Transforming Growth Factor β1 Protects Against Ischemic Demyelination via Regulating Microglial Lipid Metabolism Pathway

Stroke, Journal Year: 2025, Volume and Issue: unknown

Published: March 31, 2025

BACKGROUND: Chronic cerebral hypoperfusion-induced white matter lesions are an important cause of vascular cognitive impairment in aging life. TGF-β1 (transforming growth factor β1) is widely recognized as a multifunctional cytokine participating numerous pathophysiological processes the central nervous system. In this study, we aimed to evaluate neuroprotective potentials ischemic lesions. METHODS: A mouse model bilateral common carotid artery stenosis was established imitate The agonist pathway continuously applied via intraperitoneal injection. Morris water maze test and gait analysis system were used assess disorders modeling mice. Luxol fast blue staining, immunofluorescence, electron microscopy conducted determine severity demyelinating lesions, microglial activation, dysfunction autophagy-lysosomal microglia. Furthermore, primary cultured microglia exposed extracted myelin debris vitro explore underlying mechanisms. RESULTS: As evaluated by behavioral tests, significantly alleviated disorder stenosis-modeling lesion remyelination process also found be highly improved activation pathway. results immunostaining showed that could ameliorate lipid metabolism myelin-engulfed Mechanistically, debris, administration notably mitigated inflammatory response accumulation intracellular droplets promoting degradation pathway, quantified flow cytometry, immunostaining, Western blot, etc. Yet, application autophagy inhibitor (3-methyladenine) reversed above anti-inflammatory effects TGF-β1. CONCLUSIONS: relieved deficit, microglia-mediated neuroinflammation reducing abnormal droplet Clinically, staged may become potential target promising treatment for impairment.

Language: Английский

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Integrated transcriptomics of multiple sclerosis peripheral blood mononuclear cells explored potential biomarkers for the disease

Biochemistry and Biophysics Reports, Journal Year: 2025, Volume and Issue: 42, P. 102022 - 102022

Published: April 18, 2025

Language: Английский

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Role of BET Proteins in Inflammation and CNS Diseases

Frontiers in Molecular Biosciences, Journal Year: 2021, Volume and Issue: 8

Published: Sept. 16, 2021

B romodomain and e xtra- t erminal domain (BET) proteins consist of four mammalian members (BRD2, BRD3, BRD4, BRDT), which play a pivotal role in the transcriptional regulation inflammatory response. Dysregulated inflammation is key pathological process various CNS disorders through multiple mechanisms, including NF-κB Nrf2 pathways, two well-known master regulators inflammation. A better mechanistic understanding BET proteins’ regulating great significance since it could reveal novel therapeutic targets to reduce neuroinflammation associated with many diseases. In this minireview, we first outline structural features summarize genetic pharmacological approaches for inhibition, strategies using proteolysis-targeting chimeras (PROTACs). We emphasize vitro vivo evidence interplay between signaling pathways. Finally, recent studies showing that are essential neuropathology

Language: Английский

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Navitoclax safety, tolerability, and effect on biomarkers of senescence and neurodegeneration in aged nonhuman primates

Heliyon, Journal Year: 2024, Volume and Issue: 10(16), P. e36483 - e36483

Published: Aug. 1, 2024

Highlights•Senescent cells are often pro-inflammatory and may help drive neurological disease.•Aged monkeys have increased senescence, inflammation, damage.•The senolytic navitoclax was safe in aged monkeys, with drug detectable CSF.•Navitoclax induced trends of improvement markers neuronal dysfunction.AbstractAlzheimer's disease (AD) is the most common global dementia universally fatal. Most late-stage AD disease-modifying therapies intravenous target amyloid beta (Aβ), only modest effects on progression: there remains a high unmet need for convenient, safe, effective therapeutics. Senescent (SC) senescence-associated secretory phenotype (SASP) pathology increase severity. Preclinical studies shown improvements neuroinflammation, tau, Aβ, CNS damage; were conducted transgenic rodent models uncertain human translational relevance. In this study, cynomolgus had significant elevation biomarkers SASP, damage. Intermittent treatment reversible thrombocytopenia; no serious drug-related toxicity noted. Navitoclax reduced several senescence SASP biomarkers, CSF concentrations sufficient senolysis. Finally, TSPO-PET frontal cortex binding showed damage, synaptic dysfunction. Overall, administration well tolerated inducing biomarker changes relevant to neurodegenerative disease.Graphical abstract

Language: Английский

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The microglial P2Y6 receptor as a therapeutic target for neurodegenerative diseases

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Sept. 7, 2024

Language: Английский

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