CD38: An Immunomodulatory Molecule in Inflammation and Autoimmunity

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Nov. 30, 2020

CD38 is a molecule that can act as an enzyme, with NAD-depleting and intracellular signaling activity, or receptor adhesive functions. be found expressed either on the cell surface, where it may face extracellular milieu cytosol, in compartments, such endoplasmic reticulum, nuclear membrane, mitochondria. The main expression of observed hematopoietic cells, some cell-type specific differences between mouse human. role immune cells ranges from modulating differentiation to effector functions during inflammation, regulate recruitment, cytokine release, NAD availability. In line appears also play critical inflammatory processes autoimmunity, although whether has pathogenic regulatory effects varies depending disease, cell, animal model analyzed. Given complexity physiology been difficult completely understand biology this autoimmune inflammation. review, we analyze current knowledge controversies regarding inflammation autoimmunity novel molecular tools clarify gaps field.

Language: Английский

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Neuroinflammation in Alzheimer’s Disease

Biomedicines, Journal Year: 2021, Volume and Issue: 9(5), P. 524 - 524

Published: May 7, 2021

Alzheimer's disease (AD) is a neurodegenerative associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise increasing age. There are currently no effective modifying treatments for AD, resulting in increasingly large socioeconomic personal costs. Increasing age an increase low-grade chronic inflammation (inflammaging) that may contribute the process AD. Although exact mechanisms remain unclear, aberrant elevation reactive oxygen nitrogen species (RONS) levels from several endogenous exogenous processes brain not only affect cell signaling, but also trigger cellular senescence, inflammation, pyroptosis. Moreover, compromised immune privilege allows infiltration peripheral cells infectious agents play role. Additionally, meta-inflammation as well gut microbiota dysbiosis drive neuroinflammatory process. Considering inflammatory/immune pathways dysregulated parallel cognitive dysfunction elucidating relationship between central nervous system facilitate development safe therapy We discuss some current ideas on inflammaging appear summarize details few immunomodulatory strategies being developed selectively target detrimental aspects neuroinflammation without affecting defense against pathogens tissue damage.

Language: Английский

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Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease

Cells, Journal Year: 2022, Volume and Issue: 11(12), P. 1885 - 1885

Published: June 10, 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder molecularly characterized by the formation of amyloid β (Aβ) plaques and type 2 microtubule-associated protein (Tau) abnormalities. Multiple studies have shown that many brain’s immunological cells, specifically microglia astrocytes, are involved in AD pathogenesis. Cells innate immune system play an essential role eliminating pathogens but also regulate brain homeostasis AD. When activated, cells can cause programmed cell death through multiple pathways, including pyroptosis, apoptosis, necroptosis, PANoptosis. The often results release proinflammatory cytokines propagate response eliminate Aβ aggregated Tau proteins. However, chronic neuroinflammation, which result from death, has been linked to diseases worsen Therefore, must be tightly balanced appropriately clear these AD-related structural abnormalities without inducing neuroinflammation. In this review, we discuss responses, inflammatory cytokine secretion as they relate Therapeutic strategies targeting mechanisms will critical consider for future preventive or palliative treatments

Language: Английский

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Brain expression quantitative trait locus and network analyses reveal downstream effects and putative drivers for brain-related diseases

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(3), P. 377 - 388

Published: Feb. 23, 2023

Identification of therapeutic targets from genome-wide association studies (GWAS) requires insights into downstream functional consequences. We harmonized 8,613 RNA-sequencing samples 14 brain datasets to create the MetaBrain resource and performed cis- trans-expression quantitative trait locus (eQTL) meta-analyses in multiple region- ancestry-specific (n ≤ 2,759). Many 16,169 cortex cis-eQTLs were tissue-dependent when compared with blood cis-eQTLs. inferred cell types for 3,549 by interaction analysis. prioritized 186 31 brain-related traits using Mendelian randomization co-localization including 40 an type, such as a neuron-specific cis-eQTL (CYP24A1) sclerosis. further describe 737 trans-eQTLs 526 unique variants 108 genes. used brain-specific gene-co-regulation networks link GWAS loci prioritize additional genes five central nervous system diseases. This study represents valuable post-GWAS research on

Language: Английский

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Molecular mechanisms of ischemia and glutamate excitotoxicity

Life Sciences, Journal Year: 2023, Volume and Issue: 328, P. 121814 - 121814

Published: May 25, 2023

Excitotoxicity is classically defined as the neuronal damage caused by excessive release of glutamate, and subsequent activation excitatory plasma membrane receptors. In mammalian brain, this phenomenon mainly driven glutamate receptors (GRs). common to several chronic disorders Central Nervous System (CNS) considered primary mechanism loss function cell death in acute CNS diseases (e.g. ischemic stroke). Multiple mechanisms pathways lead excitotoxic including pro-death signaling cascade events downstream receptors, calcium (Ca2+) overload, oxidative stress, mitochondrial impairment, synaptic cleft well altered energy metabolism. Here, we review current knowledge on molecular that underlie excitotoxicity, emphasizing role Nicotinamide Adenine Dinucleotide (NAD) We also discuss novel promising therapeutic strategies treat highlighting recent clinical trials. Finally, will shed light ongoing search for stroke biomarkers, an exciting field research, which may improve diagnosis, prognosis allow better treatment options.

Language: Английский

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Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer’s Disease Progression

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 1869 - 1869

Published: Jan. 18, 2023

Aging is the most prominent risk factor for late-onset Alzheimer’s disease. associates with a chronic inflammatory state both in periphery and central nervous system, evidence thereof mechanisms leading to neuroinflammation being discussed. Nonetheless, significantly enhanced by accumulation of amyloid beta accelerates progression disease through various pathways discussed present review. Decades clinical trials targeting 2 abnormal proteins disease, tau, led many failures. As such, via different strategies could prove valuable therapeutic strategy, although much research still needed identify appropriate time window. Active focusing on identifying early biomarkers help translating these novel from bench bedside.

Language: Английский

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Alzheimer’s Disease: Novel Targets and Investigational Drugs for Disease Modification

Drugs, Journal Year: 2023, Volume and Issue: 83(15), P. 1387 - 1408

Published: Sept. 20, 2023

Novel agents addressing non-amyloid, non-tau targets in Alzheimer's Disease (AD) comprise 70% of the AD drug development pipeline currently clinical trials. Most target processes identified Common Research Ontology (CADRO) are represented by novel Inflammation and synaptic plasticity/neuroprotection CADRO categories with largest number candidate therapies. Within these categories, there few overlapping among test agents. Additional being evaluated include apolipoprotein E $$\varepsilon$$ 4 (APOE4) effects, lipids lipoprotein receptors, neurogenesis, oxidative stress, bioenergetics metabolism, vascular factors, cell death, growth factors hormones, circadian rhythm, epigenetic regulators. We highlight current drugs tested within their mechanisms. Trials will be informative regarding which can modulated to produce a slowing decline. Possible therapeutic combinations may suggested trial outcomes. Biomarkers evolving concert new agents, biomarker outcomes offer means supporting disease modification putative treatment. Identification corresponding therapeutics an important advancing treatments for AD.

Language: Английский

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The role of the ATP-adenosine axis in ischemic stroke

Seminars in Immunopathology, Journal Year: 2023, Volume and Issue: 45(3), P. 347 - 365

Published: March 14, 2023

Abstract In ischemic stroke, the primary neuronal injury caused by disruption of energy supply is further exacerbated secondary sterile inflammation. The inflammatory cascade largely initiated purine adenosine triphosphate (ATP) which extensively released to interstitial space during brain ischemia and functions as an extracellular danger signaling molecule. By engaging P2 receptors, ATP activates microglia leading cytokine chemokine production subsequent immune cell recruitment from periphery amplifies post-stroke ectonucleotidases CD39 CD73 shape balance environment stepwise degrading itself has neuroprotective anti-inflammatory properties. effects are mainly mediated through A 1 receptors inhibition glutamatergic excitotoxicity, while capacities have been primarily attributed 2A receptor activation on infiltrating cells in subacute phase after stroke. this review, we summarize current state knowledge ATP-adenosine axis discuss contradictory results, point out potential pitfalls towards translating therapeutic approaches rodent stroke models human patients.

Language: Английский

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Reactive Astrocytes and Emerging Roles in Central Nervous System (CNS) Disorders

Cold Spring Harbor Perspectives in Biology, Journal Year: 2024, Volume and Issue: 16(7), P. a041356 - a041356

Published: Feb. 5, 2024

In addition to their many functions in the healthy central nervous system (CNS), astrocytes respond CNS damage and disease through a process called "reactivity." Recent evidence reveals that astrocyte reactivity is heterogeneous spectrum of potential changes occur context-specific manner. These are determined by diverse signaling events vary not only with nature severity different insults but also location CNS, genetic predispositions, age, potentially "molecular memory" previous events. Astrocyte can be associated both essential beneficial as well harmful effects. The available information rapidly expanding much has been learned about molecular diversity reactivity. Emerging functional associations point toward roles for determining outcome disorders.

Language: Английский

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Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases

Nature Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Language: Английский

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