Previous studies have reported that senolytic drugs can reverse obesity-mediated accumulation of senescent cells in the ovary and protect against cisplatin-induced ovarian injury by removing senescent cells. Early intervention with ABT-263 has been shown to mitigate ovarian aging. However, it remains unknown whether treatment with ABT-263 could rejuvenate the aged ovary in reproductively old females. Therefore, the current study was aimed to investigate whether advanced age intervention with ABT-263 could ameliorate age-related decline in ovarian function. Fourteen 16-month-old mice with a C57/BL6 background were treated with ABT-263 (N = 7) or vehicle (N = 7) for two weeks. Mice were initially treated with ABT-263 (60 mg/kg/d) or vehicle for 7 consecutive days. After a 7-day break, the treatment was repeated for another 7 consecutive days. Six 2-month-old mice with C57BL/6 were used as a young control. The hormonal levels, estrus cycles, ovarian reserve, ovarian cell proliferation and apoptosis, ovarian fibrosis, and steroidogenic gene expression of ovarian stromal cells were evaluated. ABT-263 treatment did not rescue abnormal estrus cycles and sex hormonal levels, or inhibit the formation of multinucleated giant cells and ovarian stromal cell apoptosis in aged ovaries. However, it reduced ovarian fibrosis and preserved the steroidogenic gene expression of ovarian stromal cells in aged ovaries. Importantly, ABT-263 treatment further depleted ovarian follicles in aged mice. In conclusion, ABT-263 treatment accelerated the depletion of ovarian follicles in aged mice, suggesting that senolytic drugs for reproductively old female may adversely affect female fertility.

Intrauterine adhesions (IUAs), also known as Asherman’s syndrome (AS), represent a significant cause of uterine infertility for which effective treatment remains elusive. The endometrium’s ability to regenerate cyclically depends heavily on the growth and regression of its blood vessels. However, trauma to the endometrial basal layer can disrupt the subepithelial capillary plexus, impeding regeneration. This damage results in the replacement of native cells with fibroblasts and myofibroblasts, ultimately leading to fibrosis. Endothelial cells (ECs) play a pivotal role in the vascular system, extending beyond their traditional barrier function. Through single-cell sequencing and experimental validation, we discovered that ECs undergo senescence in IUA patients, impairing angiogenesis and fostering stromal cell fibrosis. Further analysis revealed significant interactions between ECs and PAI-1+ stromal cells. PAI-1, derived from stromal cells, promotes EC senescence via the urokinase-type plasminogen activator receptor (uPAR). Notably, prior to fibrosis onset, TGF-β upregulates PAI-1 expression in stromal cells in a SMAD dependent manner. In an IUA mouse model, inhibiting PAI-1 mitigated EC senescence and endometrial fibrosis. Our findings underscore the crucial role of EC senescence in IUA pathogenesis, contributing to vascular reduction and fibrosis. Targeting PAI-1 represents a promising therapeutic strategy to suppress EC senescence and alleviate endometrial fibrosis, offering new insights into the treatment of IUAs.

The escalating utilization of titanium dioxide nanoparticles (TiO₂ NPs) in everyday products has sparked concerns regarding their potential hazards to pregnant females and their offspring. To address these concerns and shed light on their undetermined adverse effects and mechanisms, we established a pregnant rat model to investigate the impacts of TiO₂ NPs on both maternal and offspring health and to explore the underlying mechanisms of those impacts. Pregnant rats were orally administered TiO₂ NPs at a dose of 5 mg/kg body weight per day from GD5 to GD18 during pregnancy. Maternal body weight, organ weight, and birth outcomes were monitored and recorded. Maternal pathological changes were examined by HE staining and TEM observation. Maternal blood pressure was assessed using a non-invasive blood analyzer, and the urinary protein level was determined using spot urine samples. Our findings revealed that TiO₂ NPs triggered various pathological alterations in maternal liver, kidney, and spleen, and induced maternal preeclampsia-like syndrome, as well as leading to growth restriction in the offspring. Further examination unveiled that TiO₂ NPs hindered trophoblastic cell invasion into the endometrium via the promotion of autophagy. Consistent hypertension and proteinuria resulted from the destroyed the kidney GBM. In total, an exposure to TiO₂ NPs during pregnancy might increase the risk of human preeclampsia through increased maternal arterial pressure and urinary albumin levels, as well as causing fetal growth restriction in the offspring.

Objective: This exploratory survey study aimed to evaluate the epidemiology, treatment patterns (including pharmacotherapy, rehabilitation, and supportive care), economic burden, drug preferences, and unmet needs of Chinese SMA patients. Methods: We conducted an anonymous online survey using a self-developed questionnaire from March 4 to March 31, 2024. The questionnaire collected comprehensive data on epidemiology, treatment patterns, rehabilitative interventions, nursing management, economic burden, and preferences. Data analysis was performed using descriptive statistics and chi-square tests. Results: Analysis of 82 valid questionnaires revealed that 91.5% of SMA patients had type I or II disease, with 69.5% diagnosed by genetic testing within 12 months of birth. Awareness of prenatal screening was low. Nusinersen and Risdiplam showed comparable utilization rates and efficacy, though Risdiplam was associated with significantly higher rates of adverse events. Over 75% of caregivers reported financial constraints, with more than 42% expressing long-term affordability concerns. Rehabilitation participation reached 86.6%, predominantly involving motor function training, stretching therapy, and the use of assistive devices. Critical gaps included the finding that 89.0% of caregivers lacked formal training, 40.8% of patients lacking respiratory interventions, and a high demand for emergency skills training (61.0%). Treatment preferences prioritized oral administration, liquid formulations, and fruit flavors, with efficacy, affordability, and ease of use (80.5%) being the primary decision-driving factors. Conclusion: The management of SMA in China faces three primary challenges: inadequate prevention awareness, critical caregiving deficiencies, and prohibitively high treatment costs. Urgent actions include scaling up prenatal/newborn screening, establishing multidisciplinary care models to address respiratory/nutritional gaps, and implementing policy reforms to improve affordable drug access.

Background: Recent studies have focused on investigating the role of cellular senescence in ovarian aging. Targeting cellular senescence has been proposed as a potential strategy to improve ovarian aging. p16 and p21 are classical molecules involved in mediating cellular senescence. In our previous study, we demonstrated that ablation of p16 is dispensable for premature ovarian aging induced by alkylating agents. In the present study, we investigated whether p21 deficiency could mitigate ovarian aging caused by alkylating agents.Methods: Eight-week-old wild-type (WT, n=7) and p21 knockout (KO, n=7) female mice received a single injection of busulfan (BUL, 30 mg/kg) and cyclophosphamide (CTX, 120 mg/kg) to induce premature ovarian insufficiency (POI). Untreated WT (n=4) and p21 KO (n=4) mice served as controls. Ovaries were analyzed thirteen weeks after treatment. Ovarian reserve, folliculogenesis, cell proliferation, apoptosis and senescence, multinucleated giant cells (MGCs) and their characteristics, pro-inflammatory factors, fibrosis, ovarian stromal cell properties, and the expression of cell cycle inhibitors, including p16, p19, p27, and p53, were evaluated.Results: Female mice treated with alkylating agents exhibited typical features of POI, including a dramatic reduction in the number of primordial and growing follicles; defective folliculogenesis characterized by growth arrest in early-stage follicles, extensive atresia in mid-stage follicles, dysregulated FSH receptor (FSHr) expression in antral follicles, and abnormal over-activation of primordial follicles; the presence of hemosiderin-laden MGCs and fibrosis in the ovarian cortical region. p21 deficiency did not significantly mitigate these phenotypes. There were no significantly differences in the expression of pro-inflammatory factors, folliculogenesis-regulating factors, or steroidogenesis-related factors and cell cycle inhibitors between WT and p21 KO mice treated with alkylating agents. In addition, p21 deficiency did not prevent alkylating agent-induced cellular senescence.Conclusion: These results demonstrated that p21 is dispensable for POI caused by alkylating agents, suggesting that targeting p21 alone may not mitigate ovarian aging caused by alkylating agents.