Extracellular vesicles mediate inflammasome signaling in the brain and heart of Alzheimer’s disease mice

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 17

Опубликована: Апрель 10, 2024

Introduction Alzheimer’s disease (AD) is an inflammatory neurodegenerative characterized by memory loss and cognitive impairment that worsens over time. AD associated with many comorbidities, including cardiovascular are poorer outcomes. Comorbidities, especially heart stroke, play a significant role in the demise of patients. Thus, it important to understand how comorbidities linked AD. We have previously shown extracellular vesicle (EV)-mediated inflammasome signaling plays pathogenesis brain injury acute lung after traumatic injury. Methods analyzed cortical, hippocampal, ventricular, atrial protein lysates from APP/PS1 mice their respective controls for activation. Additionally, we serum-derived EV size, concentration, content proteins as well marker CD63. Finally, performed conditioned media experiments patients healthy age-matched delivered cells culture assess EV-induced inflammation. Results show increase Pyrin, NLRP1, caspase-1, ASC cortex whereas caspase-8, ASC, IL-1β were significantly elevated ventricles when compared controls. did not find differences size or concentration between groups, but there was caspase-1 In addition, resulted activation, increases TNF-α IL-2. Conclusion These results indicate EV-mediated may development diseases

Язык: Английский

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Induction of the Inflammasome Pathway by Tyrosine Kinase Inhibitors Provides an Actionable Therapeutic Target for Hepatocellular Carcinoma

Cancers, Год журнала: 2024, Номер 16(8), С. 1491 - 1491

Опубликована: Апрель 13, 2024

During the last decade, tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib have been standard systemic treatments for advanced hepatocellular carcinoma (HCC). Previous data associated with inflammasome activation. However, role of in signaling has not described liver cancer patients. For this purpose, we analyzed inflammasome-related transcriptomic changes a murine HCC model. Our confirmed activation after both TKI treatments, sharing similar pattern increased gene expression. According to human database results, transcriptional increase genes is poorer prognosis male patients, suggesting sex-dependent therapy. In biopsies its surrounding tissue, detected durable increases or treatment Further supporting involvement action, inhibition (MCC950) enhanced anticancer activity experimental models, while no direct vitro effect was observed cell lines. Moreover, activated THP-1 macrophages released IL-1β administration, 3D Hep3B spheres displayed tumor growth addition, pointing microenvironment as key player action. summary, our results unveil pathway an actionable target therapy associate signature tissue administration. Therefore, targeting activation, principally could help overcome resistance enhance efficacy HCC.

Язык: Английский

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Sex as a Determinant of Age-Related Changes in the Brain

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(13), С. 7122 - 7122

Опубликована: Июнь 28, 2024

The notion of notable anatomical, biochemical, and behavioral distinctions within male female brains has been a contentious topic interest the scientific community over several decades. Advancements in neuroimaging molecular biological techniques have increasingly elucidated common mechanisms characterizing brain aging while also revealing disparities between sexes these processes. Variations cognitive functions; susceptibility to progression neurodegenerative conditions, notably Alzheimer’s Parkinson’s diseases; life expectancy sexes, underscore significance evaluating framework gender differences. This comprehensive review surveys contemporary literature on restructuring structures fundamental processes unfolding at cellular levels, with focus distinctions. Additionally, delves into age-related alterations, exploring factors influencing acceleration or deceleration aging, particular attention estrogen’s hormonal support central nervous system.

Язык: Английский

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Ginseng in Delaying Brain Aging: Progress and perspectives

Phytomedicine, Год журнала: 2025, Номер unknown, С. 156587 - 156587

Опубликована: Март 1, 2025

Язык: Английский

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Effects of Space Flight on Inflammasome Activation in the Brain of Mice

Cells, Год журнала: 2025, Номер 14(6), С. 417 - 417

Опубликована: Март 12, 2025

Space flight exposes astronauts to stressors that alter the immune response, rendering them vulnerable infections and diseases. In this study, we aimed determine levels of inflammasome activation in brains mice were housed International Station (ISS) for 37 days. C57BL/6 launched ISS as part NASA’s Rodent Research 1 Mission on SpaceX-4 CRS-4 Dragon cargo spacecraft from 21 September 2014 25 October 2014. Dissected mouse mission analyzed by immunoblotting signaling proteins Electrochemiluminescence Immunoassay (ECLIA) inflammatory cytokine levels. Our data indicate decreased days when compared maintained ground, corresponding baseline group sacrificed at time launching SpaceX-4. Moreover, did not detect any significant changes expression pro-inflammatory cytokines TNF-α, IL-2, IFN-γ, IL-5, IL-6, IL-12p70 IL-10 between ground control groups. Together, these studies suggest spaceflight results a decrease innate molecules govern brain mice.

Язык: Английский

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Gasdermin-D Genetic Knockout Reduces Inflammasome-Induced Disruption of the Gut-Brain Axis After Traumatic Brain Injury

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(8), С. 3512 - 3512

Опубликована: Апрель 9, 2025

Traumatic brain injury (TBI) pathology is significantly mediated by an inflammatory response involving inflammasome activation, resulting in the release of interleukin (IL)-1β and pyroptotic cell death through gasdermin-D (GSDMD) cleavage. Inflammasome components are transported extracellular vesicles (EVs) to mediate systemic inflammation peripheral organs, including gut. The purpose this study was determine protective effect GSDMD knockout (KO) on TBI-induced EV signaling, gut function. GSDMD-KO C57BL6 (WT) mice were subjected controlled cortical impact model TBI. Cytokine expression assessed with electrochemiluminescent immunoassay immunoblotting cerebral cortex EVs examined for pathology-associated markers using flow cytometry, permeability determined. attenuated IL-1β IL-6 reduced IL-18 3 days post-injury. had decreased neuronal- gut-derived compared WT post-TBI. also different surface marker after These data demonstrate that ablation improves post-TBI pathology, suggesting may serve as a potential therapeutic target improvement TBI-associated pathologies.

Язык: Английский

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Hallmarks of Cancer Cachexia: Sexual Dimorphism in Related Pathways

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(9), С. 3952 - 3952

Опубликована: Апрель 22, 2025

Cancer-associated cachexia (CAC), also known as wasting syndrome, is a systemic condition that affects multiple tissues and organs via variety of metabolic pathways. Systemic inflammation, progressive weight loss, depletion adipose tissue, skeletal muscle impairment are some the hallmark features cachexia. Despite various studies on clinical CAC, complexity syndrome continues to pose significant challenges in practice, leading late diagnoses absence standardised treatment. Men women respond differently which may be prompted by pre-existing physiologic sex differences. This review presents sexual dimorphism associated with pathways involved CAC. A comprehensive understanding these could drive research prioritise inclusion more females related order achieve personalised sex-based therapeutic approaches and, consequently, enhance treatment efficacy better patient outcomes.

Язык: Английский

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IC100 blocks inflammasome activation induced by α-synuclein aggregates and ASC specks

npj Parkinson s Disease, Год журнала: 2025, Номер 11(1)

Опубликована: Апрель 25, 2025

Parkinson's disease (PD) is associated with chronic sterile inflammation and persistent inflammasome activation involving α-synuclein ASC protein aggregates, but the underlying mechanisms of neuroinflammatory response remain unclear. Here, we used midbrain postmortem samples from donors without α-synucleinopathies to assess expression proteins in patients Parkinsonism. We show that dopaminergic neurons exhibit increased ASC, NOD-like receptor (NLRP) 1, modification phosphorylation at serine129 (pS129) within Lewy body inclusions, whereas NLRP3 was identified mainly microglial. Moreover, treatment LRRK2 cells specks PD dementia induced cytotoxicity blocked by IC100. Administration preformed aggregates microglia resulted a significant elevation pS129, this effect also Thus, IC100 may be promising therapeutic strategy for inflammatory synucleinopathies other diseases.

Язык: Английский

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A New Application for Cenicriviroc, a Dual CCR2/CCR5 Antagonist, in the Treatment of Painful Diabetic Neuropathy in a Mouse Model

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(13), С. 7410 - 7410

Опубликована: Июль 5, 2024

The ligands of chemokine receptors 2 and 5 (CCR2 CCR5, respectively) are associated with the pathomechanism neuropathic pain development, but their role in painful diabetic neuropathy remains unclear. Therefore, aim our study was to examine function these factors hypersensitivity accompanying diabetes. Additionally, we analyzed analgesic effect cenicriviroc (CVC), a dual CCR2/CCR5 antagonist, its influence on effectiveness morphine. An increasing number experimental studies have shown that targeting more than one molecular target is advantageous compared coadministration individual pharmacophores terms effect. advantage using bifunctional compounds they gain simultaneous access two at same dose, positively affecting pharmacokinetics pharmacodynamics consequently leading improved analgesia. Experiments were performed male female Swiss albino mice streptozotocin (STZ, 200 mg/kg, i.p.) model neuropathy. We found blood glucose level increased, mechanical thermal developed 7th day after STZ administration. In mice, observed increased mRNA levels Ccl2, Ccl5, Ccl7, while additional increases Ccl8 Ccl12 levels. demonstrated for first time single administration relieves similar extent mice. Moreover, repeated morphine delays development opioid tolerance, best longest-lasting achieved by alone, which reduces STZ-exposed unlike morphine, no tolerance effects CVC until Day 15 treatment. Based results, suggest CCR2 CCR5 potent therapeutic option novel treatments patients.

Язык: Английский

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Minding the Gap: Exploring Neuroinflammatory and Microglial Sex Differences in Alzheimer’s Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(24), С. 17377 - 17377

Опубликована: Дек. 12, 2023

Research into Alzheimer's Disease (AD) describes a link between AD and the resident immune cells of brain, microglia. Further, this suspected is thought to have underlying sex effects, although mechanisms these effects are only just beginning be understood. Many insights result policies put in place by funding agencies such as National Institutes Health (NIH) consider biological variable (SABV) move towards precision medicine due continued lackluster therapeutic options. The purpose review provide an updated assessment current research that summarizes differences pertaining microglia their varied responses AD.

Язык: Английский

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