Search Results (110)

Backgroud. Endometriosis is a chronic, estrogen-dependent inflammatory disease characterized by the ectopic presence of endometrial-like tissue. Although genome-wide association studies (GWAS) have identified susceptibility variants, their tissue-specific regulatory impact remains poorly understood. Objective. To functionally characterize endometriosis-associated variants by exploring their regulatory effects as expression quantitative trait loci (eQTLs) across six physiologically relevant tissues: peripheral blood, sigmoid colon, ileum, ovary, uterus, and vagina. Methods. GWAS-identified variants were cross-referenced with tissue-specific eQTL data from the GTEx v8 database. We prioritized genes either frequently regulated by eQTLs or showing the strongest regulatory effects (based on slope values, which indicate the direction and magnitude of the effect on gene expression). Functional interpretation was performed using MSigDB Hallmark gene sets and Cancer Hallmarks gene collections. Results. A tissue specificity was observed in the regulatory profiles of eQTL-associated genes. In the colon, ileum, and peripheral blood, immune and epithelial signaling genes predominated. In contrast, reproductive tissues showed the enrichment of genes involved in hormonal response, tissue remodeling, and adhesion. Key regulators such as MICB, CLDN23, and GATA4 were consistently linked to hallmark pathways, including immune evasion, angiogenesis, and proliferative signaling. Notably, a substantial subset of regulated genes was not associated with any known pathway, indicating potential novel regulatory mechanisms. Conclusions. This integrative approach highlights the com-plexity of tissue-specific gene regulation mediated by endometriosis-associated variants. Our findings provide a functional framework to prioritize candidate genes and support new mechanistic hypotheses for the molecular pathophysiology of endometriosis. Full article

Background: Polycystic ovary syndrome (PCOS) is a complex and multifactorial disorder affecting reproductive, endocrine, and metabolic functions in women of reproductive age. While environmental and lifestyle factors play a role, increasing evidence highlights the contribution of genetic and epigenetic mechanisms to its pathogenesis. Objective: This narrative review aims to provide an updated overview of the current evidence regarding the role of genetic variants, gene expression patterns, and epigenetic modifications in the etiopathogenesis of PCOS, with a focus on their impact on ovarian function, fertility, and systemic alterations. Methods: A comprehensive search was conducted across MEDLINE, EMBASE, PubMed, Web of Science, and the Cochrane Library using MeSH terms including “PCOS”, “Genes involved in PCOS”, and “Etiopathogenesis of PCOS” from January 2015 to June 2025. The selection process followed the SANRA quality criteria for narrative reviews. Seventeen studies published in English were included, focusing on original data regarding gene expression, polymorphisms, and epigenetic changes associated with PCOS. Results: The studies analyzed revealed a wide array of molecular alterations in PCOS, including the dysregulation of SIRT and estrogen receptor genes, altered transcriptome profiles in cumulus cells, and the involvement of long non-coding RNAs and circular RNAs in granulosa cell function and endometrial receptivity. Epigenetic mechanisms such as the DNA methylation of TGF-β1 and inflammation-related signaling pathways (e.g., TLR4/NF-κB/NLRP3) were also implicated. Some genetic variants—particularly in DENND1A, THADA, and MTNR1B—exhibit signs of positive evolutionary selection, suggesting possible ancestral adaptive roles. Conclusions: PCOS is increasingly recognized as a syndrome with a strong genetic and epigenetic background. The identification of specific molecular signatures holds promise for the development of personalized diagnostic markers and therapeutic targets. Future research should focus on large-scale genomic studies and functional validation to better understand gene–environment interactions and their influence on phenotypic variability in PCOS. Full article

Drug resistance remains a critical barrier to effective treatment in several cancers, particularly triple-negative breast cancer (TNBC). Estrogen receptor α36 (ERα36), a variant of the estrogen receptor in ER-negative breast cancer cells, plays important roles in cancer cell proliferation. We investigated the role of ERα36 in regulating multidrug resistance protein 1 (MDR1) in MDA-MB-231 human breast cancer cells. The activation of ERα36 by BSA-conjugated estradiol (BSA-E2) increased cell viability under Adriamycin exposure, suggesting its involvement in promoting drug resistance. BSA-E2 treatment significantly reduced the intracellular rhodamine-123 levels by activating the MDR1 efflux function, which was linked to increased MDR1 transcription and protein expression. The mechanical ERα36-mediated BSA-E2-induced activation of EGFR and downstream signaling via c-Src led to an activation of the Akt/ERK pathways and transcription factors, NF-κB and CREB. Additionally, ERα36 is involved in activating Wnt/β-catenin pathways to induce MDR1 expression. The silencing of ERα36 inhibited the BSA-E2-induced phosphorylation of Akt and ERK, thereby reducing MDR1 expression via downregulation of NF-κB and CREB as well as Wnt/β-catenin signaling. These findings demonstrated that ERα36 promotes MDR1 expression through multiple non-genomic signaling cascades, including Akt/ERK-NF-κB/CREB and Wnt/β-catenin pathways, and highlight the role of ERα36 as a promising target to enhance chemotherapeutic efficacy in TNBC. Full article

Sex-related differences are found not only in the reproductive system but also across various biological systems, such as the cardiovascular system. Compared with premenopausal women, cardiovascular disease (CVD) tends to occur more frequently in adult men and postmenopausal women (Post-MW). Also, during the reproductive years, sex hormones synthesized and released into the blood stream affect vascular function in a sex-dependent fashion. Estrogen (E2) interacts with estrogen receptors (ERs) in endothelial cells, vascular smooth muscle, and the extracellular matrix, causing both genomic and non-genomic effects, including vasodilation, decreased blood pressure, and cardiovascular protection. These observations have suggested beneficial effects of female sex hormones on cardiovascular function. In addition, the clear advantages of E2 supplementation in alleviating vasomotor symptoms during menopause have led to clinical investigations of the effects of menopausal hormone therapy (MHT) in CVD. However, the findings from these clinical trials have been variable and often contradictory. The lack of benefits of MHT in CVD has been related to the MHT preparation (type, dose, and route), vascular ERs (number, variants, distribution, and sensitivity), menopausal stage (MHT timing, initiation, and duration), hormonal environment (progesterone, testosterone (T), gonadotropins, and sex hormone binding globulin), and preexisting cardiovascular health and other disorders. The vascular effects of sex hormones have also prompted further examination of the use of anabolic drugs among athletes and the long-term effects of E2 and T supplements on cardiovascular health in cis- and transgender individuals seeking gender-affirming therapy. Further analysis of the effects of sex hormones and their receptors on vascular function should enhance our understanding of the sex differences and menopause-related changes in vascular signaling and provide better guidance for the management of CVD in a gender-specific fashion and in Post-MW. Full article

Background: Ammonia (NH₃), a harmful gas, reduces livestock productivity, threatens their health, and causes economic losses. Luteolin (Lut), an anti-inflammatory flavonoid, may counteract these effects. Methods: Our study explored luteolin’s protective mechanisms on chicken splenic lymphocytes under ammonia stress using a simulation model and four-dimensional fast data-independent acquisition (4D-FastDIA) proteomics. We identified 316 proteins, with 69 related to ammonia’s negative effects and 247 to Lut’s protection. Thirty differentially expressed proteins (DEPs) were common to both groups, with 27 showing counter-regulation with Lut. Results: Gene Ontology (GO) analysis showed DEPs enriched in molecular responses to interferons and the negative regulation of immune responses, mainly located extracellularly. Molecular function analysis revealed DEPs in antigen binding and synthase activity. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis linked DEPs to pathways like estrogen signaling, NOD-like receptor signaling, cytokine–cytokine receptor interaction, and JAK-STAT signaling. The quantitative real-time polymerase chain reaction (qRT-PCR) results indicated that the mRNA levels of Interferon Alpha and Beta Receptor subunit 2 (IFNAR2) and Signal Transducer and Activator of Transcription 1 (STAT1) were trending downward. This observation was in strong agreement with the downregulation noted in the proteomics analysis. Conclusions: Lut’s protective role against ammonia’s adverse effects on chicken splenic lymphocytes is linked to the modulation of key signaling pathways, offering insights for further research on treating ammonia exposure with Lut. Full article

Background: The reproductive performance of water buffalo significantly impacts the economic aspects of production. Traditional breeding methods are constrained by low heritability and numerous influencing factors, making it difficult to effectively improve reproductive efficiency. Genome-wide association studies (GWAS) offer new possibilities for exploring reproductive traits in water buffalo, opening up new avenues for efficient breeding. Methods: Using whole-genome resequencing, we identified quantitative trait loci (QTLs) associated with four suggestive reproductive traits: calving interval (CI), calf birth weight (CBW), dam birth weight (BW), and age at first calving (FCA). The study focused on identifying genetic variants that influence these reproductive traits. Results: Our research identified 52 suggestive regulatory loci associated with reproductive traits in water buffalo. Based on a 50 kb interval, we annotated these loci to 58 candidate genes. These loci involve genes such as AGBL4, GRM1, NCKAP5, and NRXN1, which are primarily enriched in pathways including the FOXO signaling pathway, calcium ion pathways, estrogen signaling pathway, and phospholipase D signaling pathway. These pathways directly or indirectly regulate the reproductive efficiency of water buffalo. Conclusions: This study has revealed suggestive regulatory genes (AGBL4, GRM1, NCKAP5, NRXN1) associated with reproductive traits in water buffalo. This not only enhances our understanding of the molecular mechanisms underlying complex traits but also points towards strategies for improving the reproductive capacity of water buffalo. These findings provide a solid foundation for future breeding programs aimed at enhancing water buffalo productivity. Full article

Breast cancer (BC) is a multifactorial condition and it primarily expresses the estrogen receptor α (ERα) that is encoded by the gene estrogen receptor 1 (ESR1), which modulates estrogen signaling. ESR1, by facilitating estrogen overproduction, plays an indispensable role in the progression and survival of the majority of BCs. To obtain molecular insights into these phenomena, we analyzed The Cancer Genome Atlas (TCGA) breast invasive carcinoma (BRCA) RNA-Seq datasets for the expression of ESR1 and its correlation to microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), along with its methylation patterns. Regulation of ESR1 was also assessed with a total of 43 cancerous and non-cancerous breast cell lines. Analyses of both TCGA BRCA and breast cell line RNA-Seq data revealed that specific lncRNAs, i.e., MEG3, BIK, MLL, and FAS are negatively correlated with the ESR1, in which PARP1 demonstrates a positive association. Additionally, both miR-30a and miR-145 showed negative correlations with the ESR1 expression. Of the 54 ESR1 methylation loci analyzed, the majority of them exhibited a negative correlation with the ESR1 expression, highlighting a potentially modifiable regulatory mechanism. These findings underscore the complex regulatory events influencing ESR1 expression and its interaction with diverse signaling pathways, demonstrating novel insights into breast pathogenesis and its potential therapeutics. Full article

Based on comprehensive proteomic analysis conducted across various stages of secondary hair follicles (SHFs), the growth and development regulatory mechanisms of SHFs in Jiangnan cashmere goats were studied. Proteomic analysis of skin tissue from the SHF anagen (An), catagen (Cn), and telogen (Tn) revealed 145 differentially expressed proteins (DEPs) between the An and Tn, 53 DEPs between the Cn and An, and 168 DEPs between the Cn and Tn. Gene Ontology (GO) annotations indicated that the DEPs were predominantly involved in keratin filament formation (KRTAP3-1, KRT1, KRT8), intermediate filament formation (KRT26, KRT35, KRT19, etc.), and lipid metabolism (FA2H, CERS6, ECH1, TECR, etc.). Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis identified significant enrichment of DEPs in pathways related to hair follicle growth and development. Notably, these included the PPAR signaling pathway (PLIN2, PLIN4, ACSL5, etc.), the IL-17 signaling pathway (S100A7A, LOC108633164), and the estrogen signaling pathway (KRT26, KRT35, LOC102176457.). Western blotting (WB) experiments were then performed on five DEPs (KRT28, FA2H, PLIN2, FABP7, and VNN1) to validate the consistency of the WB results with the proteomic data. Overexpression and siRNA interference of PLIN2 in dermal papilla cells (DPCs) were followed by CCK8 and flow cytometry assays, revealing that PLIN2 knockdown significantly decreased DPC proliferation while inducing apoptosis, compared to controls. These findings suggest that the PLIN2 gene plays a crucial role in modulating SHF growth cycles in cashmere goats by influencing DPC proliferation. These results provide novel insights that could inform the development of breeding strategies aimed at enhancing the cashmere yield in such goats. Full article

The hypothalamus (hyp) serves as the regulatory hub of the neuroendocrine system, synthesizing and secreting reproductive hormones that modulate estrus, follicular maturation, and embryonic development in goats. This study employed RNA-seq analysis to examine gene expression in the hypothalamic tissue of Yunshang black goats during the luteal phase in goats with high fecundity (LP_HY), during the luteal phase in goats with low fecundity (LP_LY), during the follicular phase in goats with high fecundity (FP_HY), and during the follicular phase in goats with low fecundity (FP_LY). Differential long non-coding RNAs (DE lncRNAs) and differential mRNAs (DE mRNAs) were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and the construction of co-expression networks associated with reproduction. As a result, DE lncRNAs (390, 375, 405, and 394) and DE mRNAs (1836, 2047, 2003, and 1963) were identified in the four comparisons, namely FP_LY vs. FP_HY, LP_HY vs. FP_HY, LP_LY vs. FP_LY, and LP_LY vs. LP_HY, respectively. Functional annotations indicated significant enrichment of numerous DE lncRNAs and DE mRNAs in reproduction-related pathways such as the gonadotropin-releasing hormone pathway, the prolactin signaling pathway, the estrogen signaling pathway, the Wnt signaling pathway, oocyte meiosis, and progesterone-mediated oocyte maturation. The co-expression network of lncRNAs and target genes identified the interrelationships between reproduction-related genes such as IGF1, PORCN, PLCB2, MAPK8, PRLR, and CPEB2 with our newly discovered lncRNAs. This study expands the understanding of lncRNAs and mRNAs in goat hypothalamic tissue and provides new insights into molecular mechanisms related to goat reproduction. Full article

Breast cancer poses a significant global health challenge and includes various subtypes, such as endocrine-positive, HER2-positive, and triple-negative. Endocrine-positive breast cancer, characterized by estrogen and progesterone receptors, is commonly treated with aromatase inhibitors. However, resistance to these inhibitors can hinder patient outcomes due to genetic and epigenetic alterations, mutations in the estrogen receptor 1 gene, and changes in signaling pathways. Radiogenomics combines imaging techniques like MRI and CT scans with genomic profiling methods to identify radiographic biomarkers associated with resistance. This approach enhances our understanding of resistance mechanisms and metastasis patterns, linking them to specific genomic profiles and common metastasis sites like the bone and brain. By integrating radiogenomic data, personalized treatment strategies can be developed, improving predictive and prognostic capabilities. Advancements in imaging and genomic technologies offer promising avenues for enhancing radiogenomic research. A thorough understanding of resistance mechanisms is crucial for developing effective treatment strategies, making radiogenomics a valuable integrative approach in personalized medicine that aims to improve clinical outcomes for patients with metastatic endocrine-positive breast cancer. Full article

The common octopus (Octopus vulgaris), among coleoid cephalopods, has evolved the most complex nervous system and sophisticated behaviors. Historically, O. vulgaris was a key animal model for neurophysiology research, and today, it is studied for its genomic innovations. However, unlike other models, there is no octopus farming for research, so specimens must be collected from the wild. This study assessed the impact of fishing on octopuses used in research, considering those caught using artisanal pots in the ‘Regno di Nettuno’ Marine Protected Area, Ischia (NA). To evaluate fishing stress, we identified morphological stress indicators such as chromatophore pattern and posture, and three potential molecular markers, estrogen receptor (ER), catalase (CAT), and heat shock protein (HSP70). We measured the percentage of stress signals shown by fished specimens and analyzed their differential gene expression. The transcriptional levels of octopuses caught using traps were compared to control specimens acclimated in captivity. Results indicated fluctuations in gene expression due to fishing stress. These findings suggest that an acclimation period after the stress event of fishing is crucial for ensuring the welfare of octopuses used in research, thus enhancing the quality of physiological and ethological studies. Full article

Background: Water buffaloes represent a crucial genetic resource for the global dairy industry, yet enhancements in their production performance remain relatively constrained. The advent of advanced sequencing technologies, coupled with genome-wide association studies (GWASs), has significantly boosted the potential for breeding superior-quality water buffalo. Methods: An integrated genomic analysis was performed on sequencing data from 100 water buffaloes, utilizing the high-quality UOA_WB_1 genome assembly as a reference. This study particularly emphasized reproduction-related traits, with a focus on age at first calving (AFC). Results: Our analysis revealed two significant single-nucleotide polymorphisms (SNPs). Based on these genetic markers, the GRM1 gene was identified as a candidate gene. This gene shows substantial involvement in various reproduction-associated pathways, including the FOXO signaling pathway, calcium signaling pathway, and estrogen signaling pathway. Conclusions: The identification of GRM1 as a candidate gene provides a robust theoretical basis for molecular breeding strategies aimed at enhancing fertility in water buffaloes. These findings offer critical scientific support for optimizing breeding programs, thereby improving overall production efficiency. Full article

Background: Gynecomastia, caused by an estrogen–testosterone imbalance, affects males across various age groups. With unclear mechanisms and no approved drugs, the condition underscores the need for efficient, innovative treatment strategies. Methods: This study utilized deep learning-based computational methods to discover potential drug compounds for gynecomastia. To identify genes and pathways associated with gynecomastia, initial analyses included text mining, biological process exploration, pathway enrichment and protein–protein interaction (PPI) network construction. Subsequently, drug–target interactions (DTIs) were examined to identify potential therapeutic compounds. The DeepPurpose toolkit was employed to predict interactions between these candidate drugs and gene targets, prioritizing compounds based on their predicted binding affinities. Results: Text mining identified 177 genes associated with gynecomastia. Gene Ontology (GO) biological process and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses identified critical genes and pathways, with notable involvement in signal transduction, cell proliferation and steroid hormone biosynthesis. PPI network analysis highlighted 10 crucial genes, such as IGF1, TGFB1 and AR. DTI analysis and DeepPurpose predictions identified 12 potential drugs, including conteltinib, yifenidone and vosilasarm, with high predicted binding affinities to the target genes. Conclusions: The study successfully identified potential drug compounds for gynecomastia using a deep learning-based approach. The findings highlight the effectiveness of combining text mining and artificial intelligence in drug discovery. This innovative method provides a new avenue for developing specific treatments for gynecomastia and underscores the need for further experimental validation and optimization of prediction models to support novel drug development. Full article

Background: Alpiniae oxyphyllae Fructus (AOF) is a medicinal and edible resource that holds potential to ameliorate hyperuricemia (HUA), yet its mechanism of action warrants further investigation. Methods: We performed network pharmacology, molecular docking, molecular dynamics simulation, and in vitro experiments to investigate the potential action and mechanism of AOF against HUA. Results: The results indicate that 48 potential anti-HUA targets for 4 components derived from AOF were excavated and predicted through public databases. Gene Ontology (GO) enrichment analysis indicated that there are 190 entries related to biological process, 24 entries related to cellular component, 42 entries related to molecular function, and 44 entries related to Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. The results of molecular docking showed that the main active ingredients of AOF may have potential therapeutic effects on immune system disorders and inflammation caused by HUA by binding to targets including peroxisome-proliferator-activated receptor gamma (PPARG), estrogen receptor 1 (ESR1), prostaglandin G/H synthase 2 (PTGS2), and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Subsequently, we further determined the stability of the complex between the core active ingredient and the core target proteins by molecular dynamics simulation. The results of cell experiments demonstrated that stigmasterol as the core active ingredient derived from AOF significantly upregulated the expression levels of ESR1 and PPARG (p < 0.001) to exert an anti-HUA effect. Conclusions: In summary, we have systematically elucidated that the mechanism of main active ingredients derived from AOF mainly exert their pharmacological effects by acting on multiple targets in this study. Our studies will provide a scientific basis for the precise development and utilization of AOF. Full article

Primary osteoporosis is closely linked to hormone deficiency, which disrupts the balance of bone remodeling. It affects postmenopausal women but also significantly impacts older men. Estrogen can promote the production of osteoprotegerin, a decoy receptor for RANKL, thereby preventing RANKL from activating osteoclasts. Furthermore, estrogen promotes osteoblast survival and function via activation of the Wnt signaling pathway. Likewise, androgens play a critical role in bone metabolism, primarily through their conversion to estrogen in men. Estrogen deficiency accelerates bone resorption through a rise in pro-inflammatory cytokines (IL-1, IL-6, TNF-α) and RANKL, which promote osteoclastogenesis. In the classic genomic pathway, estrogen binds to estrogen receptors in the cytoplasm, forming a complex that migrates to the nucleus and binds to estrogen response elements on DNA, regulating gene transcription. Androgens can be defined as high-affinity ligands for the androgen receptor; their combination can serve as a ligand-inducible transcription factor. Hormone replacement therapy has shown promise but comes with associated risks and side effects. In contrast, the non-genomic pathway involves rapid signaling cascades initiated at the cell membrane, influencing cellular functions without directly altering gene expression. Therefore, the ligand-independent actions and rapid signaling pathways of estrogen and androgen receptors can be harnessed to develop new drugs that provide bone protection without the side effects of traditional hormone therapies. To manage primary osteoporosis, other pharmacological treatments (bisphosphonates, teriparatide, RANKL inhibitors, sclerostin inhibitors, SERMs, and calcitonin salmon) can ameliorate osteoporosis and improve BMD via actions on different pathways. Non-pharmacological treatments include nutritional support and exercise, as well as the dietary intake of antioxidants and natural products. The current study reviews the processes of bone remodeling, hormone actions, hormone receptor status, and therapeutic targets of primary osteoporosis. However, many detailed cellular and molecular mechanisms underlying primary osteoporosis seem complicated and unexplored and warrant further investigation. Full article