Cascade-Type Microglial Pyroptosis Inhibitors for Enhanced Treatment of Cerebral Ischemia-Reperfusion Injury

ACS Nano, Год журнала: 2025, Номер unknown

Опубликована: Март 6, 2025

Neuroinflammation is a critical factor in the progression of cerebral ischemia-reperfusion injury (CIRI). Pyroptosis, which an inflammatory form programmed cell death, greatly amplifies neuroinflammatory processes. It does so by promoting release various contents that intensify overall response within central nervous system. Therefore, targeting pyroptosis represents promising therapeutic strategy for treatment CIRI. Excessive generation reactive oxygen species (ROS) overactivated microglia considered to serve as signal molecule triggers NLRP3 inflammasome-mediated pyroptosis. However, current inhibitors solely focus on eliminating existing ROS or inhibiting inflammasome are not optimal. Here, coating nanothylakoids (NTs) coengineered with fibrin-binding peptide and MG1 onto dihydrotanshinone I (DT)-loaded nanocarriers, we have developed cascade-type inhibitor (MDN-MC) comprehensively regulates ROS/NLRP3/pyroptosis axis. The incorporation catalase surface MDN-MC, along DT, facilitated cascade inhibition scavenging suppressing expression NLRP3. In rat model transient middle artery occlusion, enhanced behavioral recovery neuronal repair were achieved through at lesion site implementation interventions inhibit pyroptosis, thereby demonstrating effects. Overall, this work emphasizes importance cascade-regulated reducing neuroinflammation, offering important mechanistic understanding possible approaches

Язык: Английский

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Rationale and Study Design to Assess the Efficacy and Safety of Minocycline in Patients with Moderate to Severe Acute Ischaemic Stroke (EMPHASIS)

Stroke and Vascular Neurology, Год журнала: 2025, Номер unknown, С. svn - 003577

Опубликована: Март 26, 2025

Background Inflammation and blood-brain barrier disruption may contribute to the pathogenesis of ischaemic stroke. Minocycline was shown exert anti-inflammatory effects by attenuating microglial activation protecting in preclinical studies. Previous small-scale clinical studies have suggested that minocycline a potential beneficial effect on prognosis acute However, efficacy safety patients with stroke need be further confirmed. Study aims We designed study, Efficacy Safety Patients Moderate Severe Acute Ischaemic Stroke (EMPHASIS), evaluate improving functional outcome drug Methods The EMPHASIS study is multicentre, randomised, double-blind, placebo-controlled trial aiming recruit who had within 72 hours onset, National Institutes Health Scale score between 4 25 Ia≤1 (moderate-to-severe) will randomly allocated either or placebo groups 1:1 ratio. receive (or placebo) loading dose 200 mg, subsequent 100 mg every 12 for days. All routine guideline-based treatment. primary an excellent assessed proportion modified Rankin 0–1 at 90±7 main outcomes include number symptomatic intracranial haemorrhage 24±2 6±1 Discussion first phase III investigate whether effective safe 90 days moderate-to-severe data generated provide valuable evidence anti-inflammation treatment

Язык: Английский

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Repair-associated macrophages increase after early-phase microglia attenuation to promote ischemic stroke recovery

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

Опубликована: Март 31, 2025

Ischemic stroke recovery involves dynamic interactions between the central nervous system and infiltrating immune cells. Peripheral cells compete with resident microglia for spatial niches in brain, but how modulating this balance affects remains unclear. Here, we use PLX5622 to create peripheral cells, altering competition male mice following transient middle cerebral artery occlusion (tMCAO). We find that early-phase attenuation promotes long-term functional recovery. This intervention amplifies a subset of monocyte-derived macrophages (RAMf) reparative properties, characterized by high expression GPNMB CD63, enhanced lipid metabolism, pro-angiogenic activity. Transplantation RAMf into stroke-affected improves white matter integrity vascular repair. identify Mafb as transcription factor regulating phenotype RAMf. These findings highlight strategies optimize cell dynamics post-stroke rehabilitation. Recovery from ischemic brain. authors show reduction expanding macrophages, enhancing repair integrity.

Язык: Английский

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α -Lipoic acid alleviates Parkinson’s disease by suppressing S100A9-mediated pyroptosis

International Immunopharmacology, Год журнала: 2025, Номер 155, С. 114539 - 114539

Опубликована: Апрель 14, 2025

Язык: Английский

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Brain Targeting Bacterial Extracellular Vesicles Enhance Ischemic Stroke Therapy via Efficient ROS Elimination and Suppression of Immune Infiltration

ACS Nano, Год журнала: 2025, Номер unknown

Опубликована: Апрель 18, 2025

Ischemic stroke (IS) as a detrimental neurological disease is accompanied by oxidative-stress-induced injury, concurrent inflammatory response, overactivated brain immune microenvironment, and disruption of the blood-brain barrier (BBB). This cascade events ultimately leads to neuronal death significantly impairs recovery function. In this study, we presented extracellular vesicles derived from gut probiotic Lactobacillus reuteri (LrEVs) integrated with targeting, reactive oxygen species (ROS) scavenging, reduced infiltration cells for effective multiple therapeutic interventions IS. LrEVs inherited peptidoglycan (PGN) specifically targeted upregulated toll-like receptor 2 (TLR2) in injured region ischemic brain, achieving penetration BBB accumulation brain. meantime, prevented apoptosis after scavenging ROS overproduction modulating microglial polarization through inhibition MAPK NF-κB pathways. Furthermore, inhibited aggregation C-C motif chemokine ligand (CCL2), peripheral such macrophages neutrophils into tissue, suppressed impairment BBB, thereby improving microenvironment. The findings provide vesicle that combines modulation showcasing potential gut-probiotic-derived treat damage.

Язык: Английский

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