Search Results (262)

Previous research has demonstrated sex-specific differences in muscle cells regarding sex hormone release and steroidogenic enzyme expression after testosterone exposure. The present study aims to elucidate sex-related differences in intracellular processes involved in myogenesis and regeneration. Neonatal 46XX and 46XY human primary skeletal muscle cells were treated with increasing doses of testosterone (0.5, 2, 5, 10, 32, and 100 nM) for 24 h. The molecular pathways involved in muscle metabolism and growth, as well as the release of myokines involved in satellite cell activation, were analyzed using western blot, real-time PCR, and a Luminex assay. The unpaired Student’s t-test and one-way ANOVA for repeated measures were used to determine significant variations within and between groups. An increase in the expression and release of MYF6, IGF-I, IGF-II, and CXCL1, as well as a decrease in GM-CSF, IL-9, and IL-12, was observed in 46XX cells. Conversely, testosterone up-regulated GM-CSF and CXCL1 in 46XY cells but did not affect the release of the other myokines. Preferential activation of the MAPK pathway was observed in 46XX cells, while the PI3K/AKT pathway was preferentially activated in 46XY cells. In conclusion, our findings demonstrate differential responses to androgen exposure in 46XX and 46XY cells, resulting in the activation of muscle cell growth and energy metabolic pathways in a sex-specific manner. Full article

The anti-Müllerian hormone (amh) and its receptor, amhr2, along with the downstream bone morphogenetic protein receptors (bmprs), have been recognized as the central regulators in teleost sex determination (SD) and differentiation. However, their evolution and function in reproduction among diverse teleost lineages may represent species-specific patterns and still need more explanation. In this study, systematic investigations of amh signaling genes, including amh, amhy (Y-linked paralog of amh), amhr2, bmpr1, and bmpr2, were conducted among teleost species. The results revealed generally conserved gene copy number, phylogeny, structure, and synteny, among teleost amh signaling genes. Notably, significantly accelerated evolutionary rates (dN/dS) were found in teleost amhy compared to amh, and amh exhibited faster molecular evolution in amhy-SD teleosts than in non-amhy-SD teleosts, suggesting their enhanced evolutionary plasticity in teleosts. Expression profiling identified testis-biased expression of the most amh signaling genes in fish species with different SD genes and mechanisms, including Lateolabrax maculatus and Dicentrarchus labrax from Order Perciformes, Cynoglossus semilaevis and Paralichthys olivaceus from Order Pleuronectiformes, and Salmo salar and Oncorhynchus mykiss from Order Salmoniformes, with ovary-biased expression also found in Salmoniformes. A weighted gene co-expression network analysis further uncovered strong species-specific functional interactions between amh signaling components and genes of germ-cell development, the meiotic process, etc. Collectively, the integrated evidence from this study supports the hypothesis that amh signaling provides the key molecules governing sex differentiation in a species-specific manner in diverse teleost lineages, independent of its SD role, and interacts with functions of both testis and ovary development. Full article

Background and Objectives: Chronic pain (CP), defined as pain persisting for over 3 months, is a significant cause of global disability and affects more than 20% of individuals in Western countries, including Italy. Substantial evidence indicates a higher prevalence of CP among women, who also experience greater sensitivity, increased frequency, and a longer duration of pain. The impact of CP on quality of life, daily functioning, and employment is profound, particularly for women. However, chronic pain research has insufficiently addressed sex and gender differences, contributing to suboptimal and inequitable care. This neglect limits the development of personalized treatment strategies and, when combined with an aging population and women’s longer life expectancy, highlights an increasing societal and economic burden. Materials and Methods: The authors conducted a narrative review of studies examining biological, psychological, or social determinants of sex-related differences in CP perception or treatment. Each thematic area was reviewed by at least two authors, who critically appraised the literature. Their analyses were refined through iterative group discussions to develop concise, evidence-informed recommendations for personalized and equitable pain management. Results: Sex differences in CP arise from a range of factors, including biological mechanisms such as hormonal and genetic influences, psycho-social factors such as depression and anxiety, and socio-economic determinants, such as income and education levels. These factors also affect sex-specific outcomes of analgesic treatments currently available. Identifying these risk factors and tailoring treatment strategies to sex differences can significantly improve CP management. Such a personalized approach is essential for advancing precision medicine in CP management. Even in the absence of molecular or genomic biomarkers, adopting a biopsychosocial model that considers sex and gender differences, symptoms, physiological indicators, medical history, lifestyle, and psychological aspects may substantially enhance patient outcomes. Conclusions: This review provides a comprehensive analysis of sex differences in CP perception, stressing the importance of individualized, interdisciplinary approaches in pain management. Addressing both the biological and psycho-social contributors to pain in men and women is critical for guiding healthcare professionals in implementing precision pain medicine strategies, ultimately fostering more equitable and effective care. Full article

The Pacific white shrimp, Litopenaeus vannamei (L. vannamei), is an important aquaculture species, yet the molecular mechanisms underlying its sex differentiation and gonadal development remain poorly understood. A deeper understanding of these processes is critical for advancing broodstock quality and enabling unisex breeding strategies. While previous studies have focused on gene expression differences between females and males, structural differences in transcriptomic regulation between sexes have been largely overlooked. Here, we present a comprehensive full-length transcriptome analysis of L. vannamei testis and ovary, identifying 830 and 690 novel genes, respectively, and over 6000 new isoforms. Notably, we discovered extensive alternative splicing (AS) events, with the cartilage oligomeric matrix protein-like gene exhibiting over 300 AS isoforms in the ovary compared to only 2 in the testis, suggesting a potential role in ovarian development. Furthermore, sex-determining genes such as Fem-1a, Fem-1c, and Sxl were found to produce AS isoforms exclusively in ovarian tissue. We also identified three germ cell development-associated genes—MAD2-like, RAD51-like, and Su(dx)-like—that undergo distinct AS events in gonadal tissues, leading to sex-specific structural domain alterations. These findings highlight the complexity of AS-mediated post-transcriptional regulation in L. vannamei and provide novel insights into the molecular mechanisms governing sex differentiation and gonadal development. Full article

Background: Lung cancer is the leading cause of cancer-related death in the male sex worldwide. Non-small cell lung cancer (NSCLC) is the most prevalent type, accounting for 80–85% of cases, and lung adenocarcinoma is the most common and lethal NSCLC subtype, being responsible for ca. 50% of deaths. Despite new therapeutic strategies, lung cancer mortality rates remain high, highlighting the need for the development of new drugs. Objectives: We investigated the pharmacological potential of a series of curcumin-like compounds using two lung adenocarcinoma cell lines as models. Methods and Results: Cell viability assay led to the identification of PQM-214 as the hit compound, and other methodologies were employed to investigate the mechanisms underlying its antitumor potential, including cell cycle analysis, mitotic index determination, assessment of clonogenic capacity, senescence-associated β-galactosidase and annexin V assays, quantitative PCR, and Western blot analyses. The mechanism of action of PQM-214 was investigated in A549 cells, revealing that it effectively inhibits cell proliferation by inducing cell cycle arrest, apoptosis, or senescence. Cell cycle key regulators were significantly modulated by PQM-214, with cyclin E2, MYC, and FOXM1 being downregulated, while senescence markers such as cyclin D1, CDKN1A (p21), IL-8, TIMP1, and TIMP2 were upregulated. Moreover, Western blot results revealed upregulation of cyclin D1 and p21 in PQM-214-treated samples, with a downregulation of cyclin B. Conclusions: PQM-214 seems to act on different molecular targets in lung adenocarcinoma cells, inhibiting cell proliferation and inducing apoptosis. Further studies will be conducted to explore whether PQM-214 can also act as a senolytic agent, which would reinforce its anticancer potential. Full article

Cannabis sativa L. is a dioecious species known to produce over 1600 chemical constituents, including more than 180 cannabinoids classified into 11 structural groups. These bioactive compounds are predominantly synthesised in the glandular trichomes of female inflorescences. However, sex determination in C. sativa is influenced by both genetic and environmental factors, often leading to the development of male flowers on female plants. This unintended fertilisation reduces cannabinoid yield and increases genetic heterogeneity and challenges in medical cannabis production. Haploid and doubled haploid (DH) technologies offer a promising solution by rapidly generating homozygous lines from gametophytic (e.g., unpollinated ovaries and ovules) or sporophytic tissues (e.g., anthers and microspores) via in vitro culture or chromosome reduction during hybridisation. In land plants, the life cycle alternates between a diploid sporophyte and a haploid gametophyte generation, both capable of mitotic division to form multicellular bodies. A single genome regulates this phase transition and encodes the molecular, genetic, and epigenetic mechanisms that precisely control the developmental processes unique to each generation. While the application of haploid technology in C. sativa remains limited, through recent progress in haploid induction (HI) and CRISPR-based genome editing, the direct modification of haploid gametes or embryos enables the creation of null homozygous lines following chromosome doubling, improving genetic uniformity. Understanding the molecular mechanisms of spontaneous chromosome doubling may further facilitate the development of elite cannabis genotypes. Ultimately, enhancing the efficiency of DH production and optimising genome editing approaches could significantly increase the speed of genetic improvement and cultivar development in Cannabis sativa. Full article

HSD3B1 encodes an enzyme that catalyzes the conversion of adrenal precursors into potent sex steroids. A common germline variant (c.1100C) enhances this effect and is linked to breast cancer (BC) progression. As the HSD3B1 genotypes contribute to differences in local and adrenal steroid production, their transcriptional and phenotypic effects on cancers influenced by hormonal signaling such as BC and endometrial cancer (EC)—particularly in relation to menopausal status—remain unclear. We analyzed BC and EC sequenced from patients that received diagnostic tests in oncology clinics, and we determined the germline HSD3B1 c.1100 genotype (AA, AC, CC) from tumor DNA sequencing by using variant allele frequency, with inferred menopausal status assumed by age at molecular profiling. Whole-transcriptome RNA sequencing and gene set enrichment analysis showed that adrenal-permissive homozygous (CC) tumors in premenopausal ER + BC were enriched for hormone-related pathways, including Estrogen Response Early (NES ≈ +1.8). In premenopausal triple-negative BC, adrenal-restrictive homozygous (AA) tumors exhibited the elevated expression of immune and epithelial genes and the increased prevalence of MED12 alterations (AA 0.25% vs. CC 8%, p < 0.01). In endometrioid EC, CC tumors demonstrated the suppression of immune and proliferative pathways. Postmenopausal cases had higher progesterone receptor IHC positivity (AA 75% vs. CC 83%, p < 0.05) and numerically more frequent ESR1 copy number gains (AA 2.0% vs. CC 4.0%). Results highlight context-specific associations between germline HSD3B1 genotypes and tumor biology in BC and EC. Full article

Background: The accurate determination of bird sex is crucial in various biological fields, including ecology, behavioral research, and conservation. However, this task remains challenging in species in which males and females exhibit similar external morphologies, such as owls. Although polymerase chain reaction (PCR)-based molecular sexing techniques that target the chromodomain helicase DNA-binding protein 1 gene found on sex chromosomes Z (CHD1-Z gene) and W (CHD1-W gene) are widely used, we encountered atypical banding patterns when applying the previously reported primers 2550F and 2718R to four wild owls of unknown sex. This study aims to reveal the owl-specific genetic structure of the CHD1 gene. Methods: We developed a new primer set and determined the nucleotide sequences—including the binding sites for the primers 2550F and 2718R—within both the CHD1-Z and CHD1-W genes. Results: Sequencing analysis, conducted using a newly developed primer set that successfully amplified both Z- and W-derived CHD1 products across various owl species, revealed a unique genetic insertion of approximately 600 bp in intron 17 of the CHD1-W gene. This insertion reversed the usual length relationship between PCR products from the chromosomes Z and W. Additionally, mutations identified in the 2550F primer binding site of the CHD1-Z gene in certain owl species may explain the failure to amplify CHD1-Z-derived PCR products. Conclusion: These findings provide valuable insights for improving molecular sexing in owls. Full article

The Scatophagus argus (S. argus) is a valuable aquaculture species in southern China, with females exhibiting significantly faster growth rates than males. However, the limited understanding of its sex determination and differentiation mechanisms poses challenges for sex-controlled breeding. MicroRNAs (miRNAs), key post-transcriptional regulators, are known to modulate critical pathways governing sex determination and differentiation across several vertebrates. However, there is currently no research on miRNAs related to sex determination and differentiation in S. argus. In this study, we analyzed the expression profiles of miRNA and mRNA in the gonads of adult S. argus using high-throughput sequencing. Our analysis identified 2210 miRNAs, including 482 differentially expressed miRNAs (DEMs) between sexes. These DEMs targeted 3340 differentially expressed genes (DEGs), generating 13,773 regulatory interaction pairs. The expression of some DEGs related to sex determination and differentiation was found to be either positively or negatively correlated with expression of DEMs that might regulate them. The novel_miR_110/Foxl2, novel_miR_802/Gdf9, and novel_miR_1263/Gdf9 show opposing differential expression trends, whereas sar-miR-143-5p-4/Gsdf, sar-miR-143-5p-5/Gsdf, and novel_miR_379/Sox3 show consistent trends. The regulatory relationship between miRNA and gene in the gonads does not seem to be conserved among different fish species. This work advances our understanding of the molecular mechanisms underlying the sexual dimorphism of gonadal gene expression in S. argus. The identified miRNA–gene interactions may serve as potential targets for future sex-control strategies, contributing to advancements in aquaculture practices for this species. Full article

Multiple sclerosis (MS) is a chronic inflammatory, neurodegenerative disease with yet-unresolved mechanisms of progression. To address MS severity and neurological deficits, we analyzed seven potentially functional genetic variants and their haplotypes in 845 MS patients. Based on our previous results of targeted RNAseq on ferroptosis-related genes in distinctive MS phenotypes, we selected putative regulatory variants in the top three DEGs (CDKN1A, MAP1B and EGLN2) and investigated their association with gene expression, plasma/serum parameters and disease severity (EDSS, MSSS, gARMSS). The study included 604 patients with relapsing–remitting (RR) and 241 with progressive (P) MS. The variants CDKN1A rs3176326 and rs3176336, EGLN2 rs111833532, MAP1B rs62363242 and rs1217817 with the previously reported DYSF-ZNF638 locus rs10191329, and MTSS1 rs9643199 were genotyped using TaqMan^®, and the HLA-DRB1*15:01 status was also determined. Significant association of the rare MAP1B rs62363242 allele with PMS in females, independent of HLA-DRB1*1501, was found. The A allele-containing genotypes were associated with molecular components of iron metabolism. CDKN1A haplotypes were significantly associated with CDKN1A mRNA levels in RRMS and SPMS patients. RAB4B-EGLN2 locus rs111833532 and DYSF-ZNF638 locus rs10191329 showed significant associations with EDSS, MSSS and gARMSS. We detected haplotypes associated with the expression of CDKN1A, a part of the p53-p21 axis known to affect T cell activation/proliferation. RAB4B-EGLN2, an oxygen sensor and critical regulator of the response to hypoxia, variant rs111833532, along with DYSF-ZNF638 locus rs10191329, was associated with clinical severity. The indicated, novel, sex-specific association of MAP1B rs62363242 with the course of MS remains to be validated in larger studies. Full article

We profiled the gene expressions in the hypothalamic paraventricular nuclei of 12 male and 12 female pups from a standard rat model of infantile spasms to determine the sex dichotomy of the neurotransmission genomic fabrics. Infantile spasms were triggered in rat pups prenatally primed with two doses of betamethasone followed by the postnatal repeated administration of N-methyl-D-aspartic acid to induce spasms. Publicly available microarray data were used to characterize each gene in each condition for both sexes by the independent transcriptomic features: average expression level, control of the transcript abundance, and expression correlation with every other gene. This study revealed substantial sex differences in the expression level, control, and inter-coordination of the investigated genes among the studied groups. The transcriptomic differences assist in providing a molecular explanation of the behavioral differences and development of infantile epilepsy spasm syndrome in the two sexes. Full article

Background/Objectives: Laryngeal cancer (LC), predominantly squamous cell carcinoma (SCC), represents a considerable health burden worldwide. Tumour subsite heterogeneity (supraglottic, glottic, subglottic) influences clinical behavior and outcomes. This review synthesizes current knowledge on epidemiology, risk factors, diagnostics, histological variants, biomarkers, treatment modalities, and survival. Results: This narrative review synthesizes current literature on the epidemiology, risk factors, diagnosis, histological variants, biomarkers, and prognosis of LC. The review highlights the critical influence of tumour sites (supraglottic, glottic, subglottic) on metastatic patterns and survival. Key risk factors of LC include tobacco and alcohol use, human papillomavirus (HPV) infection, and occupational exposures. The diagnostic process encompasses clinical examination, endoscopy, biopsy, and imaging. Several biomarkers that aid in diagnosis, treatment plan determination, and prognosis prediction have been established. These biomarkers include long noncoding RNAs, cell cycle regulators, apoptosis regulators, oncogenes, tumour suppressor genes, growth factor pathway components, angiogenic factors, structural proteins, sex hormone receptors, and immunological markers. Current treatment modalities range from organ-preserving surgery and radiotherapy to combined chemoradiotherapy and total laryngectomy. Finally, survival data are presented and stratified by stage and subsite. Conclusions: The review underscores the need for a multidisciplinary approach to LC management, integrating clinical, pathological, and molecular information to optimize patient outcomes. Full article

Glioblastoma (GBM) is a fatal brain cancer known for its rapid and aggressive growth, with some studies indicating that females may have better survival outcomes compared to males. While sex differences in GBM have been observed, the underlying biological mechanisms remain poorly understood. Feature selection can lead to the identification of discriminative key biomarkers by reducing dimensionality from high-dimensional medical datasets to improve machine learning model performance, explainability, and interpretability. Feature selection can uncover unique sex-specific biomarkers, determinants, and molecular profiles in patients with GBM. We analyzed high-dimensional proteomic and metabolomic profiles from serum biospecimens obtained from 109 patients with pathology-proven glioblastoma (GBM) on NIH IRB-approved protocols with full clinical annotation (local dataset). Serum proteomic analysis was performed using Somalogic aptamer-based technology (measuring 7289 proteins) and serum metabolome analysis using the University of Florida’s SECIM (Southeast Center for Integrated Metabolomics) platform (measuring 6015 metabolites). Machine learning-based feature selection was employed to identify proteins and metabolites associated with male and female labels in high-dimensional datasets. Results were compared to publicly available proteomic and metabolomic datasets (CPTAC and TCGA) using the same methodology and TCGA data previously structured for glioma grading. Employing a machine learning-based and hybrid feature selection approach, utilizing both LASSO and mRMR, in conjunction with a rank-based weighting method (i.e., GLIO-Select), we linked proteomic and metabolomic data to clinical data for the purposes of feature reduction to identify molecular biomarkers associated with biological sex in patients with GBM and used a separate TCGA set to explore possible linkages between biological sex and mutations associated with tumor grading. Serum proteomic and metabolomic data identified several hundred features that were associated with the male/female class label in the GBM datasets. Using the local serum-based dataset of 109 patients, 17 features (100% ACC) and 16 features (92% ACC) were identified for the proteomic and metabolomic datasets, respectively. Using the CPTAC tissue-based dataset (8828 proteomic and 59 metabolomic features), 5 features (99% ACC) and 13 features (80% ACC) were identified for the proteomic and metabolomic datasets, respectively. The proteomic data serum or tissue (CPTAC) achieved the highest accuracy rates (100% and 99%, respectively), followed by serum metabolome and tissue metabolome. The local serum data yielded several clinically known features (PSA, PZP, HCG, and FSH) which were distinct from CPTAC tissue data (RPS4Y1 and DDX3Y), both providing methodological validation, with PZP and defensins (DEFA3 and DEFB4A) representing shared proteomic features between serum and tissue. Metabolomic features shared between serum and tissue were homocysteine and pantothenic acid. Several signals emerged that are known to be associated with glioma or GBM but not previously known to be associated with biological sex, requiring further research, as well as several novel signals that were previously not linked to either biological sex or glioma. EGFR, FAT4, and BCOR were the three features associated with 64% ACC using the TCGA glioma grading set. GLIO-Select shows remarkable results in reducing feature dimensionality when different types of datasets (e.g., serum and tissue-based) were used for our analyses. The proposed approach successfully reduced relevant features to less than twenty biomarkers for each GBM dataset. Serum biospecimens appear to be highly effective for identifying biologically relevant sex differences in GBM. These findings suggest that serum-based noninvasive biospecimen-based analyses may provide more accurate and clinically detailed insights into sex as a biological variable (SABV) as compared to other biospecimens, with several signals linking sex differences and glioma pathology via immune response, amino acid metabolism, and cancer hallmark signals requiring further research. Our results underscore the importance of biospecimen choice and feature selection in enhancing the interpretation of omics data for understanding sex-based differences in GBM. This discovery holds significant potential for enhancing personalized treatment plans and patient outcomes. Full article

The Lauraceae family, a keystone group in subtropical evergreen broad-leaved forest ecosystems, exhibits exceptional diversity in sexual systems (including hermaphroditic flowers, functionally unisexual flowers, and pseudo-dioecy), serving as a natural model for studying plant sexual differentiation mechanisms. This review synthesizes advances in the evolutionary mechanisms and genomic studies of sexual differentiation in Lauraceae, focusing on three key areas: (1) the evolution of taxonomic classification and floral morphology, (2) molecular trajectories of sexual differentiation, and (3) challenges and future directions in sex determination research (e.g., sex-linked marker development and gene-editing-assisted breeding). Morphological and phylogenetic analyses suggest that ancestral Lauraceae species were late Cretaceous hermaphroditic trees, with recent radiation of unisexual lineages (e.g., Cinnamomum and Laurus) linked to pollinator pressure, genome duplication events (WGD), and incipient sex chromosome evolution. Despite progress, critical challenges remain, including unresolved thresholds for sex chromosome origination, unquantified molecular pathways integrating environmental signals (e.g., photoperiod, temperature) with genetic networks, and the lack of efficient sex-specific markers and genetic transformation systems. Future studies should integrate single-cell omics, epigenetic profiling, and cross-species comparative genomics to elucidate spatiotemporal dynamics and evolutionary drivers of sexual differentiation. These efforts will advance genetic improvement and ecological restoration strategies. This review provides a systematic framework for advancing plant sexual evolution theory and promoting sustainable utilization of Lauraceae resources. Full article

Hormone-dependent phosphorylation of steroid receptors is a mechanism for modulating glucocorticoid receptor (GR) transcriptional responses. Evidence indicates that GR phosphorylation can influence receptor transcriptional activation in a gene-specific manner, which could have positive or negative impacts, where the relative level of phosphorylation is an important determinant of overall GR function. This review provides insights into the regulatory mechanism of GR phosphorylation in the brain, cellular and molecular specificity affecting neurovascular function, and the impact of GR phosphorylation in neurological disorders. Furthermore, the role of various endogenous and exogenous factors and sex-dependent associations with GR functional changes due to phosphorylation and other interlinking mechanisms are considered. Finally, we highlight the potential therapeutic approaches which have been evaluated, while challenging GR phosphorylation and the overall influence on the activity of GR in brain disorders. Full article