The thioredoxin system, comprising thioredoxin (Trx) and thioredoxin reductase (TrxR), is a central regulator of cellular redox homeostasis and plays essential roles in normal brain physiology and redox signaling. In glioblastoma (GBM), this system undergoes profound pathological rewiring, creating a redox dependency that represents a potential therapeutic vulnerability. The overexpression of Trx and TrxR in GBM promotes tumor proliferation, invasion, angiogenesis, and resistance to chemotherapy and radiotherapy, while the endogenous Trx inhibitor, thioredoxin-interacting protein (TXNIP), is frequently downregulated. This imbalance drives redox adaptation and sustains tumor survival under metabolic and therapeutic stress. Pharmacological modulation of the Trx system using synthetic inhibitors, such as auranofin, platinum-based compounds, and PX-12, as well as selected natural compounds including curcumin analogs and flavonoids, has shown efficacy in preclinical GBM models by inducing oxidative stress and enhancing sensitivity to standard therapies. Emerging evidence also suggests that Trx system targeting may modulate the tumor immune microenvironment, providing a rationale for combination strategies with immunomodulatory approaches. Overall, targeting the Trx system represents a promising precision oncology strategy for GBM. Future efforts should focus on the development of brain-penetrant inhibitors, rational combination therapies, and predictive biomarkers to facilitate clinical translation. Given the essential role of the Trx system in normal brain homeostasis, therapeutic targeting requires careful consideration of safety, therapeutic index, and tumor-selective vulnerabilities. This narrative review discusses current evidence on the physiological functions of the Trx system in the brain, its dysregulation in GBM, and its relevance as a precision therapeutic target.
We study the scattering and conductometric properties of a semiflexible polyelectrolyte, carboxymethyl cellulose (CMC), with monovalent and divalent counterions in aqueous media without added salts. The scattering patterns for the magnesium salts of CMC display a broad shoulder instead of the scattering peak observed for the monovalent salts. This suggests weaker electrostatic repulsion between chains and a consequent loss of local order. The result is consistent with conductivity measurements, which reveal that the effective charge of the backbone for MgCMC is approximately half that of NaCMC. The decrease in charge density agrees with Oosawa–Manning condensation, which expects the charge density to be inversely proportional to the counterion valence. Alkali metal counterions show large differences in ion-pair formation but only a weak effect in counterion condensation. We suggest that paired ions are a subset of condensed ions. A review of different methods to evaluate counterion condensation, including potentiometry, osmometry and viscosity-based methods is presented. Qualitative agreement between these methods is found and possible reasons for the discrepancies are discussed.
To summarize existing evidence of associations between religion and spirituality in relation to multiple dimensions of sleep health, illuminate strengths and limitations of the existing literature, and outline gaps that inform opportunities for future research. Positive dimensions of religion and spirituality, such as spiritual well-being, supportive coping, and community integration, were generally associated with better sleep outcomes across global populations. Adverse experiences, including doubt, conflict, and spiritual struggle, were often associated with poorer sleep. Among the 59 included studies, most were cross-sectional and relied on self-reported measures, used inconsistent conceptualizations of religion and spirituality, did not sufficiently assess potentially adverse religious or spiritual experiences, and were limited to certain geographic regions of the world (e.g., North America and Southwest Asia). Positive dimensions of religion and spirituality (e.g., meaning, coping) were generally associated with better sleep, while struggles and doubt were associated with poorer sleep. Future research that employs longitudinal and experimental designs, validated multidimensional measures, objective sleep assessments, and diverse populations is needed to clarify mechanisms and inform culturally responsive approaches to promoting sleep health.
Approximately 50% of prostate cancer (PCa) patients harbor fusions involving the TMPRSS2 and ERG genes. Despite this, tailored therapies targeting the fused gene, tERG, remain undeveloped. Our study analyzed biopsy samples from two clinical trials assessing the efficacy of androgen receptor (AR) signaling inhibitors (ARSIs). The results revealed that tERG promotes resistance to ARSIs and is associated with elevated levels of the glucocorticoid receptor (GR). Subsequent assays showed that GR directly interacts with tERG, alleviates allosteric autoinhibition, and prevents chemotherapy-induced tERG degradation. In PCa models, either inhibiting GR or lowering cortisol levels suppressed tumor growth in tERG-positive models, but not in tERG-negative models. In addition, patient-derived fusion-positive xenografts displayed enhanced sensitivity to combined GR and AR inhibitors. Collectively, these findings highlight TMPRSS2-ERG as a new biomarker and propose that simultaneous inhibition of GR and AR may specifically benefit tERG-positive patients. However, GR stimulatory corticosteroid therapies may not be advisable for this patient subgroup.
Rationale Alcohol use disorder (AUD) is a major contributor to the global burden of disease, yet treatments are limited. Therefore, developing evidence-based pharmacotherapies for AUD is critical. Preclinical and clinical studies suggest that spironolactone reduces alcohol intake and could be repurposed for AUD. Objective To examine associations of spironolactone prescription with AUD remission and alcohol intoxication in a real-world population. Method Target trial emulations were conducted using a population-based analytics platform of electronic health records from over 100 million US patients (TriNetX). Patients with AUD and comorbid hypertension, without prior documented AUD remission, who were prescribed spironolactone were compared with propensity-score matched controls prescribed other antihypertensive medications. The studied outcomes were AUD remission and alcohol intoxication, identified by International Classification of Diseases codes during a one-year follow-up. Results Spironolactone prescription was associated with a significantly higher hazard rate for AUD remission compared with prescriptions for all other groups of antihypertensive medications, with hazard ratios ranging from 1.24 [95% confidence interval (CI): 1.06-1.45] compared to loop diuretics and 2.07 [95% CI: 1.73-2.48] compared to angiotensin II receptor blockers. Furthermore, spironolactone prescriptions were associated with a significantly lower hazard rate for alcohol intoxication compared with most other groups of antihypertension medications. Conclusion Patients prescribed spironolactone were more likely to experience AUD remission and less likely to experience alcohol intoxication compared with propensity score-matched controls. These real-world findings further support the potential of spironolactone as a new pharmacotherapy for AUD and underscore the need for further testing in randomized controlled trials.
