Search Results (82)

Oligodendrocytes (OLs), the myelin-forming cells of the central nervous system (CNS), are principal targets of autoimmune attack in multiple sclerosis (MS), resulting in demyelination and impaired neural conduction. Recent studies indicate that white matter in patients with MS exhibits increased aerobic glycolysis alongside reduced oxygen consumption—a metabolic mismatch between glucose utilization and oxygen consumption—that correlates with disability accumulation. Dysregulated energy metabolism is also a central mechanism limiting remyelination in MS. In MS, this dysregulation is characterized primarily by abnormal availability of metabolic substrates entering the CNS; in turn, it disrupts glucose and lipid metabolism within OLs, leading to mitochondrial dysfunction and a diminished capacity for myelin repair. Pharmacological studies employing metabolic intermediates as interventions have shown that correcting energy-metabolism disturbances in OLs can promote remyelination and mitigate MS symptoms, highlighting the metabolic–epigenetic axis as a potential therapeutic target. Clinical and translational research further suggests that modulation of metabolic pathways may enhance remyelination and improve brain energy homeostasis. Future work should integrate metabolomics, multimodal imaging, and multi-omics approaches to map neuron–glia metabolic-coupling networks with precision and to test, in high-quality randomized controlled trials, the efficacy and safety of metabolism-targeted therapies. Full article

Cisplatin is a widely used antineoplastic agent whose therapeutic efficacy is often limited by its adverse effects on the central nervous system. In this exploratory study, we characterized the transcriptomic impact of a cumulative cisplatin regimen on the male Wistar rat brain using microarray technology. Differentially expressed genes were identified, and their functional roles were investigated through enrichment analyses (KEGG) and Gene Ontology (GO), and the construction of protein–protein interaction (PPI) networks. Our results revealed significant alterations in pathways related to synaptic signaling, neuroplasticity, and cellular metabolism. To generate translational hypotheses, these findings were subsequently correlated in silico with public human lower-grade glioma (LGG) datasets, which suggested a potential association between key cisplatin-regulated genes and clinical prognosis and immune cell infiltration patterns. This manuscript does not include RT-qPCR (or Western blot) validation; results should be interpreted as hypothesis-generating and require orthogonal confirmation. These findings provide a comprehensive transcriptomic map of cisplatin-induced neurotoxicity, offering novel insights into its underlying molecular mechanisms and identifying a rich set of candidate targets for future neuroprotective strategies. Full article

Thyroid hormone (TH) system disruption by chemicals poses a significant concern due to the key role the TH system plays in essential body functions, including the metabolism, growth, and brain development. Animal-based testing methods are resource-demanding and raise ethical issues. Thus, there is a recognised need for new approach methodologies, such as quantitative structure–activity relationship (QSAR) models, to advance chemical hazard assessments. This review, covering the scientific literature from 2010 to 2024, aimed to map the current landscape of QSAR model development for predicting TH system disruption. The focus was placed on QSARs that address molecular initiating events within the adverse outcome pathway for TH system disruption. A total of thirty papers presenting eighty-six different QSARs were selected based on predefined criteria. A discussion on the endpoints and chemical classes modelled, data sources, modelling approaches, and the molecular descriptors selected, including their mechanistic interpretations, was provided. By serving as a “state-of-the-art” of the field, existing models and gaps were identified and highlighted. This review can be used to inform future research studies aimed at advancing the assessment of TH system disruption by chemicals without relying on animal-based testing, highlighting areas that require additional research. Full article

Background/Objectives: The classification and staging of brainstem glioma have its own pitfalls. Surgical biopsy is only possible in a small number of cases. Diagnosis relies mainly on radiological features. Any treatment may have a significant impact on quality of life; therefore, the correct and early identification of potentially malignant lesions is essential to initiate proper therapy. Amino acid PET/CT with accurate metabolic mapping can help in this decision-making. Methods: We performed a retrospective analysis of 20 patients who underwent static FET PET/CT with uncertain brainstem lesions between November 2019 and April 2023. We used multiple tumor-to-brain ratios (TBR) to assess patient subgroups showing long-term and short-term survival. Results: The maximum Youden index was reached at TBR = 2.9. With this ratio, the estimated sensitivity was at the desired level (91.7%), both positive and negative predictive values are in the good performance range (68.8 and 75.0%), while specificity was lower than expected (37.5%). Conclusions: The prognosis of brainstem glioma remains challenging. The use of static FET PET/CT results in more accurate detection of high-grade lesions. In our analysis, we found a TBR value of 2.9 to be the most appropriate for identifying patients with a poor prognosis. Full article

Iron is critical for brain development, metabolism, and function; however, dysregulated iron disposition contributes to neurological diseases. Many neuroimaging techniques have enabled detection of iron susceptibility, and quantitative susceptibility mapping (QSM) offers a sensitive magnetic resonance imaging (MRI) technique for quantifying brain iron. To elucidate the functional role of cerebral iron and clarify the utility of QSM in establishing iron as a potential biomarker, this review synthesizes cellular and regional behaviours of iron from physiological aging to disease conditions, with a focus on neurodegeneration such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS), as well as cerebral small vessel disease (CSVD) as cerebrovascular manifestation. Distinct patterns of iron distribution in deep gray matter and selective cortical regions are associated with motor and cognitive impairment, while the interaction between iron, vascular integrity, and glial function further stresses its pathological relevance. QSM of iron may, thereby, serve as a marker to monitor iron-related disease progression and facilitate intervention. Temporal dynamics of iron in brain pathology remain underexplored, and we emphasized the need for longitudinal mapping and multi-modality biomarker integration. Establishing iron as a clinically relevant imaging biomarker requires continued investigation into its topographical, molecular, and functional correlates across aging and disease trajectories. Full article

Brain tumors elicit complex neuropsychiatric disturbances that frequently occur prior to radiological detection and hinder differentiation from major psychiatric disorders. These syndromes stem from tumor-dependent metabolic reprogramming, neuroimmune activation, neurotransmitter dysregulation, and large-scale circuit disruption. Dinucleotide hypermethylation (e.g., IDH-mutant gliomas), through the accumulation of 2-hydroxyglutarate (2-HG), execute broad DNA and histone hypermethylation, hypermethylating serotonergic and glutamatergic pathways, and contributing to a treatment-resistant cognitive-affective syndrome. High-grade gliomas promote glutamate excitotoxicity via system Xc⁻ transporter upregulation that contributes to cognitive and affective instability. Cytokine cascades induced by tumors (e.g., IL-6, TNF-α, IFN-γ) lead to the breakdown of the blood–brain barrier (BBB), which is thought to amplify neuroinflammatory processes similar to those seen in schizophrenia spectrum disorders and autoimmune encephalopathies. Frontal gliomas present with apathy and disinhibition, and temporal tumors lead to hallucinations, emotional lability, and episodic memory dysfunction. Tumor-associated neuropsychiatric dysfunction, despite increasing recognition, is underdiagnosed and commonly misdiagnosed. This paper seeks to consolidate the mechanistic understanding of these syndromes, drawing on perspectives from neuroimaging, molecular oncology, neuroimmunology, and computational psychiatry. Novel approaches, including lesion-network mapping, exosomal biomarkers or AI-based predictive modeling, have projected early detection and precision-targeted interventions. In the context of the limitations of conventional psychotropic treatments, mechanistically informed therapies, including neuromodulation, neuroimmune-based interventions, and metabolic reprogramming, are essential to improving psychiatric and oncological outcomes. Paraneoplastic neuropsychiatric syndromes are not due to a secondary effect, rather, they are manifestations integral to the biology of a tumor, so they require a new paradigm in both diagnosis and treatment. And defining their molecular and circuit-level underpinnings will propel the next frontier of precision psychiatry in neuro-oncology, cementing the understanding that psychiatric dysfunction is a core influencer of survival, resilience, and quality of life. Full article

The kynurenine (KYN) metabolic pathway sits at the crossroads of immunity, metabolism, and neurobiology, yet its clinical translation remains fragmented. Emerging spatial omics, wearable chronobiology, and synthetic microbiota studies reveal that tryptophan (Trp) metabolism is regulated by distinct cellular “checkpoints” along the gut–brain axis, finely modulated by sex differences, circadian rhythms, and microbiome composition. However, current interventions tackle single levers in isolation, leaving a key gap in the precision control of Trp’s fate. To address this, we drew upon an extensive body of the primary literature and databases, mapping enzyme expression across tissues at single-cell resolution and linking these profiles to clinical trials investigating dual indoleamine 2,3-dioxygenase 1 (IDO1)/tryptophan 2,3-dioxygenase (TDO) inhibitors, engineered probiotics, and chrono-modulated dosing strategies. We then developed decision-tree algorithms that rank therapeutic combinations against biomarker feedback loops derived from real-time saliva, plasma, and stool metabolomics. This synthesis pinpoints microglial and endothelial KYN hotspots, quantifies sex-specific chronotherapeutic windows, and identifies engineered Bifidobacterium consortia and dual inhibitors as synergistic nodes capable of reducing immunosuppressive KYN while preserving neuroprotective kynurenic acid. Here, we highlight a framework that couples lifestyle levers, bio-engineered microbes, and adaptive pharmaco-regimens into closed-loop “smart protocols.” By charting these intersections, this study offers a roadmap for biomarker-guided, multidisciplinary interventions that could recalibrate KYN metabolic activity across cancer, mood, neurodegeneration, and metabolic disorders, appealing to clinicians, bioengineers, and systems biologists alike. Full article

Tissue hypoxia is commonly observed in head cancers and contributes to both molecular and functional changes in tumour cells. It is known to stimulate erythropoiesis, angiogenesis, and metabolic alterations within tumour cells. Glioblastoma, a type of brain tumour, is characterized by rapid proliferation and aggressive growth. Recent studies have indicated that natural products may hold potential as components of cancer therapy. Among these, Polish propolis and its active compound, quercetin, have demonstrated promising anti-cancer properties. The aim of this study was to evaluate the concentrations of selected cytokines—specifically IL-6, IL-9, vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF-BB), interferon gamma-induced protein 10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1)—produced by astrocytes of the CCF-STTG1 cell line. The cytotoxic effects of ethanolic extract of propolis (EEP) and quercetin were assessed using the MTT assay. Astrocytes were stimulated with lipopolysaccharide (LPS, 200 ng/mL) and/or IFN-α (100 U/mL), followed by treatment with EEP or quercetin (25–50 µg/mL) under hypoxic conditions for two hours. Cytokine concentrations were measured using the xMAP Luminex Multiplex Immunoassay and the Multiplex Bead-Based Cytokine Kit. Our study demonstrated that Polish propolis and its component quercetin modulate the tumour microenvironment in vitro, primarily by altering the levels of specific cytokines. The HCA analysis revealed that IL-6 and MCP-1 formed a distinct cluster at the highest linkage distance (approximately 100% of Dmax), suggesting that their expression patterns are significantly different from those of the other cytokines and that they are more similar to each other than to the rest. PCA analysis showed that EEP-PL (50 μg/mL) with IFN-α and EEP-PL (50 μg/mL) with LPS exert similar activities on cytokine secretion by astrocytes. Similar effects were demonstrated for EEP-PL 50 μg/mL + LPS + IFN-α, EEP-PL 25 μg/mL + IFN-α and EEP-PL 25 μg/mL + LPS + IFN-α. Our findings suggest that Polish propolis and quercetin may serve as promising natural agents to support the treatment of stage IV malignant astrocytoma. Nonetheless, further research is needed to confirm these results. Full article

Zebrafish (Danio rerio) combine accessible behavioral phenotypes with conserved neurochemical pathways and molecular features of vertebrate brain function, positioning them as a powerful model for investigating early neurodegenerative processes and screening neuroprotective strategies. In this context, integrated behavioral and proteomic analyses provide valuable insights into the initial pathophysiological events shared by conditions such as Parkinson’s disease and related disorders—including mitochondrial dysfunction, oxidative stress, and synaptic impairment—which emerge before overt neuronal loss and offer a crucial window to understand disease progression and evaluate therapeutic candidates prior to irreversible damage. To investigate this early window of dysfunction, zebrafish larvae were exposed to 500 μM 1-methyl-4-phenylpyridinium (MPP⁺) from 1 to 5 days post-fertilization and evaluated through integrated behavioral and label-free proteomic analyses. MPP⁺-treated larvae exhibited hypokinesia, characterized by significantly reduced total distance traveled, fewer movement bursts, prolonged immobility, and a near-complete absence of light-evoked responses—mirroring features of early Parkinsonian-like motor dysfunction. Label-free proteomic profiling revealed 40 differentially expressed proteins related to mitochondrial metabolism, redox regulation, proteasomal activity, and synaptic organization. Enrichment analysis indicated broad molecular alterations, including pathways such as mitochondrial translation and vesicle-mediated transport. A focused subset of Parkinsonism-related proteins—such as DJ-1 (PARK7), succinate dehydrogenase (SDHA), and multiple 26S proteasome subunits—exhibited coordinated dysregulation, as visualized through protein–protein interaction mapping. The upregulation of proteasome components and antioxidant proteins suggests an early-stage stress response, while the downregulation of mitochondrial enzymes and synaptic regulators reflects canonical PD-related neurodegeneration. Together, these findings provide a comprehensive functional and molecular characterization of MPP⁺-induced neurotoxicity in zebrafish larvae, supporting its use as a relevant in vivo system to investigate early-stage Parkinson’s disease mechanisms and shared neurodegenerative pathways, as well as for screening candidate therapeutics in a developmentally responsive context. Full article

Background: The gut microbiome is a key modulator of the gut–brain axis and may contribute to the pathophysiology of both gastrointestinal and systemic disorders. This study aimed to evaluate gut microbiota composition and tryptophan/phenylalanine metabolism in women with unclassified irritable bowel syndrome (IBS-U), with or without coexisting chronic fatigue syndrome (CFS). Methods: Eighty women were enrolled and divided into two groups: IBS-U without CFS (Group I, n = 40) and IBS-U with coexisting CFS (Group II, n = 40). Microbial composition and diversity were assessed using the GA-map™ Dysbiosis Test, including the dysbiosis index (DI) and Shannon Diversity Index (SDI). Hydrogen and methane levels were measured in breath samples. Urinary concentrations of selected microbial and neuroactive metabolites—homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), kynurenine (KYN), kynurenic acid (KYNA), xanthurenic acid (XA), quinolinic acid (QA), hydroxyphenylacetic acid (HPA), and 3-indoxyl sulfate (3-IS)—were quantified using LC-MS/MS. Fatigue severity was assessed using the Chalder Fatigue Questionnaire (CFQ-11) and the fatigue severity scale (FSS). Results: Compared to Group I, patients with IBS-CFS showed significantly greater microbial diversity, higher breath methane levels, and elevated urinary concentrations of QA, XA, 3-IS, and HVA, alongside lower concentrations of 5-HIAA and KYN. Fatigue severity was positively correlated with urinary XA and QA levels. Conclusions: Women with IBS and coexisting CFS exhibit distinct gut microbiota and tryptophan metabolite profiles compared to those without fatigue. The observed metabolite–symptom associations, particularly involving neuroactive kynurenine derivatives, warrant further investigation. These preliminary findings should be interpreted as hypothesis-generating and require validation through high-resolution microbiome analyses, functional pathway profiling, and longitudinal or interventional studies to clarify causality and clinical significance. Full article

Sweet sensing is a fundamental sensory experience that plays a critical role not only in food preference, reward and dietary behaviour but also in glucose metabolism. Sweet taste receptors (STRs), composed of a heterodimer of taste receptor type 1 member 2 (T1R2) and member 3 (T1R3), are now recognised as being widely distributed throughout the body, including the gastrointestinal tract. Preclinical studies suggest these receptors are central to nutrient and glucose sensing, detecting energy availability and triggering metabolic and behavioural responses to maintain energy balance. Both internal and external factors tightly regulate their signalling pathways, and dysfunction within these systems may contribute to the development of metabolic disorders such as obesity and type 2 diabetes (T2D). Functional magnetic resonance imaging (fMRI) has provided valuable insights into the neural mechanisms underlying sweet sensing by mapping brain responses to both lingual/oral and gastrointestinal sweet stimuli. This review highlights key findings from fMRI studies and explores how these neural responses are modulated by metabolic state and individual characteristics such as body mass index, habitual intake and metabolic health. By integrating current evidence, this review advances our understanding of the complex interplay between sweet sensing, brain responses, and health and identifies key gaps and directions for future research in nutritional neuroscience. Full article

Background/Objectives: Despite extensive research, the underlying causes of amyotrophic lateral sclerosis (ALS) remain unclear. This umbrella review aims to synthesize a vast body of evidence from advanced magnetic resonance imaging (MRI) studies of ALS, encompassing a wide range of neuroimaging techniques and patient cohorts. Methods: Following the PRISMA guidelines, we conducted an extensive search of four databases (PubMed, Scopus, Web of Science, and Embase) for articles published until 3 December 2024. Data extraction and quality assessment were independently performed using the AMSTAR2 tool. Results: This review included 18 studies that incorporated data from over 29,000 ALS patients. Structural MRI consistently showed gray matter atrophy in the motor and extra-motor regions, with significant white matter (WM) atrophy in the corticospinal tract and corpus callosum. Magnetic resonance spectroscopy revealed metabolic disruptions, including reduced N-acetylaspartate and elevated choline levels. Functional MRI studies have demonstrated altered brain activation patterns and functional connectivity, reflecting compensatory mechanisms and neurodegeneration. fMRI also demonstrated disrupted motor network connectivity and alterations in the default mode network. Diffusion MRI highlighted microstructural changes, particularly reduced fractional anisotropy in the WM tracts. Susceptibility-weighted imaging and quantitative susceptibility mapping revealed iron accumulation in the motor cortex and non-motor regions. Perfusion MRI indicated hypoperfusion in regions associated with cognitive impairment. Conclusions: Multiparametric MRI consistently highlights widespread structural, functional, and metabolic changes in ALS, reflecting neurodegeneration and compensatory mechanisms. Full article

T-cadherin (CDH13) is an atypical, glycosyl-phosphatidylinositol-anchored cadherin with functions ranging from axon guidance and vascular patterning to adipokine signaling and cell-fate specification. Originally identified as a homophilic cue for migrating neural crest cells, projecting axons, and growing blood vessels, it later emerged as a dual metabolic receptor for cardioprotective high-molecular-weight adiponectin and atherogenic low-density lipoproteins. We recently showed that mesenchymal stem/stromal cells lacking T-cadherin are predisposed to adipogenesis, underscoring its role in lineage choice. Emerging evidence indicates that CDH13 expression and function are fine-tuned by non-coding RNAs (ncRNAs). MiR-199b-5p, miR-377-3p, miR-23a/27a/24-2, and the miR-142 family directly bind CDH13 3′-UTR or its epigenetic regulators, affecting transcription or accelerating decay. Long non-coding RNAs (lncRNAs), including antisense transcripts CDH13-AS1/AS2, brain-restricted FEDORA, and context-dependent LINC00707 and UPAT, either sponge these miRNAs or recruit DNMT/TET enzymes to the CDH13 promoter. Circular RNAs (circRNAs), i.e.circCDH13 and circ_0000119, can add a third level of complexity by sequestering miRNA repressors or boosting DNMT1. Collectively, this ncRNA circuitry regulates T-cadherin across cardiovascular, metabolic, oncogenic, and neurodegenerative conditions. This review integrates both experimentally validated data and in silico predictions to map the ncRNA-CDH13 crosstalk between health and disease, opening new avenues for biomarker discovery and RNA-based therapeutics. Full article

Background: Pediatric high-grade glioma (pHGG) is a highly aggressive cancer with unique biology distinct from adult high-grade glioma, limiting the effectiveness of standard treatment protocols derived from adult research. Objective: The purpose of this report is to present preliminary results from an ongoing pilot study integrating spectroscopic magnetic resonance imaging (sMRI) to guide proton beam therapy and longitudinal imaging analysis in pediatric patients with high-grade glioma (pHGG). Methods: Thirteen pediatric patients under 21 years old with supratentorial WHO grade III-IV glioma underwent baseline and serial whole-brain spectroscopic MRI alongside standard structural MRIs. Radiation targets were defined using T1-weighted contrast enhanced, T2-FLAIR, and Cho/NAA ≥ 2X maps. Longitudinal analyses included voxel-level metabolic change maps and spatial overlap metrics comparing pre-proton therapy and post-. Results: Six patients had sufficient longitudinal data; five received sMRI-guided PBT. Significant positive correlation (R² = 0.89, p < 0.0001) was observed between T2-FLAIR and Cho/NAA ≥ 2X volumes. Voxel-level difference maps of Cho/NAA and Choline revealed dynamic metabolic changes across follow-up scans. Analyzing Cho/NAA and Cho changes over time allowed differentiation between true progression and pseudoprogression, which conventional MRI alone struggles to achieve. Conclusions: Longitudinal sMRI enhanced metabolic tracking in pHGG, detects early tumor changes, and refines RT targeting beyond structural imaging. This first in-kind study highlights the potential of sMRI biomarkers in tracking treatment effects and emphasizes the complementary roles of metabolic and radiographic metrics in evaluating therapy response in pHGG. Full article

Background: Autism spectrum disorder (ASD) is increasingly linked to systemic metabolic dysfunction, potentially influenced by gut–brain axis dysregulation, but the underlying mechanisms remain unclear. Methods: We developed Personalized Metabolic Margin Mapping (PM³), a computational systems biology framework, to analyze RNA-seq data from 12 ASD and 12 control postmortem brain samples. The model focused on 158 curated metabolic genes selected for their roles in redox balance, mitochondrial function, neurodevelopment, and gut–brain interactions. Results: Using unsupervised machine learning (Isolation Forest) to detect outlier expression patterns, Euclidean distance, and percent expression difference metrics, PM³ revealed a consistent downregulation of glycolysis (e.g., −5.4% in PFKM) and mitochondrial enzymes (e.g., −12% in SUCLA2). By incorporating cofactor dependency and subcellular localization, PM³ identified a coordinated suppression of multivitamin transporters (e.g., −4.5% in SLC5A6, −3.5% in SLC19A2), potentially limiting cofactor availability and compounding energy deficits in ASD brains. Conclusions: These findings suggest a convergent metabolic dysregulation signature in ASD; wherein the subtle suppression of cofactor-dependent pathways may impair energy metabolism and neurodevelopment. We propose that chronic microbial lipopolysaccharide (LPS) exposure in ASD suppresses vitamin transporter function, initiating mitochondrial dysfunction and transcriptomic reprogramming. Validation in LPS-exposed systems using integrated transcriptomic–metabolomic analysis is warranted. Full article