Journal of Ovarian Research最新文献

Background: Polycystic ovary syndrome (PCOS), a common endocrine-metabolic disorder, is driven by hyperandrogenism and chronic low-grade inflammation that impair follicular development. Granulosa cell pyroptosis is increasingly recognized as a key pathogenic mechanism in PCOS. Luteolin (LUT), a natural flavonoid found in many traditional medicinal plants, exhibits potent anti-inflammatory properties. However, its role in regulating granulosa cell pyroptosis within the context of PCOS has not been elucidated.

Methods: We established a dehydroepiandrosterone (DHEA)-induced PCOS rat model to evaluate LUT's therapeutic effects. Hormone and cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA), while network pharmacology and molecular docking were used to predict molecular targets. In vitro, dihydrotestosterone (DHT)-treated KGN cells served as a model for granulosa cell dysfunction. Pyroptosis was assessed by Cell Counting Kit-8 (CCK-8), lactate dehydrogenase (LDH) release, and transmission electron microscopy. The expression and activation of androgen receptor (AR), Signal Transducer and Activator of Transcription 3 (STAT3), and NOD-like Receptor Pyrin domain-containing protein 3 (NLRP3) inflammasome components were analyzed by Western blot and immunohistochemistry, with their roles confirmed using specific inhibitors.

Results: Luteolin (LUT) treatment alleviated hormonal imbalance and ovarian morphological abnormalities in PCOS rats. LUT suppressed STAT3 phosphorylation, pro-inflammatory cytokine expression, and NLRP3 inflammasome activation in both in vivo and in vitro models. Network pharmacology identified STAT3 as a high-affinity target of LUT (binding energy: - 8.589 kcal/mol). Mechanistically, LUT attenuated granulosa cell pyroptosis by suppressing the AR/STAT3/NLRP3 axis.

Conclusion: Luteolin inhibits androgen-induced granulosa cell pyroptosis by targeting the AR/STAT3/NLRP3 signaling pathway. These findings provide a robust mechanistic basis for luteolin's therapeutic potential in PCOS, supporting its development as a targeted therapy for this and other inflammatory reproductive disorders.

Ligands for the activating immune receptor NKG2D (NKG2DLs) are frequently overexpressed on malignant cells while largely absent in healthy tissues. Elevated expression of various NKG2DLs has been reported in ovarian cancer, one of the most lethal gynecologic malignancies due to chemoresistance and relapse. Despite the advent of monoclonal antibodies (mAbs) in cancer therapy, patients with ovarian cancer have yet to benefit from this treatment modality. Natural killer (NK) cells play a crucial role in the efficacy of antitumor mAbs by mediating antibody-dependent cellular cytotoxicity (ADCC). Strategies to enhance ADCC often involve Fc region modifications to improve CD16 binding and NK cell activation.The tumor-associated expression of NKG2DLs was exploited by developing an Fc-optimized NKG2D-Ig fusion protein (NKG2D-ADCC) to trigger NK cell ADCC against ovarian cancer cells. The NKG2D-Ig fusion protein with a wildtype Fc version (NKG2D-WT) was modified in the Fc part by introducing the S239D/I332E mutations, thereby enhancing the binding affinity to the Fc receptor CD16. Flow cytometric analysis revealed a diverse range of expression patterns for NKG2DLs across ovarian cancer cell lines. Functionally, NKG2D-ADCC induced stronger NK cell activation than NKG2D-WT, promoting degranulation and secretion of effector molecules, including IFN-γ and granzymes. The unrelated control protein lacked such effects, confirming specificity. Notably, NKG2D-ADCC induced robust NK cell-mediated lysis of ovarian cancer cells in both short- and long-term cytotoxicity assays.Together, these findings demonstrate that the NKG2D-ADCC fusion protein potently enhances NK cell responses against ovarian cancer cells, supporting its promise as a novel immunotherapeutic strategy.

Background: Response Evaluation Criteria in Solid Tumors (RECIST) and CA-125 criteria are widely used to evaluate disease progression (PD) in ovarian cancer patients undergoing chemotherapy. However, the recurrent patterns and prognostic factors based on CA-125 and RECIST criteria in patients receiving poly (ADP-ribose) polymerase (PARP) inhibitors remains unclear. This study aimed to assess the recurrent patterns based on RECIST and CA-125 criteria, and to analyse prognostic factors in ovarian cancer patients treated with PARP inhibitors.

Methods: Patients were categorized into two groups based on the status of CA-125 PD within a ± 7-day window: RECIST PD group (no CA-125 PD within 7 days) and CA-125 PD group (CA-125 PD within 7 days). Recurrent patterns and progression-free survival (PFS) following PARPi resistance were analyzed.

Results: A total of 133 patients were included, with 69 (51.9%) in RECIST PD group and 64 (48.1%) in CA-125 PD group. The concordance between RECIST and CA-125 criteria for diagnosing disease progression was 18.8%(n = 25). Patients in RECIST PD group showed lower rates of lymph nodes progression (20.3% vs. 50.0%, p < 0.001) and multi-sites progression (24.6% vs. 45.3%, p = 0.012). Patients in CA-125 PD group exhibited poorer response to subsequent treatment after PARPi resistance (median PFS: 5.8 vs. 9.3 months, HR = 2.054, p < 0.001). Multivariate analysis showed that factors associated with PFS after PARPi resistance included residual lesions after primary surgery (No vs. Yes, HR = 0.517, p = 0.028), PARPi treatment duration (≤ 6 vs. >6 months, HR = 2.488, p < 0.001), and recurrence criteria (CA-125 vs. RECIST, HR = 2.431, p < 0.001).

Conclusions: Patients with RECIST PD but without CA-125 PD were less likely to progress in lymph nodes or multiple sites and might achieve better responses to subsequent anti-tumor therapies.

Background: There has been little research on the association of exposure to environmental factors on polycystic ovary syndrome (PCOS), nor on the interaction between environmental factors and liver and kidney function. Anti-mullerian hormone (AMH) has been proposed to add significance to diagnosis of PCOS in case of ambiguity. We hypothesize that long-term inhalation exposure to environmentally relevant levels of these factors may induce changes in hepatic and renal function, thereby exacerbating the risk of developing PCOS.

Methods: The study used a cross-sectional study. Cases were newly diagnosed PCOS patients from a tertiary hospital. Controls were age - and BMI - matched healthy women recruited from the same communities. Data on age and various blood test results were collected from medical records. Meteorological factors and air pollutants were obtained from the National Oceanic and Atmospheric Administration (NOAA). After feature selection, we employed logistic regression, weighted quantile sum (WQS) regression, and neural network models to analyze the associations between relevant variables and the risk characteristics and prediction of PCOS including different aged groups.

Results: There were 384 subjects in this retrospective study, randomly including 178 PCOS patients and 206 controls. The levels of most sexual function (FSH, LH, PRL, T, AMH) and liver function indicators (TP, Alb, A/G, ALP, PA, TBA) in PCOS patients were significantly higher than those in the control group. Overall, the AMH level in the PCOS population was 1.133 times that of the non-affected population (95% confidence interval [CI]: 1.077, 1.192). Within the 21-35 years age group, the levels of air pressure and albumin in PCOS patients were 1.060 (95% CI: 1.028, 1.093) and 1.098 (95% CI: 1.002, 1.204) times higher, respectively, than in the non-affected population. Based on the results obtained from the stratified analysis, we incorporated several variables into the prediction model, namely PM₂.₅, air pressure, FSH, PRL, T, AMH, Alb and PA. The overall population demonstrated good PCOS predictive performance in internal validation using the neural network model (test AUC = 0.864, train AUC = 0.992; test R² = 0.342, train R² = 0.910).

Conclusions: Significant elevations in levels of AMH and Alb were detected in women with PCOS. The back-propagation (BP) neural network demonstrated good PCOS predictive performance for the models mediated by environmental factors (PM₂.₅, air pressure). This suggests that these factors may probably exacerbate the effects of sexual function (FSH, PRL, T, AMH) and liver function indicators (Alb, PA) on the risk of developing PCOS. Our results support a potential association between environmental factor exposure and the consequences of PCOS in women.

Premature ovarian insufficiency (POI) is a significant clinical disorder characterized by the loss of ovarian function before the age of 40, and its global prevalence is rising. The development of effective therapies is hindered by an incomplete understanding of its pathogenesis. Growing evidence indicates that dysregulated mitochondrial fission in granulosa cells (GCs) is a pivotal contributor to POI, although the upstream regulatory mechanisms remain elusive. This review synthesizes recent findings to propose a novel hypothesis: that aberrant lysine succinylation (Ksucc) of mitochondrial fission factor (MFF) may act as a crucial metabolic switch linking mitochondrial dynamics to ovarian aging. Specifically, hyper-succinylation of MFF at specific residues (e.g., K302) is hypothesized to induce a charge reversal, potentially promoting the excessive recruitment and oligomerization of dynamin-related protein 1 (DRP1) on the mitochondrial membrane. We hypothesize that this leads to mitochondrial fragmentation, bioenergetic deficits, and subsequent apoptosis of GCs and oocytes. This pathogenic cascade is theorized to be driven by a metabolic milieu of elevated succinyl-CoA and diminished desuccinylase activity of SIRT5 in POI. Evidence from related disease models suggests that reversing this imbalance through genetic or pharmacological modulation of SIRT5 can reduce MFF succinylation and restore mitochondrial dynamics. We explore the potential of targeting the SIRT5-MFF axis as a promising therapeutic strategy. Furthermore, detecting elevated MFF succinylation in clinical samples may be explored as a novel diagnostic biomarker for POI, though significant translational hurdles remain.

Background and aim: Presence of peritoneal metastasis in ovarian cancer is one of the most important factors affecting the prognosis of the disease. In this study we aimed to investigate the additive value of dedicated abdomen ¹⁸F-FDG PET/MR imaging to whole body¹⁸F-FDG PET/CT in the detection of peritoneal recurrence in ovarian cancer patients with elevated serum Ca-125 levels.

Material-methods: This prospective study included 45 ovarian cancer patients with elevated serum Ca-125 levels during postoperative follow-up, all of whom underwent whole-body ¹⁸F-FDG PET/CT followed by dedicated abdominal PET/MRI.

Results: With the addition of PET/MR imaging to PET/CT, peritoneal recurrence was detected in 35 patients (78%), whereas PET/CT alone detected recurrence in 26 patients (57%) (p = 0.012). The total number of regions with peritoneal uptake was 100 with PET/CT alone, but increased to 170 when PET/MRI was added (p < 0.001). Furthermore, distant organ metastases that were not detected on PET/CT were identified in 3 patients with the addition of PET/MRI. In our study, additional findings from PET/MRI led to changes in the treatment strategy for 15 patients (33%).

Conclusion: The addition of dedicated abdominal PET/MRI to whole-body PET/CT enhances the detection of peritoneal metastases in patients with recurrent ovarian cancer and elevated Ca-125 levels. This combined imaging approach provides complementary information, improving diagnostic accuracy and aiding in the selection of optimal treatment strategies.