Contributions of Genetic Variation in Astrocytes to Cell and Molecular Mechanisms of Risk and Resilience to Late‐Onset Alzheimer's Disease

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

Published: Feb. 3, 2025

ABSTRACT Reactive astrocytes are associated with Alzheimer's disease (AD), and several AD genetic risk variants genes highly expressed in astrocytes. However, the contribution of within to cellular processes relevant pathogenesis remains ill‐defined. Here, we present a resource for studying using large collection induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals range neuropathological cognitive outcomes. IPSC 44 were differentiated into followed by unbiased molecular profiling RNA sequencing tandem mass tag‐mass spectrometry. We demonstrate utility this examining gene‐ pathway‐level associations clinical traits, as well analyzing resilience factors through parallel analyses iPSC‐astrocytes brain tissue same individuals. Our reveal that pathways altered iPSC‐derived concordantly dysregulated tissue. This includes increased levels prefoldin proteins, extracellular matrix factors, COPI‐mediated trafficking components reduced proteins involved respiration fatty acid oxidation. Additionally, resilient high neuropathology show elevated basal interferon response secretion gamma. Correspondingly, higher polygenic scores lower study establishes an experimental system integrates information matched iPSC data cohort identify contributions affecting resilience.

Language: Английский

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Antiretroviral drug therapy does not reduce neuroinflammation in an HIV-1 infection brain organoid model

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: March 5, 2025

HIV-1-associated neurocognitive impairment (HIV-1-NCI) is marked by ongoing and chronic neuroinflammation with loss decline in neuronal function even when antiretroviral drug therapy (ART) successfully suppresses viral replication. Microglia, the primary reservoirs of HIV-1 central nervous system (CNS), play a significant role maintaining this neuroinflammatory state. However, understanding how generated sustained HIV-1, or impacted ART, difficult due to limited access human CNS tissue. We an vitro model admixed hematopoietic progenitor cell (HPC) derived microglia embedded into embryonic stem (ESC) Brain Organoids (BO). Microglia were infected prior co-culture. Infected co-cultured brain organoids BOs infiltrate establish for infection, "HIV-1 M-BO". M-BOs treated ART variable directions. infection was monitored p24 ELISA digital droplet PCR (ddPCR). Inflammation measured cytokine p-NF-kB levels using multiplex ELISA, flow cytometry confocal microscopy. could be create "brain" infection. Although initial source pro-inflammatory cytokines, astrocytes, neurons neural cells also had increased levels, along elevated CCL2 supernatant compared Uninfected M-BOs. suppressed virus below limit detection but did not decrease neuroinflammation. These findings indicate that are pro-inflammatory. significantly inflammation persisted ART-treated Together, these infiltrated provides robust understand impact on

Language: Английский

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Divergent Processing of Cell Stress Signals as the Basis of Cancer Progression: Licensing NFκB on Chromatin

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8621 - 8621

Published: Aug. 7, 2024

Inflammation is activated by diverse triggers that induce the expression of cytokines and adhesion molecules, which permit a succession molecules cells to deliver stimuli functions help immune system clear primary cause tissue damage, whether this an infection, tumor, or trauma. During inflammation, short-term changes in secretion strong mediators inflammation occur, while long-term occur specific groups cells. Long-term include cellular transdifferentiation for some types need regenerate damaged tissue, as well death can be detrimental integrity if they remain active beyond boundaries essential function. The transcriptional regulator NFκB enables fundamental gene during development. recurrence malignant disease, cell stress-induced alterations enable growth cancer clones are substantially resistant therapeutic intervention system. A number those due significant defects feedback signal cascades control activity NFκB. Specifically, stress contributes it overrides modules otherwise protect host tissue. involved both suppression promotion cancer, key distinctive feature determines its net effect remains unclear. This paper aims provide answer at least one aspect question, namely mechanism divergent response critical inflammatory general.

Language: Английский

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Aquaporins: Gatekeepers of Fluid Dynamics in Traumatic Brain Injury

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(12), P. 6553 - 6553

Published: June 14, 2024

Aquaporins (AQPs), particularly AQP4, play a crucial role in regulating fluid dynamics the brain, impacting development and resolution of edema following traumatic brain injury (TBI). This review examines alterations AQP expression localization post-injury, exploring their effects on overall outcomes. We discuss underlying molecular mechanisms expression, highlighting potential therapeutic strategies to modulate function. These insights provide comprehensive understanding AQPs TBI suggest novel approaches for improving clinical outcomes through targeted interventions.

Language: Английский

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Regulation of pyroptosis by NF-κB signaling

Frontiers in Cell Death, Journal Year: 2025, Volume and Issue: 3

Published: Jan. 7, 2025

Pyroptosis is a form of proinflammatory cell death characterized by inflammasome activation, pore formation, and the release pro-inflammatory cytokines such as interleukin-1β (IL-1β) IL-18 upon rupture. Nuclear factor-κB (NF-κB), prototypical transcription factor, plays critical role in immune system regulation. Recent research highlights multifaceted roles NF-κB signaling pyroptosis. Various immunologically relevant ligands their receptors can activate pathway to promote pyroptosis, with Toll-like (TLRs), IL-1 (IL-1Rs), TNF (TNFRs) being most prominent. regulates key components inflammasomes involved particularly NLRP3 inflammasome. studies also indicate that modulates activation NLRC4 AIM2 through distinct pathways diverse inflammatory conditions, acute lung injury neuroinflammation. Additionally, mediates production cytokines, including IL-1β, IL-33, TNF-α, which further regulate This review examines recent advances understanding regulating pyroptosis during infection inflammation.

Language: Английский

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Aqueous Vernonia amygdalina leaf extract in drinking water mitigates aflatoxin B1 toxicity in broilers: effects on performance, biomarker analysis, and liver histology

Mycotoxin Research, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Language: Английский

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Neurodegenerative diseases and neuroinflammation-induced apoptosis

Open Life Sciences, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 1, 2025

Abstract Neuroinflammation represents a critical pathway in the brain for clearance of foreign bodies and maintenance homeostasis. When neuroinflammatory process is dysregulate, such as over-activation microglia, which results excessive accumulation free oxygen inflammatory factors brain, among other factors, it can lead to an imbalance homeostasis development various diseases. Recent research has indicated that numerous neurodegenerative diseases closely associated with neuroinflammation. The pathogenesis neuroinflammation intricate, involving alterations genes proteins, well activation inhibition signaling pathways. Furthermore, inflammation result neuronal cell apoptosis, further exacerbate extent disease. This article presents summary recent studies on relationship between apoptosis caused by aim identify link two provide new ideas targets exploring pathogenesis, prevention treatment

Language: Английский

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Dexmedetomidine pretreatment alleviates brain injury in middle cerebral artery occlusion (MCAO) model rats by activating PI3K/AKT/NF-κB signaling pathway

Journal of Toxicology and Environmental Health, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 11

Published: Feb. 24, 2025

Cerebral ischemia-reperfusion injury (CIRI) is a prevalent clinical complication associated with reperfusion following ischemic stroke resulting in neuronal damage and cognitive impairment. Dexmedetomidine (DEX), highly selective α2-adrenoceptor agonist sedative, analgesic properties, frequently utilized as sedative anesthetic surgeries, believed to play crucial role the prognosis of patients suffering from CIRI. However, mechanism underlying DEX CIRI remains be determined. This study aimed investigate neuroprotective effects Dex rats In treatment group, (50 µg/kg) was administered intraperitoneally 30 min prior surgery. Middle cerebral artery occlusion (MCAO) used model occurred for 2 h followed by blood 24, 72, 120 or 168 h. Neurological function assessed Longa neurological score test demonstrated significantly reduced scores increased % infarct size MCAO group which blocked suggesting that might effective treating stroke. animals, 2,3,5-triphenyltetrazolium chloride (TTC) showed large marked areas infarction were diminished DEX. Using Western blot analysis, results protein expression levels TNF-α IL-6 accompanied PI3K/AKT signaling pathway. pretreatment reversed evidenced decrease elevated PI3K/AKT/NF-κB Data improved neuromotor performance functions animals consequences diminishing inflammation activation

Language: Английский

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Application of curcuminoids in inflammatory, neurodegenerative and aging conditions - Pharmacological potential and bioengineering approaches to improve efficiency

Biotechnology Advances, Journal Year: 2025, Volume and Issue: unknown, P. 108568 - 108568

Published: March 1, 2025

Language: Английский

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The effects of Myo-inositol on antioxidant capacity and immunity in freshwater crayfish

Aquaculture International, Journal Year: 2025, Volume and Issue: 33(4)

Published: April 3, 2025

Language: Английский

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