Rationale and Study Design to Assess the Efficacy and Safety of Minocycline in Patients with Moderate to Severe Acute Ischaemic Stroke (EMPHASIS) DOI Creative Commons
Yao Lu, Ling Guan,

Meiyang Zhang

et al.

Stroke and Vascular Neurology, Journal Year: 2025, Volume and Issue: unknown, P. svn - 003577

Published: March 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

Language: Английский

Targeted mRNA Nanoparticles Ameliorate Blood–Brain Barrier Disruption Postischemic Stroke by Modulating Microglia Polarization DOI
Mingzhu Gao, Yan Li, William Ho

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(4), P. 3260 - 3275

Published: Jan. 16, 2024

The ischemic stroke is a major global health concern, with high mortality and disability rates. Unfortunately, there dearth of effective clinical interventions for managing poststroke neuroinflammation blood–brain barrier (BBB) disruption that are crucial the brain injury evolving neurological deficits. By leveraging pathological progression an stroke, we developed M2 microglia-targeting lipid nanoparticle (termed MLNP) approach can selectively deliver mRNA encoding phenotype-switching interleukin-10 (mIL-10) to brain, creating beneficial feedback loop drives microglial polarization toward protective phenotypes augments homing mIL-10-loaded MLNPs (mIL-10@MLNPs) regions. In transient middle cerebral artery occlusion (MCAO) mouse model our findings demonstrate intravenously injected mIL-10@MLNPs induce IL-10 production enhance microglia. resulting positive reinforces resolution neuroinflammation, restores impaired BBB, prevents neuronal apoptosis after stroke. Using permanent distal MCAO neuroprotective effects have been further validated by attenuation sensorimotor cognitive Furthermore, mRNA-based targeted therapy has great potential extend therapeutic time window at least up 72 h poststroke. This study depicts simple versatile LNP platform selective delivery therapeutics lesions, showcasing promising addressing associated conditions.

Language: Английский

Citations

34
Mitochondrial DNA leakage: underlying mechanisms and therapeutic implications in neurological disorders DOI Creative Commons
Guangming Zhang,

Huayuan Wei,

Anliu Zhao

et al.

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

Published: Feb. 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.

Language: Английский

Citations

3
The SGLT2 inhibitor Empagliflozin promotes post-stroke functional recovery in diabetic mice DOI Creative Commons
Ellen Vercalsteren, Dimitra Karampatsi, Carolina Buizza

et al.

Cardiovascular Diabetology, Journal Year: 2024, Volume and Issue: 23(1)

Published: Feb. 29, 2024

Abstract Type-2 diabetes (T2D) worsens stroke recovery, amplifying post-stroke disabilities. Currently, there are no therapies targeting this important clinical problem. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) potent anti-diabetic drugs that also efficiently reduce cardiovascular death and heart failure. In addition, SGLT2i facilitate several processes implicated in recovery. However, the potential efficacy of to improve recovery T2D has not been investigated. Therefore, we determined whether a intervention with Empagliflozin could mice. was induced C57BL6J mice by 8 months high-fat diet feeding. Hereafter, animals were subjected transient middle cerebral artery occlusion treated vehicle or SGLTi (10 mg/kg/day) starting from 3 days after stroke. A similar study non diabetic conducted. Stroke assessed using forepaw grip strength test. To identify mechanisms involved Empagliflozin-mediated effects, metabolic parameters assessed. Additionally, neuronal survival, neuroinflammation, neurogenesis vascularization analyzed immunohistochemistry/quantitative microscopy. significantly improved but non-diabetic Improvement functional associated lowered glycemia, increased serum levels fibroblast growth factor-21 (FGF-21), normalization T2D-induced aberration parenchymal pericyte density. The global T2D-epidemic fact is major risk factor for drastically increasing number people need efficacious Our data provide strong incentive use treatment sequelae T2D.

Language: Английский

Citations

13
Myricetin Oligomer Triggers Multi-Receptor Mediated Penetration and Autophagic Restoration of Blood-Brain Barrier for Ischemic Stroke Treatment DOI
Lei Liu, Zhifang Ma,

Qiaoyi Han

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(14), P. 9895 - 9916

Published: March 27, 2024

Restoration of blood-brain barrier (BBB) dysfunction, which drives worse outcomes ischemic stroke, is a potential target for therapeutic opportunities, whereas sealed BBB blocks the therapeutics entrance into brain, making protection strategy paradoxical. Post hypoxia/hypoglycemia provokes up-regulation transmembrane glucose transporters and iron due to multiple metabolic disorders, especially in brain endothelial cells. Herein, we develop myricetin oligomer-derived nanostructure doped with Ce bypass cointermediated by such as 1 (GLUT1), sodium/glucose cotransporters (SGLT1), transferrin(Tf) reporter (TfR). Moreover, it exhibits restoration capacity regulating expression tight junctions (TJs) through activation protective autophagy. The oligomers scaffold not only acts targeting moiety but prominent active entity that inherits all diverse pharmacological activities myricetin. suppression oxidative damage, M1 microglia activation, inflammatory factors makes multitasking nanoagent single component scaffold, domain curative components.

Language: Английский

Citations

12
Anti-neuroinflammatory agent rhein lysinate-based self-assembled injectable hydrogel loaded with ZL006 for promoting post-stroke functional recovery DOI

Jiamei Song,

Jiaqi Zeng,

Xialin Chen

et al.

Biomaterials, Journal Year: 2025, Volume and Issue: unknown, P. 123124 - 123124

Published: Jan. 1, 2025

Language: Английский

Citations

1
Polyphenylalanine-Baicalein Nanomicelles Reduce Nerve Cell Apoptosis and Inflammation to Enhance Neuroprotection and Poststroke Rehabilitation DOI
Lingkun Zhang, Li Liu, Ziqing Li

et al.

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

Published: Jan. 28, 2025

Cerebral ischemic stroke, neuronal death, and inflammation bring difficulties in neuroprotection rehabilitation. In this study, we developed designed the ability of natural lactoferrin-polyethylene glycol-polyphenylalanine-baicalein nanomicelles (LF-PEG-PPhe-Bai) to target reduce these pathological processes, such as neurological damage cognitive impairment stages poststroke. Nanomicelles made from biocompatible materials have improved bioavailability targeted distribution afflicted brain areas. The results showed that LF-PEG-PPhe-Bai greatly antioxidation, antiapoptosis, anti-inflammation activity vitro. Meanwhile, behavioral 2-VO model mice, protected nerve cells hippocampus, reduced at injury site vivo. conclusion, are employed for enhancing poststroke development technology might provide a new technique neural repair after ischemia future.

Language: Английский

Citations

1
Deubiquitination of RIPK3 by OTUB2 potentiates neuronal necroptosis after ischemic stroke DOI Creative Commons

Fuqi Mei,

Dongrui Deng,

Zi-Jun Cao

et al.

EMBO Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 28, 2025

Abstract As a common and severe cerebrovascular disease, ischemic stroke casts significant shadow over global health. Unfortunately, the mechanisms regulating neuronal death in affected areas remain largely unclear. Here, we found that deletion of deubiquitinating enzyme Otubain-2 (OTUB2) significantly alleviated ischemia-induced cerebral infarction neurological deficits, accompanied by reduction loss, glial activation, neuroinflammation. OTUB2 was predominantly expressed neurons its decreased receptor-interacting protein kinase 3 (RIPK3)-mediated necroptosis. Moreover, increased RIPK3 abundance inhibiting proteasomal degradation RIPK3. Mechanistically, removed K48-linked polyubiquitin chains from through active site C51. Importantly, pharmacological inhibition brain injury mice reduced oxygen-glucose deprivation-induced human organoids. These results demonstrate critically regulates potentiating necroptosis, suggesting may become potential therapeutic approach for treating stroke.

Language: Английский

Citations

1
Ubiquitous regulation of cerebrovascular diseases by ubiquitin‐modifying enzymes DOI Creative Commons
Jingyong Huang,

Zhenhu Zhu,

Dirk Schlüter

et al.

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(5)

Published: May 1, 2024

Abstract Cerebrovascular diseases (CVDs) are a major threat to global health. Elucidation of the molecular mechanisms underlying pathology CVDs is critical for development efficacious preventative and therapeutic approaches. Accumulating studies have highlighted significance ubiquitin‐modifying enzymes (UMEs) in regulation CVDs. UMEs group that orchestrate ubiquitination, post‐translational modification tightly involved Functionally, regulate multiple pathological processes ischemic hemorrhagic stroke, moyamoya disease, atherosclerosis. Considering important roles CVDs, they may become novel druggable targets these diseases. Besides, techniques applying UMEs, such as proteolysis‐targeting chimera deubiquitinase‐targeting chimera, also revolutionize therapy future.

Language: Английский

Citations

7
Nanosystems for targeted drug Delivery: Innovations and challenges in overcoming the Blood-Brain barrier for neurodegenerative disease and cancer therapy DOI

Nesa Rafati,

Atefeh Zarepour, Ashkan Bigham

et al.

International Journal of Pharmaceutics, Journal Year: 2024, Volume and Issue: 666, P. 124800 - 124800

Published: Oct. 5, 2024

Language: Английский

Citations

7
Age-Related Alterations in Peripheral Immune Landscape with Magnified Impact on Post-Stroke Brain DOI Creative Commons
Jianan Lü, Huaming Li, Guoqiang Zhang

et al.

Research, Journal Year: 2023, Volume and Issue: 6

Published: Jan. 1, 2023

Immunosenescence refers to the multifaceted and profound alterations in immune system brought about by aging, exerting complex influences on pathophysiological processes of diseases that manifest upon it. Using a combination single-cell RNA sequencing, cytometry time flight, various immunological assays, we investigated characteristics immunosenescence peripheral blood aged mice its impact cerebral environment after ischemic stroke. Our results revealed some features immunosenescence. We observed an increase neutrophil counts, concurrent with accelerated characterized altered expression aging-associated markers like CD62L consequential changes neutrophil-mediated functions. Monocytes/macrophages exhibited enhanced antigen-presentation capabilities. T cell profiles shifted from naive effector or memory states, specific rise helper 1 cells 17 subpopulations increased regulatory activation CD4 cells. Furthermore, CD8 marked Klra decreased while subpopulation exhausted-like expanded, retaining potent immunostimulatory proinflammatory Critically, these inherent disparities not only persisted but were further amplified within hemispheres following In summary, our comprehensive insights into key attributes provide vital theoretical foundation for understanding strokes also other age-associated diseases.

Language: Английский

Citations

16