Metabolic reprogramming and polarization of microglia in Parkinson’s disease: Role of inflammasome and iron

Ageing Research Reviews, Год журнала: 2023, Номер 90, С. 102032 - 102032

Опубликована: Авг. 10, 2023

Язык: Английский

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Dual-Atom Nanozyme Eye Drops Attenuate Inflammation and Break the Vicious Cycle in Dry Eye Disease

Nano-Micro Letters, Год журнала: 2024, Номер 16(1)

Опубликована: Фев. 19, 2024

Dry eye disease (DED) is a major ocular pathology worldwide, causing serious discomfort and even visual impairment. The incidence of DED gradually increasing with the high-frequency use electronic products. Although inflammation core cause vicious cycle, reactive oxygen species (ROS) play pivotal role in cycle by regulating from upstream. Therefore, current therapies merely targeting show failure treatment. Here, novel dual-atom nanozymes (DAN)-based drops are developed. antioxidative DAN successfully prepared embedding Fe Mn bimetallic single-atoms N-doped carbon material modifying it hydrophilic polymer. vitro vivo results demonstrate endowed superior biological activity scavenging excessive ROS, inhibiting NLRP3 inflammasome activation, decreasing proinflammatory cytokines expression, suppressing cell apoptosis. Consequently, effectively alleviate inflammation, promote corneal epithelial repair, recover goblet density tear secretion, thus breaking cycle. Our findings open an avenue to make as intervention form ROS-mediated inflammatory diseases.

Язык: Английский

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NLRP3 inflammasome signalling in Alzheimer's disease

Neuropharmacology, Год журнала: 2024, Номер 252, С. 109941 - 109941

Опубликована: Март 31, 2024

Every year, 10 million people develop dementia, the most common of which is Alzheimer's disease (AD). To date, there no way to prevent cognitive decline and therapies are limited. This review provides a neuroimmunological perspective on progression AD, discusses immune-targeted that in preclinical clinical trials may impact development this disease. Specifically, we look role NLRP3 inflammasome, its triggers brain how activation can contribute dementia. We summarise range inhibitors targeting inflammasome downstream pathways under investigation, discuss future therapeutic perspectives for devastating condition.

Язык: Английский

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Multifaceted mitochondria in innate immunity

npj Metabolic Health and Disease, Год журнала: 2024, Номер 2(1)

Опубликована: Май 27, 2024

Abstract The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding mitochondria, highlighting their significance as key signal-transducing organelles with essential roles immunity that extend beyond bioenergetic function. Importantly, retain bacterial motifs a remnant endosymbiotic origin are recognised by innate immune cells trigger inflammation and participate anti-microbial defence. This review aims explore how mitochondrial physiology, spanning oxidative (OxPhos) signalling nucleic acids, metabolites, lipids, influences effector functions phagocytes. These myriad include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, signalling, cytokine regulation. Strict regulation these processes is critical for organismal homeostasis when disrupted may cause injury or contribute disease. Thus, expanding body literature, which continues highlight central role system, provide insights development next generation therapies inflammatory diseases.

Язык: Английский

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The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer’s disease

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Март 4, 2025

The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing damage-associated molecular patterns (DAMPs), inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation this pathway culminates in AD-related neuroinflammation neurodegeneration. A substantial body mitochondria are involved critical pathogenic mechanisms AD, whose damage leads release mitochondrial (mtDNA) into extramitochondrial space. This leaked mtDNA serves DAMP, various pattern recognition receptors defense networks brain, including cGAS-STING pathway, ultimately leading an imbalance homeostasis. Therefore, modulation mtDNA-cGAS-STING restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In review, we focus on during stress activation pathway. Additionally, delve research progress further discuss primary directions potential hurdles developing targeted therapeutic drugs, gain deeper understanding pathogenesis provide new approaches its therapy.

Язык: Английский

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Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Март 27, 2025

Abstract Alzheimer’s disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play central role. These immune cells undergo reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, HIF-1α orchestrating these processes. Microglial metabolism adapts environmental stimuli, shifting oxidative phosphorylation glycolysis. Hexokinase-2 facilitates glycolytic flux, while AMPK acts an energy sensor, coordinating lipid glucose metabolism. TREM2 APOE regulate microglial homeostasis, influencing Aβ clearance responses. LPL ABCA7, both associated AD risk, modulate processing cholesterol transport, linking neurodegeneration. PPARG further supports by regulating inflammatory Amino acid also contributes function. Indoleamine 2,3-dioxygenase controls the kynurenine pathway, producing neurotoxic metabolites linked pathology. Additionally, glucose-6-phosphate dehydrogenase regulates pentose phosphate maintaining redox balance activation. Dysregulated metabolism, influenced genetic variants APOE4, impair responses exacerbate progression. Recent findings highlight interplay regulators like REV-ERBα, which modulates inflammation, Syk, influences clearance. insights offer promising therapeutic targets, including strategies aimed at modulation, could restore function depending on stage. By integrating metabolic, immune, factors, this review underscores importance of immunometabolism AD. Targeting pathways provide novel for mitigating restoring function, ultimately paving way innovative treatments neurodegenerative diseases.

Язык: Английский

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VSTM2L protects prostate cancer cells against ferroptosis via inhibiting VDAC1 oligomerization and maintaining mitochondria homeostasis

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 29, 2025

Ferroptosis is a form of iron-dependent programmed cell death, which distinct from apoptosis, necrosis, and autophagy. Mitochondria play critical role in initiating amplifying ferroptosis cancer cells. Voltage-Dependent Anion Channel 1 (VDAC1) embedded the mitochondrial outer membrane, exerts roles regulation ferroptosis. However, mechanisms VDAC1 oligomerization regulating are not well elucidated. Here, we identify that binding protein V-Set Transmembrane Domain Containing 2 Like (VSTM2L), mainly localized to mitochondria, positively associated with prostate (PCa) progression, key regulator Moreover, VSTM2L knockdown PCa cells enhances sensitivity RSL3-induced Mechanistically, forms complex hexokinase (HK2), enhancing their affinity preventing oligomerization, thereby inhibiting maintaining mitochondria homeostasis vitro vivo. Collectively, our findings reveal pivotal for mitochondria-localized driving resistance highlight its potential as ferroptosis-inducing therapeutic target treatment PCa.

Язык: Английский

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Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Фев. 7, 2025

Mitochondrial dysfunction is a pivotal instigator of neuroinflammation, with mitochondrial DNA (mtDNA) leakage as critical intermediary. This review delineates the intricate pathways leading to mtDNA release, which include membrane permeabilization, vesicular trafficking, disruption homeostatic regulation, and abnormalities in dynamics. The escaped activates cytosolic sensors, especially cyclic gmp-amp synthase (cGAS) signalling inflammasome, initiating neuroinflammatory cascades via pathways, exacerbating spectrum neurological pathologies. therapeutic promise targeting discussed detail, underscoring necessity for multifaceted strategy that encompasses preservation homeostasis, prevention leakage, reestablishment dynamics, inhibition activation sensors. Advancing our understanding complex interplay between neuroinflammation imperative developing precision interventions disorders.

Язык: Английский

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Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation

Nature Metabolism, Год журнала: 2025, Номер unknown

Опубликована: Фев. 19, 2025

Abstract Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals; however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show LPS-stimulated bone-marrow-derived macrophages produce reverse electron transport (RET) at complex I chain. Using chemical biology genetic approaches, demonstrate production driven metabolic reprogramming, which increases proton motive force (∆p), primarily elevated membrane potential (Δψ m ) maintains a reduced CoQ pool. The key changes are repurposing ATP from oxidative phosphorylation to glycolysis, reduces reliance on F 1 O -ATP synthase activity resulting in higher ∆p, while oxidation succinate sustains Furthermore, mtROS RET regulates IL-1β release during NLRP3 inflammasome activation. Thus, ROS generated an important signal macrophage cytokine production.

Язык: Английский

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Adaptive Nanoparticle-Mediated Modulation of Mitochondrial Homeostasis and Inflammation to Enhance Infected Bone Defect Healing

ACS Nano, Год журнала: 2023, Номер 17(22), С. 22960 - 22978

Опубликована: Ноя. 6, 2023

Infected bone defects (IBDs) exhibit impaired healing due to excessive inflammation triggered by pathogen-associated molecular patterns (PAMPs) from bacteria. As a vital factor in orchestrating immune responses, mitochondrial homeostasis maintenance is central blockade. This research developed chameleon-like nanoplatform covering hydroxyapatite nanoparticles with cerium ion coordinated tannic acid supramolecular network (HA@Ce-TA), which adaptively functions regulate based on intra- and extracellular environments. Extracellularly, acidic conditions activate HA@Ce-TA's peroxidase/oxidase-mimicking activity produce reactive oxygen species (ROS), external near-infrared (NIR) irradiation excites nanoscale Ce-TA hyperthermia, found explained chemical computation. ROS production photothermal therapy can eliminate bacteria effectively reduce stress. Intracellularly, HA@Ce-TA remodels dynamics upregulating fusion genes eliminates mimicking superoxidase/catalase. Consequently, this comprehensive modulation of inhibits inflammasome overactivation. In vitro vivo studies showed modulate the mitochondria-centered inflammatory cascade enhance IBD treatment, highlighting potential engineering nanotherapeutics recalibrate as an infected disease-modifying intervention.

Язык: Английский

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