Persons with multiple sclerosis reveal distinct kynurenine pathway metabolite patterns: a multinational cross-sectional study

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Abstract Neuroaxonal damage in multiple sclerosis (MS) results from an interplay of neurotoxic pathomechanisms combined with a reduced neuroprotective capacity neurons and glia to resist damage. Kynurenine pathway (KP) imbalance resembles some the molecular mechanisms central incompletely understood MS pathophysiology. To study role KP MS, we performed targeted metabolomics on serum samples 353 persons 111 healthy individuals, detected MS-specific differences concentrations most kynurenines. Using exploratory factor analysis, then identified two distinct metabolite patterns: inflammation-driven pattern „NeuroTox“ „NeuroPro“. Our show that greater lower „NeuroPro“ were associated higher disease severity. The novelty our data-driven approach patterns advocates for future studies using comparable approaches investigate whether follows similar disease-specific diseases other than MS.

Language: Английский

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Transcriptomic profiling identifies ferroptosis and NF-κB signaling involved in α-dimorphecolic acid regulation of microglial inflammation

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: March 4, 2025

Microglia-evoked neuroinflammation contributes to neurodegenerative diseases such as multiple sclerosis (MS). Metabolic reprogramming, including changes in polyunsaturated fatty acids (PUFAs), plays a critical role MS pathophysiology. Previous studies identified reduced plasma α-dimorphecolic acid (α-DIPA), linoleic derivative, patients. This study investigated the anti-inflammatory effects of α-DIPA on microglia and underlying pathways. Lipopolysaccharide (LPS)-induced BV-2 microglial inflammation was used an vitro model. were assessed via ELISA for nitric oxide (NO) release, flow cytometry examine cell proliferation, activation polarization, transcriptomic analysis applied identify key signaling pathways regulated by α-DIPA. results showed that exogenous treatment significantly inhibited LPS-induced NO release from cells concentration-dependent manner. Moreover, suggested 40 µM repressed activation, well M1 M2 type polarization. Furthermore, transcriptome revealed extensively drastically decreased transcriptional level numerous genes are involved regulation inflammatory responses, instance, proinflammatory Tnf Ccl3 related IL-17 TNF-α signaling. In addition, we also observed expression NF-κB greatly α-DIPA, Nfkb2 Nfkbia. Notably, robustly suppressed mRNA abundant participating ferroptosis pathway, Acsl4, Slc7a11, Me1, Hmox1. Interestingly, expressions ferroptosis-related specifically but not LPS, Acsl5, Acsl6, Alox5, Cars, Dpp3, Dpp10, Slc2a5, Slc7a1. inhibits likely through regulating These provided preliminary evidence potential therapeutic candidate like MS.

Language: Английский

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The role of the adaptive immune system in the initiation and persistence of multiple sclerosis

Seminars in Immunology, Journal Year: 2025, Volume and Issue: 78, P. 101947 - 101947

Published: April 4, 2025

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) in which complex networks interacting immune cells initiate and sustain disease. The pathogenesis relapsing MS driven by adaptive that become activated outside CNS compartment then migrate into to a presumably autoimmune inflammatory process. Recent technological advances, particularly single-cell analyses, have revealed substantial heterogeneity T B involved this stage Disease progression involves different mechanisms, with compartmentalized inflammation chronic activation CNS-resident becoming predominant features. contribution tissue-resident pathology progressive MS, including CD8+ meningeal compart, increasingly debated. Here, we will discuss concepts how might maintain CNS, while responses intrinsic cells, astrocytes, oligodendrocytes, neurons, are described elsewhere [1-5] not be particular focus overview. Finally, it aim review conceptualize grounds for efficient therapeutic interventions targeting players but also MS.

Language: Английский

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Neuroprotective effects of ghrelin in cuprizone-induced rat model of multiple sclerosis

Metabolic Brain Disease, Journal Year: 2025, Volume and Issue: 40(4)

Published: April 11, 2025

Language: Английский

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Novel Isoxazolidines Derivatives as RIPK1 Inhibitors for Treating Neurodegenerative Diseases

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

Language: Английский

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Vitamin B6 status is related to disease severity and modulated by endurance exercise in individuals with multiple sclerosis: a secondary analysis of a randomized controlled trial

American Journal of Clinical Nutrition, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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Brain health – time matters: multiple sclerosis, neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and related conditions. 2024 report

Multiple Sclerosis and Related Disorders, Journal Year: 2025, Volume and Issue: unknown, P. 106456 - 106456

Published: April 1, 2025

Language: Английский

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The NR4A2/VGF pathway fuels inflammation-induced neurodegeneration via promoting neuronal glycolysis

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(16)

Published: June 18, 2024

A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), chronic inflammatory disease the central nervous system. To understand how hyperexcitability contributes to neuronal loss MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I increased vulnerability inflammation-induced neurodegeneration. This revealed prominent induction nuclear receptor NR4A2 neurons. Mechanistically, susceptibility excitotoxicity by stimulating continuous VGF secretion leading glycolysis-dependent cell death. Extending these findings people MS (pwMS), observed levels serum brain biopsies. Notably, neuron-specific deletion Vgf mouse model ameliorated These underscore detrimental effect persistent metabolic shift driven excitatory activity fundamental mechanism

Language: Английский

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Nervous system in colorectal cancer

Cancer Letters, Journal Year: 2024, Volume and Issue: unknown, P. 217431 - 217431

Published: Dec. 1, 2024

Language: Английский

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Protective effect of TCR-mediated MAIT cell activation during experimental autoimmune encephalomyelitis

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Oct. 28, 2024

Abstract Mucosal-associated invariant T (MAIT) cells express semi-invariant cell receptors (TCR) for recognizing bacterial and yeast antigens derived from riboflavin metabolites presented on the non-polymorphic MHC class I-related protein 1 (MR1). Neuroinflammation in multiple sclerosis (MS) is likely initiated by autoreactive perpetuated infiltration of additional immune cells, but precise role MAIT MS pathogenesis remains unknown. Here, we use experimental autoimmune encephalomyelitis (EAE), a mouse model MS, find an accumulation inflamed central nervous system (CNS) enriched MAIT17 (RORγt + ) MAIT1/17 (T-bet RORγt subsets with inflammatory protective features. Results transcriptome profiling Nur77GFP reporter mice show that these CNS are activated via cytokines TCR. Blocking TCR activation anti-MR1 antibody exacerbates EAE, whereas enhancing cognate antigen, 5-(2-oxopropylideneamino)−6-D-ribitylaminouracil, ameliorates EAE severity, potentially induction amphiregulin (AREG). In summary, our findings suggest TCR-mediated inflammation, involving AREG.

Language: Английский

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