Search Results (1,031)

Endometriosis is a chronic, estrogen-dependent inflammatory disorder that is increasingly recognized as a systemic condition with profound implications for female reproductive potential. In addition to pelvic distortion and impaired folliculogenesis, growing evidence indicates that intrinsic alterations in oocyte morphology, mitochondrial function, and developmental competence contribute to infertility. The disease is driven by a multifactorial interplay of somatic mutations, epigenetic remodeling, immune dysregulation, and aberrant steroid signaling, which together create a pro-inflammatory, oxidative, and fibrotic microenvironment. Elevated cytokines, reactive oxygen species, and disrupted granulosa-cell function within the follicular niche impair meiotic progression, cytoplasmic maturation, and mitochondrial integrity, potentially accelerating oocyte aging and diminishing reproductive longevity. Epigenetic and post-transcriptional disturbances—including altered DNA methylation, histone modifications, and RNA-splicing defects—further reinforce estrogen dominance, progesterone resistance, and impaired decidualization, with downstream consequences for ovarian–endometrial communication. Although morphological abnormalities have been documented in oocytes from women with endometriosis, clinical outcomes remain heterogeneous, highlighting the need for integrative models that connect molecular alterations to functional reproductive endpoints. A deeper understanding of these mechanisms is essential for identifying biomarkers of oocyte competence and modifiable strategies—ranging from nutritional optimization to reduction of environmental risk factors—in clinical care to safeguard the reproductive potential of women with endometriosis. Full article

Sex steroid hormones play a pivotal role in maintaining systemic homeostasis throughout life. Their age-related decline is closely associated with the onset of frailty, including sarcopenia and dementia. Here, this article provides a narrative review of the existing literature about the multifaceted roles of sex steroid hormones, particularly estrogens and androgens, in aging and age-related diseases. Sex steroid action is mediated by nuclear receptors such as estrogen receptor alpha (ERα) and androgen receptor (AR). Transcriptional activation through these receptors is orchestrated by epigenetic mechanisms, including histone modifications and chromatin remodeling. Beyond their reproductive functions, sex hormones also influence systemic physiology, metabolism, immune responses, and neuroplasticity. Clinical studies on hormone-deprivation therapies for prostate and breast cancers, as well as animal models, have revealed the key contributions of AR and ER activity to muscle integrity, bone density, and cognitive function. The sexual dimorphism in cognitive decline, especially in postmenopausal women, suggests the therapeutic potential of hormone supplementation and receptor-targeted strategies. Thus, AR- and ER-associated genes are considered promising targets for preventing frailty, sarcopenia, osteoporosis, and dementia. This review summarizes the current knowledge on sex hormone signaling in aging, with an emphasis on translational implications and future research directions. Full article

Endometriosis is a chronic, estrogen-dependent inflammatory condition affecting approximately 10% of women of reproductive age worldwide. It is characterized by the presence of endometrial-like tissue outside the uterine cavity, which frequently results in dysmenorrhea, chronic pelvic pain, dyspareunia, and infertility. While hormonal medications and surgical procedures are common treatments, they are often constrained by adverse effects and high recurrence rates. The aim was to systematically identify, critically appraise, and synthesize randomized controlled trials evaluating vitamin D, C, and E supplementation in women with endometriosis, focusing on their effects on pelvic pain, dysmenorrhea, dyspareunia, quality of life, oxidative and inflammatory biomarkers, and fertility-related outcomes, and to highlight methodological gaps that can inform future research and integrated therapeutic strategies. Following PRISMA guidelines, seven eligible RCTs were identified from databases including PubMed, Scopus, and ScienceDirect. The quality of these studies was assessed using the Jadad Scoring System and Cochrane RoB 2 tool. High-dose supplementation of vitamin D (50,000 IU) was found to significantly reduce pelvic pain and improve biochemical markers such as hs-CRP and total antioxidant capacity (TAC). Vitamin D appears to modulate endometrial pathways by reducing active β-catenin protein activity, which may disrupt signaling associated with lesion invasion and survival. Additionally, combined Vitamin C and E therapy (typically 1000 mg/day of Vitamin C and 800 IU/day of Vitamin E) acts synergistically to scavenge free radicals. This intervention significantly decreased oxidative stress markers, including malondialdehyde (MDA) and reactive oxygen species (ROS). Patients reported significant improvements in symptoms, including a 43% reduction in daily pelvic pain and a 37% reduction in dysmenorrhea. Despite physiological improvements, there was no statistically significant increase in pregnancy rates observed across the trials. Vitamin supplementation with D, C, and E represents a safe, low-cost adjunct therapy that can effectively mitigate endometriosis-related oxidative stress and pelvic pain. While these vitamins show promise for symptom relief, further research with larger sample sizes is required to determine their long-term impact on fertility outcomes and lesion regression. Full article

Osteoporosis is a prevalent metabolic bone disorder characterized by reduced bone mass, compromised microarchitecture, and increased fracture risk. Its pathogenesis extends beyond simple bone mineral density (BMD) loss and reflects complex disruptions in bone remodeling governed by osteoblast–osteoclast coupling and systemic metabolic factors. This review lays particular emphasis on diabetes mellitus-related osteoporosis (DOP) and estrogen deficiency-induced osteoporosis (EDOP), discussing bone remodeling between osteoclastogenesis and osteoblast differentiation regulated by key signaling pathways, including the RANKL/RANK/OPG, Wnt/β-catenin, BMP–Smad, Hedgehog, and inflammatory cytokine networks. This review then explores how chronic hyperglycemia, insulin deficiency or resistance, oxidative stress, ferroptosis, advanced glycation end products, and low-grade inflammation disrupt bone homeostasis in diabetes, resulting in impaired bone quality and elevated fracture risk, particularly in type 2 diabetes. In parallel, we discuss the genomic and non-genomic actions of estrogen in maintaining skeletal integrity and elucidate how estrogen deficiency accelerates bone resorption and suppresses bone formation through altered cytokine signaling, oxidative stress, and impaired mechanotransduction. Advances in diagnostic strategies beyond BMD, including trabecular bone score, high-resolution peripheral quantitative computed tomography, and emerging biomarkers, are reviewed. Finally, this review summarizes current and emerging therapeutic approaches tailored to DOP and EDOP, emphasizing the need for mechanism-based, individualized management. A deeper understanding of these shared and distinct pathways may facilitate improved risk stratification and the development of targeted interventions for osteoporosis. Full article

Background: This study is part of the HEAL ITALIA partnership, funded by the National Recovery and Resilience Plan (PNRR) and the European Union. Heart failure (HF) is a serious health problem, with a reduced density of the β1-adrenergic receptor (β1-AR) in the myocardium as a hallmark. It is unclear whether this downregulation causes dysfunction or represents an epiphenomenon. Recent evidence implicates oxidative stress and mitochondrial signaling, particularly through the 18 kDa translocator protein (TSPO), in the regulation of the β1-AR, with possible modulation by estrogen. Objectives: To determine (1) the role of β1-AR desensitization in the onset and development of HF; (2) whether monocytes can represent a suitable ex vivo model for sex-oriented mechanistic studies in the cardiac field; (3) whether monocytes isolated from peripheral blood of patients can represent a diagnostic and/or therapy response biomarker by monitoring β1-AR density; (4) whether and how the mitochondrial receptor TSPO is involved in the β1-AR dysregulation observed in HF; and (5) whether the mechanisms linked to the onset of HF are regulated in a sex-specific manner through the effect of estrogen and/or the X chromosome on the expression of specific microRNAs. Methods: Using an integrated in vitro-ex vivo-in vivo methodological approach, we will evaluate the density of β1/β2-AR receptors, the downstream signaling (GRK2/β-arrestin), mitochondrial and redox parameters, and miRNA profiles in human monocytes and cardiomyocytes, and in mouse hearts after HF following pressure overload. Conclusions: The goal is to better understand the mechanisms underlying β1-AR desensitization, verify monocytes as peripheral markers of disease progression and response to therapy, and provide potentially useful information for the development of gender-specific therapies for heart failure. Full article

Fine particulate matter (PM2.5)-induced ovarian damage has attracted widespread attention, but differences in cytotoxicity and underlying mechanisms of water-soluble (WS-PM2.5) and water-insoluble (WIS-PM2.5) fractions are unclear. To investigate potential effects of PM2.5 from livestock farming environments on animal ovaries, PM2.5 samples were collected from large-scale cattle barns. There were significant differences between fractions regarding elemental composition, proportion of water-soluble ions, polycyclic aromatic hydrocarbon content, and endotoxin concentrations. Based on transcriptome sequencing results, in a cowshed PM2.5 exposure model (rats), differentially expressed ovarian mRNAs were significantly enriched in signaling pathways such as cytokine interaction and the Hippo pathway, with the expression of thioredoxin-interacting protein (Txnip) significantly increased. In vitro (primary rat ovarian granulosa cells), short-term exposure to WS-PM2.5 (12 h) significantly induced inflammatory factor release, acute oxidative stress, mitochondrial dysfunction, and intracellular Ca²⁺ overload, with characteristics of rapid acute injury. However, extended (24 h) WIS-PM2.5 exposure had greater disruptive effects on estrogen homeostasis, intracellular enzyme release (LDH), and mitochondrial structure (subacute characteristics). Furthermore, downregulating Txnip expression via inhibitors effectively mitigated cowshed PM2.5-induced ovarian granulosa cell toxicity, oxidative stress, and mitochondrial and hormonal dysfunction. In summary, solubility of cowshed PM2.5 components affected cytotoxic characteristics, and Txnip was a key factor linking oxidative stress to granulosa cell damage. The study provided a mechanistic basis and potential targets for preventing and controlling PM2.5-induced ovarian damage in livestock environments. Full article

Breast cancer is a significant cause of death worldwide. Recent research has focused on identifying natural compounds for developing effective cancer treatments. Resiniferatoxin, a transient receptor potential vanilloid 1 (TRPV1) agonist, is a common diterpene in Euphorbia bicolor Engelm. & A. Gray (Euphorbiaceae), a plant native to the southern United States that has not been studied before. We investigated the antiproliferative activities and mechanisms of action of E. bicolor xylene extract in estrogen receptor-positive T47D and triple-negative MDA-MB-231 cell lines. The extract significantly reduced the viability of T47D and MDA-MB-231 cells in a dose-dependent manner. In MDA-MB-231 cells, the extract induced apoptosis via intracellular calcium overload, triggered by TRPV1 activation. This effect was diminished by the TRPV1 antagonist capsazepine and the calcium chelator BAPTA-AM. Intracellular calcium influx was confirmed through Fura-2 AM staining, revealing that E. bicolor phytochemicals activated TRPV1 in MDA-MB-231 cells. Treatment of T47D cells with E. bicolor xylene extract resulted in apoptosis associated with reactive oxygen species (ROS) generation (10-fold higher in T47D cells than in MDA-MB-231 cells) and mitochondrial calcium overload. These effects were significantly blocked when cells were pretreated with N-acetyl-l-cysteine (NAC), a ROS inhibitor. Both cell lines underwent apoptosis via multiple mitochondrial- and endoplasmic reticulum stress–mediated pathways. This was supported by the activation of caspases 3, 8, and 9; increased expression of FAS, XBP1s, and CHOP; upregulation of BAX; and downregulation of BCL-2. In addition, PI3K, AKT, and pAKT protein expressions were also reduced in both cell lines, indicating downregulation of PI3K/Akt signaling pathway. Phytochemicals in E. bicolor xylene extract could become promising ingredients for developing breast cancer therapeutics. Full article

Women exhibit a higher prevalence of depression, anxiety, stress-related disorders, and autoimmune conditions compared to men, yet the biological mechanisms underlying this sex difference remain incompletely understood. Growing evidence identifies neuroinflammation as a central mediator of psychiatric vulnerability in women, shaped by interactions between sex hormones, immune activation, and neural circuit regulation. Throughout the female lifespan, fluctuations in estrogen and progesterone, such as those occurring during puberty, the menstrual cycle, pregnancy, postpartum, and perimenopause, modulate microglial activity, cytokine release, and neuroimmune signaling. These hormonal transitions create windows of heightened sensitivity in key brain regions involved in affect regulation, including the amygdala, hippocampus, and prefrontal cortex. Parallel variations in systemic inflammation, mitochondrial function, and hypothalamic–pituitary–adrenal (HPA) axis responsivity amplify stress reactivity and autonomic imbalance, contributing to increased risk for mood and anxiety disorders in women. Emerging data also highlight sex-specific interactions between the immune system and monoaminergic neurotransmission, gut–brain pathways, endothelial function, and neuroplasticity. This review synthesizes current neuroscientific evidence on the sex-dependent neuroinflammatory mechanisms that bridge hormonal dynamics, brain function, and psychiatric outcomes in women. We identify critical periods of vulnerability, summarize converging molecular pathways, and discuss novel therapeutic targets including anti-inflammatory strategies, estrogen-modulating treatments, lifestyle interventions, and biomarkers for personalized psychiatry. Understanding neuroinflammation as a sex-specific process offers a transformative perspective for improving diagnosis, prevention, and treatment of psychiatric disorders in women. Full article

Background: Lung adenocarcinoma in non-smoking women represents a distinct clinical entity that cannot be fully explained by traditional exposure-centered carcinogenic models. Although ambient air pollution is a recognized risk factor, sex-specific vulnerability suggests the involvement of additional biological modulators shaping inflammatory, immune, and proliferative responses. Main body: In this conceptual review, we integrate epidemiological, experimental, and mechanistic evidence to propose a multisystem framework of lung carcinogenesis in non-smoking women. We delineate a central carcinogenic spine encompassing lung epithelial injury, chronic inflammation, growth factor signaling activation—particularly epidermal growth factor receptor (EGFR) pathways—and tumor microenvironment remodeling. Within this framework, three interacting domains function as biological modulators that amplify carcinogenic processes: chemosensory–neural–immune modulation, hormonal–endocrine signaling including estrogen–EGFR crosstalk, and psychosocial stress–hypothalamic–pituitary–adrenal (HPA) axis dysregulation. These domains converge through feedback mechanisms that reinforce systemic dysregulation and tumor-promoting microenvironments. Implications: This integrative model provides a biologically grounded perspective on female-specific vulnerability to lung adenocarcinoma and informs precision prevention, risk stratification, and ESG-informed public health strategies beyond conventional exposure reduction. Full article

Estrogen receptor-positive (ER⁺) breast cancer represents the most prevalent molecular subtype of breast cancer, characterized by hormone-dependent growth, relatively indolent progression, and a pronounced tendency to metastasize to bone. While endocrine therapies remain the cornerstone of treatment, a significant proportion of ER⁺ tumors eventually develop resistance, culminating in distant metastases—most frequently to the bone. Bone metastasis substantially compromises patient survival and quality of life, highlighting the critical need to elucidate its molecular underpinnings. Recent multi-omics and mechanistic studies have shed light on the complex interplay between tumor-intrinsic signaling pathways, such as dysregulated ER signaling, PI3K/AKT/mTOR, TGF-β, and Hippo pathways, and the bone microenvironment, including osteoclast activation, immune suppression, and stromal remodeling. This review systematically summarizes the current understanding of the molecular mechanisms driving bone metastasis in ER⁺ breast cancer, with a particular focus on tumor–bone microenvironment crosstalk and key regulatory pathways. Additionally, we discuss recent advances in therapeutic strategies, encompassing next-generation endocrine therapies, CDK4/6 inhibitors, bone-targeted agents, and pathway-specific inhibitors. Together, these insights pave the way for more effective and personalized interventions against ER⁺ breast cancer with bone involvement. Full article

Objectives: To systematically analyze the expression profiles of long non-coding RNAs (lncRNAs) in serum-derived exosomes from patients with age-related hearing loss (ARHL), and to further identify key regulatory lncRNAs involved in the pathogenesis and progression of ARHL. Methods: Peripheral blood samples were collected from patients with ARHL and age-matched normal-hearing controls. Serum was separated and exosomes were extracted. The exosomes were identified by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and Western blot. Subsequently, total RNA was extracted from the purified exosomes for lncRNA transcriptome sequencing. Based on the sequencing results, we identified differentially expressed lncRNAs and mRNAs and conducted multi-dimensional functional analysis, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome pathway database (Reactome), and Disease Ontology (DO). Finally, four key mRNAs (THAP2, ZNF225, MED12, and RNF141) and four differentially expressed lncRNAs (DE-lncRNAs), namely MSTRG.150961.7, ENSG00000273015, MSTRG.336598.1, and ENSG00000273493, were experimentally verified by quantitative real-time polymerase chain reaction (RT-qPCR) technology. Results: Exosomes were successfully isolated from serum and confirmed by particle size, morphological examination, and the expression of exosome-labeled proteins. A total of 2874 DE-lncRNAs were identified, among which 988 were downregulated and 1886 were upregulated. Similarly, 2132 DE-mRNAs were detected, among which 882 were downregulated and 1250 were upregulated. GO analysis revealed significant enrichment in biological processes such as “phospholipid binding”, “phosphatidylinositol binding”, “phosphatase binding”, “phosphatidylinositol bisphosphate binding”, “phosphatidylinositol-4,5-bisphosphate binding”, “phosphatidylinositol-3,5-bisphosphate phosphatase activity”. KEGG is significantly enriched in signaling pathways including “Wnt signaling pathway”, “Hippo signaling pathway”, “Cushing syndrome”, and “Nucleocytoplasmic transport”. The functional annotations of Reactome were significantly enriched in biomolecular pathways including “tRNA processing”, “Cellular response to heat stress”, “Extra-nuclear estrogen signaling”, “Metabolism of non-coding RNA”, and “CTNNB1 T41 mutants aren’t phosphorylated”. DO is significantly enriched in diseases or pathological conditions such as “hepatitis”, “bacterial infectious disease”, “cystic fibrosis”, and “vasculitis”. Conclusions:THAP2, ZNF225, MED12, and RNF141 may serve as potential candidate biomarker for ARHL. Additionally, lncRNA MSTRG.150961.7, lncRNA MSTRG.336598.1, and lncRNA ENSG00000273493 may play significant roles in the pathogenesis of this condition. Full article

Obesity has reached epidemic proportions, driven by energy imbalance and limited capacity for adaptive thermogenesis. Brown (BAT) and beige adipose tissues dissipate energy through non-shivering thermogenesis (NST), primarily via uncoupling protein-1 (UCP1), making them attractive targets for increasing energy expenditure (EE). The canonical β-adrenergic pathway robustly activates NST in rodents through β3 adrenoceptors; however, translational success in humans has been limited by low β3 expression, off-target cardiovascular effects, and the emerging dominance of β2-mediated signaling in human BAT. Consequently, attention has shifted to non-adrenergic and UCP1-independent mechanisms that offer greater tissue distribution and improved safety profiles. This review examines a broad spectrum of alternative receptors and pathways—including GPRs, TRP channels, TGR5, GLP-1R, thyroid hormone receptors, estrogen receptors, growth hormone, BMPs, sirtuins, PPARs, and interleukin signaling—as well as futile substrate cycles (Ca²⁺, creatine, and glycerol-3-phosphate) that sustain thermogenesis in beige adipocytes and skeletal muscle. Pharmacological agents (natural compounds, peptides, and small molecules) and non-pharmacological interventions (cold exposure, exercise, diet, and time shift) targeting these pathways are critically evaluated. We highlight the translational gaps between rodent and human studies, the promise of multimodal therapies combining low-dose adrenergic agents with non-adrenergic activators, and emerging strategies such as sarco/endoplasmic reticulum calcium ATPase protein (SERCA) modulators and tissue-specific delivery. Ultimately, integrating adrenergic and non-adrenergic approaches holds the greatest potential for safe, effective, and sustainable obesity management. Full article

Soybean (Glycine max L.) is an essential food and economic crop in China, yet its growth and yield are severely constrained by saline–alkali stress. A saline–alkali soil exacerbates root absorption barriers, leading to 30–50% yield losses. Understanding the mechanisms underlying alkali tolerance is therefore crucial for developing stress-resilient soybean varieties and improving the productivity of saline–alkali land. In our previous study, we evaluated 99 soybean germplasms from Northeast China and obtained the alkali-tolerant varieties HN48 and HN69, along with the alkali-sensitive varieties HNWD4 and HN83. In this study, fifteen-day-old soybean seedlings were subjected to (30 mM NaHCO₃) alkali stress for 72 h, and whole plants were sampled to assess their morphology and physiology, while leaf tissues were harvested for biochemical analysis. For transcriptomic analysis, soybean seedlings were exposed to alkali stress (50 mM NaHCO₃, pH 9.0) for 6 h, and leaf and root tissues were harvested for RNA sequencing. The results showed that alkali-tolerant varieties mitigated these effects by suppressing excessive ROS generation by 55–63%, decreasing malondialdehyde (MDA) accumulation by 37–39%, and increasing photosynthetic efficiency by 18.3%, as well as accumulating more osmoprotectants and activating antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) under alkaline stress. Transcriptome analysis showed that the alkali-tolerant variety HN69 exhibited cultivar-specific enrichment of metabolism cytochrome P450, estrogen signaling, and GnRH signaling pathways under alkali stress. These results collectively indicate that alkali-tolerant soybean varieties adapt to alkali stress through coordinated multi-pathway responses, with differential pathway enrichment potentially underlying the variation in alkali tolerance between cultivars. Overall, this study elucidates the physiological and molecular mechanisms of alkali tolerance in soybean, providing a theoretical foundation for breeding stress-tolerant germplasms. Full article

Thyroid hormones (THs) regulate metabolism, proliferation, and genomic stability. Clinical studies have linked levothyroxine therapy with higher Oncotype DX Recurrence Scores in breast cancer (BC), suggesting a potential effect of thyroid hormone signaling on genomic risk. Here, we investigated the impact of triiodothyronine (T3) on DNA damage and repair pathways in estrogen receptor-positive T47D breast cancer and non-tumorigenic MCF10A cells. RNA sequencing revealed significant upregulation of RAD51 and enrichment of DNA repair pathways following 24 h T3 exposure. Consistently, T3 increased γH2AX and 53BP1 nuclear foci, indicating transient activation of the DNA damage response (DDR). These effects were transient, returning to baseline after 48 h, suggesting cellular adaptation. T3 also enhanced proliferation at 10 μM but inhibited growth at higher concentrations. Our findings indicate that acute exposure to T3 induces transient genomic stress, providing a potential mechanistic basis for the observed association between thyroid hormone therapy and increased BC recurrence risk. Full article

Osteoporosis is a prevalent skeletal disorder characterized by reduced bone mass and microarchitectural deterioration, leading to increased fracture risk, particularly in aging populations. Postmenopausal osteoporosis (PMOP) remains the most common primary form and results from abrupt estrogen deficiency after menopause, which disrupts bone remodeling by accelerating the receptor activator of nuclear factor-κB ligand (RANKL)-mediated osteoclastogenesis, suppressing Wnt/β-catenin signaling, and promoting inflammatory cytokine production. In contrast, drug-induced osteoporosis (DIOP) encompasses a heterogeneous group of secondary bone disorders arising from pharmacologic exposures. Glucocorticoids suppress osteoblastogenesis, enhance osteoclast activity, and increase reactive oxygen species; long-term bisphosphonate therapy may oversuppress bone turnover, resulting in microdamage accumulation; denosumab withdrawal triggers a unique rebound surge in RANKL activity, often leading to rapid bone loss and multiple vertebral fractures. Medications including aromatase inhibitors, SSRIs, proton pump inhibitors, heparin, and antiepileptic drugs impair bone quality through diverse mechanisms. Standard antiresorptive agents remain first-line therapies, while anabolic agents such as teriparatide, abaloparatide, and romosozumab provide enhanced benefits in high-risk or drug-suppressed bone states. Transitional bisphosphonate therapy is essential when discontinuing denosumab, and individualized treatment plans—including drug holidays, lifestyle interventions, and monitoring vulnerable patients—are critical for optimizing outcomes. Emerging approaches such as small interfering RNA (siRNA)-based therapeutics, anti-sclerostin agents, digital monitoring technologies, and regenerative strategies show promise for future precision medicine management. Understanding the distinct and overlapping molecular mechanisms of osteoporosis is essential for improving fracture prevention and long-term skeletal health. Full article