Search Results (312)

Hormone-dependent breast cancer, particularly in its treatment-resistant forms, remains a significant therapeutic challenge. In this study, we applied a fully computational strategy to design steroid-based compounds capable of simultaneously targeting three key receptors involved in disease progression: progesterone receptor (PR), estrogen receptor alpha (ER-α), and HER2. Using a robust 3D-QSAR model (R² = 0.86; Q²_LOO = 0.86) built from 52 steroidal structures, we identified molecular features associated with high anticancer potential, specifically increased polarizability and reduced electronegativity. From a virtual library of 271 DFT-optimized analogs, 31 compounds were selected based on predicted potency (pIC₅₀ > 7.0) and screened via molecular docking against PR (PDB 2W8Y), HER2 (PDB 7JXH), and ER-α (PDB 6VJD). Seven candidates showed strong binding affinities (ΔG ≤ −9 kcal/mol for at least two targets), with Estero-255 emerging as the most promising. This compound demonstrated excellent conformational stability, a robust hydrogen-bonding network, and consistent multitarget engagement. Molecular dynamics simulations over 100 nanoseconds confirmed the structural integrity of the top ligands, with low RMSD values, compact radii of gyration, and stable binding energy profiles. Key interactions included hydrophobic contacts, π–π stacking, halogen–π interactions, and classical hydrogen bonds with conserved residues across all three targets. These findings highlight Estero-255, alongside Estero-261 and Estero-264, as strong multitarget candidates for further development. By potentially disrupting the PI3K/AKT/mTOR signaling pathway, these compounds offer a promising strategy for overcoming resistance in hormone-driven breast cancer. Experimental validation, including cytotoxicity assays and ADME/Tox profiling, is recommended to confirm their therapeutic potential. Full article

Brassinosteroids (BRs) are steroid hormones that are essential for plant growth, development, and environmental adaptation. They control the division, elongation, and differentiation of various cell types throughout the entire plant life cycle, affecting growth and the stress response. Therefore, fine-tuning of BR biosynthesis and modulation of signaling pathways offer possibilities for developing cultivars characterized by adjusted plant architecture or improved stress tolerance to benefit crop production. Additionally, precise BR treatments can be employed to increase the productivity of crop plants. This review aims to provide a comprehensive summary of the genetic basis of traits related to BR metabolism and signaling in cucurbits, the second largest vegetable family, which contributes significantly to global vegetable production and nutritional security. We summarize the current knowledge concerning BR biosynthesis mutants, the role of BRs in stress mitigation, and the potential of the exogenous application of BRs to alleviate stress during cucurbit production. We also discuss how genes related to BR metabolism can be used to develop gene editing strategies to advance precision breeding in cucurbits. Full article

Seasonal reproduction in sheep reduces reproductive efficiency. Melatonin (MT) plays a crucial role in reproductive processes. The purpose of this study was to assess the effects of a 5-day MT implant pretreatment on estrus synchronization and reproductive performance in sheep during seasonal anestrus. A total of 40 multiparous Mongolian sheep were selected and randomly divided into two groups. In the MT group (n = 20), the ewes received an MT implant for 5 days, and then, they were given a progesterone (P4)-containing vaginal sponge for 14 days with equine chorionic gonadotropin (eCG) administered (330 I.U. per ewe; I.M.) at sponge removal. Control (CON) ewes (n = 20) were similarly treated but did not receive MT implants. The results demonstrated that MT implantation significantly improved serum levels of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GSH-Px), increased post-ovulatory luteal diameter and serum P4 levels, and reduced ovarian apoptosis. Compared with the CON group, the MT group showed significantly higher pregnancy (68.23% vs. 50.59%) and lambing rates (63.53% vs. 47.06%; number of lambed ewes/number of total ewes) following cervical-timed artificial insemination. Ovarian transcriptome analysis revealed 522 differentially expressed genes (DEGs) in the MT group compared with the CON group, including 355 upregulated and 167 downregulated DEGs. In addition, MT significantly enhanced proliferation and inhibited apoptosis in cultured granulosa cells (GCs) and luteal cells (LCs) in vitro. Moreover, it enhanced the antioxidant capacity of GCs and LCs probably by activating the NRF2 signaling pathway as well as stimulating steroid hormone synthesis. In conclusion, MT implantation 5 days before applying the conventional P4-eCG protocol enhances ovine reproductive outcomes during seasonal anestrus. MT implantation has a beneficial role on the growth and function of ovarian cells. These findings offer novel evidence supporting the functional role of MT in mammalian reproduction, and would be informative for optimizing estrus synchronization in sheep. Full article

The discovery of bioactive natural compounds from microbes holds promise for regenerative medicine. In this study, we identified and characterized a steroid-like compound, 3,12-dioxochola-4,6-dien-24-oic acid (DOCDA), from a crude extract of Rhodococcus sp. DOCDA significantly promoted wound healing by enhancing HaCaT cell invasion and migration. It upregulated key growth factors (EGF, VEGF-A, IGF, TGF-β, and HGF), indicating the activation of regenerative signaling. Additionally, DOCDA increased the expression of genes related to focal adhesion and cytoskeletal regulation (ITGB1, ITGA4, FAK, SRC, RHOA, CDC42, RAC1, and paxillin), supporting enhanced cellular motility and remodeling. Notably, DOCDA promoted stem-like properties in HaCaT cells, as shown by increased spheroid formation and elevated levels of the stemness markers ALDH1 and CD44. Target prediction and molecular docking identified the glucocorticoid receptor (GR) as the primary target of DOCDA, with a docking score of −7.7 kcal/mol. Network and pathway enrichment analysis revealed that GR-linked pathways were significantly associated with wound healing, including steroid hormone signaling, inflammation, immune responses, and cell migration. In vivo, the topical application of DOCDA led to over 70% wound closure in mice by day 5. These findings suggest that DOCDA is a steroid-like compound that accelerates wound healing and may serve as a potential agent in regenerative therapy. Full article

Background: Prolactin (PRL) is a key reproductive hormone that regulates follicular development through endocrine and paracrine mechanisms. However, its specific role in porcine follicular development remains unclear. Methods: In the in vivo experiments, follicular fluid and tissue cells were obtained from small (1–2 mm), medium (3–4 mm), and large (5–6 mm) porcine follicles. PRL levels in follicular fluid were measured by ELISA. The expression levels of genes and proteins related to follicular development were assessed using quantitative real-time PCR (RT-qPCR) and Western blotting (WB). In the in vitro experiments, CCK-8, RT-qPCR, and WB were used to detect the effects of different concentrations (0, 30, and 300 ng/mL) of recombinant porcine prolactin (prPRL) on granulosa cell (GC) proliferation, steroid hormone synthesis, and angiogenesis, and transcriptome sequencing was performed. Results: The PRL concentration was significantly higher in large follicles compared to small and medium follicles. During follicular development, expression levels of PRL, PRL receptor (PRLR), proteolytic enzymes (CTSD, MMP2, MMP14, and BMP-1), and angiogenic factors (VEGFA and FGF-2) increased and then decreased. Moreover, prPRL promoted GC proliferation, increased the expression of PCNA and cyclin D1, upregulated steroidogenesis-related genes CYP11A1 and 3β-HSD, and significantly enhanced the expression of key angiogenic factors VEGFA and FGF-2. RNA-seq analysis identified 226 differentially expressed genes (DEGs), which were mainly enriched in signaling pathways such as the Hippo, JAK/STAT, and Rap1 pathways. Conclusions: PRL may regulate porcine follicle development by affecting cell proliferation and angiogenesis in GCs through the Hippo, JAK/STAT and Rap1 signaling pathways. Full article

Neurosteroids pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone have been actively studied in the last years as candidates for the treatment of neurodegenerative diseases and postinjury rehabilitation. The neuroprotective mechanisms of these neurosteroids have been shown in clinical studies of depression, epilepsy, status epilepticus, traumatic brain injury, fragile X syndrome, and chemical neurotoxicity. However, only the allopregnanolone analogs brexanolone and zuranolone have been recently approved by the FDA for the treatment of depression. The aim of this review was to evaluate whether the endogenous neurosteroids can be used in clinical practice as neuroprotectors. Neurosteroids are multitarget compounds with strong anti-inflammatory, immunomodulatory, and cytoprotective action; they stimulate the synthesis and release of BDNF and increase remyelination and regeneration. In addition to nuclear and membrane steroid hormone receptors, such as PR, mPR, PGRMC1,2, ER, AR, CAR, and PXR, they can bind to GABAA receptors, NMDA receptors, Sigma-1 and -2 receptors (σ1-R/σ2-R). Among these, mPRs, PGRMC1,2, sigma receptors, and mitochondrial proteins attract comprehensive attention because of strong binding with the P4 and DHEA, but subsequent signaling is poorly studied. Other plasma membrane and mitochondrial proteins are involved in the rapid nongenomic neuroprotective action of neurosteroids. P-glycoprotein, BCL-2 proteins, and the components of the mitochondrial permeability transition pore (mPTP) play a significant role in the defense against the injuries of the brain and the peripheral nervous system. The role of these proteins in the molecular mechanisms of action in neuroprotection and neuroinflammation has not yet been clearly established. The aspects of their participation in these pathological processes are discussed. New formulations, such as lipophilic emulsions, nanogels, and microneedle array patches, are attractive strategies to overcome the low bioavailability of these neurosteroids for the amelioration and treatment of various nervous disorders. Full article

This study investigates the role of melatonin in alleviating the oxidative stress and apoptosis of TM3 Leydig cells induced by 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), the primary active metabolite of Bisphenol A, and clarifies its potential mechanisms involving the SIRT1/PGC-1α pathway. We found that melatonin effectively mitigated MBP-induced cytotoxicity in TM3 cells (p < 0.05). The testosterone levels and steroid hormone synthesis proteins were significantly restored by melatonin. Furthermore, there was a significant reduction in apoptosis after melatonin treatment both in MBP-treated TM3 cells and Bisphenol A-treated testicular interstitial tissues (p < 0.05), along with a significant decrease in the pro-apoptotic markers Bax and cleaved caspase 3, and a significant increase in the anti-apoptotic Bcl-2 level and the Bcl-2/Bax ratio in TM3 cells (p < 0.05). Additionally, the mitochondrial membrane potential improved significantly, ROS and MDA levels were down-regulated, and ATP production was elevated following melatonin treatment in TM3 cells. Mechanistically, melatonin promoted PGC-1α expression and activated the SIRT1 signaling pathway in MBP-treated TM3 cells and Bisphenol A-treated testicular interstitial tissues. This leads to increased expression of NRF2 and its downstream antioxidant genes, mitochondrial respiratory chain complex-related genes, mitochondrial biogenesis genes, and mitochondrial fusion genes while significantly reducing mitochondrial fission genes (p < 0.05). The PGC-1α inhibitor SR-18292 reversed these protective effects, confirming the critical role of this pathway. Conclusively, melatonin exerts a protective effect against MBP-induced oxidative stress and apoptosis in TM3 cells through the SIRT1/PGC-1α pathway, indicating its potential as a therapeutic agent for improving male reproductive health compromised by environmental toxins. Full article

Granulosa cell (GC) dysfunction contributes to diminished ovarian reserve (DOR). We collected GC and follicular fluid samples from the patients of normal ovarian reserve (NOR) and DOR. RNA-seq of GCs showed that cholesterol/sterol metabolism and biosynthesis and extracellular matrix organization were enriched in the DOR group. Metabolomics of follicular fluid revealed enrichment in steroid hormone biosynthesis, tryptophan metabolism, and fatty acid β-oxidation in DOR. The apoptosis rate was increased, whereas the proliferative rate was decreased in GCs of DOR. The Prussian blue staining rate was increased whilst GPX4 and SLC7A11 expression were downregulated in GCs of DOR. Mitochondrial morphology displayed the features of ferroptosis in GCs of DOR. FSHR, CYP19A1, NR5A1, and phosphorylated CREB levels were substantially downregulated in GCs, accompanied by increased androgen levels in follicular fluids in DOR. The key factors linked to the mevalonate pathway, HMGCR, SQLE, and SREBF2, were robustly increased in DOR. FSHR and NR5A1 levels were correlated with CYP19A1 levels, whilst CYP19A1 levels were positively correlated with GPX4 and SLC7A11 levels. Our findings indicate ferroptosis and dysregulation of cholesterol/sterol metabolism and biosynthesis occurrence in GCs of DOR, which might be associated with reduced FSHR signaling and decreased conversion of androgen to estrogen. 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

Cold-inducible RNA-binding protein (CIRBP) has been reported to be involved in various cellular functions by regulating programmed cell death (PCD). However, the specific mechanism and function of CIRBP in regulating mitochondrial autophagy are still unclear. In this study, we found that CIRBP induced mitophagy through the AMPK/mTOR pathway to improve the function of yak cumulus cells (YCCs). We observed that low temperatures (32 °C) activated autophagy, increased E2 and P4 secretion, and up-regulated CIRBP expression. CIRBP overexpression activated mitophagy in YCCs, promoted cumulus diffusion, enhanced E2 and P4 synthesis and secretion, and inhibited apoptosis. CIRBP overexpression significantly attenuated the dysfunction of YCCs induced by the inhibition of mitophagy, whereas the activation of mitophagy exerted the same effect as CIRBP overexpression. DOX HCL is an AMPK/mTOR pathway inhibitor. CIRBP overexpression can successfully alleviate the inhibition of mitophagy caused by DOX HCL inhibiting the AMPK/mTOR pathway and can significantly enhance the mitophagy induced by AMPK/mTOR pathway activation in YCCs. Furthermore, we found that the increased expression of CIRBP protein alleviated the apoptosis caused by AKT pathway activation. In summary, CIRBP promoted mitophagy by activating AMPK/mTOR pathway, thereby promoting the synthesis and secretion of steroid hormones and cumulus diffusion in YCCs and enhancing YCCs survival through activating autophagy and AKT signaling pathway, and then improve the function of YCCs. Our research provided new perspectives on CIRBP’s regulation of cell death and highlighted its potential role in female reproductive systems. Full article

Yak (Bos grunniens) is the main economic animal growing in the Qinghai–Tibet Plateau. Because of its poor growing environment, copper deficiency is common. Studies have shown that appropriate copper supplementation can improve the reproductive performance of heifers. In this study, the primary granulosa cells of yak were isolated, and different copper levels were established by adding copper chelator and copper sulfate. Biochemical, Western blot and transcriptome methods were used to reveal the mechanism of copper on the hormone secretion function of granulosa cells. The results showed that copper promoted hormone secretion by regulating the expression of steroid synthase such as StAR, CYP19A1 and CYP11A1. Transcriptome analysis showed that copper ion levels significantly affected the function of cells, and changes in copper ion level affected genes related to protein phosphorylation, lipid metabolism, lipid biosynthesis, steroid hormone synthesis and the MAPK pathway. In conclusion, copper can promote steroid hormone synthesis in the granulosa cells of yak follicles, and the MAPK signaling pathway may be involved. Full article

Cats are different from dogs, and many questions remain open concerning the establishment of pregnancy. In cats, as in dogs, no feto-maternal signaling leading to establishment of pregnancy is known. But as opposed to dogs, the placenta is a source of steroid hormones and corticotropin-releasing hormone (CRH). Scarce information is available on physiological mechanisms at the uterine level during early gestation; more studies are needed on lymphocyte subsets, feto-maternal crosstalk and other mechanisms leading to local immunosuppression, allograft acceptance and embryo nidation and invasion. Recent studies investigate the function of extracellular vesicles (EVs); however, there is no study on embryo- or endometrium-derived EV. During pregnancy, anti-Müllerian hormone (AMH) serum concentrations were found to be higher than in non-pregnant cats, and a recent study found that supraphysiological levels may lead to pregnancy loss; the function of AMH during pregnancy warrants investigation. Most information is available on corpus luteum development and function, showing some similarities to dogs. Some information on maintenance of feline pregnancy was obtained by ovariectomy (OE) or the use of endocrine disruptors, showing that OE does not lead to pregnancy loss in all cases, especially when performed after day 35; the variable effect is still not fully understood. Antiprogesterone, dopamine agonists and prostaglandins were used in different dosages and treatment schemes and showed variable effect during the second half of gestation, highlighting progesterone and prolactin as key hormones for the maintenance of gestation. Some events during early gestation are comparable with the canine species, even though they appear earlier, like the entrance of the zygote into the uterus and implantation; however, significant differences are present concerning the histomorphology of the placenta and, in a few cases, even the gross morphology as in some cats, where the zonary placenta does not completely surround the fetus. Sonographical monitoring of feline pregnancy requires knowledge of species-specific developmental steps and the differential appearance of fetal and maternal structures in comparison with dogs. Full article

Background/Objectives: Pyrrhalta aenescens, a major pest of elm trees, causes extensive ecological and economic damage through rapid population growth and defoliation. Existing research mainly focuses on its biological traits and chemical control, with little knowledge about its reproductive development mechanisms, a key factor in population expansion. In other insects, the steroid hormone 20-hydroxyecdysone (20E) regulates development and reproduction via microRNA (miRNA)-mediated pathways, but this has not been studied in P. aenescens. This study aimed to systematically identify miRNAs responsive to 20E in P. aenescens and unravel their roles in regulating reproduction and metabolic pathways, providing foundational insights into hormone–miRNA crosstalk in this ecologically significant pest. Methods: Adult beetles (collected from Baotou, Inner Mongolia) were injected with 1.0 μg/μL 20E or control. Total RNA from three biological replicates (10 adults each) was sequenced, followed by miRNA identification, differential expression analysis, target prediction, and functional enrichment. Results: Small RNA sequencing identified 205 miRNAs (162 conserved, 43 novel), with 12 DEMs post-20E treatment. Target prediction linked these miRNAs to 7270 genes, including key regulators of the FoxO signaling pathway and MAPK signaling pathway. KEGG analysis highlighted lipid metabolism and stress response pathways. Conclusions: This study revealed that 20E modulates miRNA networks to regulate FoxO and MAPK pathways in P. aenescens, suggesting hormonal control of lipid metabolism and developmental processes. As the first miRNA resource for this pest, our findings provide mechanistic insights into 20E–miRNA crosstalk and identify potential molecular targets for disrupting its reproductive biology, laying a foundation for eco-friendly pest control. Full article

The steroid hormone 20-hydroxyecdysone (20E), which is known to regulate insect molting and metamorphosis, is crucial for the normal development of silk glands (SGs) in the silkworm Bombyx mori. However, how the 20E signaling pathway and its core members function in the SG remains largely unclear. Here, we report that the orphan nuclear receptor BmHR3, a 20E-response factor, plays an essential role in regulating SG development and silk protein synthesis. First, we showed that tissue-specific BmHR3 overexpression and knockout result in severe developmental defects in posterior silk glands (PSGs). Second, we revealed that BmHR3 dysfunction in PSGs dramatically represses the transcription of silk fibroin protein-coding genes, thereby inhibiting fibroin protein synthesis. Finally, we confirmed that BmHR3 can regulate fibroin protein-coding gene expression via direct and indirect mechanisms. This study elucidates the vital function of BmHR3 in B. mori SG and provides valuable information for thoroughly understanding the regulatory roles of 20E signaling in specialized insect organs. Full article

Background/Objectives: Flavonoids are common ubiquitous components of plants and are consumed by humans and livestock in their diets. Many different activities have been proposed for a variety of flavonoids that play a role in the benefits of a plant-rich diet. On the downside, excessive exposure to some flavonoids comes with a risk of endocrine disruption. Our objective was to define the structural elements of flavones and selected other flavonoids required for endocrine-disrupting activities on each of four steroid receptors, estrogen, androgen, progesterone, and glucocorticoid receptors. Methods: This work presents a systematic screen for the hormone agonist or antagonist activity of a selected panel of flavonoids on estrogen, androgen, progesterone, and glucocorticoid receptors. The screen is focused on the positional requirements of hydroxyl substituents on the flavone backbone. Results: Each receptor exhibited a distinct pattern for structural requirements of the flavones to impact receptor signaling. The most active flavones exhibited antagonist activity on androgen and progesterone receptors with an IC₅₀ of 0.5 and 2 µM, respectively. Flavones only exhibited weak antagonism on glucocorticoid receptors. When active, flavones acted as estrogen receptor agonists. The findings were utilized to design and synthesize a novel flavone, 3-fluoro, 6,4′-dihydroxyflavone 14, that displays increased potency as an estrogen agonist (EC₅₀~30 nM). Modeling of the binding of this novel flavone predicts increased preference for ERα versus ERβ relative to the estrogenic phytoestrogen, genistein. Conclusions: The structural requirements for flavones to act as estrogen agonists and antagonists of other steroid receptors are defined. The synthesis of a novel flavone offers potential for topical applications where systemic estrogen activity is undesired. However, the results highlight the potential for endocrine disruption when certain flavones are consumed in quantity as supplements. Full article