Neurodegeneration and demyelination in multiple sclerosis

Neuron, Год журнала: 2024, Номер unknown

Опубликована: Июнь 1, 2024

Язык: Английский

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Macrophage-induced enteric neurodegeneration leads to motility impairment during gut inflammation

EMBO Molecular Medicine, Год журнала: 2025, Номер 17(2), С. 301 - 335

Опубликована: Янв. 6, 2025

Abstract Current studies pictured the enteric nervous system and macrophages as modulators of neuroimmune processes in inflamed gut. Expanding this view, we investigated impact neuron–macrophage interactions on postoperative trauma subsequent motility disturbances, i.e., ileus. In early postsurgical phase, detected strong neuronal activation, followed by transcriptional translational signatures indicating death synaptic damage. Simultaneously, our study revealed neurodegenerative profiles macrophage-specific transcriptomes after trauma. Validating role resident monocyte-derived macrophages, depleted CSF-1R-antibodies used CCR2 −/− mice, known for reduced monocyte infiltration, POI studies. Only CSF-1R-antibody-treated animals showed decreased lessened decay, emphasizing significance macrophages. human gut samples taken late during abdominal surgery, substantiated mouse model data found reactive apoptotic neurons dysregulation genes, a species’ overarching mechanism. Our demonstrates that surgical activates induces neurodegeneration, mediated introducing neuroprotection an option faster recovery surgery.

Язык: Английский

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Ai-Driven Discovery of Brain-Penetrant Galectin-3 Inhibitors for Alzheimer's Disease Therapy

Опубликована: Янв. 1, 2025

Язык: Английский

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Membrane organization by tetraspanins and galectins shapes lymphocyte function

Nature reviews. Immunology, Год журнала: 2023, Номер 24(3), С. 193 - 212

Опубликована: Сен. 27, 2023

Язык: Английский

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Involvement of Matricellular Proteins in Cellular Senescence: Potential Therapeutic Targets for Age-Related Diseases

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(12), С. 6591 - 6591

Опубликована: Июнь 15, 2024

Senescence is a physiological and pathological cellular program triggered by various types of stress. Senescent cells exhibit multiple characteristic changes. Among them, the flattened enlarged morphology exhibited in senescent observed regardless stimuli causing senescence. Several studies have provided important insights into pro-adhesive properties senescence, suggesting that cell adhesion to extracellular matrix (ECM), which involved morphological changes, may play pivotal roles Matricellular proteins, group structurally unrelated ECM molecules are secreted environment, unique ability control binding receptors, including integrins. Recent reports certified matricellular proteins closely Through this biological function, thought pathogenesis age-related diseases, fibrosis, osteoarthritis, intervertebral disc degeneration, atherosclerosis, cancer. This review outlines recent on role inducing We highlight integrin-mediated signaling senescence provide new therapeutic options for diseases targeting

Язык: Английский

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Targeting SMOX Preserves Optic Nerve Myelin, Axonal Integrity, and Visual Function in Multiple Sclerosis

Biomolecules, Год журнала: 2025, Номер 15(2), С. 158 - 158

Опубликована: Янв. 21, 2025

Multiple sclerosis (MS) is a highly disabling chronic neurological condition affecting young adults. Inflammation, demyelination, and axonal damage are key pathological features of MS its animal model, experimental autoimmune encephalomyelitis (EAE). Our previous work demonstrated that inhibiting spermine oxidase (SMOX) with MDL72527, selective irreversible pharmacological inhibitor, significantly reduced clinical symptoms, retinal ganglion cell (RGC) loss, optic nerve inflammation in EAE mice. The present study explored the broader therapeutic potential SMOX inhibition, focusing on myelin preservation, integrity, visual function model. Electron microscopy cross-sections showed significant preservation thickness integrity due to inhibition. quantitative assessment g-ratio axon count metrics were improved MDL72527-treated mice compared their vehicle-treated counterparts. Immunofluorescence studies confirmed these findings, showing increased proteins group. Functional (Electroretinography) improvement RGC conduction treated MDL72527. Furthermore, inhibition downregulated expression galectin3 (Gal3), mediator neuroinflammation, indicating Gal3’s role SMOX-mediated neuroprotection. This provides compelling evidence for as strategy multiple other demyelinating disorders.

Язык: Английский

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Proteomic analysis reveals candidate molecules to mediate cortical pathology and identify possible biomarkers in an animal model of multiple sclerosis

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Фев. 13, 2025

Introduction Multiple Sclerosis (MS) is a complex neurodegenerative disease marked by recurring inflammatory episodes, demyelination, axonal damage, and subsequent loss of function. MS presents wide range clinical courses, with the progressive forms leading to irreversible neurological disability. Cortical demyelinating lesions are central pathology these forms, gaining critical importance in recent decades due their strong correlation physical disability cognitive decline. Despite this, underlying mechanisms driving cortical lesion formation remain poorly understood, no specific treatments currently available. A significant challenge lies lack animal models that accurately mirror key characteristics lesions. Methods We developed focal model replicates many features lesions, including impairment. This study focuses on conducting proteomic analyses both cerebrospinal fluid (CSF) from animals, aiming identify proteins biomarkers could be validated patients. Results Proteomic differences between frontal cortex tissue CSF were observed when comparing experimental animals controls. Among identified proteins, some have been previously described patients models, while others represent novel discoveries. Notably, we two S100A8 orosomucoid-1, highly expressed regions. Conclusions These findings suggest prognostic molecules this facilitate discovery new or relevant MS, particularly mainly characterized disease.

Язык: Английский

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Folding-Based End-To-End Chemical Drug Design with Uncertainty Estimation: Tackling Hallucination in the Post-GPT Era

Journal of Medicinal Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 8, 2025

In the post-GPT era, Llama-Gram represents a promising advancement in AI-driven chemical drug discovery, grounded principle that molecular structure determines properties. This folding-based end-to-end framework seeks to address hallucination issues of traditional large language models by integrating protein folding embeddings, graph-based representations, and uncertainty estimation better capture structural complexities protein–ligand interactions. By leveraging frozen-gradient ESMFold model Graph Transformer variant, aims enhance predictive accuracy reliability through grouped-query attention Gram layer inspired support points theory. incorporating information, demonstrates competitive performance against state-of-the-art approaches such as CPI 2.0 Graph-DTA, offering improvements compound–target interaction. provides scalable innovative theory could contribute accelerating discovery process.

Язык: Английский

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Assessment of Cardiovascular Risk in the PURE Poland Cohort Study Using the Systematic Coronary Risk Evaluation (SCORE) Scale and Galectin-3 Concentrations: A Cross-Sectional Study

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(7), С. 3064 - 3064

Опубликована: Март 27, 2025

The SCORE (Systematic Coronary Risk Evaluation) scale is useful for cardiovascular disease (CVD) risk stratification. However, there a new biomarker, namely, galectin-3 (gal-3), that offers additional predictive value. This cross-sectional study assessed the relationship between serum gal-3 concentrations and CVD based on in Polish cohort from PURE study. A total of 259 participants with complete cholesterol, blood pressure (BP), smoking data were included. Individuals myocardial infarction, stroke, diabetes, or renal failure excluded. Gal-3 measured using ELISA, statistical analyses examined associations categories. median concentration was 221.32(161.64-360.00) ng/mL. Higher found older individuals, smokers, those elevated BP(p < 0.05). Positive correlations observed values (r = 0.39) systolic BP 0.64). Participants ≥5% had significantly higher concentrations. ROC analysis showed moderate diagnostic value ≥ 10% (sensitivity 0.618 specificity 0.810). diastolic are independent factors increased concentrations, explaining 79.5% variance studied group. Serum associated estimated by SCORE, supporting its potential role

Язык: Английский

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Dynamic Proteome Changes in Cuprizone-Induced Demyelination and Remyelination in the Mouse Brain

Journal of Proteome Research, Год журнала: 2025, Номер unknown

Опубликована: Апрель 30, 2025

This study aimed to gain insights into the dynamic proteome changes and underlying molecular mechanisms of de/remyelination in a cuprizone model, widely used preclinical model multiple sclerosis (MS). Longitudinal sampling control or cuprizone-treated mouse brains was executed at 6 time points over weeks. Data analysis included 8489 quantified proteins. Differential proteomic GO analyses revealed that 5.9% altered, including reported novel de/remyelination-relevant protein pathways. We found oligodendrocyte proteins (Fa2h Ugt8) were significantly changed during demyelination, suggesting dysregulated sphingolipid metabolism MS may stem from pathology. Importantly, we showed cholesterol biosynthesis pathway most enriched biological process subset proteins, where myelination highly enriched. further validated through targeted GC-MS intermediate sterols, supporting critical role de/remyelination. Unexpectedly, myelin-associated Mbp Plp1, minimal, while Ermn significant reduction tracking with indicating some myelin are more sensitive demyelination. Together list altered results this could benefit future remyelination research.

Язык: Английский

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