Search Results (862)

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

Breast cancer is the most common malignancy affecting women, manifesting as a heterogeneous disease with diverse molecular characteristics and clinical presentations. Recent studies have elucidated the role of epigenetic modifications in the pathogenesis of breast cancer, including drug resistance and efflux characteristics, offering potential new diagnostic and prognostic markers, treatment efficacy predictors, and therapeutic agents. Key modifications include DNA cytosine methylation and the covalent modification of histone proteins. Unlike genetic mutations, reprogramming the epigenetic landscape of the cancer epigenome is a promising targeted therapy for the treatment and reversal of drug resistance. Epidrugs, which target DNA methylation and histone modifications, can provide novel options for the treatment of breast cancer by reversing the acquired resistance to treatment. Currently, the most promising approach involves combination therapies consisting of epidrugs with immune checkpoint inhibitors. This review examines the aberrant epigenetic regulation of breast cancer initiation and progression, focusing on modifications related to estrogen signaling, drug resistance, cancer progression, and the epithelial–mesenchymal transition (EMT). It examines existing epigenetic drugs for treating breast cancer, including agents that modify DNA, inhibitors of histone acetyltransferases, histone deacetylases, histone methyltransferases, and histone demethyltransferases. It also delves into ongoing studies on combining epidrugs with other therapies and addresses the upcoming obstacles in this field. 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

Bisphenol A (BPA) is a typical environmental estrogen that is distributed worldwide and has the potential to pose a hazard to the ecological environment and human health. The development of an efficient and sensitive sensing strategy for the monitoring of BPA residues is of paramount importance. A novel electrochemical sensor based on carbon black and carbon nanofibers composite (CB/f-CNF)-assisted signal amplification has been successfully constructed for the amperometric detection of BPA in foods. Herein, the hybrid CB/f-CNF was prepared using a simple one-step ultrasonication method, and exhibited good electron transfer capability and excellent catalytic properties, which can be attributed to the large surface area of carbon black and the strong enhancement of the conductivity and porosity of carbon nanofibers, which promote a faster electron transfer process on the electrode surface. Under the optimized conditions, the proposed CB/f-CNF/GCE sensor exhibited a wide linear response range (0.4–50.0 × 10⁻⁶ mol/L) with a low limit of detection of 5.9 × 10⁻⁸ mol/L for BPA quantification. Recovery tests were conducted on canned peaches and boxed milk, yielding satisfactory recoveries of 86.0–102.6%. Furthermore, the developed method was employed for the rapid and sensitive detection of BPA in canned meat and packaged milk, demonstrating comparable accuracy to the HPLC method. This work presents an efficient signal amplification strategy through the utilization of carbon/carbon nanocomposite sensitization technology. Full article

Evidence indicates a bidirectional link between depressive symptoms and neuroinflammation. This study evaluated chronic cannabidiol (CBD) treatment effects in male and female rats subjected to the unpredictable chronic mild stress (UCMS) model of depression. We analyzed the gene expression related to neuroinflammation, cannabinoid signaling, estrogen receptors, and specific microRNAs in the ventromedial prefrontal cortex (vmPFC), CA1, and ventral subiculum (VS). UCMS influenced immobility in a sex-specific manner, increasing it in males and decreasing it in females, effects that were reversed by CBD. CBD also normalized the UCMS-induced upregulation of tumor necrosis factor α (TNF-α) in the CA1 and VS in males. In both sexes, UCMS induced the upregulation of the nuclear factor kappa B subunit 1 (NF-κB1) gene in the VS, which was unaffected by CBD. Additionally, CBD reversed CB1 downregulation in the VS of males but not in the vmPFC of either sex. In males, CBD restored the UCMS-induced downregulation of VS estrogen receptor genes ERα and ERβ. UCMS also altered miR-146a-5p expression, downregulating it in females (VS) and upregulating it in males (CA1), with no CBD effect. These findings highlight the sex-specific mechanisms of CBD’s antidepressant effect, with hippocampal neuroinflammatory and estrogenic pathways playing a key role in males. Full article

Hypothyroidism causes ovarian dysfunction and infertility in women and animals and impairs the hypothalamic expression of kisspeptin (Kp). However, kisspeptin is also expressed in the genital system, and the lack of the Kp receptor (Kiss1r) in the uterus is linked to reduced implantation rates. This study investigated the impact of hypothyroidism on the uterine expression of Kp and Kiss1r in female rats throughout the estrous cycle and the associated changes in uterine activity modulators. Hypothyroidism was induced through daily administration of propylthiouracil (PTU) over a period of 14 days. Plasma levels of LH, E₂, and P₄, cyclicity, body and uterine weight, uterine histomorphometry, and the gene and/or protein expression of Kiss1, Kiss1r, estrogen receptor α (ERα), progesterone receptor (PR), and thyroid hormone receptor α (TRα) were assessed. Additionally, proliferative activity (CDC-47) and the gene expression of uterine receptivity mediators (SMO, WNT4, BMP2, HAND2, MUC1, and LIF) were evaluated. Hypothyroidism prolonged the diestrus and increased progesterone levels during this phase, while decreasing luteinizing hormone and estradiol on proestrus. In the uterus, hypothyroidism reduced Kp immunostaining on diestrus and KISS1R mRNA levels on proestrus. These changes were accompanied by reduced endometrial glands, reduced uterine proliferative activity, and reduced ERα gene and protein expression. Additionally, hypothyroidism led to reduced uterine gene expression of LIF, BMP2, WNT4, and HAND2. On the other hand, thyroid hypofunction increased uterine PR and TRα immunostaining, while it reduced PGR gene expression on diestrus. These findings demonstrate that hypothyroidism reduces the expression of Kiss1/Kiss1r system in the uterus, which is associated with disrupted uterine estrogen and progesterone signaling and reduced expression of uterine receptivity mediators across the rat estrous cycle. Full article

Background/Objectives: Endocrine therapies that comprise anti-estrogens and aromatase inhibitors (AIs) are the standard treatment for estrogen receptor-positive (ER+) (Luminal A) breast cancer—the most prevalent subtype. However, the emergence of resistance restricts their success by causing tumor relapse and re-growth, which demands a switch towards other therapeutic approaches in order to minimize or overcome resistance. Indeed, this clinical limitation highlights the search for new molecules to improve cancer treatment. Recently, strategies that address multiple targets have been emerging, and multi-target drugs have the potential to become the future anti-cancer molecules. Our group has been searching for new multi-target compounds, and as part of this, our study aims to understand the anti-cancer and multi-target potential of three new steroidal aromatase inhibitors (AIs): 7α-methylandrost-4-en-17-one (6), 7α-methylandrost-4-ene-3,17-dione (10a) and androsta-4,9(11)-diene-3,17-dione (13). Methods: Their in vitro actions and molecular mechanisms were elucidated in a sensitive ER+ aromatase-overexpressing breast cancer cell line, MCF-7aro cells, as well as in an AI-resistant ER+ breast cancer cell line, LTEDaro cells. Results: All the new AIs (10 µM) prevented the proliferation of MCF-7aro cells by arresting cell cycle progression. Interestingly, all AIs (10 µM) act as androgen receptor (AR) agonists and modulate ER levels, synthesis and signaling to induce the apoptosis of ER+ breast cancer cells. Additionally, these new AIs (10 µM) also re-sensitize resistant cells by promoting apoptosis, offering a therapeutic benefit. Conclusions: Overall, new steroidal polypharmacological compounds have been discovered that, by acting as AIs, ER modulators and AR agonists, impair ER+ breast cancer cell growth. Overall, this study is a breakthrough on drug discovery as it presents new molecules with appealing anti-cancer properties and multi-target action for the treatment of ER+ breast cancer. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with cardiometabolic risk. Although studies have shown that estradiol positively contributes to energy metabolism via estrogen receptor alpha (ERα), its role specifically in the liver is not defined. Therefore, this study aimed to evaluate the effects of ERα overexpression, specifically in the liver in mice fed a high-fat diet (HFD). Methods: Male C57BL/6J mice were divided into four groups, vehicle fed with regular chow (RC) (RC-Vehicle); vehicle fed an HFD (HFD-Vehicle); AAV-treated fed with RC (RC-AAV); and AAV-treated fed an HFD (HFD-AAV), for 6 weeks (8–10 mice per group). AAV was administered intravenously to induce ERα overexpression. Results: We demonstrate that overexpression of ERα in RC-fed mice reduces body fat (28%). These mice show increased oxygen consumption in cultured primary hepatocytes, both in basal (19%) and maximal respiration (34%). In HFD-fed mice, we showed a decrease in hepatic TAG content (43%) associated with improved hepatic insulin sensitivity (145%). Conclusions: From this perspective, our results prove that hepatic ERα signaling is responsible for some of the metabolic protective effects of estrogen in mice. Overexpression of ERα improves hepatocyte mitochondrial function, consequently reducing hepatic lipid accumulation and protecting animals from hepatic steatosis and hepatic insulin resistance. Further investigations will be needed to determine the exact molecular mechanism by which ERα improves hepatic metabolic health. Full article

Background/Objectives: Transient Receptor Potential Melastatin 8 (TRPM8) is a non-selective, Ca²⁺-permeable cation channel involved in thermoregulation and other physiological processes, such as basal tear secretion, cell differentiation, and insulin homeostasis. The activation and deactivation of TRPM8 occur through genetic modifications, channel interactions, and signaling cascades. Recent evidence suggests a significant role of TRPM8 in the hypothalamus and amygdala related to pain sensation and sexual behavior. Notably, TRPM8 has been implicated in neuropathic pain, migraines, and neurodegenerative diseases such as Parkinson’s disease. Our laboratory has identified testosterone as a high-affinity ligand of TRPM8. TRPM8 deficiency appears to influence behavioral traits in mice, like increased aggression and deficits in sexual satiety. Here, we aim to explore the pathways altered in brain tissues of TRPM8-deficient mice using the expression and methylation profiles of messenger RNA (mRNA) and long non-coding RNA (lncRNA). Specifically, we focused on brain regions integral to behavioral and hormonal control, including the olfactory bulb, hypothalamus, amygdala, and insula. Methods: RNA was isolated and purified for microarray analysis collected from male wild-type and TRPM8 knockout mice. Results: We identified various differentially expressed genes tied to multiple signaling pathways. Among them, the androgen–estrogen receptor (AR-ER) pathway, steroidogenesis pathway, sexual reward pathway, and cocaine reward pathway are particularly worth noting. Conclusions: These results should bridge the existing gaps in the knowledge regarding TRPM8 and inform potential targets for future studies to elucidate its role in the behavior changes and pathology of the diseases associated with TRPM8 activity. Full article

Sushi domain-containing protein 2 (SUSD2), a transmembrane protein containing a sushi motif, has been reported to have tumor-promoting functions in various types of cancer, including breast cancer. However, the regulatory mechanism of SUSD2 and its function in HER2-positive (HER2+) breast cancer have not been fully identified as yet. In this study, we explored the potential of targeting SUSD2 to overcome trastuzumab (TRZ) resistance in HER2+ breast cancer. SUSD2 expression was found to be significantly increased in HER2-overexpressing cells. Endogenous SUSD2 expression was observed in HER2+ breast cancer cells but not in estrogen receptor-positive or triple-negative breast cancer cells. We also found that SUSD2 expression was positively correlated with HER2 expression in a publicly available human primary breast cancer dataset. Although SUSD2 expression was associated with HER2, its expression levels were not affected by TRZ. Through kinase array experiments, we found that SUSD2 expression was modulated downstream of STAT3-dependent signaling in breast cancer cells overexpressing HER2. STAT3 activity was increased in EGFR+ HER2+ breast cancer cells compared to EGFR+ cells. Furthermore, we observed that SUSD2 expression was decreased by C188-9, a STAT3-specific inhibitor. Finally, we analyzed the association between patient survival and SUSD2 expression in breast cancer. Our results showed that SUSD2 expression had a negative correlation with the relapse-free survival of patients with EGFR+ HER2+ breast cancer when compared to EGFR+ breast cancer patients. Collectively, our results demonstrate that SUSD2 expression is mediated by STAT3 and imply the potential of using SUSD2 as a biomarker to stratify HER2+ breast cancer. 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

Ovarian cancer remains one of the leading causes of cancer-related deaths in women. There are several processes that are described to have a causal relationship in ovarian cancer development, progression, and metastasis formation, that occur both at the genetic and epigenetic level. One of the mechanisms involved in its pathogenesis and progression is estrogen signaling. Estrogen receptors (ER) α, ERβ, and G-protein coupled estrogen receptor 1 (GPER1), in concert with various coregulators and pioneer transcription factors, mediate the effects of estrogens primarily by the transcriptional regulation of estrogen responsive genes, thereby exerting pleiotropic effects including the regulation of cellular proliferation and apoptosis. The expression and activity of estrogen receptors and their coregulators have been demonstrated to be regulated by epigenetic mechanisms like histone modifications and DNA methylation. Here, we intend to summarize and to provide an update on the current understanding of epigenetic mechanisms regulating estrogen signaling and their role in ovarian cancer. For this purpose, we reviewed publications on this topic listed in the PubMed database. Finally, we assess to which extent drugs acting on the epigenetic level might be suitable for the treatment of ovarian cancer. Full article

Vascular diseases, such as hypertension, atherosclerosis, cerebrovascular, and peripheral arterial diseases, present major clinical and public health challenges, largely due to their common underlying process: vascular remodeling. This process involves structural alterations in blood vessels, driven by a variety of molecular mechanisms. The inhibitor of DNA-binding/differentiation-3 (ID3), a crucial member of ID family of transcriptional regulators, has been identified as a key player in vascular biology, significantly impacting the progression of these diseases. This review explores the role of ID3 in vascular remodeling, emphasizing its involvement in processes such as apoptosis, cell proliferation, and extracellular matrix regulation. Furthermore, we examine how oxidative stress, intensified by exposure to estrogenic endocrine disruptors (EEDs) like polychlorinated biphenyls (PCBs) and bisphenol A (BPA), affects ID3 activity and contributes to vascular disease. Understanding the interaction between ID3 signaling and EED exposure provides critical insights into the molecular mechanisms underlying vascular remodeling and its role in the development and progression of vascular diseases. Full article

Radiotherapy is a critical treatment for cancer but poses significant risks to ovarian tissue, particularly in young females, leading to premature ovarian failure (POF). This study examines the therapeutic potential of etoricoxib nanostructured lipid carriers (ETO-NLC) in mitigating radiation-induced ovarian damage in female Wistar rats. Twenty-four female rats were randomly assigned to four groups: a control group receiving normal saline, a group exposed to a single dose of whole-body gamma radiation (6 Gy), a group treated with etoricoxib (10 mg/kg) post-radiation, and a group treated with ETO-NLC for 14 days following radiation. Histopathological evaluations and oxidative stress biomarker assessments were conducted, including ELISAs for reactive oxygen species (ROS), pro-inflammatory cytokines (IL-1β, TNF-α), and signaling molecules (PI3K, AKT, P38MAPK, AMH). Serum levels of estrogen, FSH, and LH were measured, and gene expression analysis for TGF-β and Nrf2 was performed using qRT-PCR. The findings indicate that ETO-NLC has the potential to ameliorate the harmful effects of ovarian damage induced by γ-radiation. These therapeutic effects were achieved through the modulation of oxidative stress, inflammation, augmentation of antioxidant defenses (including Nrf2 activation), support for cell survival pathways (via PI3K/Akt signaling), regulation of MAPK, mitigation of fibrosis (TGF-β), and preservation of ovarian reserve (as evidenced by AMH, FSH/LH, and estrogen levels). ETO-NLC shows promise as an effective strategy for attenuating radiation-induced ovarian damage, highlighting the need for further research to enhance therapeutic interventions aimed at preserving ovarian function during cancer treatment. Full article

Alcohol consumption has been consistently linked to an increased risk of several cancers, including breast and ovarian cancer. Despite substantial evidence supporting this association, the precise mechanisms underlying alcohol’s contribution to cancer pathogenesis remain incompletely understood. This narrative review focuses on the key current literature on the biological pathways through which alcohol may influence the development of breast and ovarian cancer. Key mechanisms discussed include the modulation of estrogen levels, the generation of reactive oxygen species, the production of acetaldehyde, the promotion of chronic inflammation, and the induction of epigenetic changes. Alcohol’s impact on estrogenic signaling, particularly in the regulation of estrogen and progesterone, is explored in the context of hormone-dependent cancers. Additionally, the role of alcohol-induced DNA damage, mutagenesis, and immune system modulation in tumor initiation and progression is examined. Overall, this review emphasizes the importance of alcohol as a modifiable risk factor for breast and ovarian cancer and highlights the need for further research to clarify its role in cancer biology. Full article