Reproductive Sciences最新文献

Male infertility accounts for nearly half of all infertility cases globally, often resulting from oxidative stress and hormonal dysregulation. Conventional treatments offer limited efficacy, prompting interest in multi-target botanical therapies. This study evaluates a standardized polyherbal formulation (PHP), comprising Mucuna pruriens, Anacyclus pyrethrum, Asparagus racemosus, and Tribulus terrestris, for its protective effects against carbon tetrachloride (CCl₄)-induced reproductive toxicity. In vitro, assays confirmed the antioxidant capacity of PHP, with dose-dependent radical scavenging in DPPH and FRAP assays and inhibition of GC-1/GC-2 spermatogonia cell proliferation. In vivo, PHP administration (100, 300, 500 mg/kg) in carbon tetrachloride (CCl₄)-exposed rats significantly reduced oxidative stress, including a 52% reduction in thiobarbituric acid reactive substances (TBARS), 47% reduction in hydrogen perocide (H₂O₂), and normalization of enzymatic antioxidants glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD); P < 0.01 vs. CCl₄. Hepatic injury biomarkedly improved, with alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin levels reduced by 40-55% compared to CCl₄ group (P < 0.01). PHP also restored reproductive hormones testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and Prolactin levels elevated by 1.8 to 2.2-fold relative to intoxicated controls (p < 0.05). Gene expression analysis revealed significant recovery, with sex-hormone-binding globulin (SHBG), protein kinase B (AKT1), and androgen receptor (AR) transcripts upregulated 2.0-2.5-fold in PHP-treated animals (p < 0.05 vs. CCl₄), approaching control values. Histopathological analysis confirmed structural restoration of testicular architecture, with reduced seminiferous tubule degeneration and active spermatogenesis. In silico docking identified luteolin and acacetin as key phytochemicals. Luteolin exhibits strong binding to the androgen receptor (AR: -9.6 kcal/mol), AKT1 (-9.9 kcal/mol), and SHBG (-9.5 kcal/mol). It complied with Lipinski's rule of five and displayed favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Collectively, these findings suggest that PHP exerts multi-target protective effects against CCl₄-induced male infertility by mitigating oxidative stress, restoring hormonal balance, and modulating key reproductive signaling pathways. Further mechanistic and clinical investigations are warranted to validate its therapeutic potential.

Fetal hypoxia remains a major unresolved clinical challenge. Using artificial placenta (AP) technology, we established a standardized model of progressive hypoxia that induces brain injury in fetal sheep. To support the development of new antenatal monitoring strategies, we further profiled gestation-specific physiological, biochemical, protein, and cfRNA responses during progressive hypoxia. Seven fetuses at 123 days gestational age (dGA) and eight fetuses at 98 dGA (term = 150 dGA) were supported on the AP. Following a 12-h stabilization period, during which FiO₂ and gas flow to the AP oxygenator were adjusted to maintain fetal SO₂ at 65-75% and pCO₂ at 35-45 mmHg, both parameters were reduced by 5% every 30 min until termination criteria were met (arterial pH < 7.0 or base excess < -12). This protocol produced 240-300 min of progressive hypoxia. Physiological parameters, blood gases, biochemical markers, and cardiac and vascular ultrasound were assessed hourly. At the end of the experiment, brain histology and plasma cfRNA profiling were performed. Progressive hypoxia induced significant increases in pCO₂ and lactate and decreases in SO₂, CtO₂, pH, and BE in both groups (p < 0.05). Gestation-specific differences were observed in pO₂, glucose, and vital signs (heart rate, mean arterial pressure, and circuit flow). AST, ALT, and NSE rose significantly only at 123 dGA (p < 0.05), whereas S100B and NT-proBNP increased in both groups. Histology confirmed hypoxic brain injury at both gestational ages. In 123 dGA fetuses, iliac artery pulsatility index and heart rate predicted dysregulation of pH, BE, SO₂, and lactate (R² = 0.538-0.745, p < 0.05). Plasma cfRNA analysis demonstrated distinct gestation-specific gene expression patterns consistent with hypoxia-induced injury. We developed a standardized, regulable model of fetal hypoxia and demonstrated brain injury accompanied by gestation-specific physiological, biochemical, and transcriptomic responses. Plasma cfRNA profiling highlighted its potential as an antenatal biomarker of hypoxic insult. This platform may facilitate the development of new diagnostic tools and guide evaluation of postnatal interventions.

Abnormal levels of Inhibin B (INH-B), a major regulator of ovarian activity, are closely linked to the development and prognosis of several ovarian disorders. Understanding the molecular mechanisms governing its regulation in granulosa cells is essential for both diagnosis and therapy. Our earlier work demonstrated the precise localization of lncPrep + 96 kb in granulosa cells and its central influence on the estrogen biosynthetic pathway. In this study, the impact of lncPrep + 96 kb on INH-B expression was investigated further. We created knockout mice lacking the long non-coding RNA lncPrep + 96 kb, which is specifically expressed in granulosa cells of the ovary. RNA sequencing revealed that the inhibin subunit βB (INHBB) was significantly elevated in knockout mice. ELISA was utilized to quantify INH-B levels in serum and granulosa cell supernatants, revealing a significant increase in knockout mice compared to wild-type controls. Overexpression of lncPrep + 96 kb fragments (2.2 kb and 2.8 kb) reduced INH-B expression. Endothelial differentiation-related factor 1 (EDF1), a key intracellular transcription factor, was found to be upregulated by lncPrep + 96 kb, resulting in decreased INH-B expression. In summary, lncPrep + 96 kb regulates INH-B secretion in granulosa cells by modulating of EDF1, providing new insights into the mechanism of INH-B expression and offering new research directions for diagnostic and therapeutic studies of abnormal ovarian functions.

The "double-edged sword" effect of dexamethasone on fetal development has attracted significant attention. Currently, the "one-size-fits-all" prenatal corticosteroid regimen fails to confer uniform benefits to all pregnant women and fetuses. Simultaneously, there exist controversies regarding the wide time window for administration and the insufficient consideration of individual factors in dosage selection. Therefore, this study aimed to establish a precise prenatal dexamethasone exposure (PDE) mouse model that closely mimics clinical use, to evaluate its effects on placental morphology, development, differentiation, vascular formation, and nutrient transporter function. Dexamethasone was injected subcutaneously at diverse gestational stages, doses, and courses. The late-stage, high-dose, single-course PDE exhibited the most pronounced effects, including reduced placental weight, a decreased labyrinth-to-junctional zone (LZ/JZ) ratio, impaired trophoblast proliferation and differentiation, increased apoptosis, and decreased vascular endothelial growth factor (VEGF) expression. Amino acid and cholesterol transporter levels increased in both sexes, whereas glucose transporters showed sex-specific alterations-elevated in males but reduced in females. Further investigation revealed that PDE suppressed the "glucocorticoid (GC)-insulin-like growth factor 1 (IGF1) axis" programming, which was highly correlated with placental development and function indicators. In conclusion, PDE induced alterations in placental morphology, development, and nutrient transport function, which were influenced by stages, doses, courses, and sex differences. These changes may be associated with the "GC-IGF1 axis" programming. This study provides experimental and theoretical evidence to more precisely guide the clinical application of prenatal dexamethasone.

Uteroplacental insufficiency (UPI) disrupts fetal brain development and induces oxidative damage. This study evaluates the neuroprotective effects of ferulic acid (FA) on oxidative stress biomarkers, neuroinflammation, the Akt/GSK-3β signaling pathway, and neuronal density in the medial prefrontal cortex (mPFC) following UPI in rats. Twenty pregnant Wistar rats were randomly assigned to four groups: Control, Sham Surgery, UPI + Vehicle (UPI + normal saline), and UPI + FA (UPI + FA at 100 mg/kg). UPI was induced via permanent ligation of the uterine arteries on embryonic day (ED) 18. FA or normal saline was administered orally from ED14 to ED21. On ED21, fetal brain tissue was analyzed for oxidative stress biomarkers (8-hydroxy-2'-deoxyguanosine, protein carbonyl, 4-hydroxy-2-nonenal, and malondialdehyde), inflammatory cytokines (interleukin-6 [IL-6], IL-1β, tumor necrosis factor-alpha [TNF-α], and IL-10), Akt/GSK-3β gene expression, and neuronal density in the mPFC. FA treatment significantly reduced oxidative stress biomarkers and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) while decreasing GSK-3β expression and increasing Akt expression. Additionally, FA enhanced neuronal density in the mPFC and elevated IL-10 levels compared to the UPI + Vehicle group (p < 0.05). Pre-treatment with FA prior to UPI induction mitigated oxidative stress, modulated the Akt/GSK-3β signaling pathway, suppressed neuroinflammation, and preserved cortical integrity in the fetal brain.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting 5-20% of reproductive-age women. Besides genetic factors, environmental triggers are considered major underlying causes that play a role through epigenetic alterations. Since epigenetic studies can be a possible link to explain the complexity of multifactorial disorders, it is worthwhile to investigate differentially methylated regions (DMRs) associated with PCOS. Therefore, a systematic review was conducted to identify epigenetic modifications associated with PCOS and analyse their functional role in the pathogenesis of the syndrome. After following inclusion and exclusion criteria, various databases (PubMed, Google Scholar, Central Cochrane Library, and Science Direct) were searched with predetermined keywords up to 30th June 2025, and quality of the selected articles assessed through the Newcastle Ottawa scale (NOS). In-silico analysis was performed by STRING, and Shiny GO. A total of 46 eligible studies were included, were further sub-categorized based on the sample type. A total of one hundred eleven genes were identified with altered DMRs, out of which thirty seven genes were reported from the ovarian tissues alone. Their GO analysis shows a significant interaction with other PCOS-susceptible genes and their functions in female sex differentiation and gonadal development. However, in-silico analysis of thirty six genes identified in blood showed their functions were significantly involved in the insulin-like growth factor binding activity. Gene enrichment analysis of fifteen genes with altered methylation identified in adipose tissue shows the significant involvement of female sex differentiation and insulin-activated receptor functions. Further, alterations in methylation of which genes (INSR, AMHR2, YAP1, CYP19A1, LHCGR, CDKN1A, LINE-1, AMH and TOX3) have been reported by at least two separate studies, irrespective of sample type. Their in-silico analysis shows significant involvement of these genes in the female sex characters, and gonadal development The current study highlights tissue-specific epigenetic modifications in PCOS, summarizes DMRs of genes which are involved in reproductive and insulin-related pathways. DMRs of identified genes may have a role in the pathogenesis of PCOS, insight into which may provide novel therapeutic targets in the future.

Recent advances in microbiome research have illuminated the complex bidirectional interactions between gut health and reproductive well-being. Understanding the gut microbiome's influence on the reproductive system and vice versa reveals how both of them can affect hormone production, immune function, and ultimately overall reproductive health. Dysbiosis, an imbalance in the gut microbial community, has been linked with a range of reproductive issues, including decreased sperm count and motility, erectile dysfunction, polycystic ovary syndrome (PCOS), endometriosis, infertility, and adverse pregnancy outcomes. This review critically evaluates emerging therapeutic interventions aimed at restoring microbial balance and enhancing reproductive health, such as use of prebiotics, probiotics, bacteriophage therapy, and fecal microbiota transplantation (FMT). By exploring the intricate interplay between gut microbiota and reproductive health, this review also emphasizes the need for integrated approaches in research and clinical practice to develop effective microbiome-based therapies for better reproductive health outcomes.

Polycystic ovary syndrome (PCOS) is a common and frequent disease and always leads to endocrine and metabolic disorders among women of reproductive age. In most PCOS patients, the serum level of anti-mullerian hormone (AMH) is significantly higher than that of normal women of childbearing age. AMH is an important auxiliary diagnostic method for PCOS. AMH may play an important role in the occurrence and development of PCOS and potentially affect the success of in vitro fertilization (IVF) treatments, although the exact mechanisms remain unclear. This review focuses on the relationships and mechanisms of dysregulated AMH and follicular development in PCOS based on recent research. It is mainly manifested in the regulation of related signal pathways, the negative feedback regulatory loop of several gonadal hormones such as follicle-stimulating hormone, luteinizing hormone, estradiol, and testosterone, as well as the influence of AMH on IVF in PCOS patients. Additionally, it puts forward some suggestions, which will provide some helpful ideas or directions for future further research on PCOS.

A thin endometrial lining, typically defined as an endometrial thickness of less than 7 mm, is commonly associated with failed embryo implantation, recurrent pregnancy loss, and infertility. This review summarizes the current understanding of the pathophysiological mechanisms underlying thin endometrium and highlights emerging therapeutic approaches. Published studies indicate that impaired uterine perfusion and downregulation of vascular endothelial growth factor (VEGF) compromise angiogenesis, resulting in tissue-level reproductive defects. Hypoxia, together with the activation of the hypoxia-inducible factor 1-alpha (HIF-1α) and RhoA/Rho-associated protein kinase (ROCK) pathways, has been shown to disrupt epithelial cell integrity and exacerbate endometrial atrophy. Immune impairments characterized by abnormal cytokine signaling, reduced natural killer (NK) cell activity, and chronic endometritis further reduce endometrial tolerance. Additionally, epigenetic modifications, such as aberrant DNA methylation and microRNA (miRNA) dysregulation, have been linked to altered expression of key implantation-related genes, including homeobox A10 (HOXA10). Conventional therapies, such as estrogen supplementation, vasodilators, and granulocyte colony-stimulating factor (G-CSF), have variable efficacy. In contrast, regenerative strategies, including stem cell-based therapies, platelet-rich plasma (PRP), and biomaterial-based interventions, have shown promising potential for restoring endometrial function. A comprehensive understanding of these mechanisms is essential for improving diagnostic and therapeutic strategies, and while regenerative approaches represent a promising avenue for enhancing endometrial receptivity and reproductive success, further preclinical and clinical studies are warranted to optimize these novel therapies and evaluate their long-term safety and efficacy.

Objective: This study aims to investigate the genetic associations of endometrial cancer (EC), ovarian cancer (OC), and cervical cancer (CC), identify potential key genes using multiple genomic analysis approaches, and analyze their roles in cancer development.

Methods: We integrated large-scale genome-wide association study (GWAS) data from Jiang L et al. and Zhou W et al., combined with blood eQTL data. We employed S-PrediXcan, SMR, and mBAT-combo to assess gene associations with EC, OC, and CC. Additionally, RNA sequencing data were used to analyze the expression levels of key genes across different tissues, followed by functional enrichment analysis to explore their potential biological functions. Results: Through S-PrediXcan, SMR, and mBAT-combo analyses, we identified 690, 620, and 624 genes associated with OC, CC, and EC, respectively. Among them, 79, 59, and 61 genes were consistently significant across all three methods, suggesting their crucial roles in cancer development. Furthermore, we identified multiple comorbidity-related genes, including SPX, which exhibited a negative association with OC, CC, and EC. Transcriptomic analysis revealed that 26 key genes displayed significant expression differences between tumor and normal tissues. Functional enrichment analysis further identified the molecular pathways potentially involved. Conclusion: This study identified a set of key genes associated with EC, OC, and CC and suggested that SPX may play a protective role in cancer development. The integration of multilevel genetic and transcriptomic analyses provides new insights into the molecular mechanisms underlying gynecological malignancies and offers potential biomarkers for future precision medicine research.