Search Results (188)

Paraneoplastic neurological syndromes (PNSs) are immune-mediated disorders caused by an antitumor response that cross-reacts with the nervous system, leading to severe and often irreversible neurological disability. Once considered exceedingly rare, PNSs are now increasingly recognized owing to the identification of novel neural autoantibodies, wider use of commercial testing, and the emergence of immune checkpoint inhibitor (ICI)-related neurotoxicity that phenotypically overlaps with classic PNS. In this narrative review, we performed a structured search of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, without date restrictions, to summarize contemporary advances in the epidemiology, pathogenesis, diagnosis, and management of PNS. Population-based data show rising incidence, largely reflecting improved ascertainment and expanding indications for ICIs. Pathogenetically, we distinguish T-cell-mediated syndromes associated with intracellular antigens from antibody-mediated disorders targeting neuronal surface proteins, integrating emerging concepts of molecular mimicry, tumor genetics, and HLA-linked susceptibility. The 2021 PNS-Care criteria are also reviewed, which replace earlier “classical/non-classical” definitions with risk-stratified phenotypes and antibodies, and demonstrate superior diagnostic performance while underscoring that “probable” and “definite” PNS should be managed with equal urgency. Newly described antibodies and methodological innovations such as PhIP-Seq, neurofilament light chain, and liquid biopsy are highlighted, which refine tumor search strategies and longitudinal monitoring. Management principles emphasize early tumor control, prompt immunotherapy, and a growing repertoire of targeted agents, alongside specific considerations for ICI-associated neurological syndromes. Remaining challenges include diagnostic delays, limited high-level evidence, and the paucity of validated biomarkers of disease activity. Future work should prioritize prospective, biomarker-driven trials and multidisciplinary pathways to shorten time to diagnosis and improve long-term outcomes in patients with PNS. Full article

Microplastics (MPs) and antibiotics have emerged as contaminants of global concern, posing potential threats to ecosystem security and organismal health. To investigate the individual and combined toxicity of microplastics (PS-MPs) and sulfamethoxazole (SMX), we conducted a 120 h acute exposure experiment using embryo–larval zebrafish as a toxicological model. Our findings demonstrate that both PS-MPs and SMX can induce neurodevelopmental toxicity in embryo–larval zebrafish during embryonic development. Notably, PS-MPs and SMX exerted a significant synergistic effect. PS-MPs 1 µm in diameter were restricted to the chorion surface of pre-hatching zebrafish, whereas post-hatching, PS-MPs accumulated mainly in the gut and gills, with accumulation levels increasing progressively with exposure duration. Individual exposure to PS-MPs or SMX reduced spontaneous locomotion, decreased heart rate, and shortened body length in embryo–larval zebrafish. In addition to exacerbating these effects, coexposure further increased the incidence of malformations such as pericardial effusion and spinal curvature. PS-MPs and SMX significantly decreased the levels of dopamine (DA), serotonin (5-HT), and γ-aminobutyric acid (GABA) in zebrafish while also suppressing acetylcholinesterase (AChE) activity and increasing acetylcholine (ACh) levels. Moreover, upon coexposure at high concentrations, PS-MPs and SMX acted synergistically to reduce the levels of DA and GABA. The downregulation of key neurodevelopmental genes (elavl3, gap43, and syn2a) and related neurotransmitter pathway genes indicates that PS-MPs and SMX impaired structural development and functional regulation of the nervous system. An integrated biomarker response (IBR) index confirmed that PS-MPs and SMX significantly enhanced developmental neurotoxicity during early neurodevelopment in embryo–larval zebrafish through synergistic effects. Our study provides critical toxicological evidence for the scientific assessment of the ecological risks posed by microplastic–antibiotic cocontamination. Full article

Background: Alcohol use disorder (AUD) is associated with chronic heavy or repeated binge alcohol abuse, which can cause alcohol-related brain damage (ARBD) marked by neurobehavioral, cognitive, and motor deficits. The anterior frontal lobe and cerebellar vermis are two of the major targets of ARBD in humans with AUD and in experimental alcohol exposed models. Alcohol’s neurotoxic and neurodegenerative effects include impairments in signaling through insulin and insulin-like growth factor (IGF) pathways that regulate energy metabolism. This human AUD study was inspired by a recent report suggesting that dysfunction of the frontal lobe incretin network in experimental ARBD is linked to known impairments in brain insulin/IGF signaling. Objective: The overarching goal was to investigate whether AUD is associated with dysfunction of the brain’s incretin network, focusing on the cerebellum and frontal lobe. Methods: Fresh frozen postmortem cerebellar vermis and anterior frontal lobe tissues from adult male AUD (n = 6) and control (n = 6) donors were processed for protein extraction. Duplex enzyme-linked immunosorbent assays (ELISAs) were used to assess immunoreactivity to neurofilament light chain (NfL) as a marker of neurodegeneration. A multiplex ELISA was used to measure immunoreactivity to a panel of gut hormones, including incretin polypeptides. Results: AUD was associated with significantly increased NfL immunoreactivity in both the cerebellar vermis and anterior frontal lobe. However, the patterns of AUD-related alterations in gut hormone immunoreactivity differed regionally. AUD reduced pancreatic polypeptide immunoreactivity in the cerebellar vermis, and GIP, GLP-1, leptin, and ghrelin in the frontal lobe. Conclusions: (1) Increased NfL may serve as a useful biomarker of neurodegeneration in AUD. (2) AUD’s adverse effects on neuroendocrine signaling networks differ in the cerebellar vermis and anterior frontal region, although both are significant targets of ARBD. (3) The finding of AUD-associated reductions in frontal lobe GIP and GLP-1 suggests that therapeutic targeting with incretin receptor agonists may help restore energy metabolism and neurobehavioral and cognitive functions linked to their networks. Full article

Landfills represent increasingly common anthropogenic habitats that provide food resources but also expose wildlife to complex chemical mixtures. White Storks (Ciconia ciconia) have recently expanded breeding near such sites, yet little is known about the physiological consequences of landfill dependence across time. In 2025, we assessed biomarker responses in White Stork (Ciconia ciconia) nestlings from the Jakuševec landfill (Zagreb, Croatia), a post-remediated site still in partial operation, three years after the initial studies conducted in 2021 and 2022. Activities of acetylcholinesterase (AChE), carboxylesterase (CES), glutathione S-transferase (GST) and glutathione reductase (GR), as well as levels of reduced glutathione (GSH) and reactive oxygen species (ROS), were quantified in extracellular (plasma) and intracellular (post-mitochondrial S9) blood fractions. Neurotoxicity biomarkers (AChE, CES) showed small increases in 2022, followed by significant declines in 2025, indicating potential changes in exposure to neuroactive compounds. Oxidative-stress biomarkers displayed contrasting patterns: GST and GR decreased progressively, whereas ROS rose and GSH shifted in opposite directions between fractions, together suggesting rising oxidative challenge and altered redox balance. The combined biomarker response suggests continuing low-level exposure to neurotoxic and redox-active compounds despite landfill remediation. Our findings highlight that urban landfills, even in post-closure phases, remain physiologically active systems influencing wildlife health and should be incorporated into long-term ecotoxicological and conservation monitoring frameworks. While independent long-term monitoring shows that the Jakuševec White Stork colony has continued to grow over the past decade, the physiological responses detected in nestlings highlight the importance of assessing how chronic low-level exposure might influence population health in the long term. Full article

This study estimates the levels of chemical contamination and the responses of biochemical and cytogenetic biomarkers in Unio pictorum from the Nemunas River after a large-scale fire at a tire storage and processing warehouse (in October 2019), as well as after the subsequent discharge of partially cleaned water used for firefighting. The impact of firefighting water (FW) on the River Nemunas ecosystem was assessed. Elevated levels of trace metals (Pb, Cu, Co, Cr, Al, Zn) in U. pictorum mussels collected downstream from the wastewater treatment plant (WTP) discharger were measured in the first year after the accident. Genotoxic aberrations in gill cells were significantly more frequent in mussels collected downstream of the WTP discharger, along with higher frequencies of cytotoxic damage and changes in acetylcholinesterase activity. PAH metabolite concentrations, including naphthalene (Nap) and benzo(a)pyrene (B(α)P), were also elevated in haemolymph in U. pictorum gathered downstream from the discharger, but differences were not statistically significant. The total sum of 16 PAH concentrations in mussels collected in 2021 and 2022 was over 5 times higher than those in 2020, and the profile of accumulated metals shifted, with Ni, Cd, Cr, and Pb concentrations decreasing while Zn increased significantly. Mussel haemolymph in 2021 contained the highest levels of B(α)P-type PAH metabolites, indicating increased oxidative stress and neurotoxic impact. The results of chemical analysis and the values of genotoxic aberrations determined in gill cells of U. pictorum collected in 2021 and 2022 indicate an increase in PAH contamination and geno-cytotoxic impact compared to the results of 2020; these changes might be related to the gradual cancellation of COVID-19 restrictions and restoration of routine activities. The study provided an opportunity to demonstrate the unique response of a less anthropogenically stressed ecosystem to the extreme impact of contamination related to the fire on the tire recycling plant. Full article

Background: Resveratrol (3,5,4′-trihydroxy-trans-stilbene, RVT) is one of the most extensively studied natural polyphenols, with numerous health benefits documented in the literature. One of its most characterized biological properties is the strong antioxidant capacity. However, its poor biopharmaceutical properties limit its in vivo applicability. In this study, we conducted a detailed comparative analysis of the antioxidant and protective capacity of pure and loaded into Pluronic micelles resveratrol. Methods: Various in vitro antioxidant assays, such as DPPH, ABTS, superoxide anion radical scavenging, ferric (FRAP), and copper-reducing power assay (CUPPRAC), and iron-induced lipid peroxidation were performed. In addition, the in vitro 6-OHDA model of neurotoxicity in brain synaptosomes and the in vivo scopolamine (Sco)-induced model of cognitive impairment in rats were also employed. The main antioxidant biomarkers—the levels of lipid peroxidation (LPO) and total glutathione (GSH), as well as activities of superoxide dismutase, catalase, and glutathione peroxidase—were measured in the cortex and hippocampus. Results: The results from the in vitro tests demonstrated better ferric-reducing power activity and better neuroprotective capacity of the micellar resveratrol (mRVT), as evidenced by preserved synaptosomal viability and maintained GSH levels in a concentration-dependent manner in 6-OHDA-induced neurotoxicity. Regarding the in vivo results, mRVT (10 µM concentration) was the most effective treatment in supporting recognition memory formation in dementia rats. Further, mRVT demonstrated better LPO protective capacity in the hippocampus and GSH preserving activity in the cortex than the pure drug. Conclusions: The incorporation of resveratrol in polymeric micelles could enhance its antioxidant and neuroprotective effects. Full article

Background/Objectives: Cytarabine (Ara-C) remains central to acute myeloid leukemia therapy but is limited by unpredictable systemic toxicities. Preclinical studies have long documented multi-organ injury, yet findings remain fragmented. This systematic review synthesizes animal evidence to clarify the spectrum, dose–response patterns, and mechanisms of cytarabine-induced toxicity. Methods: Following PRISMA 2020 guidelines and PROSPERO registration (CRD420251081384), a comprehensive search of PubMed, MEDLINE, Scopus, Cochrane Library and Embase identified eligible in vivo animal studies. Data extraction covered animal models, dosing regimens, routes of administration, histopathological and biochemical endpoints and mechanistic findings. Risk of bias and study quality were assessed using SYRCLE’s tool, CAMARADES checklist and an adapted Newcastle–Ottawa Scale, with reporting benchmarked against ARRIVE 2.0. Results: Eighty-one studies (1964–2024) were included. Cytarabine produced dose- and regimen-dependent toxicities across multiple organs. Neurotoxicity was most frequently reported, followed by intestinal mucositis, ocular injury, alopecia, hepatotoxicity, nephrotoxicity, and developmental anomalies. Mechanistic analyses consistently implicated oxidative stress, inflammatory cascades, apoptosis, and epigenetic dysregulation. Study quality was moderate, with frequent deficiencies in randomization, blinding, and sample-size justification, raising concerns about reproducibility. Cardiotoxicity, despite clinical relevance, was virtually absent from preclinical evaluation. Conclusions: Preclinical evidence suggests cytarabine’s systemic toxicity as a multifactorial process extending beyond rapidly proliferating tissues. While animal studies provide mechanistic insights, methodological weaknesses and translational gaps limit predictive value. Future research must adopt rigorous design, systematically assess underexplored toxicities, and integrate molecular profiling to identify biomarkers and protective strategies. Full article

Per- and polyfluoroalkyl substances are persistent environmental contaminants increasingly implicated in neurotoxicity. Establishing causality and mechanisms relevant to Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis requires human-relevant systems that capture exposure, barrier function, and brain circuitry. We review advanced cellular platforms—iPSC-derived neuronal and glial cultures, cerebral and midbrain organoids, and chip-based microphysiological systems—that model disease-relevant phenotypes (Aβ/tau pathology, dopaminergic vulnerability, myelination defects) under controlled PFAS exposures and defined genetic risk backgrounds. Modular, fluidically coupled BBB-on-chip → brain-organoid microphysiological systems have been reported, enabling chronic, low-dose PFAS perfusion under physiological shear, real-time barrier integrity readouts such as transepithelial/transendothelial electrical resistance (TEER), quantification of PFAS partitioning and translocation, and downstream neuronal–glial responses assessed by electrophysiology and multi-omics. Across platforms, convergent PFAS-responsive processes emerge—mitochondrial dysfunction and oxidative stress, lipid/ceramide dysregulation, neuroinflammatory signaling, and synaptic/network impairments—providing a mechanistic scaffold for biomarker discovery and gene–environment interrogation with isogenic lines. We outline principles for exposure design (environmentally relevant ranges, longitudinal paradigms), multimodal endpoints (omics, electrophysiology, imaging), and cross-lab standardization to improve comparability. Together, these models advance the quantitative evaluation of PFAS neurotoxicity and support translation into risk assessment and therapeutic strategies. Full article

Obesity and depression are two of the most prevalent diseases with increasing trends worldwide; it has been some time since the first epidemiological associations were first described. Currently, there is abundant evidence showing the physiology and the molecular aspects that intersect the biology of both ailments. This narrative review aims to synthesize current evidence on the epidemiology and shared pathophysiology of obesity and major depressive disorder, emphasizing convergent inflammatory, neuroendocrine, metabolic, genetic, and gut–brain mechanisms. We aggregate evidence for a bidirectional relationship mediated by: (1) chronic low-grade inflammation (elevated CRP, IL-6, TNF-α; microglial activation); (2) HPA axis dysregulation (hyper/corticosteronemia, impaired feedback, altered CRH/ACTH signaling); (3) metabolic and neurotrophic signaling deficits (insulin and leptin resistance, dysregulated adipokines such as leptin/adiponectin, impaired BDNF and synaptic plasticity); (4) lipid-derived neurotoxicity and mitochondrial stress (saturated fatty acids, ceramides, oxidative stress); and (5) gut–brain axis perturbations (microbiota dysbiosis, increased intestinal permeability, LPS-driven endotoxemia, altered short-chain fatty acids and tryptophan–kynurenine metabolism). We highlight how these convergent pathways promote neuroinflammation and mood dysregulation in individuals with obesity and summarize clinical consequences for screening, integrated management, and targeted interventions that modulate immune, neuroendocrine, metabolic, and microbial processes. Finally, we outline priorities for identifying shared biomarkers and advancing personalized strategies via multi-omics and systems medicine to improve prevention, diagnosis, and treatment. Full article

Small-cell lung cancer (SCLC) is an aggressive malignancy that exhibits high prevalence for brain metastases. Furthermore, chemotherapy and metastasis-preventive approaches are also linked to neurotoxicity, further aggravating cognitive impairment. Despite evidence supporting structural and functional brain alterations in SCLC, the application of machine learning (ML) to new connectivity biomarkers has remained unexplored. This study is—to the best of our knowledge—the first to apply ML to structural brain connectomics in SCLC, using diffusion tensor imaging (DTI) to identify features discriminating between post-chemotherapy SCLC patients and healthy controls. Specifically, we constructed structural networks via deterministic tractography, applying an adapted feature reduction technique to identify the most informative connections without selection bias. This process isolated 16 connections involving 26 brain regions, predominantly in the frontal, temporal, and parietal lobes, showcasing primarily intra-hemispheric and left-lateralized alterations. Our optimal model leveraged a Gaussian Support Vector Machine (SVM), achieving a weighted accuracy of 0.92, a sensitivity of 0.93, a specificity of 0.91, and an area under the curve of 0.94. The selected feature subset retained high performance when tested with other classifiers, confirming its robustness. Our findings differ from prior studies based on statistically derived features, highlighting the ML-driven connectomics’ potential in uncovering DTI-derived SCLC patterns, offering interpretable insights for neuroimaging-based diagnostics. Full article

Conventional plastics are widely utilised across industrial sectors and in consumer products. However, the growing use of plastics has led to plastic pollution, including the formation of nanoplastics (NPs), which are harmful to aquatic organisms. Bioplastics are emerging alternatives. They are renewable and/or biodegradable and are supposed to be more environmentally friendly. However, the toxicity and environmental fate of bioplastics are not yet fully understood. This study evaluated the toxicity and fate of commercially available plain or fluorescent polylactic acid (PLA) NPs (250 nm) on aquatic organisms. Confocal microscopy demonstrated the uptake of fluorescent PLA NPs by the test organisms, marine rotifers (Brachionus plicatilis), brine shrimps (Artemia salina) and zebrafish (Danio rerio) embryos. However, the results of the bioassays indicate that plain PLA NPs did not induce acute toxicity in either of the two zooplankton species and did not cause substantial mortality, malformations, or hatching delays in zebrafish embryos at the tested concentrations (up to 100 mg/L). However, brine shrimp showed a significant decrease in ingestion capability. The biochemical biomarkers, catalase activity induction, as an indicator of oxidative stress, and acetylcholinesterase inhibition, as a marker of neurotoxicity, showed no significant alterations compared to the control of both zooplankton species and that of zebrafish embryos. Overall, the findings suggest a pattern of no acute and low sublethal toxicity for the tested plain PLA NPs in the studied organisms. Nonetheless, further research is imperative to comprehensively assess the environmental fate of bioplastics found in various consumer products, as these may contain harmful chemical additives, as well as the effects of prolonged exposure and their impact on physiological parameters, ensuring informed decisions before their widespread commercialisation and presence in the environment. Full article

Background: Chimeric Antigen Receptor T-cell (CAR-T) cell therapy has revolutionized cancer treatment and is now being explored as a novel approach to treat refractory autoimmune diseases by targeting autoreactive immune components, especially B cells. Objective: Our aim was to provide a narrative review of the current evidence, mechanisms, efficacy, safety, and future directions of CAR-T cell therapy in autoimmune diseases. Methods: A structured literature search was conducted in MEDLINE via PubMed using keywords such as “CAR-T”, “chimeric antigen receptor T-cell”, “autoimmune diseases”, “lupus”, “rheumatoid arthritis”, “multiple sclerosis”, and “vasculitis”. Studies on CAR-T mechanisms, efficacy, safety, and clinical outcomes were included. Results: CAR-T cell therapies, especially CD19-directed constructs, demonstrated sustained drug-free remission in all patients across early SLE case series (n = 5–7), with normalization of serological markers and improved renal outcomes. Emerging preclinical and early clinical data in rheumatoid arthritis, multiple sclerosis, ANCA-associated vasculitis, juvenile autoimmune diseases, and idiopathic inflammatory myopathies also report clinical improvement and biomarker normalization. Reported adverse events in autoimmune cohorts were limited to mild cytokine release syndrome in a minority of cases, with no severe neurotoxicity or life-threatening infections, suggesting a more favorable safety profile compared to oncology settings. In parallel, next-generation innovations—including dual-target CARs, CAR-Tregs, and molecular safety switches—are advancing toward clinical translation. Conclusions: CAR-T cell therapy is emerging as a transformative strategy for autoimmune disease management, especially in refractory cases. Although initial outcomes are promising, long-term safety, cost-effectiveness, and broader accessibility remain key challenges. Future research should focus on optimizing cell targets, minimizing off-target effects, and improving affordability. Full article

Protein aggregates are central to the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. This comprehensive review explores the mechanisms of protein misfolding and aggregation, their prion-like propagation, and the critical role of oligomeric species in neurotoxicity. It further examines cellular clearance pathways, including the ubiquitin–proteasome system and autophagy, alongside the regulatory functions of molecular chaperones. The review also covers advanced diagnostic imaging and biomarker techniques, as well as emerging therapeutic strategies such as pharmacological agents, gene therapy, and immunotherapy. Controversies regarding the toxicity of aggregates and future directions, including novel degradation technologies and targeted therapeutic approaches, are discussed. By integrating current knowledge, this review aims to provide a broad yet detailed overview of the field, highlighting both established concepts and promising avenues for research and treatment. Full article

Cognitive decline can result from various factors, including direct neurotoxic injury, brain tissue damage, inflammation, and disruptions in coagulation and fibrinolysis. This study aimed to examine the relationship between biochemical markers associated with cognitive function and cognitive performance in men with prostate cancer (PC) following radical prostatectomy. Participants underwent a comprehensive evaluation, including clinical assessments (demographic information, medical history, PC progression, and complications such as erectile dysfunction [IIEF-5] and urinary incontinence [ICIQ-UI]), biochemical testing (testosterone, prostate-specific antigen, phosphorylated neurofilament heavy chain [pNF-H], brain-derived neurotrophic factor [BDNF], neuroserpin [NSP], and interleukin-6 [IL-6]), and neuropsychological assessment of cognitive functions. Statistical analysis revealed significant positive correlations between BDNF and NSP levels and performance on delayed memory tasks, specifically the number of correct responses. No other significant associations were found between protein biomarkers and cognitive test outcomes. These findings suggest that the relationship between biochemical markers and cognitive function is complex. However, BDNF and NSP may serve as potential biomarkers for delayed memory impairment in men post-prostatectomy. Full article

Cancer neuroscience is an emerging field revealing how malignancies interact with the nervous system to shape disease progression and symptom burden. In colorectal cancer (CRC), increasing evidence suggests a direct interplay between tumor cells and peripheral sensory neurons, contributing not only to cancer progression but also to chemotherapy-induced side effects such as peripheral neuropathy. Chemokines, particularly CCL3, appear to be key players in this bidirectional communication. This literature review aims to critically examine the role of CCL3 in CRC and chemotherapy-induced peripheral neuropathy (CIPN), with a focus on identifying potential mechanistic overlaps. Specifically, we evaluate whether CCL3 may serve as a molecular link between cancer progression and the development of neuropathic pain. In CRC, CCL3 is frequently upregulated, promoting tumor proliferation, invasion, and immune remodeling through CCR5- and MAPK-dependent pathways. Elevated CCL3 expression correlates with advanced stage, nerve infiltration, and worse prognosis, while select studies suggest it may also enhance antitumor immunity via dendritic cell recruitment. In parallel, CCL3 is also upregulated in the nervous system during CIPN, where it contributes to chronic pain through activation of glial cells, sensitization of nociceptive pathways (e.g., TRPV1, P2X7), and desensitization of opioid receptors. Notably, MAPK signaling is a shared downstream pathway in both contexts, suggesting a potential mechanistic bridge between tumor biology and neurotoxicity. In conclusion, CCL3 emerges as a central molecule at the intersection of CRC and CIPN. Understanding its context-dependent roles may offer new opportunities for risk prediction, biomarker development, and therapeutic intervention—contributing to the broader goals of cancer neuroscience in improving both oncologic and neurologic outcomes. Full article