The role of the endoplasmic reticulum (ER) stress response in hyperemesis gravidarum (HG) remains incompletely understood. This study evaluated circulating PERK and ATF-4 levels and their associations with clinical and laboratory characteristics in HG. This prospective case-control study, conducted from August to November 2024, included 85 pregnant women with HG within the first 16 weeks of gestation and 85 healthy pregnant controls. Serum PERK and ATF-4 levels were measured using ELISA. Group comparisons, Spearman correlation analyses, and receiver operating characteristic (ROC) analysis were performed. Serum ATF-4 levels were significantly lower in the HG group than in controls [4.55 (0.82-42.86) vs. 6.16 (2.23-29.27) ng/mL; p = 0.002], whereas PERK levels did not differ between groups [3.73 (0.16-15.37) vs. 3.29 (0.67-19.36) ng/mL; p = 0.965]. Strong positive correlations were observed between ATF-4 and PERK in the HG group (ρ = 0.837), control group (ρ = 0.709), and overall study population (ρ = 0.765) (all p < 0.001). Within the HG group, ATF-4 levels did not differ significantly according to urinary ketone positivity (p = 0.282). ATF-4 showed limited discriminatory performance for HG (AUC = 0.638; p = 0.001; sensitivity 45.9%; specificity 77.6%). HG is associated with lower circulating ATF-4 levels without a corresponding change in PERK. These findings support further molecular and longitudinal investigation of the PERK-ATF-4 axis in HG.

Hydrogen sulfide (H2S) plays an important role in placental function. Its bioavailability depends on the balance between enzymatic synthesis by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE/CTH) and 3-mercaptopyruvate sulfurtransferase (3-MST/MPST), and mitochondrial oxidation through sulfide:quinone oxidoreductase (SQOR), persulfide dioxygenase (ETHE1) and thiosulfate sulfurtransferase (TST). However, the extent to which H2S synthesis, oxidation and experimental modulation have been investigated in placental systems remains unclear. This scoping review mapped the placental H2S literature to identify where evidence is concentrated and where gaps remain. Following JBI methodology and PRISMA-ScR reporting, Scopus, Embase, MEDLINE and Web of Science were searched for primary studies involving placental or trophoblast H2S biology. Sixty-four studies were included. Pre-eclampsia dominated the literature (n = 27), while most other pregnancy conditions were sparsely represented. CBS and CSE/CTH were investigated in 34 and 29 studies respectively, while 3-MST/MPST was investigated in only seven studies. None of the included studies assessed the principal mitochondrial sulfide-oxidation enzymes SQOR, ETHE1 or TST. Sulfide concentrations, relative assay signals or H2S production were reported in 23 studies across six analytical approaches. Sulfide measurement was highly heterogeneous across studies, making direct comparison between studies limited. H2S was experimentally modulated in 85 intervention applications but measured in only 23. Overall, placental H2S research is concentrated on biosynthetic enzyme expression and pre-eclampsia, while sulfide clearance, early gestation and standardised measurement remain major gaps. These gaps limit interpretation of changes in placental H2S bioavailability and the evaluation of donor-based therapeutic strategies.

The role of the endoplasmic reticulum (ER) stress response in hyperemesis gravidarum (HG) remains incompletely understood. This study evaluated circulating PERK and ATF-4 levels and their associations with clinical and laboratory characteristics in HG. This prospective case-control study, conducted from August to November 2024, included 85 pregnant women with HG within the first 16 weeks of gestation and 85 healthy pregnant controls. Serum PERK and ATF-4 levels were measured using ELISA. Group comparisons, Spearman correlation analyses, and receiver operating characteristic (ROC) analysis were performed. Serum ATF-4 levels were significantly lower in the HG group than in controls [4.55 (0.82-42.86) vs. 6.16 (2.23-29.27) ng/mL; p = 0.002], whereas PERK levels did not differ between groups [3.73 (0.16-15.37) vs. 3.29 (0.67-19.36) ng/mL; p = 0.965]. Strong positive correlations were observed between ATF-4 and PERK in the HG group (ρ = 0.837), control group (ρ = 0.709), and overall study population (ρ = 0.765) (all p < 0.001). Within the HG group, ATF-4 levels did not differ significantly according to urinary ketone positivity (p = 0.282). ATF-4 showed limited discriminatory performance for HG (AUC = 0.638; p = 0.001; sensitivity 45.9%; specificity 77.6%). HG is associated with lower circulating ATF-4 levels without a corresponding change in PERK. These findings support further molecular and longitudinal investigation of the PERK-ATF-4 axis in HG.

Premature ovarian failure (POF) refers to ovarian failure and its occurrence and development are closely related to the apoptosis signaling pathway. However, the mechanism of bone mesenchymal stem cells (BMSCs) affect the regulation of apoptosis in POF has not been fully elucidated. The GSE128240 microarray dataset were downloaded from the Gene Expression Omnibus. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) databases were used to analyse the functional and pathway enrichment of genes in the most important modules. A mouse model of POF induced by cyclophosphamide (CTX) treatment was established. POF model mice were treated with mBMSCs for 4 weeks. Ovarian failure was evaluated by haematoxylin-eosin (HE) staining, the levels of oestradiol (E2), follicle stimulating hormone (FSH) and luteinizing hormone (LH), and the number of follicles. Western blotting and immunohistochemical methods were used to measure the levels of Bcl-2, Bax and Caspase-3 proteins in the ovarian tissue of mice. Total of 1816 differentially expressed genes (DEGs) identified. The PI3K-Akt signaling pathway and ovarian steroidogenesis were functionally enriched through GO enrichment and KEGG analyses. Furthermore, the number of follicles and E2 concentration were significantly increased, and the FSH and LH concentrations were significantly decreased in CTX-induced mice treated with mBMSCs. mBMSCs attenuated apoptosis in CTX-induced mouse ovaries. Levels of Bax and Caspase-3 proteins were significantly decreased in the ovarian tissue of CTX-treated mice and significantly increased after mBMSCs treatment. Thus, mBMSCs attenuated apoptosis in CTX-induced mouse ovaries by regulating the Bcl2/Caspase3 signaling pathway, effectively treating POF.

Globally, cervical cancer is a prevalent cancer among women and ranks as the fourth leading cause of mortality in gynecological cancers. However, how telomeres affect cervical cancer remains uncertain. The research entailed the procurement of telomere-associated genes (TRGs) from TelNet. The Cancer Genome Atlas (TCGA) database provided the clinical data and TRG expression rates in patients with cervical cancer. Within the TCGA-CESC dataset, 327 TRGs were identified, differentiating between cancerous and healthy tissues. Subsequently, we combined genes linked to aging and telomeres, leading to 31 overlapping genes and performing an analysis of functional enrichment on these essential genes. Genes unique to telomeres and closely associated with cervical cancer play various roles, mainly in the cell cycle, DNA replication, and DNA repair processes. Key genes, such as those associated with cell aging, homologous recombination, and Human T-cellleukemia virus 1 infection, are vital in the life cycle of a cell. Dysfunction in these genes could lead to irregularities in cellular synthesis and apoptosis processes, potentially accelerating the progression of cervical cancer. Subsequently, the data was analyzed sequentially using single-factor Cox regression, Lasso regression, and multi-factor Cox regression techniques, leading to the development of the TRGs risk model.Among the pinpointed TCGA group (p < 0.001), cervical cancer sufferers with high-risk TRGs showed poorer outcomes. Furthermore, the TRGs risk score emerged as an independent risk factor for cervical cancer. Additionally, communities susceptible to TRGs could benefit from specific medical interventions. To conclude, our team developed a genetic risk model associated with telomeres to predict outcomes in cervical cancer patients, potentially assisting in selecting suitable treatment drugs for them.

Endometriosis and adenomyosis are characterized by the presence of endometrial-like tissue outside its normal anatomical location and are associated with pain, infertility, and other clinical manifestations. Although they share pathogenic features, including inflammation, hormonal responses, immune dysregulation, and fibrosis, their clinical and histopathological phenotypes are highly heterogeneous. This review integrates tissue mechanics and mechanobiology with inflammation, hormonal signaling, oxidative stress, angiogenesis, and neurogenesis to propose a microenvironment-dependent framework for understanding lesion formation, maintenance, and progression. Direct measurements of tissue stiffness, including elastography, have been reported, but standardized comparisons among lesion types remain limited. Existing evidence suggests that tissue stiffening may affect cellular proliferation, invasion, fibrosis, and tissue remodeling through mechanotransduction pathways such as integrin signaling. However, much of this evidence derives from in vitro studies, experimental models, or other fibrotic diseases, and direct causal relationships in human endometriosis and adenomyosis remain insufficiently established. Conversely, chronic inflammation, recurrent bleeding, and ECM accumulation may contribute to both tissue stiffening and fibrosis, indicating reciprocal interactions between mechanical and biological processes. Thus, lesion phenotypes may reflect interactions among lesion origin, cell-intrinsic properties, and the local microenvironment. Mechanobiology may complement established inflammatory, hormonal, immune, and fibrotic concepts and provide hypotheses for understanding lesion heterogeneity and progression. Longitudinal, lesion-level studies integrating mechanical and biological parameters are needed to test these hypotheses.

Combination antiretroviral therapy (cART) has improved human immunodeficiency virus (HIV) management, but long-term use is associated with reproductive dysfunction. This study investigated TLD (Tenofovir, Lamivudine and Dolutegravir)-based cART effects on ovarian function using animal models and exploratory clinical investigations in women living with HIV. In the animal study, female Wistar rats were randomized into control, TLD-based cART (22 mg/kg), and dolutegravir alone (2.5 mg/kg) groups, administered orally for 28 days. Estrous cycle, histology, oxidative stress, reproductive hormones, and ova count were assessed. Both TLD-based cART and dolutegravir significantly prolonged diestrus (p = 0.0083 and p = 0.0007, respectively) and reduced metestrus (p = 0.0057 and p = 0.0083, respectively). Treated groups showed significantly reduced ova counts (p = 0.0002 and 0.0003, respectively). Histology revealed structural alterations of the ovary, including atretic follicles, distorted stroma, and sparse theca cells. Additionally, treated groups showed increased malondialdehyde (p = 0.0421) and decreased glutathione (p = 0.0046) and catalase activities (p = 0.0411), indicating oxidative stress. Serum follicle-stimulating and luteinizing hormones were significantly reduced in both treated groups (FSH: p < 0.0001 and p = 0.0002; LH: p < 0.0001 and p = 0.0108, respectively). In the clinical investigation, serum anti-Müllerian hormone (AMH) levels were evaluated in HIV-positive women (n = 20) receiving TLD-based cART. Ten participants (50%) had AMH in low/very low categories (< 1.0 ng/mL), while 11 (55%) had AMH below the normal reference range (< 1.5 ng/mL). Menstrual interval and dysmenorrhea showed no significant changes. These preliminary findings suggest Dolutegravir and TLD-based cART may negatively affect female reproductive function by altering ovarian structure, hormonal balance, and ovarian reserve, potentially predisposing women living with HIV to fertility complications.

Polycystic ovary syndrome (PCOS) is a complicated, endocrine-endemic disorder with a prevalence rate of 8-13% in reproductive-age women in the world, which manifests through insulin resistance, hyperandrogenism, and reproductive dysfunction. Despite its high global prevalence, existing therapeutic interventions focus predominantly on symptom management rather than targeting the heterogeneous and multifactorial pathophysiology of the syndrome. Intestinal barrier integrity is destroyed by dysbiosis of the gut microbiota and induces endotoxemia and chronic low-grade inflammation through signalling pathways, such as LPS-TLR4-NF-kB signalling, which contribute to increased insulin resistance and androgen excess. These mechanistic pathways we dissect include changes in short-chain fatty acids (SCFAs), bile acid metabolism, involvement of FXR and TGR5 receptors, neuroendocrine regulation of the gut-brain axis, and microbial metabolites (tryptophan and agmatine), which altogether alter metabolic and reproductive abnormalities in PCOS. The preclinical evidence in the area of fecal microbiota transplantation proves the causal component of microbiota imbalance in the phenotype of PCOS. Dietary interventions that have been reviewed are fiber and resistant starch modulation, probiotics, prebiotics, synbiotics, fecal microbiota transplantation, and pharmacotherapies like metformin, which also alter the microbiome. They are heading towards individualized microbiome-based therapies and diagnostics, aided by artificial intelligence and standardized biomarkers. This review explains the emerging role of the gut-insulin axis as an important factor in the pathogenesis of PCOS and uses a novel way of combining them as a radical intervention for personalized and innovative PCOS treatment, which has the potential to enhance metabolic and endocrine health, as well as reproductive outcomes.

The prostate is a hormone-sensitive gland, in which stromal composition is important for epithelial regulation. Fibrotic alterations in the stroma may enhance epithelial imbalance and pre-neoplastic lesions. The purpose of this study was to assess the time-dependent antifibrotic effects of mycophenolate mofetil (MMF) in rat prostate. Male Wistar rats were treated with MMF for 7 or 30 days, and prostate samples were histologically and immunohistochemically examined. Stromal fiber content, hormone receptor expression, and immune cell incidence were analyzed. Collagen III and elastin fibers decreased at 7 days, with increased matrix metalloproteinases 2 expression and reduced androgen receptor in the epithelium, resulting in decreased proliferation and enhanced apoptosis. Collagen I breakdown at 30 days was associated with increased matrix metalloproteinases 13 and reduced smooth muscle area, with increased non-muscular stroma and vascular density. Degranulated mast cells were increased early on, and macrophages at 30 days, reflecting their successive involvement in stromal remodeling. These findings define two time windows of MMF-induced remodeling: initial extracellular matrix disassembly with epithelial influence, and later structural reorganization with vascular and immune components. This study provides relevant information about MMF as a potential tool for the study of antifibrotic response and stroma-epithelium interactions in androgen-dependent organs.

Early follicular development and primordial follicle formation are essential for ovarian reserve establishment, and disruption of this process may contribute to fertility disorders such as premature ovarian insufficiency (POI). Figla is an oocyte-specific transcription factor required for primordial follicle formation, but its candidate downstream genes and associated pathways remain incompletely understood. This study aimed to investigate the role of Figla in early follicular development and to explore its potential downstream regulatory events. A Figla knockout mouse model was generated to evaluate the effects of Figla deficiency on ovarian development and primordial follicle formation. ChIP-seq, motif analysis, and promoter activity assays were performed to identify FIGLA-associated chromatin regions and candidate genes. In addition, Figla overexpression and Ywhab knockdown experiments were conducted in a granulosa cell line, together with ovarian tissue Western blot analysis, to assess changes in growth activity, migration, ERK phosphorylation, and apoptosis-related markers. Figla was highly expressed in late embryonic and early postnatal ovaries, and its deletion primarily disrupted perinatal primordial follicle assembly, accompanied by progressive oocyte loss. ChIP-seq, motif, and promoter analyses supported Ywhab as a candidate gene potentially regulated by Figla. In KGN cells, Figla overexpression increased Ywhab expression and coincided with greater growth activity, migration, ERK phosphorylation, and changes in BAD/BCL-2/BAX-related markers. These cellular and signaling changes were attenuated by Ywhab knockdown. Additional ovarian tissue analysis showed reduced p-ERK/ERK and increased p-BAD/BAD ratios in Figla(-/-) ovaries. These findings support Ywhab as a candidate downstream gene potentially regulated by Figla and suggest a possible link between Figla-associated transcriptional regulation and cellular processes relevant to early follicular development. Further validation is needed before extending these findings to ovarian reserve establishment more broadly or to POI-related reproductive disorders.

Sertoli cells play a pivotal role in spermatogenesis by providing structural support and delivering essential nutrients and signaling molecules to developing germ cells. A key function of these cells is the regulation of androgen-binding protein (ABP), which maintains the high intratesticular testosterone levels necessary for proper spermatogenic progression. Despite the critical nature of ABP, the mechanisms underlying its degradation within Sertoli cells remain poorly understood. This study investigates the role of the valosin-containing protein (p97/VCP) in the autophagic degradation of ABP, with a particular focus on molecular pathways that may contribute to male infertility and testicular dysfunction. Sertoli 15P-1 cells were treated with testosterone, chloroquine, and rapamycin, and subjected to single and double immunofluorescence staining, Western blotting, and siRNA-mediated knockdown experiments to explore the interaction between p97/VCP and ABP. Western blot analysis demonstrated that p62 expression was highest in the chloroquine + testosterone (CQ + T) group compared to control siRNA (Csi), although not statistically significant (p > 0.05). LC3 expression peaked in the chloroquine (CQ) group (p > 0.05). As expected, the lowest expression of p97/VCP was detected in the VCPsi group following siRNA transfection. Immunofluorescence analyses revealed significant differences in protein colocalization patterns across all treatment groups, except for p62 in rapamycin-treated samples. These findings provide the first evidence in the literature of a direct relationship between p97/VCP and ABP within Sertoli cells, underscoring the relevance of autophagic pathways in the regulation of male reproductive hormones. The data suggest a novel regulatory mechanism by which p97/VCP may influence spermatogenesis and male fertility through ABP degradation. Furthermore, this work lays a foundational framework for future investigations in other ABP-expressing tissues such as the brain, liver, and placenta, potentially linking p97/VCP expression to ABP-associated endocrine and pathophysiological disorders beyond the testis.

The endoplasmic reticulum (ER) plays a pivotal role in protein folding and cellular homeostasis and is highly sensitive to oxidative stress. Nicotine is a potent pro-oxidant; however, its effects on ER stress signaling in testicular tissue and the protective potential of melatonin and coenzyme Q10 (CoQ10) remain insufficiently defined. This study investigated nicotine-induced sperm dysfunction and the involvement of oxidative stress-mediated ER stress pathways in rat testes. Two-month-old male Wistar albino rats (n = 48) were assigned to control, nicotine, nicotine + melatonin, nicotine + CoQ10, nicotine + melatonin + CoQ10, and melatonin + CoQ10 groups. Sperm quality was evaluated, and testicular tissue was analyzed for oxidative stress markers, ER stress-related gene expression, histopathological alterations, and immunohistochemical localization of proteins. Nicotine exposure significantly impaired sperm motility and membrane integrity and increased abnormal morphology, mortality, and apoptosis (p < 0.001). These effects were associated with elevated lipid peroxidation and depletion of antioxidant defenses, including reduced glutathione, glutathione peroxidase, and catalase (p < 0.001). Melatonin and/or CoQ10 partially restored sperm quality and antioxidant capacity. Moreover, antioxidant treatment significantly downregulated ER stress-associated genes (Activating transcription factor 4-ATF4; Activating transcription factor 6-ATF6; C/EBP homologous protein-CHOP; 78 kDa glucose-regulated protein-GRP78; inositol-requiring enzyme 1 alpha-IRE1α; and protein kinase RNA-like endoplasmic reticulum kinase-PERK) and reduced CHOP immunoreactivity, while CoQ10 selectively enhanced XBP-1 immunoreactivity. In conclusion, nicotine-induced testicular dysfunction is mediated by oxidative stress-driven ER stress activation, whereas melatonin and CoQ10 confer protection through modulation of redox balance and ER stress signaling.

This study aimed to develop trimester-specific and combined prediction models for early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE) based on maternal clinical characteristics, uterine artery pulsatility index (UtA-PI), and 3D placental parameters, identify the optimal models, and construct static nomograms. A total of 1602 singleton pregnant women were prospectively enrolled from October 8, 2020 to May 31, 2025. All maternal clinical data were collected and participants were followed up until delivery. UtA-PI and 3D placental ultrasound parameters, including placental volume (PV), placental quotient (PQ), and placental blood flow vascularization index (PBVFI), were measured at 11-14 and 15-18 weeks of gestation, and the placental vascular growth rate (PVGR) was calculated. According to the gestational age at preeclampsia onset, participants were divided into the EOPE group (n = 29), LOPE group (n = 58), and normal control group (n = 1515). Univariable and multivariable Firth's logistic regression analyses were performed to identify independent predictors. Model performance was evaluated using receiver operating characteristic (ROC) curves, bootstrap-based calibration and decision curve analysis (DCA). Static nomograms were constructed based on the optimal combined models. Chronic hypertension was an independent risk factor for both EOPE and LOPE, while elevated placental perfusion parameters exerted a protetive effect. The combined model achieved optimal predictive performance, with AUCs of 0.980 (95% CI 0.968-0.992) for EOPE and 0.827 (95% CI 0.765-0.889) for LOPE. Internal bootstrap validation confirmed acceptable calibration, and DCA demonstrated positive net clinical benefit. Static nomograms established based on the optimal models enable individualized risk assessment for EOPE and LOPE. We developed and internally validated trimester-specific and combined prediction models to assess the risks of EOPE and LOPE, and constructed static nomograms based on the optimal models. The models achieved favorable apparent performance in this single-center cohort. Nevertheless, their generalizability remains unclear. External validation using independent cohorts is required before large-scale application in routine antenatal screening.

To evaluate and compare the protective effects of cytokine-rich serum (ACRS) and platelet-rich plasma (PRP) against ovarian ischemia-reperfusion (I/R) injury in a rat model of ovarian torsion and detorsion. Forty-two female Wistar albino rats were randomly allocated into control, PRP, ACRS, I/R, I/R + PRP, I/R+ACRS, and donor groups. Ovarian torsion was induced for two hours followed by detorsion. PRP or ACRS was administered following detorsion. Ovarian tissues were evaluated using histopathological assessment, follicle counting, and immunohistochemical analysis of anti-Müllerian hormone (AMH), cleaved Caspase-3, VEGFA, and α-SMA. Ischemia-reperfusion injury resulted in marked ovarian damage, characterized by increased follicular degeneration, congestion, hemorrhage, edema, stromal connective tissue changes, inflammatory cell infiltration, and elevated apoptotic activity. Both PRP and ACRS attenuated histopathological injury and apoptotic activity while improving follicular preservation. Compared with PRP, ACRS was associated with better preservation of primordial and tertiary follicles, fewer atretic follicles, higher AMH immunoreactivity, lower cleaved Caspase-3 immunoreactivity, and increased VEGFA immunoreactivity. No significant differences were observed in α-SMA immunoreactivity among groups. Both PRP and ACRS exert protective effects against ovarian I/R injury; however, ACRS was associated with more pronounced histological and molecular benefits. These findings suggest that ACRS may represent a promising biological approach in ischemic ovarian pathologies.