ABSTRACT Background Glioma cells are characterized by rapid proliferation, a high degree of invasiveness, and significant heterogeneity. Despite the application of various treatment regimens in recent years, the prognosis for glioma remains poor. The induction of ferroptosis in tumor cells has emerged as a promising therapeutic approach. Solasonine (SS), a steroidal alkaloid derived from plants of the Solanaceae family, has multiple antitumor effects. However, whether it can inhibit glioma growth and its mechanism of action have not been studied. Methods The effects of SS on ferroptosis in glioma cells were analyzed by detecting the levels of ferrous ions, reactive oxygen species, and malondialdehyde. The role of activating transcription factor 3 (ATF3) in SS‐induced ferroptosis in glioma cells was analyzed using western blotting, immunofluorescence, and confocal microscopy. An in vivo mouse model of glioma was constructed to further investigate the effects of SS. Results We found that SS inhibited the proliferation of glioma cells and promoted their ferroptosis. SS treatment increased the intracellular ferrous ion, malondialdehyde, and reactive oxygen species levels. It increased the intracellular hydrogen peroxide level by regulating ATF3 to inhibit glycolysis and suppress the antioxidant system. Increased hydrogen peroxide levels activated nuclear receptor coactivator 4–dependent ferritinophagy and increased intracellular iron levels. Furthermore, SS activated the protein kinase RNA–like endoplasmic reticulum kinase/ATF4 endoplasmic reticulum stress pathway by inhibiting glycolysis and promoted ATF3 expression. This process formed a positive feedback loop. In a murine model, SS significantly inhibited glioma cell growth by inducing ferroptosis. Conclusion These results indicate that SS promotes glioma cell ferroptosis in vitro and in vivo by inhibiting glycolysis through ATF3.
ABSTRACT Background Biological heterogeneity remains a major challenge in Alzheimer's disease (AD), even among individuals with biomarker‐confirmed disease. The apolipoprotein E (APOE) ε4 allele is associated with greater amyloid burden, neurodegeneration, and vascular dysfunction. We investigated whether retinal microvascular imaging provides complementary information beyond plasma and neuroimaging biomarkers for characterizing APOE ε4‐associated neurovascular heterogeneity in biologically defined AD. Methods Eighty‐four amyloid‐positive patients with AD underwent color fundus photography, swept‐source optical coherence tomography angiography (OCTA), plasma biomarker assessment, amyloid positron emission tomography, and magnetic resonance imaging. Retinal vascular parameters were compared between APOE ε4 carriers and non‐carriers using generalized estimating equations. Candidate multimodal biomarkers were identified using least absolute shrinkage and selection operator (LASSO) regression, followed by multivariable logistic regression to evaluate the incremental contribution of retinal biomarkers within a multimodal phenotyping model. Results Compared with non‐carriers, APOE ε4 carriers demonstrated significantly lower retinal superficial vascular complex (SVC) and deep vascular complex densities, reduced retinal vascular fractal dimension, higher amyloid PET standardized uptake value ratios, increased peak width of skeletonized mean diffusivity, and smaller hippocampal volumes (all p < 0.05). Following penalized feature selection, retinal SVC density remained independently associated with APOE ε4 status alongside amyloid burden, hippocampal volume, and white matter microstructural injury. Incorporation of SVC modestly improved discrimination and calibration of the multimodal model compared with neuroimaging biomarkers alone. Conclusions Retinal microvascular alterations are associated with APOE ε4‐related biological heterogeneity in biomarker‐confirmed AD. Retinal vascular imaging provides complementary information beyond established plasma and neuroimaging biomarkers and may enhance multimodal characterization of neurovascular phenotypes rather than serve as a surrogate for genetic testing.
ABSTRACT Background Optimal surgical management of adult‐type diffuse gliomas (ADGs) varies substantially by subtype, making accurate preoperative subtyping crucial for individualized surgical planning. This study aimed to develop a radiomics‐based model for preoperative subtyping of ADG in accordance with the 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors. Methods A total of 382 patients with ADGs were enrolled and randomly assigned to a training set ( n = 267) and an independent test set ( n = 115). Tumor masks were automatically segmented and refined by experienced neurosurgeons. Radiomics features were extracted from MRI after standardized preprocessing and dimensionality reduction. Fourteen machine learning classifiers were evaluated, and the best‐performing model was optimized and validated on the independent test set. Model performance was assessed using AUC, accuracy, recall, precision, F1 score, Kappa coefficient, and Matthews correlation coefficient. Results After LASSO (Least Absolute Shrinkage and Selection Operator) regression, 50 key features were retained. Random Forest showed the best preliminary performance and was selected for optimization. On the independent test set, the optimized model achieved a macro‐average AUC of 0.9084, with favorable results across other metrics. Texture features contributed most strongly to prediction. Conclusion This radiomics model enables robust preoperative ADG subtyping under the 2021 WHO classification and may support individualized surgical planning using routine MRI features. Owing to its retrospective single‐center design, multicenter prospective external validation is required prior to widespread clinical application.
ABSTRACT Background Neuromyelitis optica spectrum disorder (NMOSD) predominantly affects women of childbearing age, accompanied by markedly elevated relapse risks during pregnancy and postpartum periods, bringing great challenges to perigravid management. At present, there is no standardized gestational therapeutic regimen for NMOSD worldwide, and data on perigravid application of B‐cell depleting agents including rituximab and inebilizumab remain limited. For patients exposed to B‐cell depleting agents before conception, balancing disease control and fetal safety is an urgent clinical problem to be solved. Objective This multicenter prospective cohort study aimed to evaluate the efficacy and safety of a three‐stage multidisciplinary “sandwich” management regimen in AQP4‐IgG‐positive pregnant women with NMOSD exposed to B‐cell depleting agents before conception. Maternal disease activity, pregnancy outcomes, neonatal conditions, and offspring growth and developmental characteristics within the first year of life were analyzed. Methods A total of 8 AQP4‐IgG‐positive pregnant women with NMOSD who received B‐cell depleting agents within 9 months prior to conception were enrolled from multiple centers between January 2022 and October 2024, including 3 patients treated with inebilizumab and 5 patients treated with rituximab. All subjects received a unified three‐stage intervention: B‐cell depleting agents were discontinued upon confirmed pregnancy; low‐dose azathioprine combined with low‐dose glucocorticoids was administered during gestation; B‐cell depleting agents were reinitiated at 2 weeks postpartum. Multidisciplinary teams consisting of neurology, obstetrics, clinical pharmacy, and neonatology departments conducted full‐cycle monitoring and follow‐up. Primary observation indicators included maternal relapse events, Expanded Disability Status Scale (EDSS) scores, B‐cell counts, gestational complications, gestational age at delivery, neonatal physical indicators, Apgar scores, congenital malformations, as well as offspring growth and neurodevelopment and vaccination safety from birth to 1 year of age. Results All subjects achieved term live births without severe obstetric complications. Seven patients remained relapse‐free throughout pregnancy and postpartum period with stable or improved EDSS scores; one patient discontinued all medications during gestation and suffered a relapse at 1 month postpartum. Neonatal physical indicators and Apgar scores were generally normal, one neonate presented mild hypospadias and two developed transient neonatal abnormalities; neonatal B‐cell counts at birth and 1 month of age were within normal ranges. One‐year follow‐up showed normal physical and neurodevelopment in all offspring with safe vaccination procedures. Conclusions For AQP4‐IgG‐positive pregnant women with NMOSD exposed to B‐cell depleting agents before conception, the multidisciplinary “sandwich” regimen featuring B‐cell depletion before conception and postpartum plus gestational bridging therapy with low‐dose azathioprine combined with glucocorticoids is safe and effective, reduces disease relapse risk and yields favorable overall maternal and fetal outcomes. This regimen may serve as a promising perigravid management strategy that warrants further validation in larger cohorts.
ABSTRACT Aims Deanna Protocol (DP) is an anaplerotic, mechanism‐based therapy designed to address impaired cellular energy flux. The present study aims to investigate the effects of DP in treating Alzheimer's disease (AD) by using cortical neurons derived from AD patient iPSCs carrying a PSEN1 mutation, while cortical neurons differentiated from iPSCs of a healthy subject serve as control. Methods PSEN1 cortical neurons were treated with DP acutely (24 h) and chronically (1–3 weeks). The effect of DP was assessed by utilizing TMRE assay for mitochondrial function, immunofluorescent staining for AD neuron morphological pathology, whole cell patch clamp for neuron electrophysiological property, and microelectrode array (MEA) analysis of long‐term potentiation (LTP) for neurocircuit function. Results PSEN1 cortical neurons demonstrated impaired mitochondrial function, elevated pathological biomarkers, reduced neurite complexity, altered electrophysiology, and decreased LTP. DP treatment significantly ameliorated all these phenotypes. Conclusion This study, while confirming iPSC‐ PSEN1 cortical neurons as a valid AD model, demonstrated the efficacy of DP on ameliorating structural and functional pathologies in AD neurons. It highlights that targeting energy production could be an effective approach in treating neurodegeneration in AD and suggests its potential efficacy in other neurodegenerative diseases.
