Polycystic Ovary Syndrome (PCOS) is a heterogeneous endocrine-metabolic disorder characterized by ovulatory dysfunction, hyperandrogenism, and insulin resistance, in which mitochondrial dysfunction has been increasingly implicated. Mitochondria regulate energy metabolism and oxidative stress, with mitophagy maintaining cellular balance. Dysregulated mitophagy relates to PCOS metabolic issues like obesity and inflammation. This study analyzed gene expression datasets to find autophagy-related genes in PCOS, identifying AMFR, FABP5, and HMOX1 as key genes. We built a diagnostic model and confirmed their elevated expression in a hyperandrogenism-induced PCOS cell model, revealing potential small-molecule drugs targeting these genes. Our integrative bioinformatics analysis and systematic molecular experiments suggest that FABP5 and HMOX1 are potential PCOS diagnostic targets, with high-affinity compounds as therapies,highlighting the pathological relevance of mitophagy-related genes in PCOS.

This matched comparative study investigates whether unoperated ovarian endometriomas (OMAs) influence the prevalence of tubal pathology as detected by hysterosalpingography (HSG) in infertile women. A total of 266 infertile women with unilateral or bilateral OMAs ≥ 2 cm and 539 matched controls without endometriomas were included between January 2021 and October 2024. Diagnosis of OMAs was confirmed by transvaginal ultrasonography and, if necessary, MRI, and all participants underwent standardized HSG assessment. Tubal pathologies were classified into nine distinct categories. The OMA group showed significantly higher rates of tubal abnormalities (31.6% vs. 10.8%, p < 0.001), with unilateral hydrosalpinx and phimosis being notably more common. Logistic regression identified age and OMA presence as independent predictors, and ROC analysis suggested a cutoff of 4.5 cm for increased risk. These findings indicate that unoperated OMAs, especially when ≥ 4.5 cm, are associated with a markedly increased risk of tubal pathology. Early tubal assessment may be beneficial for individualized fertility planning in this population.

This study aims to evaluate the protective effects of betaine (BTN), an antioxidant agent, against ovarian and uterine toxicity caused by favipiravir (FVP), an antiviral agent, through multifaceted damage pathways. A total of 28 Wistar rats were divided into four experimental groups: Control, BTN (250 mg/kg), FVP (200 mg/kg), and FVP + BTN. At the end of the 10-day protocol, blood samples were collected along with ovarian and uterine tissue samples. Subsequently, the samples were subjected to biochemical analysis, qRT-PCR analysis, histological evaluation, and immunohistochemical studies. These methods assessed oxidative stress, inflammatory, apoptotic, and autophagic responses, hormonal changes, and overall tissue damage. FVP administration significantly increased oxidative stress (MDA, p < 0.001), inflammation (NF-κB, TNF-α, IL-1β, p < 0.001), apoptosis (Caspase-3, Bax, p < 0.001), and autophagy (Beclin-1, LC3A, p < 0.001); while decreasing antioxidant levels, Bcl-2, and steroidogenesis genes (CYP11A1, CYP17A1, CYP19A1, p < 0.001), and reducing serum AMH, E2, FSH, and LH values (p < 0.001). When BTN was administered concomitantly, most of these changes were reversed, antioxidant and hormonal balance were significantly restored, and the increases in oxidative, inflammatory, and apoptotic markers were reduced (p < 0.05-0.001). Histologically, betaine preserved tissue integrity by mitigating ovarian and uterine damage caused by FVP (p < 0.05). FVP caused multifaceted oxidative, inflammatory, apoptotic, and hormonal damage in ovarian and uterine tissues, while BTN significantly reduced these effects, preserving tissue integrity and function.

Endometrial injury is an important cause of infertility and adverse reproductive outcomes, but current treatments often fail to fully restore uterine structure and function. Tissue engineering strategies, including hydrogels, biodegradable scaffolds, 3D bioprinting, organoids, and microfluidic systems, have emerged as promising approaches for endometrial repair. This systematic review evaluated the available evidence on tissue engineering strategies for endometrial regeneration. PubMed, Web of Science, and Scopus were searched for studies published between January 2014 and May 2024. Of 3,381 records identified, 117 studies met the inclusion criteria. Due to substantial heterogeneity in study design and outcome measures, findings were synthesized qualitatively. Hydrogels and biomaterial scaffolds were the most frequently studied approaches, whereas organoids and 3D bioprinting showed potential for disease modeling and personalized regeneration. Microfluidic systems were rarely studied but may have future translational relevance. Tissue engineering approaches appear promising for endometrial repair. However, clinical evidence remains limited, and further human studies are needed to establish safety, efficacy, and long-term durability before routine clinical translation. REGISTRATION NUMBER: CRD420251046577.

High-fructose corn syrup (HFCS) consumption has been increasingly associated with reproductive dysfunction, yet the potential protective role of natural probiotic products such as kefir remains insufficiently explored. This study investigated the effects of kefir supplementation on HFCS-induced testicular damage in juvenile male Wistar rats. Twenty-four four-week-old rats (≈ 100 g) were maintained under controlled environmental conditions and randomly assigned to four groups: Control, Kefir, HFCS, and HFCS+Kefir. Kefir was administered by gastric gavage at 1 mL/100 g body weight daily, while HFCS-55 was provided ad libitum in drinking water (20%, w/v) for eight weeks. At the end of treatment, rats were anesthetized, and testicular tissues were collected for biochemical, histological, and immunohistochemical analyses. HFCS exposure markedly increased apoptotic and inflammatory markers, including p53, Caspase-3, Bax, TNF-α, and Nf-κB, while reducing the antiapoptotic marker Bcl-2. IGF-1Rα expression, seminiferous tubule diameters, and Johnsen's scores were also significantly impaired, accompanied by a pronounced rise in TUNEL-positive cells. Kefir supplementation substantially ameliorated HFCS-induced alterations, reflected by decreased apoptotic and inflammatory marker expression, improved histological architecture, and partial restoration of spermatogenic activity. These findings suggest that kefir mitigates HFCS-induced testicular injury through its antiapoptotic and anti-inflammatory effects. Kefir may therefore serve as a beneficial dietary supplement for protecting male reproductive health against fructose-related metabolic stress.

Mitochondrial phosphoenolpyruvate carboxykinase (PCK2) is a key rate-limiting enzyme in gluconeogenesis. In cancers originating from non-gluconeogenic organs, PCK2 often exhibits a pro-tumorigenic effect, primarily through metabolic reprogramming. Through cancer database analyses and validation using tissue samples from patients with cervical cancer, we found that PCK2 exhibits oncogenic activity in cervical cancer and is localized in ribosomes within cervical cancer cells. A combination of in vitro cellular experiments, in vivo xenograft models, molecular biology techniques, transcriptomic and proteomic sequencing revealed a novel mechanism by which PCK2 drives cervical cancer progression: PCK2 enhances translational efficiency by directly interacting with the ribosome-associated protein hnRNPK. This newly identified oncogenic role of PCK2 expands our understanding of its function and provides a mechanistic foundation for its contribution to tumorigenesis in cancers arising from non-gluconeogenic tissues.

To determine whether a pre-trained deep neural network (ResNet50) can non-invasively evaluate oocyte quality and predict subsequent embryonic development by extracting cytoplasmic features from static bright-field images acquired immediately before piezo-intracytoplasmic sperm injection. This prospective cohort study included 306 metaphase II oocytes obtained from 63 patients (73 cycles). Immediately before piezo-intracytoplasmic sperm injection, spindle visibility was scored using PolScope, and static bright-field images were acquired. The cytoplasmic regions were automatically segmented and fed into a pre-trained ResNet50 model to extract intermediate layer features from layers 1 and 3. The resulting feature vectors were reduced to 20 components via principal component analysis. Logistic regression and support vector machines with stratified five-fold cross-validation were used to evaluate classification performance for spindle presence, normal fertilization, blastocyst formation, and high-quality blastocyst rates. Single ResNet-derived features were assessed individually. Logistic regression principal component analysis of 20 components achieved an area under the curve of 0.679 for spindle detection (sensitivity: 84.2%; specificity: 45.5%) and 0.521 for fertilization (sensitivity: 92.8%; specificity: 18.8%). Our support vector machine yielded marginal improvements. Single-feature analysis demonstrated high specificity for spindle detection (area under the curve, 0.656; specificity, 93.9%) and moderate specificity for fertilization (area under the curve, 0.607; specificity, 81.2%). Blastocyst prediction remained limited (area under the curve ≤ 0.64). Spindle-negative oocytes exhibited markedly better fertilization prediction (area under the curve, 0.835; specificity, 81.8%). Our deep neural network-based automated cytoplasmic image analysis system quantitatively and non-invasively assessed oocyte maturity without requiring large training datasets and predicted subsequent fertilization.

Warm distension media have been introduced in office hysteroscopy to reduce procedure-related pain, yet concerns persist that vasodilation from warmed fluid may accelerate intravasation and increase fluid deficit. Evidence linking irrigation fluid temperature with intravasation risk is limited and largely theoretical. The aim of this study was to evaluate the association between the irrigation fluid temperature on the fluid deficit during hysteroscopic procedures. This is a randomized controlled study conducted at a medical center, including all women scheduled for operative hysteroscopy due to preoperative diagnoses of polyps, endometrial thickening, or uterine fibroids (FIGO classification: type 0, 1, or 2). Participants were randomized to receive irrigation fluid at either room temperature (24 °C) or body temperature (37 °C) and were blinded to allocation. The primary outcome was the time to reach a 250 mL fluid deficit. A total of 91 women met inclusion criteria, of whom 44(48%) were in the room temperature group and 47(52%) were in the body temperature group. Indications, age, BMI, device type, and tissue-shaver use were similar between groups. No significant difference was observed in the time to reach a 250 mL fluid deficit [155 (67-314) vs. 219 (83-444) seconds for the room temperature and body temperature groups, respectively; p = 0.25]. Exploratory analyses at higher fluid deficit thresholds similarly showed no significant differences between groups. A trend of a higher visual analog pain score (VAS) was reported by the women in the room temperature group compared to the warmed fluid group [4(0-6) vs. 1(0-6); p = 0.38]. Irrigation fluid temperature did not significantly impact fluid deficit during hysteroscopy. Warmed fluid may offer improved patient comfort without increasing intravasation risk. SYNOPSIS: Warm distension fluid is used in office hysteroscopy to reduce pain, but it may limit procedure duration due to increased vascular expansion and fluid deficit. This study compared fluid deficits at 24 °C (room temperature) and 37 °C (body temperature) during hysteroscopy. Results showed no significant impact of fluid temperature on deficits, regardless of the procedure indication.

MicroRNAs (miRNAs) are single stranded, short, non-coding, and highly conserved RNA molecules with around 22 nucleotides. They regulate gene expression at the co- and post-transcriptional levels. The accumulated research reports showed dysregulated miRNA expression in various female reproductive disorders most notably polycystic ovary syndrome (PCOS). PCOS is an endocrine disorder that affects women of reproductive age. The clinical manifestations of this disease are dominated by hyperandrogenism, polycystic ovaries, and chronic anovulation. Recently, evidence has confirmed abnormal expression of miRNAs in theca cells, granulosa cells, follicular fluid, blood, and serum of women with PCOS. Although some of these reports are controversial, the variability could be attributed to different analysis methods and small sample sizes. Overall, these findings point toward the role of miRNAs in the occurrence and progression of PCOS. However, the exact mechanism of its etiology largely remains unknown. This review takes us beyond the traditional localized dysregulation to explore the regulatory role of the gut microbiota-miRNA axis, exosomal miRNAs and the complexity of competitive endogenous RNA (ceRNA) networks where long non coding RNAs (lncRNAs) and circular RNAs (circRNAs) act as sponges to modulate miRNA activity. miRNAs can be used as pharmacogenomic biomarkers to predict the therapeutic responses to clinical interventions through the integration of machine learning algorithms for enhanced diagnostic accuracy. While research investigations are predominantly based on in vitro and clinical samples, we emphasize the need for more in vivo research to decode the precise etiology of PCOS. This review provides comprehensive update on the functional and clinical potential of miRNAs as non-invasive biomarkers and therapeutic targets for the management of PCOS.

Women of advanced age exhibit significant heterogeneity in ovarian reserve, categorized as normal (NOR) or diminished (DOR). This study aims to distinguish physiological age-related decline from pathological accelerated aging in DOR, and to explore underlying molecular mechanisms for optimizing assisted reproductive strategies. In vitro fertilization-embryo transfer (IVF-ET) outcomes were retrospectively compared in advanced-age women (≥ 40 years) with NOR or DOR treated at our center (January 2022 - December 2024). Simultaneously, follicular fluid (FF) was collected from both groups (n = 20). After centrifugation, metabolomic analysis was performed on metabolites, and transcriptomic sequencing on isolated granulosa cells (GCs). Despite comparable fertilization and cleavage-stage embryo quality, the DOR group showed significantly lower rates of oocyte maturation, blastocyst formation, clinical pregnancy, and live birth (P < 0.05). Metabolomic analysis revealed 28 differential metabolites (DMs) in FF, primarily enriched in galactose metabolism. Transcriptomics of GCs identified 246 differentially expressed mRNAs (DEmRNAs), prominently enriched in immune-related pathways. Protein-protein interaction analysis highlighted five hub genes (CX3CR1, CD69, FCER1A, EOMES, SPRR2A). Integrated analysis of the top 50 DEmRNAs with the top 400 DEmRNA-DM correlation pairs identified five key genes-IGLC3, RNVU1-29, FAM110C, NPY2R, and KCNN4-bridging GC transcriptome and FF metabolome, with key pairs including RNVU1-29 with lysylhydroxyproline and a sterane derivative, and FAM110C with 16-hydroxyhexadecanoic acid. In conclusion, DOR in advanced age may represent a distinct pathological aging state characterized by a dysregulated follicular microenvironment potentially shaped by immune activation and metabolic reprogramming. The identified key gene-metabolite pairs offer candidate molecular links to compromised oocyte developmental competence.

Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disorder characterized by aberrant nuclear factor kappa B (NF-κB)-mediated inflammation and impaired nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant defense. This study represents the first investigation of fucoxanthin's concurrent regulatory effects on these opposing signaling axes in PCOS ovarian pathophysiology. Prepubertal female C57BL/6 mice (n = 40; postnatal day 25) were assigned to the following groups: control (sesame oil, 0.1 mL/day subcutaneously, n = 10), dehydroepiandrosterone (DHEA)-induced PCOS (6 mg/100 g body weight in sesame oil, n = 15), or DHEA+fucoxanthin (0.2% w/w in chow, n = 15) for 21 days. Estrous cyclicity was assessed by vaginal cytology. Ovarian morphology used hematoxylin-eosin staining. Serum testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-1 (IGFBP-1), and insulin were measured by enzyme-linked immunosorbent assay. Intraperitoneal glucose/insulin tolerance tests evaluated metabolism. Ovarian malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) were quantified. Western blotting analyzed phosphoinositide 3-kinase (PI3K) p85α, protein kinase B (AKT), phospho-AKT, Nrf2, heme oxygenase-1 (HO-1), and NF-κB p65. Fucoxanthin restored estrous cyclicity in 60% of DHEA mice (vs. 0%), increased corpora lutea/large antral follicles, reduced testosterone/LH/IGF-1/insulin (P < 0.05), and elevated FSH/IGFBP-1. Insulin tolerance improved (P < 0.05). Ovarian MDA/TNF-α/IL-1β/IL-6 decreased (P < 0.05); SOD/CAT/T-AOC increased (P < 0.05). Fucoxanthin upregulated PI3K p85α, p-AKT/AKT, Nrf2/HO-1 and downregulated NF-κB p65 (P < 0.05). Collectively, these findings suggest that fucoxanthin coordinately modulates NF-κB suppression and Nrf2/HO-1 activation, establishing a novel multi-targeted therapy for PCOS.

Early-onset preeclampsia remains a significant cause of maternal and neonatal morbidity; however, its multifactorial etiology is not yet fully elucidated. This narrative review aims to synthesize current evidence on the progression from placental ischemia to cellular stress, with a specific focus on how the unfolded protein response (UPR) drives the pathogenesis of early-onset preeclampsia. For a thematic synthesis of the literature, data from human clinical samples, animal models, and cell cultures were integrated to construct a comprehensive mechanistic model. At its core, a critical "vicious cycle" exists where defective spiral artery remodeling and reduced NO bioavailability trigger persistent hypoxia. This hypoxic environment disrupts endoplasmic reticulum (ER) calcium homeostasis by impairing ATP-dependent SERCA activity, subsequently activating the UPR. The synergistic interaction between reactive oxygen species (ROS) accumulation and ER stress serves as the primary driver for trophoblast apoptosis and the systemic release of anti-angiogenic factors (sFlt-1, sEng), ultimately resulting in maternal endothelial dysfunction. ER stress pathways represent viable therapeutic targets. In experimental models, chemical chaperones such as 4-PBA and TUDCA have been shown to mitigate ER stress-induced placental damage and improve angiogenic balance. However, clinical translation requires longitudinal cohort studies to validate UPR biomarkers (GRP78/XBP1) across different trimesters.

Polycystic ovarian syndrome (PCOS) is a common endocrine-metabolic condition characterized by persistent anovulation, and hormonal imbalance leading to disrupted follicular maturation, and overall ovarian dysfunction. This study aimed to investigate the regenerative effects of adipose-derived mesenchymal stem cell-derived exosomes (AD-MSCs-Exo) on ovarian restoration, and granulosa cells (GCs) functionality in a PCOS murine model. PCOS was induced via a single subcutaneous injection of estradiol valerate. Exosomes were isolated from AD-MSCs using the ExoCIB kit and characterized by DLS, TEM and flowcytometery. NMRI mice received intraperitoneal injection of AD-MSCs-Exo (25, 50, 75, and 100 µg/kg body weight) twice over a two-week period. Following treatment, the mice were anaesthesia and sacrificed by cervical dislocation. The harvested ovarian tissues were subjected to histological assessment; FSH, LH, and estradiol levels were measured from serum. Further, GCs were isolated, and identified through FSH expression. Subsequently, the levels of GCs key regulator genes including FOXO3, Map1lc3b, and SF-1 were assessed by qRT-PCR. AD-MSCs-Exosome-like nanovesicles isolated in range of 30-80 nm with bi-membrane spherical shape and 54.8% expression of CD9. The hormonal analysis revealed improved estradiol levels and a lowered LH/FSH ratio, indicating endocrine stabilization under exposure with AD-MSCs-Exo. In addition, treatment with AD-MSCs-Exo significantly improved ovarian histoarchitecture, and the optimum response was observed following exposure to 75 µg/kg of AD-MSCs-Exo. However, administration of the highest dose (100 µg/kg) was associated with inflammatory responses and partial tissue degeneration. Gene expression analysis also showed a marked up-regulation of FOXO3, along with increased Map1lc3b and SF-1 levels. Accordingly, AD-MSCs-Exosome like nanovesicles at optimum concentration exert regenerative effects on PCOS-induced ovarian dysfunction, which emphasizes the necessity for precise dose selection to achieve maximal therapeutic efficacy as a promising cell-free strategy for PCOS treatment.