Search Results (531)

Background: Drug–drug interactions (DDIs) may occur when two or more drugs are taken together, leading to undesired side effects or potential synergistic effects. Most clinical effects of drug combinations have not been assessed in clinical trials. Therefore, predicting DDIs can provide better patient management, avoid drug combinations that can negatively affect patient care, and exploit potential synergistic combinations to improve current therapies in women’s healthcare. Methods: A DDI prediction model was built to describe relevant drug combinations affecting reproductive treatments. Approved drug features (chemical structure of drugs, side effects, targets, enzymes, carriers and transporters, pathways, protein–protein interactions, and interaction profile fingerprints) were obtained. A unified predictive score revealed unknown DDIs between reproductive and commonly used drugs and their associated clinical effects on reproductive health. The performance of the prediction model was validated using known DDIs. Results: This prediction model accurately predicted known interactions (AUROC = 0.9876) and identified 2991 new DDIs between 192 drugs used in different female reproductive conditions and other drugs used to treat unrelated conditions. These DDIs included 836 between drugs used for in vitro fertilization. Most new DDIs involved estradiol, acetaminophen, bupivacaine, risperidone, and follitropin. Follitropin, bupivacaine, and gonadorelin had the highest discovery rate (42%, 32%, and 25%, respectively). Some were expected to improve current therapies (n = 23), while others would cause harmful effects (n = 11). We also predicted twelve DDIs between oral contraceptives and HIV drugs that could compromise their efficacy. Conclusions: These results show the importance of DDI studies aimed at identifying those that might compromise or improve their efficacy, which could lead to personalizing female reproductive therapies. Full article

The activation mechanism of the reproductive axis in Kazakh ewes during the non-breeding season was explored by supplementation with glycerol complex (7% glycerol + tyrosine + vitamin B9). The experiment divided 50 ewes into five groups (n = 10). After 90 days of intervention, it was found that significant changes in serum DL-carnitine, N-methyl-lysine and other differential metabolites were observed in the GLY-Tyr-B9 group (p < 0.05, “p < 0.05” means significant difference, “p < 0.01” means “highly significant difference”). The bile acid metabolic pathway was specifically activated (p < 0.01). The group had a 50% estrus rate, ovaries contained 3–5 immature follicles, and HE staining showed intact granulosa cell structure. Serum E2/P4 fluctuated cyclically (p < 0.01), FSH/LH pulse frequency increased (p < 0.01), peak Glu/INS appeared on day 60 (p < 0.05), and LEP was negatively correlated with body fat percentage (p < 0.01). Molecular mechanisms revealed: upregulation of hypothalamic kiss-1/GPR54 expression (p < 0.01) drove GnRH pulses; ovarian CYP11A1/LHR/VEGF synergistically promoted follicular development (p < 0.05); the HSL of subcutaneous fat was significantly increased (p < 0.05), suggesting involvement of lipolytic supply. Glycerol activates the reproductive axis through a dual pathway—L-carnitine-mediated elevation of mitochondrial β-oxidation efficacy synergizes with kisspeptin/GPR54 signalling enhancement to re-establish HPO axis rhythms. This study reveals the central role of metabolic reprogramming in regulating seasonal reproduction in ruminants. Full article

Porcine reproductive and respiratory syndrome virus (PRRSV), an enveloped single-stranded positive-sense RNA virus, poses a significant threat to global swine production. Despite the availability of modified live virus and inactivated vaccines, their limited efficacy and safety concerns highlight the urgent need for novel antiviral therapeutics. This study aimed to investigate the molecular mechanisms by which lycopene inhibits PRRSV replication. Initial assessments confirmed that lycopene did not adversely affect cellular viability, cell cycle progression, or apoptosis. Using fluorescence microscopy, flow cytometry, immunoblotting, quantitative real-time PCR (qRT-PCR), and viral titration assays, lycopene was shown to exhibit potent antiviral activity against PRRSV. Mechanistic studies revealed that lycopene suppresses reactive oxygen species (ROS) production, which is critical for PRRSV proliferation. Additionally, lycopene attenuated PRRSV-induced inflammatory responses, as demonstrated by immunoblotting, ELISA, and qRT-PCR assays. These findings suggest that lycopene inhibits PRRSV replication by modulating ROS levels and mitigating inflammation, offering a promising avenue for the development of antiviral therapeutics. This study provides new insights and strategies for combating PRRSV infections, emphasizing the potential of lycopene as a safe and effective antiviral agent. Full article

Endometriosis is a chronic inflammatory condition affecting approximately 10% of women of reproductive age, characterized by pelvic pain, dysmenorrhea, and infertility. Emerging evidence suggests a potential link between gut microbiota dysbiosis and endometriosis pathogenesis, mediated through hormonal regulation, immune modulation, and systemic inflammation. Dienogest (DNG) is widely used for endometriosis management, but its effects on gut microbiota remain underexplored. This study investigates the impact of DNG on gut microbial composition in endometriosis patients, aiming to elucidate its therapeutic mechanisms beyond hormonal modulation. DNG therapy led to a significant reduction in the Bacillota/Bacteroidota ratio (p = 0.0421), driven by decreased Staphylococcus spp. (p = 0.0244) and increased commensal bacteria such as Lactobacillus spp. and Collinsella aerofaciens (p = 0.049). Species richness and alpha diversity indices showed a non-significant upward trend. Notably, C. aerofaciens, a butyrate producer linked to gut barrier integrity, was detected twice as frequently during therapy. The study also observed reductions in facultative anaerobes like Enterococcus spp. and a trend toward higher titers of beneficial Bacteroidota. This study provides the first evidence that DNG therapy modulates gut microbiota in endometriosis patients, favoring a composition associated with anti-inflammatory and barrier-protective effects. The observed shifts—reduced opportunistic pathogens and increased symbionts—suggest a novel mechanism for DNG’s efficacy, potentially involving the microbial regulation of estrogen metabolism and immune responses. Full article

Olive mill wastewaters (OMWWs) are an environmental problem in the Mediterranean region, and it is crucial to explore strategies for their treatment and repurposing. The chemical precipitation technique (CPT) has been presented as a cost-effective wastewater treatment solution that might be applied to OMWW. The CPT-resulting precipitant subproducts (sludge) may be reprocessed (e.g., agricultural fertilizer and/or soil amendment), while the treated wastewater may be repurposed or reused (e.g., irrigation, aquaponic, or industrial processes). This study aimed to evaluate the efficacy of CPT in treating wastewater from the olive oil industry from an ecotoxicological perspective. Additionally, to assess the safe use of the obtained sludge in CPT treatment, its effects on soil biota were assessed. For this, a set of ecotoxicological assays using freshwater (Raphidocelis subcapitata, Daphnia magna and Danio rerio), terrestrial invertebrates (Folsomia candida and Enchytraeus crypticus), and plants (Brassica oleracea and Lolium perenne) were used as model organisms. Results demonstrated that CPT reduced OMWW toxicity to freshwater organisms, offering a favorable outlook on CPT’s potential as a wastewater treatment method. Increasing application rates of sludge in soil reduced the shoot biomass and the hydric content of both plants compared to the control. Survival of F. candida and E. crypticus was not affected by sludge in soil at any tested application rate, yet sludge application negatively affected the reproduction of both species, even at relevant sludge application rates (2%) of sludge in soils. Overall, the applicability of this sludge obtained by the CPT treatment in soils should be carefully evaluated due to the observed adverse effects on soil biota. Although the results of CPT were promising in reducing the toxicity of OMWW for these aquatic species, some adjustments/improvements should be performed to improve this technique and use all the obtained resources (treated water and sludge) in a fully circular perspective. Full article

Objectives: To investigate the efficacy and underlying mechanisms of IBCar’s biological activity in breast cancer models, both in cell culture and in mice, and to compare its effects on cancer versus normal cells. Methods: The cytotoxicity of IBCar was evaluated using the MTS assay to assess metabolic activity and the clonogenic assay to determine reproductive integrity. The impact of IBCar on microtubule integrity, mitochondrial function, and multiple signaling pathways was analyzed using Western blotting, microarray analysis, and live cell imaging. The therapeutic effectiveness of orally administered IBCar was assessed in a transgenic mouse model of Luminal B breast cancer and in mice implanted with subcutaneous triple-negative breast cancer xenografts. Results: IBCar demonstrated potent cytotoxicity across a diverse panel of breast cancer cell lines, including those with mutant or wild-type TP53, and cell lines with short and long doubling times. Comparative analysis revealed distinct responses between normal and cancer cells, including differences in IBCar’s effects on the mitochondrial membrane potential, endoplasmic reticulum stress and activation of cell death pathways. In breast cancer cells, IBCar was cytotoxic at nanomolar concentrations, caused irreversible microtubule depolymerization leading to sustained mitochondrial dysfunction, endoplasmic reticulum stress, and induced apoptosis. In normal cells, protective mechanisms included reversible microtubule depolymerization and activation of pro-survival signaling via the caspase-8 and riptosome pathways. The therapeutic potential of IBCar was confirmed in mouse models of Luminal B and triple negative BC, where it exhibited strong antitumor activity without detectable toxicity. Conclusions: These findings collectively support IBCar as a promising, effective, and safe therapeutic candidate for breast cancer treatment. Full article

Background: Uterine fibroids (UFs) and endometriosis are gynecological conditions that significantly increase morbidity among women of reproductive age. Relugolix, a novel gonadotropin-releasing hormone receptor antagonist, is approved in combined therapy for the management of symptoms related to these disorders. However, its potential impact on bone mineral density (BMD) and osteoporosis risk should be considered when using a gonadotropin-releasing hormone (GnRH) antagonist. This systematic review aims to evaluate the effects of daily relugolix intake in monotherapy and combination therapy on BMD, ensuring safe long-term management. Methods: A systematic literature review was conducted following PRISMA 2020 guidelines. Searches were performed in PubMed, Medline, and the Cochrane Library. Relevant clinical guidelines from international societies were also reviewed. Studies assessing the impact of relugolix on BMD were selected, and data on treatment efficacy, adverse effects, and bone health outcomes were synthesized. Results: Relugolix monotherapy has been associated with significant BMD loss due to its potent estrogen-suppressing effect. To mitigate this, combination therapy with estradiol and norethisterone acetate has been developed. Although initial monotherapy before transitioning to combination therapy results in transient BMD reduction, clinical trials have demonstrated that relugolix combination therapy maintains BMD over two years while effectively reducing endometriosis- and UF-related symptoms. Conclusions: Relugolix combination therapy is an effective and well-tolerated treatment for UFs and endometriosis, minimizing the risk of hypoestrogenism-related bone loss while maintaining clinical benefits. Although monotherapy may lead to transient BMD reduction, combination therapy appears to stabilize bone health. Full article

Iron deficiency (ID) is the most prevalent micronutrient deficiency globally, affecting approximately one in four individuals, with a particularly high burden among children, women of reproductive age, and populations in low- and middle-income countries. It contributes significantly to the global burden of disease, with consequences ranging from impaired cognitive and motor development in children to increased risks during pregnancy, including low birth weight, preterm delivery, and maternal mortality, as well as reduced physical performance and quality of life in adults. ID often precedes iron deficiency anemia (IDA), though clinical and functional impairments—such as cognitive deficits, immune dysfunction, and fatigue—can occur even in the absence of anemia. Despite its widespread nature, challenges remain in precisely defining, diagnosing, and treating ID effectively. Advances in diagnostic tools allow for earlier detection, while novel therapeutic strategies, including updated oral dosing regimens and modern intravenous iron formulations, offer improved efficacy and tolerability. These approaches are particularly valuable in minimizing gastrointestinal side effects and enhancing patient adherence. This review is based on a comprehensive literature search conducted primarily through PubMed and Scopus, emphasizing studies published within the past 10–15 years. It is thematically structured to explore the epidemiology, health consequences, diagnostic complexities, and therapeutic developments related to ID. It highlights the multifactorial nature of ID and underscores the urgent need for early identification, targeted interventions, and updated clinical guidelines to reduce the long-term health and societal impacts of this preventable and treatable condition. Full article

Menopause is characterized by a decline in estrogen levels, leading to symptoms such as vasomotor instability, osteoporosis, and increased cardiovascular and cognitive risk. Hormone replacement therapy (HRT) remains the gold standard for managing menopausal symptoms; however, concerns regarding its long-term safety, including elevated risks of cancer and cardiovascular events, have prompted interest in alternative therapies. Phytoestrogens, particularly the isoflavones daidzein and genistein, are plant-derived compounds structurally similar to 17β-estradiol (E2) and capable of binding estrogen receptors. Found abundantly in soybeans and red clover, these compounds exhibit selective estrogen receptor modulator (SERM)-like activity, favoring ERβ over ERα, which underlies their tissue-specific effects. In vitro, in silico, and in vivo studies demonstrate their ability to modulate estrogenic pathways, inhibit oxidative stress, and influence reproductive and neurological function. Clinical trials show that daidzein and genistein, especially in equol-producing individuals, can reduce vasomotor symptoms such as hot flashes and night sweats. While results across studies vary, consistent findings support their safety and modest efficacy, particularly for women unable or unwilling to use HRT. Pharmacokinetic studies reveal moderate bioavailability and interindividual variability due to gut microbiota metabolism. At dietary levels, these compounds are generally safe, although high-dose supplementation is discouraged in individuals with hormone-sensitive cancers. Emerging evidence suggests lifelong consumption of soy-based foods may reduce cancer risk. In conclusion, daidzein and genistein represent promising, well-tolerated natural alternatives to conventional HRT, offering symptom relief and additional health benefits. Further research is warranted to optimize dosing, improve clinical outcomes, and clarify long-term safety in diverse populations, particularly with genetic variations in isoflavone metabolism. Full article

Toscana virus (TOSV) and Schmallenberg virus (SBV) are arthropod-borne viruses from the Bunyaviricetes class, posing significant human and animal health threats. TOSV, endemic to the Mediterranean region, is a notable human pathogen detected in various animals, suggesting potential zoonotic reservoirs. SBV emerged in Europe in 2011, affecting ruminants and causing reproductive issues, with substantial economic implications. The rapid spread of both viruses underscores the need for novel antiviral strategies. Host defense peptides (HDPs), particularly those derived from scorpion venom, are gaining attention for their antiviral potential. This study investigated pantinin-1 and pantinin-2 for their inhibitory activity against TOSV and SBV by plaque reduction assay, tissue culture infective dose (TCID₅₀) determination, and the analysis of M gene expression via qPCR. Both peptides exhibited potent virucidal activity, with IC₅₀ values of approximately 10 µM, depending on the specific in vitro cell model used. Additionally, the selectivity index (SI) values were favorable across all virus/cell line combinations, with particularly optimal results observed for pantinin-2. In human U87-MG neuronal cells, both peptides effectively blocked TOSV infection, a critical finding given the virus’s association with neurological conditions like encephalitis. The strong efficacy of these peptides against these viruses underscores the broader applicability of venom-derived peptides as promising antiviral agents, particularly in the context of emerging viral pathogens and increasing resistance to conventional therapeutics. Further studies are needed to optimize their antiviral potency and to assess their safety in vivo using animal models. Full article

Background/Objectives: Ovarian cancer (OC) remains one of the most lethal malignancies of the female reproductive system. Glucose oxidase (GOx) has emerged as a potential therapeutic agent in cancer treatment by inducing tumor starvation through glucose depletion. Nonetheless, its clinical application is constrained due to its systemic toxicity, immunogenicity, poor in vivo stability, and short half-life. These challenges can be addressed through nanotechnology; in particular, biogenic mesoporous silica nanoparticles (MSNs) offer promise as drug delivery systems (DDSs) that enhance therapeutic efficacy while minimizing side effects. Methods: Biogenic MSNs were extracted from the Equisetum myriochaetum plant via acid digestion, functionalized with 3-aminopropiltrietoxysilane (APTES) and glutaraldehyde (GTA), and loaded with GOx. The free and immobilized MSNs were characterized using FTIR, DLS, XRD, SEM/EDX, and BET techniques. A colorimetric approach was employed to quantify the enzymatic activity of both the free and immobilized GOx. The MTT assay was employed to assess the viability of SKOV3 cells. The obtained IC₅₀ concentration of the nanoformulation was administered to SKOV3 cells to analyze the expression of cancer-related genes using RT-qPCR. Results: IC₅₀ values of 60.77 ng/mL and 111.6 µg/mL were ascertained for the free and immobilized GOx, respectively. Moreover, a significant downregulation of the oncogene β-catenin (CTNNB1) was detected after 24 h with the nanoformulation. Conclusions: Our findings indicate that GOx-loaded biogenic MSNs may serve as a potential therapeutic agent for ovarian cancer. This is, to the best of our knowledge, the first report exploring the effect of GOx-loaded biogenic MSNs on SKOV3 cells. Full article

Background: Endometrial cancer (EC) is the most common gynecological malignancy, increasingly affecting premenopausal women. While hysterectomy is the standard treatment, it eliminates reproductive potential, highlighting the need for effective fertility-sparing alternatives. Current ESHRE/ESGO/ESGE guidelines recommend progestin-based therapies, often with hysteroscopic resection. However, these are based on limited pharmacological options and moderate to low-quality evidence. Novel and combination therapies have shown promise but remain absent from current clinical guidelines. This review aims to evaluate the efficacy and safety of fertility-preserving treatments for early-stage EC, emphasizing the need to update current strategies based on emerging data. Methods: A systematic review and meta-analysis will follow PRISMA guidelines and the Cochrane Handbook. Eligible studies, including randomized and non-randomized designs, will assess fertility-preserving treatments for early-stage EC. Data will be extracted on complete response, recurrence, and long-term fertility outcomes. The GRADE system will assess evidence certainty. Risk of bias will be evaluated using RoB 2 for RCTs and ROBINS-I for non-randomized studies. Meta-analysis will be performed if sufficient data are available. Conclusions: This review will provide a comprehensive analysis of fertility-sparing treatments for early-stage EC, support personalized strategies, identify evidence gaps, and guide future research. Trial registration—Prospero: CRD420251032161. Full article

Endometriosis is a chronic gynecological pathology marked by the aberrant proliferation of tissue analogous to the endometrial lining outside the uterine cavity. This disorder frequently engenders persistent pelvic discomfort, infertility, and an extensive array of additional manifestations, including menorrhagia, dyspareunia, and gastrointestinal anomalies. Affecting an estimated 10% of women within the reproductive age demographic globally, endometriosis continues to present as a multifaceted and formidable challenge. The precise etiology remains elusive, leading to extended diagnostic intervals and personalized, often inadequate, therapeutic approaches. The intrinsic heterogeneity of endometriosis, evident in its varied phenotypes and clinical manifestations, further complicates both precise diagnosis and efficacious treatment. Conventional management hinges on hormonal interventions, which may not be appropriate for women desiring conception or for those experiencing substantial adverse effects. While surgical procedures are accessible, they do not provide a conclusive resolution, and the probability of recurrence remains high. Progress in diagnostic methodologies, such as non-invasive biomarker analyses, combined with an expanding understanding of the molecular and immunological frameworks that underpin the condition, presents promising prospects for the development of more targeted and individualized non-hormonal treatment modalities in the near future. Full article

Early embryonic loss is a major cause of reproductive inefficiency in cattle, primarily due to premature luteolysis. Interferon tau (IFN-τ), secreted by the trophoblast, plays a critical role in maternal recognition of pregnancy by maintaining corpus luteum function. However, its practical application has been limited by its rapid degradation and short half-life in vivo. Here, we developed a novel formulation of recombinant bovine IFN-τ, combining chitosan-based microencapsulation with starch–chitosan hydrogel delivery, enabling sustained intrauterine release. This dual-delivery strategy offers a significant improvement over conventional IFN-τ administration methods that rely on repeated intrauterine infusions of soluble protein. The rbIFN-τ was expressed in Pichia pastoris, purified to 90.1% homogeneity, and structurally validated via homology modeling and molecular docking, confirming its interaction with type I interferon receptors. The encapsulated formulation retained antiviral activity, stimulated transcription of interferon-stimulated genes (PKR, OAS1, OAS2), and showed sustained release in vitro for up to 26 days. In vivo evaluation demonstrated safety and biological efficacy, with treated cattle showing inhibited luteolysis, sustained serum progesterone levels, and preserved corpus luteum integrity. This formulation represents a promising biotechnological approach to improve reproductive efficiency through a long-acting, species-specific IFN-τ delivery system. Full article

The Luhua chicken is an outstanding local breed in China that has been placed under conservation due to the impact of specialized breeding and the widespread adoption of commercial varieties. As such, this study analyzed reproductive traits across three consecutive generations and utilized whole-genome resequencing data from 60 Luhua chickens to assess conservation efficacy through genetic diversity, run of homozygosity (ROH) distribution, kinship, and population structure so as to better conserve the breed. The results show that, across generations, the body weight at first egg increased, the age at first egg was delayed, and the egg weight at first laying increased. No significant variations were found in the body weight at 300 d or the total egg number. The key genetic parameters of the polymorphism information content (PIC), expected heterozygosity (HE), observed heterozygosity (HO), and mean identical-by-state (IBS) distance were 0.234, 0.351, 0.277, and 0.782, respectively. The majority of ROHs ranged from 0.5 to 1 Mb, and the inbreeding coefficient based on ROHs was calculated at 0.021. The findings reveal that these traits remained unchanged across the three generations. Our research suggests that optimizing the mating plan of Luhua chickens is essential to minimize inbreeding risk. Furthermore, the methodology applied in this study provides a valuable reference for the conservation monitoring of other indigenous chicken breeds. Full article