The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.
Sedative-hypnotics, including benzodiazepines (BZDs) and non-benzodiazepine hypnotics (Z-drugs), are widely prescribed for insomnia and anxiety, particularly in older adults. Their long-term cognitive safety and potential association with Alzheimer's disease (AD) remain uncertain. We examined whether use of BZDs and Z-drugs is associated with incident AD and assessed variation by drug class, pharmacokinetics, and methodological factors. PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception to 16 August 2025 without language restrictions. Reference lists of eligible articles and reviews were screened. We included observational cohort and nested case-control studies enrolling adults without dementia at baseline that compared BZD or Z-drug users with non-users and reported incident AD diagnosed using validated clinical or administrative criteria (e.g., ICD-9/10, NINCDS-ADRDA, or NIA-AA). We excluded reviews, case reports, conference abstracts, studies with overlapping populations, and studies without extractable effect estimates. Two reviewers independently screened studies, extracted data, and assessed risk of bias using ROBINS-E. Random-effects meta-analyses were performed separately for odds ratios (ORs) and hazard ratios (HRs). Heterogeneity was quantified with I2. Publication bias was evaluated with funnel plots and Egger test when applicable. Subgroup and meta-regression analyses assessed clinical and methodological modifiers. Certainty of evidence was rated using GRADE. The protocol was prospectively registered (PROSPERO CRD420251141623). Thirteen studies (N = 721,354 subjects) were included. Overall sedative-hypnotic use was associated with higher odds of AD (OR 1.29; 95% CI, 1.10-1.53; I2 = 86.5%). Estimates restricted to HRs were attenuated and not statistically significant (HR 1.17; 95% CI, 0.87-1.58; I2 = 73.1%). In subgroup analyses, BZDs overall (OR 1.21; 95% CI 1.07-1.36), Z-drugs (OR 1.14; 95% CI 1.10-1.18; I2 = 0%), and short-acting agents (OR 1.19; 95% CI 1.04-1.36) were associated with higher odds of AD, whereas broad-acting BZDs were not (OR 1.01; 95% CI 0.98-1.05). Long-acting agents showed a borderline estimate (OR 1.44; 95% CI 0.99-2.09). Age-stratified analyses showed higher odds in individuals aged <75 years (OR 1.36; 95% CI 1.24-1.49), but not in those aged ≥75 years (OR 1.14; 95% CI 0.61-2.11). Estimates were also higher in studies using ICD-based definitions (OR 1.47; 95% CI 1.16-1.86) than in those using clinical criteria (OR 1.13; 95% CI 0.84-1.52). Meta-regression identified drug class and publication year as significant moderators. Risk of bias was rated moderate to serious in several studies, mainly due to residual confounding and exposure misclassification. Certainty of evidence ranged from very low to moderate. Use of BZDs and Z-drugs was associated with increased odds of AD, with variation across drug classes and pharmacokinetic profiles. Short-acting agents, BZDs overall, and Z-drugs were associated with higher risk, whereas broad-acting BZDs were not; this finding should be interpreted with caution given subgroup heterogeneity and limited statistical power. Residual confounding and reverse causation limit causal inference. These results support careful prescribing and the need for prospective studies with detailed characterization of exposure, dose, duration, and clinical indication to clarify whether observed associations reflect drug-related effects or underlying disease processes. PROSPERO protocol number: CRD420251141623.
PSMA PET has become central to prostate cancer imaging as advanced disease incidence rises and prostate-specific membrane antigen (PSMA)-targeted theranostics expand clinical use, yet accurate interpretation requires an understanding of prostate anatomy and physiology that extends beyond rote imaging patterns. Here we review prostate zonal anatomy, multimodality imaging features from ultrasound, multiparametric MRI, and PSMA PET/CT, and the underlying biology of PSMA expression, and androgen receptor signaling, and tumor dedifferentiation. We highlight physiologic and pathologic variations in PSMA uptake, common diagnostic pitfalls, and characteristic imaging changes after androgen-deprivation therapy, radiation, and prostatectomy. By relating anatomy, molecular physiology, and treatment effects to PSMA PET findings, this article provides nuclear medicine practitioners with a practical foundation to improve diagnostic accuracy and optimize patient selection for PSMA-based imaging and therapy.
Response to anti-programmed cell death protein-1 (anti-PD-1) immunotherapy remains limited in patients with metastatic non-small cell lung cancer (NSCLC), whose tumors exhibit low or absent programmed death-ligand 1 (PD-L1) expression, and subsequent second-line therapy has poor efficacy. To address this limitation, we evaluated the efficacy and safety of combined ipilimumab and nivolumab (IPI/NIVO) with subablative radiotherapy (RT) in patients with metastatic NSCLC with negative or low PD-L1 expression, who had progressed on prior anti-PD-1 therapy. This single-arm, prospective phase II trial aimed to enroll 30 evaluable patients with metastatic NSCLC exhibiting low (1-49%) or negative (<1%) PD-L1 tumor expression who had progressed after first-line anti-PD-1 therapy. Primary endpoints were safety, disease control rate (DCR), and objective response rate (ORR) at 6 and 12 weeks, assessed in non-irradiated tumor lesions. Treatment consisted of IPI 1 mg/kg every 6 weeks (Q6W) and NIVO 240 mg every 2 weeks for 6 weeks combined with subablative RT (3×8 Gy to 1-4 lesions). Thereafter, IPI 1 mg/kg Q6W and NIVO 360 mg every 3 weeks were continued. In 31 patients of the intention-to-treat population, ORR was 7% and 10% at 6 and 12 weeks, and reached 29% as the best response. DCR was 58% and 39% at 6 and 12 weeks. Overall survival (OS) differed significantly by best response, with a median OS of 3.1, 13.5 and 22.5 months for progressive disease, stable disease and partial/complete response (p<0.001). Baseline sum of longest diameters, together with age, blood inflammatory markers and albumin levels, were prognostic of treatment response. All patients experienced treatment-related adverse events (AEs), with grade 3 as the highest severity in eight patients (26%). Immune-related AEs led to treatment discontinuation in five patients (16%). Early T-cell activation in peripheral blood samples (day 8) was detectable and more pronounced in responders than in progressors. In patients with metastatic NSCLC and low or negative tumor PD-L1 expression, IPI/NIVO/RT was able to induce objective clinical responses in a subset of patients who had progressed after first-line anti-PD1 therapy. Treatment was associated with a strong T-cell activation, improved OS and an acceptable safety profile. 2020-001097-29.
In brief: Diabetes mellitus negatively impacts reproductive health in males. This study demonstrates the protective effects of a combination of metformin and vitamin C on diabetes-induced testicular damage. Abstract: This study aimed to investigate the potential protective effects of combined metformin (Met) and vitamin C (VitC) therapy on diabetes mellitus (DM)-induced testicular damage, sperm parameters, and the regulation of gene and protein expression associated with reproductive function. 36 C57BL mice were divided into six groups: control, VitC, DM, DM+VitC, DM+Met, and DM+VitC+Met. Diabetes mellitus was induced with streptozotocin, and treatment with Met (250 mg/kg/day) and VitC (100 mg/kg/day) for 40 days. Sperm parameters and serum oxidative stress markers were also evaluated. Sperm viability and apoptosis were assessed using Muse Cell Analyzer. Dnah7 and Tomm20 gene expression in the testis was determined by real-time PCR. Spermatogenesis was evaluated using the Johnsen score. Caspase-3 and proliferating cell nuclear antigen levels in the testes were assessed using western blotting and immunohistochemistry. Hyperglycaemia and decreased superoxide dismutase levels were observed in the DM group. Combination therapy resulted in higher sperm viability, Johnsen score, and testicular Tomm20 and Dnah7 mRNA expression levels than monotherapy. The combined administration of Met and VitC has significant potential for managing DM-associated reproductive dysfunction by maintaining sperm viability, Johnsen scores, and testicular protein profiles. Our results suggest that combination therapy holds promise for protecting testicular function and modulating key molecular markers, thereby mitigating DM-induced testicular damage at the molecular level.
Background and Objectives: Head and neck cancers are heterogeneous malignancies with variable biological behavior and treatment response, contributing to high morbidity and mortality. Conventional imaging techniques are limited in their ability to capture tumor biology, highlighting the need for advanced functional imaging. This review aims to evaluate the role of multiparametric magnetic resonance imaging (MRI) in characterizing the tumor microenvironment. Materials and Methods: A narrative review was conducted based on a targeted literature search of databases, including PubMed and Google Scholar. Studies addressing advanced MRI techniques for assessing tumor cellularity, vascularity, molecular features, and oxygenation were selected and analyzed. Results: Perfusion techniques, such as dynamic contrast-enhanced MRI (DCE-MRI) and arterial spin labeling (ASL), provide a quantitative assessment of tumor vascularity and show value in predicting treatment response. Diffusion-based methods, including diffusion-weighted imaging (DWI), intravoxel incoherent motion (IVIM), and diffusion kurtosis imaging (DKI), enable evaluation of tissue cellularity and heterogeneity. Molecular approaches, such as chemical exchange saturation transfer (CEST) and amide proton transfer (APT), offer insights into protein content and proliferation. Oxygenation-sensitive techniques, such as blood oxygenation level dependent MRI (BOLD MRI) and oxygen-enhanced MRI (OE-MRI), allow non-invasive assessment of tumor hypoxia. Conclusions: Multiparametric MRI provides a comprehensive and biologically relevant evaluation of the tumor microenvironment in head and neck cancer, with potential to improve treatment prediction and support personalized therapeutic strategies.
This study aimed to elucidate the mechanism by which salvianolic acid B (Sal B) protects against reperfusion-induced vascular damage following cerebral infarction, specifically investigating its role in preserving microvascular integrity through the ACSL4/Nrf2 axis-mediated inhibition of ferroptosis. A mouse model of cerebral ischemia/reperfusion injury was established via middle cerebral artery occlusion (MCAO). Mice were divided into Sham, MCAO, MCAO+Sal B, and MCAO+Sal B + ML385 (Nrf2 inhibitor) groups. We employed RNA sequencing, TTC staining, behavioral tests, histopathology, and molecular biology techniques to assess infarct volume, neurological function, ferroptosis markers (ACSL4, GPX4, TFR1), iron deposition, oxidative stress, inflammation, and Nrf2 pathway activity. Sal B markedly reduced infarct volume and improved neurological outcomes. At the mechanistic level, Sal B suppressed pro-ferroptotic mediators ACSL4 and TFR1 while enhancing Nrf2 nuclear translocation and upregulating its downstream effectors HO-1 and GPX4. These changes were associated with decreased iron deposition, reduced lipid peroxidation, and alleviated neuroinflammation. Importantly, pharmacological inhibition of Nrf2 with ML385 largely abolished these protective effects, underscoring the central role of Nrf2 signaling. Sal B alleviates reperfusion-associated damage post-cerebral infarction by synergistically downregulating the pro-ferroptotic gene ACSL4 and activating the Nrf2/HO-1 antioxidant pathway, thereby cooperatively inhibiting ferroptosis, preserving BBB integrity, and reducing neuronal injury.
Diabetic cardiomyopathy (DCM) is a serious complication driven by diabetes-associated oxidative stress and ferroptosis. This study compared the cardioprotective efficacy of metformin and empagliflozin in streptozotocin (STZ)-induced diabetic rats, focusing on ferroptosis-related mechanisms. Forty adult male Sprague-Dawley rats were divided into a control group (n = 10) and a diabetic group induced by STZ (55 mg/kg; n = 30). Following successful induction, the surviving diabetic rats were subdivided into untreated, metformin-treated (200 mg/kg/day), and empagliflozin-treated (10 mg/kg/day) subgroups (n = 8 each). After 12 weeks, biochemical, molecular, and histological analyses were conducted. Diabetic rats showed a 6.4-fold increase in fasting blood glucose (FBG) and a 3.9-fold rise in lactate dehydrogenase (LDH). These systemic changes were accompanied by marked myocardial oxidative stress imbalance and a 1.5-fold increase in cardiac iron. BTB and CNC homology 1 (BACH1) mRNA expression was upregulated 2.2-fold, coupled with suppression of heme oxygenase 1 (HO-1) and glutathione peroxidase 4 (GPX4) to 0.5 and 0.7-fold, respectively. Histological analysis revealed a 4-fold increase in the percentage area of collagen fibers, alongside a 6.2-fold and 4.5-fold increase in Yes-associated protein 1 (YAP1) and programmed death ligand 1 (PD-L1), respectively, and a 0.3-fold reduction in nuclear factor erythroid 2-related factor 2 (NRF2) expression, accompanied by ultrastructural damage characteristic of ferroptosis. Empagliflozin significantly improved antioxidant status, molecular and immunohistochemical marker expression, and myocardial integrity more effectively than metformin. Empagliflozin demonstrated greater cardioprotective effects than metformin in STZ-induced DCM, though further clinical studies are needed to confirm the translational relevance.
This study aimed to develop and evaluate a dual-drug-loaded PLGA nanoparticle system incorporating quercetin (QUE) and chlorhexidine (CHX) for localized, sustained delivery, with potential application in biofilm-associated pathologies. Single- and dual-drug systems containing CHX and QUE at different concentrations (1.5%, 5%, and 15%) were successfully loaded into poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) with high encapsulation efficiency. Physicochemical characterization was performed using dynamic light scattering (DLS), zeta potential analysis, SEM-EDX, FTIR, and thermal analysis (DSC and TGA). Release kinetics of QUE- and CHX-loaded nanoparticles were evaluated in an artificial saliva environment, and the amounts of CHX and QUE released were quantified by high-performance liquid chromatography (HPLC). Antimicrobial activity was assessed against Staphylococcus aureus and Escherichia coli using the disc diffusion method. The prepared nanoparticles displayed spherical morphology with sizes ranging from 54.08 to 356.1 nm and zeta potentials from - 2.11 to -12.46 mV, indicating colloidal stability. FTIR and thermal analysis confirmed molecular dispersion of drugs and polymer-drug interactions. QUE showed complete release within 168 h in the single-drug system, whereas co-loading with CHX extended QUE retention, with 20% remaining after 240 h. CHX release reached ∼80% in both formulations. CHX/QUE nanoparticles demonstrated superior antibacterial activity compared to QUE-only systems, effectively inhibiting both Gram-positive and Gram-negative bacteria. These compounds and formulations are designed for clinical applications due to their slow, controlled release of the dual-active PLGA NP system.
Angiostatin (ANG) is an endogenously cleaved protein of the plasminogen-plasmin conversion pathway which is activated during tumor angiogenesis and oxidative stress. One of the hallmarks of sub-clinical oxidative stress are persistent aggregation of platelets and neutrophils (and other immune cells) leading to endothelial activation. The goal of the study was to develop and test the specificity of a highly glycosylated form of ANG, derived from neutrophil elastase, as an in vivo radiopharmaceutical marker of oxidative stress and to monitor the progression of vascular and platelet activation. Sequential PET imaging of radiolabeled ANG ([89Zr]Zr-ANG) in a combined ozone and LPS induced murine model of oxidative stress (n = 8 per group) was followed by whole-body, fractionated blood, aortic ring and platelet biodistribution studies. In vitro, platelets were exposed to H2O2 and/or LPS to induce oxidative stress. Compared with sham mice, the uptake of [89Zr]Zr-ANG in the exposed lungs was 4.8 to 8.5-fold (male mice) and 4.2 to 11.6-fold (female mice) higher over 72 h after ozone and LPS exposure (p < 0.0001). Ex vivo biodistribution and microPET/CT imaging revealed accumulation of [89Zr]Zr-ANG in platelets and multiple organs including lungs highlighting vascular inflammation and platelet activation in response to ozone and LPS. Uptake of ANG in aorta and platelets was confirmed by injecting ozone and LPS exposed mice with fluorescent angiostatin. Lastly, platelets subjected to oxidative stress preferentially bind ANG compared to untreated platelets and split them into ATP-rich ultra-small (0.7-10 nm) vesicles and large (1-10 μm) micro-particles. This binding is dependent upon ATP inhibitory factor, IF1's displacement to bind with ATP synthase subunit β (ATPβ). [89Zr]Zr-ANG is a stable, ATP synthase directed endothelial cell and platelet-specific imaging tool for detection of acute murine oxidative stress-induced lung as well as systemic inflammation. Thus, the current study provides evidence towards potential applications of [89Zr]Zr-ANG in understanding the fate of platelets in chronic disease models.
The serine/threonine phosphatase-2 (PP2A) controls mitogen-associated signaling and DNA replication. The WEE1 protein tyrosine kinase controls S phase progression and G2/M phase transition. Databases disclose that the levels of PP2A and WEE1 are associated with poor prognosis of leukemic patients (p = 0,0017/0,025; n = 54-163). We applied advanced, clinically used drugs that block PP2A and WEE1 to human cultured leukemia cells, primary pre-leukemic and chronic myeloid leukemia cells, and pancreatic ductal adenocarcinoma cells. Combined application of the drugs depleted cells in all cell cycle phases, synergistically triggered apoptosis, and evoked the induction of DNA stress foci and mitotic catastrophe. In 93 lymphoid, 40 myeloid, and 47 pancreatic cancer cells, genetic depletion of PP2A-Cα and WEE1 stalls the proliferation of most cells. Unlike cancer cells, normal human immune cells are not killed upon inhibition of PP2A and WEE1. This is linked to higher expression of PP2A and WEE1 in chronic myeloid (n = 274), acute myeloid (n = 1858) and acute lymphoblastic leukemia cells (n = 1817) than in normal blood cells. These data suggest that pharmacological modulators of serine/threonine and tyrosine signaling allow targeted chemotherapy.
Radionuclides emitting beta- particles and Auger electrons present real or perspective radioactive components of radiopharmaceuticals used or developed for radionuclide therapy. Two important representatives of such radionuclides, lutetium-177 and terbium-161 have been applied as radiotoxic components of biomolecules and low-molecular agents developed for targeted radionuclide therapy. However, limited knowledge exists regarding the pharmacokinetics of potential contaminants or their final metabolic forms, such as chelate-radionuclide complexes or free radionuclides. These chemical forms can result from the radiolabeling process or the metabolism of radioimmunoconjugates in the organism. Since the pharmacokinetics of the undesired ionic forms of terbium-161 and lutetium-177 have not been fully explored using one experimental model and appropriate chemical forms of the radionuclides, this head-to-head study in mice was conducted. The experiment compared the biodistribution of a model 161Tb- or 177Lu-labeled antibody ramucirumab, 161Tb- or 177Lu-labeled DOTA-complexes, and free metal forms (161Tb3+ and 177Lu3+). Organ distribution was examined at selected time points (4 or 6, 24, 72, 144, and 240 h) following administration. Plasma binding was determined as an important distribution parameter. [161Tb]Tb-DOTA-ramucirumab and [177Lu]Lu-DOTA-ramucirumab distribution parameters exhibited typical pharmacokinetic characteristics of radioimmunoconjugates, such as a long elimination half-life and long-term retention in the liver or spleen. The general pharmacokinetic behavior of the congeners was very similar. A significant accumulation of free cationic form in bone and liver was observed. Whereas liver accumulation was transient, bone radioactivity did not decrease up to the last experimental interval. In contrast, [161Tb]Tb-DOTA and [177Lu]Lu-DOTA were eliminated rapidly from the organism without any significant organ retention. The high elimination rate of DOTA complexes was also supported by negligible binding to plasma. The obtained data demonstrate similar pharmacokinetic behavior for 161Tb- and 177Lu-labeled congeners, which may be useful for the development of future radiopharmaceuticals.
Antioxidant therapy represents a promising intervention for ischemic stroke, yet no targeted drug has successfully entered clinical application. While IKKβ is a known target in inflammatory and oncological diseases, its potential as an antioxidant target in stroke remains underexplored, and no IKKβ inhibitor has been approved clinically. Starting from the lead compound EF24, an IKKβ inhibitor with undefined mechanism, we first optimized its scaffold to obtain the safer derivative JH, then developed more potent analogs. A Random Forest-based QSAR model (R2 = 0.9098) highlighted molecular charge distribution, topology, and lipophilicity as key activity determinants. The optimized compound JHB-17 showed ∼70-fold higher potency than EF24 and acted as a non-ATP competitive inhibitor, targeting a novel allosteric site on IKKβ. In an H₂O₂-induced SH-SY5Y cell injury model, JHB-17 demonstrated significant dual antioxidant cytoprotective effects, and IKKβ overexpression reversed the protective effect of JHB-17. H₂O₂ exposure induced IKKβ phosphorylation. Conversely, silencing IKKβ exerts antioxidant cytoprotective effects by upregulating heme oxygenase-1 (HO-1). JHB-17 markedly inhibited IKKβ phosphorylation, promoted Nrf2 nuclear translocation, subsequently upregulated HO-1, and concurrently elevated the ferroptosis suppressor SLC7A11 and glutathione. In a rat MCAO/R model, JHB-17 reduced cerebral infarct volume and improved neurobehavioral outcomes. JHB-17 exhibits favorable pharmacokinetic parameters, and the comet assay and acute toxicity test demonstrate its good safety profile. This study preliminarily reveals a novel allosteric site on IKKβ, identifies JHB-17 as a novel IKKβ allosteric inhibitor with dual antioxidant activity, proposes IKKβ as a novel antioxidant target for cerebral ischemia-reperfusion injury, and reveals a novel mechanism by which IKKβ inhibition upregulates SLC7A11 to suppress ferroptosis, providing insights for targeted ischemic stroke therapy.
Resistance to mTOR inhibitors in glioblastoma (GBM) is mediated in part by activation of internal ribosome entry site (IRES)-dependent translation, enabling continued synthesis of key cell cycle regulators. This salvage mechanism involves methylation-dependent activation of the IRES-trans-acting factor (ITAF) hnRNP A1 by PRMT5. However, the upstream regulators of this PRMT5/hnRNP A1 axis remain unclear. To identify upstream effectors, a yeast two-hybrid screen using PRMT5 revealed PKA-Cα as an interacting partner. This interaction was validated via coimmunoprecipitation and colocalization in GBM cells. Functional relevance was assessed using biochemical, genetic, and pharmacological approaches to modulate PKA activity and examine effects on PRMT5 phosphorylation, hnRNP A1 methylation, IRES activity, and mTOR inhibitor resistance. PKA associated with PRMT5 and was activated in response to mTOR inhibition, correlating with increased cyclin D1 and c-myc mRNA IRES activity. PKA knockdown or inhibition attenuated IRES activation following mTOR inhibitor exposure. PRMT5 was phosphorylated at ser15 by PKA and this modification was required for PRMT5-hnRNP A1 interaction and downstream arginine methylation at residues R218/R225. A non-phosphorylatable PRMT5 S15A mutant failed to bind hnRNP A1, whereas a phosphomimetic S15E variant enhanced this association. PKA activation increased hnRNP A1 methylation, while combined inhibition of PKA and mTOR reduced GBM cell viability, suppressed IRES-mediated translation, and induced apoptosis both in vitro and in intracranial xenografts. These findings identify a PKA/PRMT5/hnRNP A1 signaling axis that promotes IRES-dependent translation and contributes to mTOR inhibitor resistance in GBM. Dual inhibition of PKA and mTOR may represent a promising therapeutic strategy.
Solitary fibrous tumor (SFT) is a rare and aggressive sarcoma driven by NAB2::STAT6 gene fusions, yet effective targeted therapies remain unavailable. Here, we report that the NAB2ex4::STAT6ex2 fusion variant forms nuclear condensates via liquid-liquid phase separation (LLPS) in engineered fibroblast models and primary SFT cells. These condensates co-localize with BRD4S and EGR1, key transcriptional regulators, and are functionally active, driving widespread transcriptional reprogramming. Treatment with Mithramycin A, a compound that disrupts EGR1-DNA interactions, dissolves NAB2::STAT6 condensates and reverses their aberrant gene expression and chromatin binding signatures. Our findings uncover a previously unrecognized role for NAB2::STAT6 in condensate-mediated oncogenic signaling and provide a mechanistic rationale for condensate-targeted therapy in SFT.
Fasciolosis, caused by Fasciola hepatica and Fasciola gigantica, is a major parasitic disease of livestock and humans. The increasing reports of drug resistance emphasize the need for novel therapeutic targets. However, before identifying a drug target, the parasite's biological processes need to be understood. F. gigantica, the predominant species in Asia, inhabits the bile duct, suggesting adaptation to bile-rich environments. We previously reported the discovery of a type-1 nuclear receptor from F. gigantica (FgNR1). We hypothesized that it functions as a bile salt-responsive transcription factor essential for parasite biology, but the exact functions have never been reported. Sequence analysis revealed that the ligand-binding domain (LBD) of FgNR1 (FgNR1-LBD) contains a conserved nuclear receptor signature motif (Tτ) and shares high homology with bile salt-responsive nuclear receptors in mammals, indicating conserved ligand recognition mechanisms. Using a luciferase reporter assay in a double-stable mammalian cell system, we demonstrate that the bile salts taurocholic acid (TCA) and glycocholic acid (GCA) significantly activate FgNR1-LBD-dependent transcriptional activity. Consistently, molecular docking analyses showed strong binding affinities of these bile salts within the predicted ligand-binding pocket of FgNR1-LBD. These findings provide the first functional evidence for bile salt regulation of gene expression via FgNR1. Importantly, this study establishes FgNR1-LBD as a tractable, parasite-specific molecular target, providing a foundation for understanding host-parasite interactions and furthering the discovery of agonists, antagonists, or inhibitors to disrupt parasite biological processes.
Purpose To perform a systematic review and meta-analysis of liver background uptake across four prostate-specific membrane antigen (PSMA)-targeting PET radiotracers (fluorine 18 [18F]-piflufolastat, gallium 68 [68Ga]-PSMA-11, 18F-flotufolastat, and 18F-PSMA-1007) and evaluate the potential impact on patient selection for PSMA-targeted therapy. Materials and Methods A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and Cochrane through May 12, 2025, to identify human studies reporting quantitative liver background uptake for the four PSMA-targeted PET radiotracers of interest. For each eligible study, liver background uptake was extracted as standardized uptake values (SUVs) and summarized and compared by radiotracer using random effects models with robust variance estimation. Results Among 652 unique records, 17 studies with 1497 total patients met inclusion criteria and reported liver background SUVs. Summary mean liver background SUV was 5.0 (95% CI: 3.6, 6.3) for 18F-piflufolastat, 5.1 (95% CI: 4.3, 5.9) for 68Ga-PSMA-11 (P = .579 compared with 18F-piflufolastat), 7.2 (95% CI: 6.3, 8.2) for 18F-flotufolastat (P = .005), and 12.1 (95% CI: 11.4, 12.9) for 18F-PSMA-1007 (P < .001). Conclusion Liver background uptake differed across PSMA-targeted PET radiotracers and may influence patient eligibility for PSMA-targeted therapy when liver activity is used as a reference for defining PSMA-positive metastatic prostate cancer. Keywords: PET, Genital/Reproductive, Prostate, 68Ga-PSMA-11, 18F-piflufolastat, 18F-flotufolastat, 18F-PSMA-1007, PSMA-targeted PET, PSMA-targeted Therapy Supplemental material is available for this article. © RSNA, 2026.
Fibroblast activation protein alpha (FAP) is a pan-tumor target highly expressed on cancer-associated fibroblasts. We developed 4AH29, a single-domain antibody binding FAP, and investigated the biodistribution of [131I]I-GMIB-4AH29 and [111In]In-DOTA-4AH29 in Göttingen minipigs. Following radiopharmaceutical administration, blood activity profile was determined by gamma-counter and biodistribution kinetics were determined using SPECT/CT imaging, respectively. The data obtained with [111In]In-DOTA-4AH29 were used as a surrogate for its 177Lu- and 225Ac-labeled analogues and extrapolation to human absorbed dose was calculated for all analogues. Radiolabeled 4AH29 showed good tolerability within the studied time frame. It displayed fast blood clearance driven by renal excretion. Kidney clearance dynamics of [131I]I-GMIB-4AH29 and [111In]In-DOTA-4AH29 were distinct, likely driven by the different radiolabeling chemistry for halogen or metal conjugation. However, the contrasting patterns did not translate into relevant differences in mean residence time (MRT), nor was there a significant difference in bone marrow or liver MRTs when comparing halogen and metal-radiolabeled 4AH29. Extrapolated human absorbed doses for [131I]I-GMIB-4AH29 and [177Lu]Lu-DOTA-4AH29 were compared given their similar particle decay and comparable physical half-lives. In kidneys, [131I]I-GMIB-4AH29 led to an extrapolated human absorbed dose of 8.23E-01 mGy/MBq, whereas [177Lu]Lu-DOTA-4AH29 reached 5.86E-01 mGy/MBq. Consequently, the maximum tolerable administered activities were 28 and 39 GBq, respectively, to reach the renal absorbed dose limit of 23 Gy as determined by external beam radiation therapy (EBRT). In red marrow, the equivalent dose for [131I]I-GMIB-4AH29 was 3.8E-02 mGy/MBq and 1.36E-02 mGy/MBq with [177Lu]Lu-DOTA-4AH29. Thus, 53 GBq and 148 GBq can be administered, respectively, before reaching the EBRT set absorbed dose threshold of 2 Gy. 4AH29 radiolabeled with 131I or 111In is well tolerated in Göttingen minipigs within the studied time frame. Extrapolated dosimetry of radiolabeled 4AH29 using OLINDA software indicates that its administration within a clinically relevant range is possible without exceeding toxicity limits in critical organs.
Neointimal hyperplasia (NH) is a prominent pathological consequence following vascular injury and is driven in part by aberrant vascular smooth muscle cell (VSMC) proliferation. COP9 signalosome (CSN) subunit 5 (CSN5/JAB1/COPS5) is the deneddylase component of the CSN holocomplex responsible for deneddylation of cullin-RING ligases. Although CSN5/CSN is well studied in cancer biology, the role of CSN5/CSN in NH and vascular biology remains largely unexplored. Here, we investigated whether selective inhibition of CSN deneddylase activity using CSN5i-3 could mitigate neointimal remodeling following arterial injury. Adult mice were subjected to daily intraperitoneal injections of CSN5i-3 (20 mg/kg/day) or vehicle and left common carotid artery ligation. The left and the right common carotid arteries were then assessed for VSMC phenotypic modulation and neointima formation after 7 days of treatment. CSN5i-3 treatment markedly attenuated the ligation-induced changes in the mRNA level of COL1A1, FN1, CCND1, and CCND2, genes associated with extracellular matrix deposition and cell-cycle progression, but did not alter expression changes of canonical smooth muscle differentiation markers (MYOCD, MYH11, and ACTA2) and KLF4 in the ligated vessel. Importantly, CSN5i-3 significantly blunted the increases of proliferating cell nuclear antigen (PCNA) expression and Ki67-positive VSMCs and reduced neointimal areas. These findings demonstrate that CSN deneddylase activity is dispensable for the dedifferentiation of contractile VSMCs into the synthetic state but promotes VSMC proliferation, supporting the concept that the dedifferentiation and proliferation of VSMCs in neointimal formation are separately regulated processes and differentially regulated by different CSN actions. This study also indicates that CSN5i-3 is highly promising in preventing neointimal hyperplasia.NEW & NOTEWORTHY This study provides compelling in vivo evidence that selective inhibition of COP9 signalosome (CSN) deneddylation activity by CSN5i-3 suppresses neointimal hyperplasia through reducing proliferation of vascular smooth muscle cells without impacting their dedifferentiation. This not only identifies CSN5i-3 as a promising agent in preventing neointimal hyperplasia but also supports the new concept that dedifferentiation and proliferation of vascular smooth muscle cells in neointimal formation are separately regulated processes and differentially regulated by CSN-mediated deneddylation.
The present study was initiated to analyze ticks collected periodically from the vegetation in an urban marshy biotope of central Europe. During the one-year-long study period, 1960 ticks were found, including Ixodes ricinus (n = 1037), Dermacentor reticulatus (n = 610) and Haemaphysalis concinna (n = 313). DNA was extracted from 199 Dermacentor reticulatus and 47 Ixodes ricinus, selected from the beginning of their questing period. Molecular analysis of the cytochrome c oxidase subunit I (cox1) barcoding gene with the classical Folmer primers revealed that among 37 D. reticulatus all except two ticks had serial mutations along a 129-bp-long part of the gene. The majority of these ticks were young, freshly molted adults. However, when the complete mitogenome was sequenced from two such "aberrant" ticks, these serial mutations were absent. In D. reticulatus, host DNA was detected from four synanthropic bird species, the dog, the red fox, the bank vole, the Eurasian shrew and the wild boar. Besides long-known endemic tick-borne pathogens, specimens of D. reticulatus and I. ricinus were shown to contain the DNA of Ehrlichia muris. Babesia microti had very high, 36% prevalence in I. ricinus. In conclusion, mutations in the cox1 fragment amplified with the Folmer primers were not present in the complete mitochondrial genome of D. reticulatus, indicating that probably nuclear mitochondrial DNA (NUMT) was amplified with the first method. To our knowledge, similarly high local prevalence of B. microti was only reported in ticks in North America, where this piroplasm is responsible for most cases of human babesiosis (unlike in Europe).