in Kuwait, to assess its role as a carrier of endocrine-disrupting chemicals (EDCs), specifically estrogens. Biological effects were evaluated using biomarkers such as cytochrome P450 1A (CYP1A) and vitellogenin (Vtg) gene expression. Virgin LDPE MPs were exposed to influent and effluent from a wastewater treatment plant (WWTP) for four weeks to facilitate estrogen absorption. The MPs were then incorporated into fish feed pellets for dietary exposure experiments. Fish were divided into three treatment groups—exposed to either virgin MPs, WWTP-influent MPs, or WWTP-effluent MPs—and monitored over four weeks. The results showed that WWTP-exposed MPs carried detectable levels of estrogen, leading to physiological effects on yellowfin bream. Fish in the control group, which received MP-enriched diets without estrogen, experienced significant weight loss due to nutrient deprivation. In contrast, weight patterns in the treatment groups were influenced by estrogen exposure. The condition factor (CF) decreased across groups during the experiment but remained within acceptable health ranges. A significant reduction in the hepatosomatic index (HSI) was observed in the effluent-exposed group, likely due to lower estrogen levels reducing physiological stress. The findings confirm that LDPE MPs can act as carriers for estrogens, impairing fish growth and metabolism while disrupting biological processes such as cytochrome oxidase function. These results highlight the potential risks of MPs in marine ecosystems and underscore the need for further research to understand their long-term effects. Full article

Activated charcoal (AC) is an adsorbent that can prevent the accumulation of boar taint-causing compounds in the fat, but is not an approved dietary additive for livestock animals. Biochar (BC) is a similar feed-approved charcoal adsorbent that may be an alternative dietary additive to control boar taint. This study was conducted to evaluate AC and BC, both in vitro and in vivo, as dietary treatments for boar taint. This was done by first conducting an in vitro binding study to compare binding between AC, BC, and spent filter aid (SFA) for boar taint compounds. Results of the in vitro study showed that both AC and BC had significantly higher B_max for androstenone (AC: 97.2 ± 0.4% and BC: 84.5 ± 0.8%) and skatole (AC: 106.1 ± 0.2%, BC: 113.2 ± 0.7%), compared to SFA with a B_max of 50.5 ± 0.2% for androstenone and 97.1 ± 5.3% for skatole. AC and BC were then tested as feed additives in finisher diets fed to slaughter weight boars. Both adsorbents were successful at preventing boar taint in a subset of animals (83%), while having no effect on plasma levels of estrone sulfate or androstenone, and growth and performance parameters. These findings suggest that BC is a suitable alternative for AC as a dietary additive to prevent boar taint. Full article

Breast cancer (BC) remains a leading cause of cancer-related mortality in women. Extracellular matrix (ECM) remodeling is a critical modulator of tumor invasion and metastasis. Three-dimensional (3D) cell culture models have been proposed as advanced systems better mimicking the tumor microenvironment (TME), potentially offering enhanced insights into underlying mechanisms compared to conventional two-dimensional (2D) cultures. This study highlights how BC cells develop metastatic potential and tumor progression independently from ECM contact using advanced 3D spheroid culture models compared to traditional 2D cultures in triple-negative breast cancer (TNBC) cell lines. Spheroids were formed using ultra-low adhesion plates, and their morphological and functional properties were assessed via phase-contrast and scanning electron microscopy (SEM), along with functional assays. Both cell lines formed compact spheroids exhibiting mesenchymal-to-epithelial transition (MET) characteristics. Functional assays showed enhanced cell migration and dissemination of spheroid-derived cancer cells. Gene expression profiling revealed increased expression of ECM remodeling enzymes, cell surface receptors, and adhesion molecules in 3D cultures compared to 2D. MicroRNA analysis highlighted distinct regulatory patterns specifically associated with metastasis and epithelial-to-mesenchymal transition (EMT). These findings demonstrate that 3D spheroid models effectively recapitulate the complexity of TNBC, providing valuable insights into ECM dynamics, epigenetic regulation, and metastatic behavior and potentially guiding improved therapeutic strategies. Full article

Antrodia camphorata (AC), a medicinal fungus native to Taiwan, contains bioactive compounds such as triterpenoids with anticancer properties. However, their high lipophilicity results in poor aqueous solubility and limited bioavailability, restricting their therapeutic application. To address this issue, a nanoparticle-based delivery system was developed using chitosan, alginate, and hyaluronic acid to encapsulate AC extracts. AC-loaded nanoparticles (AC-NPs) with a particle size less than 100 nm improved drug solubility and facilitated intracellular accumulation. Assessment of cytotoxicity revealed that AC-NPs significantly and more effectively suppressed the growth of breast cancer cells than free AC extracts. After 72 h, IC₅₀ values for MDA-MB-231 (triple-negative) and MCF-7 (estrogen receptor-positive) were 46.9 and 75.6 μg/mL, respectively, with greater sensitivity observed in MDA-MB-231 cells. AC-NPs exhibited minimal toxicity toward normal mammary epithelial cells (NMuMG), indicating good biocompatibility. Fluorescently labeled AC-NPs showed rapid, time-dependent uptake in both cancer cell lines. Particularly, MDA-MB-231 cells exhibited rapid internalization, whereas MCF-7 cells likely benefited from hyaluronic acid-mediated targeting of CD44 receptors. In conclusion, AC-NPs enhanced the solubility, cellular uptake, and anticancer efficacy of AC while maintaining biocompatibility, thereby suggesting their robust potential as nanocarrier platforms for breast cancer therapy. Full article

BQ323636.1 (BQ) is a splice variant of NCOR2. Its overexpression is associated with endocrine therapy and chemoresistance in estrogen receptor-positive (ER+ve) breast cancer. This study investigates how BQ overexpression drives doxorubicin (DOX) resistance by enhancing androgen receptor (AR) signaling and non-homologous end joining (NHEJ). BQ overexpressed breast cancer cell lines (MCF-7, T-47D, BT-549, MDA-MB-453), showed increased AR activity (ARE-luciferase assay) and demonstrated DOX resistance (EC50 > 10-fold with DHT, p < 0.05), as assessed via cell viability, TUNEL, and comet assays. RNA-sequencing (GSE295979, GSE2048) revealed the involvement of AR signaling. BQ upregulated cell cycle-related kinase (CCRK), stabilizing KU70, a key NHEJ protein, resulting in enhanced NHEJ activity (EJ5-GFP assay, p < 0.01). Co-immunoprecipitation confirmed the interaction between CCRK and KU70, and CCRK was found to modulate the protein stability of KU70. AR inhibition with bicalutamide in BQ overexpressing cells reversed DOX resistance. Xenograft models validated AR-dependent DOX resistance. In ER+ve breast cancer patient samples, high CCRK expression correlated with DOX resistance (p = 0.002) and metastasis (p = 0.001). Kaplan–Meier analysis showed poorer overall survival (p < 0.001) and disease-specific survival (p < 0.001) in cancers with high CCRK. Cox-regression analysis showed that high CCRK was a poorer prognostic factor of overall survival (p < 0.001; RR 3.056, 95% CI 1.661, 5.621, AR (p < 0.001; RR 3.420, 95% CI 1.783, 6.562), and disease-specific survival (p < 0.001; RR 2.731, 95% CI 1.472, 5.067). The BQ-AR-CCRK-KU70 axis represents a novel mechanism of DOX resistance in ER+ve breast cancer, suggesting AR or CCRK inhibition as a potential therapeutic strategy. Full article

Background: Premenopausal women typically exhibit superior glucose metabolism compared to males, but this metabolic advantage is lost after menopause. The primary cause is the sharp decline in estrogen levels post-menopause. Genistein, a natural compound predominantly derived from leguminous plants, possesses structural similarity to estrogen. This enables specific binding to estrogen receptors, allowing genistein to exert estrogen-mimicking effects under conditions of estrogen deficiency. The aim of this study was to investigate the effects and potential mechanisms of genistein on glucose metabolism in the liver and skeletal muscle of ovariectomized (OVX) mice fed a high-fat diet (HFD). Methods: Animal experiments were performed using 8-week-old mice that were OVX to construct a model of estrogen deficiency and impaired their glucose metabolism by a continuous HFD. Genistein was administered by gavage (50 mg/kg-day) for 10 weeks and 17β-estradiol was administered subcutaneously (50 μg/kg) every 4 days for 10 weeks as a positive control. Results: Genistein significantly improved glucose metabolism (including fasting glucose, postprandial glucose, serum glucose levels, and HOMA-IR index) but did not affect serum estrogen levels and uterine weights in OVX mice. Genistein promoted increased expression and translocation of glucose transporter 4 (GLUT4) in the gastrocnemius muscle, enhanced phosphorylation of the PI3K/AKT pathway, and upregulated expression of the G protein-coupled estrogen receptor (GPER). Concurrently, it stimulates hepatic glycogen accumulation and upregulates GLUT2 expression in the liver. Conclusions: GEN improves glucose metabolism in ovariectomized mice, and this improvement is primarily attributed to increased expression and membrane translocation of GLUT4 in the gastrocnemius muscle mediated by the GPER-PI3K/AKT pathway. Full article