Role of the CXCR6/CXCL16 axis in autoimmune diseases

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 121, P. 110530 - 110530

Published: June 20, 2023

Language: Английский

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Characterizing molecular and synaptic signatures in mouse models of late‐onset Alzheimer's disease independent of amyloid and tau pathology

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(6), P. 4126 - 4146

Published: May 12, 2024

Abstract INTRODUCTION MODEL‐AD (Model Organism Development and Evaluation for Late‐Onset Alzheimer's Disease) is creating distributing novel mouse models with humanized, clinically relevant genetic risk factors to capture the trajectory progression of late‐onset disease (LOAD) more accurately. METHODS We created LOAD2 model by combining apolipoprotein E4 (APOE4), Trem2*R47H, humanized amyloid‐beta (Aβ). Mice were subjected a control diet or high‐fat/high‐sugar (LOAD2+HFD). assessed disease‐relevant outcome measures in plasma brain including neuroinflammation, Aβ, neurodegeneration, neuroimaging, multi‐omics. RESULTS By 18 months, LOAD2+HFD mice exhibited sex‐specific neuron loss, elevated insoluble Aβ42, increased neurofilament light chain (NfL), altered gene/protein expression related lipid metabolism synaptic function. Imaging showed reductions volume neurovascular uncoupling. Deficits acquiring touchscreen‐based cognitive tasks observed. DISCUSSION The comprehensive characterization reveals that this important preclinical studies seeking understand LOAD prior independent amyloid plaques tau tangles. Highlights unlike (e.g., fed diet, CD), presented subtle but significant loss neurons cortex, levels Ab42 brain, (NfL). Transcriptomics proteomics changes gene/proteins relating variety processes In vivo imaging revealed an age‐dependent reduction region (MRI) uncoupling (PET/CT). also demonstrated deficits acquisition tasks.

Language: Английский

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Restore Intestinal Barrier Integrity: An Approach for Inflammatory Bowel Disease Therapy

Journal of Inflammation Research, Journal Year: 2024, Volume and Issue: Volume 17, P. 5389 - 5413

Published: Aug. 1, 2024

The intestinal barrier maintained by various types of columnar epithelial cells, plays a crucial role in regulating the interactions between contents (such as microbiota), immune system, and other components. Dysfunction mucosa is significant pathophysiological mechanism clinical manifestation inflammatory bowel disease (IBD). However, current therapies for IBD primarily focus on suppressing inflammation, no disease-modifying treatments specifically target barrier. Given side effects associated with chronic immunotherapy, effective alternative that promote mucosal healing are highly attractive. In this review, we examined function mechanisms behind its disruption IBD. We illustrated complex process proposed therapeutic approaches to strategies These included application stem cell transplantation organ-like tissue engineering generate new tissue. Finally, discussed potential restore treatment

Language: Английский

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Astrocytes as Neuroimmunocytes in Alzheimer’s Disease: A Biochemical Tool in the Neuron–Glia Crosstalk along the Pathogenetic Pathways

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(18), P. 13880 - 13880

Published: Sept. 9, 2023

This work aimed at assessing Alzheimer’s disease (AD) pathogenesis through the investigation of astrocytic role to transduce load amyloid-beta (Aβ) into neuronal death. The backbone this review is focused on deepening molecular pathways eliciting activation astrocytes crucial phenomena in understanding AD as an autoimmune pathology. complex relations among astrocytes, Aβ and tau, together with played by tripartite synapsis are discussed. A studies published from 1979 2023 Scopus, PubMed Google Scholar databases was conducted. selected papers not only morphological metabolic characteristics but also latest notions about their multifunctional involvement pathogenesis. Astrocytes participate pathways, including pruning sprouting, which neurodegeneration evolves aggregopathy neuroinflammation, loss synapses A1 stimulate production pro-inflammatory molecules have been correlated progression cognitive impairment. Further research needed “hold back” polarization and, thus, slow worsening disease. clinical expression result dysfunctional interactions, end a process involving plurality protagonists. One these astrocyte, whose importance intends put under spotlight scenario, reflecting multifaceted nature functional versatility glial population.

Language: Английский

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Identification of metabolism-related subtypes and feature genes in Alzheimer’s disease

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Sept. 15, 2023

Owing to the heterogeneity of Alzheimer's disease (AD), its pathogenic mechanisms are yet be fully elucidated. Evidence suggests an important role metabolism in pathophysiology AD. Herein, we identified metabolism-related AD subtypes and feature genes.The datasets were obtained from Gene Expression Omnibus database metabolism-relevant genes downloaded a previously published compilation. Consensus clustering was performed identify subclasses. The clinical characteristics, correlations with metabolic signatures, immune infiltration subclasses evaluated. Feature screened using weighted correlation network analysis (WGCNA) processed via Ontology Kyoto Encyclopedia Genes Genomes pathway analyses. Furthermore, three machine-learning algorithms used narrow down selection genes. Finally, diagnostic value expression dataset quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis.Three identified, namely Metabolism Correlated (MC) A (MCA), MCB, MCC MCA contained signatures associated high progression may represent high-risk subclass compared other two exhibited related glycolysis, fructose, galactose metabolism, whereas citrate cycle pyruvate downregulated infiltration. Conversely, MCB elevated checkpoint Using WGCNA, 101 exhibit strongest association poor progression. application enabled us successfully eight genes, which employed develop nomogram model that could bring distinct benefits for patients As indicated by qRT-PCR analysis, these intimately progression.Metabolic dysfunction is Hypothetical molecular based on provide new insights developing individualized therapy highly correlated included GFAP, CYB5R3, DARS, KIAA0513, EZR, KCNC1, COLEC12, TST.

Language: Английский

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Cardiovascular risk burden, dementia risk and brain structural imaging markers: a study from UK Biobank

General Psychiatry, Journal Year: 2024, Volume and Issue: 37(1), P. e101209 - e101209

Published: Jan. 1, 2024

Cardiovascular risk burden is associated with dementia and neurodegeneration-related brain structure, while the role of genetics incident cardiovascular disease (CVD) remains unclear. To examine association overall major subtypes volumes related regions in a large sample, to explore CVD onset. A prospective study among 354 654 participants free (2006-2010, mean age 56.4 years) was conducted within UK Biobank, magnetic resonance imaging (MRI) measurement available for 15 104 since 2014. evaluated by Framingham General Risk Score (FGCRS). Dementia diagnosis ascertained from inpatient death register data. Over median 12.0-year follow-up, 3998 all-cause cases were identified. Higher FGCRS increased after adjusting demographic, lifestyle, clinical factors polygenic score (PRS) Alzheimer's disease. Comparing high versus low tertile FGCRS, odds ratios (ORs) 95% confidence intervals (CIs) 1.26 (1.12 1.41) dementia, 1.67 (1.33 2.09) 1.53 (1.07 2.16) vascular (all ptrend<0.05). Incident stroke coronary heart accounted 14% (95% CI: 9% 21%) between dementia. Interactions not detected PRS on any subtype. We observed an 83% 47% 128%) higher comparing high-high low-low FGCRS-PRS category. For volumes, greater log-transformed white matter hyperintensities, smaller cortical volume grey volume. Our findings suggest that positive also applies subtypes. The largely independent onset genetic predisposition

Language: Английский

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Glycolytic dysregulation in Alzheimer’s disease: unveiling new avenues for understanding pathogenesis and improving therapy

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(8), P. 2264 - 2278

Published: July 29, 2024

Alzheimer’s disease poses a significant global health challenge owing to the progressive cognitive decline of patients and absence curative treatments. The current therapeutic strategies, primarily based on cholinesterase inhibitors N-methyl-D-aspartate receptor antagonists, offer limited symptomatic relief without halting progression, highlighting an urgent need for novel research directions that address key mechanisms underlying disease. Recent studies have provided insights into critical role glycolysis, fundamental energy metabolism pathway in brain, pathogenesis Alterations glycolytic processes within neurons glial cells, including microglia, astrocytes, oligodendrocytes, been identified as contributors pathological landscape Glycolytic changes impact neuronal function, thus offering promising targets intervention. purpose this review is consolidate knowledge modifications glycolysis associated with explore by which these abnormalities contribute onset progression. Comprehensive focus pathways through dysfunction influences pathology should provide potential strategies pave way groundbreaking treatments, emphasizing importance understanding metabolic quest clarification management

Language: Английский

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A personalized metabolic modelling approach through integrated analysis of RNA-Seq-based genomic variants and gene expression levels in Alzheimer’s disease

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: March 27, 2025

Generating condition-specific metabolic models by mapping gene expression data to genome-scale (GEMs) is a routine approach elucidate disease mechanisms from perspective. On the other hand, integrating variants that perturb enzyme functionality same RNA-seq may enhance GEM accuracy, offering insights into genome-wide pathology. Our study pioneers extraction of both transcriptomic and genomic reconstruct personalized models. We map genes with significantly higher load pathogenic in Alzheimer's (AD) onto human together data. Comparative analysis resulting patient control shows enhanced accuracy detecting AD-associated pathways compared case where only mapped on GEM. Besides, several otherwise would-be missed are annotated AD considering effect variants. The authors used iMAT algorithm associated Disease (GEMs).

Language: Английский

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Multiomics from Alzheimer’s Brains and Mesenchymal Stem Cell-Derived Extracellular Vesicles Identifies Therapeutic Potential of Specific Subpopulations to Target Mitochondrial Proteostasis

Journal of Central Nervous System Disease, Journal Year: 2025, Volume and Issue: 17

Published: April 1, 2025

Background Alzheimer’s disease (AD) is characterized by complex molecular alterations that complicate its pathogenesis and contribute to the lack of effective treatments. Mesenchymal stem cell-derived extracellular vesicles (EVs) have shown promise in AD models, but results across different EV subpopulations remain inconsistent. Objectives This study investigates proteomic transcriptomic data from publicly available postmortem brain datasets identify changes at both gene protein levels. These findings are then compared with proteomes various subpopulations, differing size distribution, determine most promising subtype for compensating degeneration AD. Design We conducted a comprehensive analysis 788 samples, including 481 cases 307 healthy controls, examining mRNA levels uncover AD-associated changes. were potential therapeutic candidates. Methods A multi-omics approach was employed, integrating analysis, miRNA transcription factor profiling, protein-protein network construction, hub identification, enrichment analyses. aimed explore brains pinpoint relevant intervention. Results identified common cAMP signaling pathway coagulation cascade Distinct energy metabolism observed level not level. specific subtype, broader distribution obtained through high-speed centrifugation, as capable dysregulated mitochondrial proteostasis brains. Network biology analyses further highlighted regulators key proteins within this subtype. Conclusion underscores critical role identifies subpopulation, enriched targeting proteostasis, strategy

Language: Английский

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Exploring the metabolic implications of blue light exposure during daytime in rats

Ecotoxicology and Environmental Safety, Journal Year: 2024, Volume and Issue: 278, P. 116436 - 116436

Published: May 8, 2024

Excessive exposure to light is a global issue. Artificial pollution has been shown disrupt the body's natural circadian rhythm. To investigate impacts of on metabolism, we studied Sprague-Dawley rats chronically exposed red or blue during daytime nighttime. Rats in experimental group were extended for 4 hours nighttime simulate effects excessive usage. Strikingly, found systemic metabolic alterations only induced by daytime. Furthermore, conducted metabolomic analyses cerebrospinal fluid, serum, heart, liver, spleen, adrenal, cerebellum, pituitary, prostate, spermatophore, hypothalamus and kidney from control Significant changes metabolites have observed Metabolic encompassing pyruvate glutathione metabolism homocysteine degradation, phosphatidylethanolamine biosynthesis, phospholipid exhibit analogous patterns those inherent specific physiological processes, notably neurodevelopment, cellular injury, oxidative stress, autophagic pathways. Our study provides insights into tissue-specific may help explain potential mechanisms photopathogenesis.

Language: Английский

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