Targeted mRNA Nanoparticles Ameliorate Blood–Brain Barrier Disruption Postischemic Stroke by Modulating Microglia Polarization

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

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Interleukin-4 from curcumin-activated OECs emerges as a central modulator for increasing M2 polarization of microglia/macrophage in OEC anti-inflammatory activity for functional repair of spinal cord injury

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: March 6, 2024

Abstract Microglia/macrophages are major contributors to neuroinflammation in the central nervous system (CNS) injury and exhibit either pro- or anti-inflammatory phenotypes response specific microenvironmental signals. Our latest vivo vitro studies demonstrated that curcumin-treated olfactory ensheathing cells (aOECs) can effectively enhance neural survival axonal outgrowth, transplantation of aOECs improves neurological outcome after spinal cord (SCI). The therapeutic effect is largely attributed aOEC activity through modulation microglial polarization from M1 M2 phenotype. However, very little known about what viable molecules actively responsible for switch underlying mechanisms polarization. Herein, we show Interleukin-4 (IL-4) plays a leading role triggering phenotype, appreciably decreasing levels markers IL‑1β, IL‑6, tumour necrosis factor-alpha (TNF-α) inducible nitric oxide synthase (iNOS) elevating Arg-1, TGF-β, IL-10, CD206. Strikingly, blockade IL-4 signaling by siRNA neutralizing antibody medium reverses transition M2, activated microglia stimulated with lacking significantly decreases neuronal neurite outgrowth. In addition, improved function deficits SCI rats. More importantly, crosstalk between JAK1/STAT1/3/6-targeted downstream signals NF-κB/SOCS1/3 predominantly orchestrates IL-4-modulated event. These results provide new insights into molecular driving M1-to-M2 shift shed light on therapies

Language: Английский

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From Lab to Life: Exploring Cutting-Edge Models for Neurological and Psychiatric Disorders

Biomedicines, Journal Year: 2024, Volume and Issue: 12(3), P. 613 - 613

Published: March 8, 2024

Neuroscience, neurology, and psychiatry are rapidly evolving fields that aim to understand the complex mechanisms underlying brain function dysfunction, as well develop effective interventions for various neurological psychiatric disorders [...]

Language: Английский

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From Lab to Life: Exploring Cutting-Edge Models for Neurological and Psychiatric Disorders

Published: March 5, 2024

Delve into the dynamic realms of neuroscience, neurology, and psychiatry with this groundbreaking editorial, unveiling intricate mechanisms brain function dysfunction. Explore latest advancements in molecular biology, genetics, epigenetics, pharmacology, neuroimaging that are revolutionizing our understanding neurological psychiatric disorders. Uncover challenges gaps translating cutting-edge research practical clinical applications, aiming to enhance lives patients their families. Discover pivotal role neuroplasticity reshaping brain's adaptability throughout life, alongside promising potential non-invasive stimulation techniques like transcranial magnetic direct current stimulation. Embark on a journey innovation collaboration as researchers clinicians strive bridge gap between bench bedside, offering hope for improved diagnosis, prevention, treatment complex conditions. Join us exploration transformative ideas novel interventions hold key brighter future individuals society.

Language: Английский

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Glial Cells as Therapeutic Approaches in Brain Ischemia-Reperfusion Injury

Cells, Journal Year: 2021, Volume and Issue: 10(7), P. 1639 - 1639

Published: June 30, 2021

Ischemic stroke is the second cause of mortality and first long-term disability constituting a serious socioeconomic burden worldwide. Approved treatments include thrombectomy rtPA intravenous administration, which, despite their efficacy in some cases, are not suitable for great proportion patients. Glial cell-related therapies progressively overcoming inefficient neuron-centered approaches preclinical phase. Exploiting ability microglia to naturally switch between detrimental protective phenotypes represents promising therapeutic treatment, similar way what happens with astrocytes. However, duality present many roles these cells upon ischemia poses notorious difficulty disentangling precise pathways target. Still, promoting M2/A2 microglia/astrocyte inhibiting M1/A1 neurotoxic profiles globally rendering results different vivo models stroke. On other hand, described oligodendrogenesis after brain seems be strictly beneficial, although less studied players paradigm negative effects could oligodendrocytes next years. Here, we review recent advances understanding role mentioned glial cell types main pathological events ischemic stroke, including inflammation, blood barrier integrity, excitotoxicity, reactive oxygen species management, metabolic support, neurogenesis, among others, special attention tested approaches.

Language: Английский

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Microglia-mediated neuroinflammation and neuroplasticity after stroke

Frontiers in Cellular Neuroscience, Journal Year: 2022, Volume and Issue: 16

Published: Aug. 16, 2022

Stroke remains a major cause of long-term disability and mortality worldwide. The immune system plays an important role in determining the condition brain following stroke. As resident innate cells central nervous system, microglia are primary responders defense network covering entire parenchyma, exert various functions depending on dynamic communications with neurons, astrocytes, other neighboring under both physiological or pathological conditions. Microglia activation polarization is crucial for damage repair ischemic stroke, considered double-edged sword neurological recovery. can exist pro-inflammatory states promote secondary damage, but they also secrete anti-inflammatory cytokines neurotrophic factors facilitate recovery In this review, we focus mechanisms microglia-mediated neuroinflammation neuroplasticity after ischemia relevant potential microglia-based interventions stroke therapy.

Language: Английский

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Microglia dynamics in aging-related neurobehavioral and neuroinflammatory diseases

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: Nov. 17, 2022

Abstract Microglia represent the first line of immune feedback in brain. Beyond surveillance, they are essential for maintaining brain homeostasis. Recent research has revealed microglial cells' spatiotemporal heterogeneity based on their local and time-based functions trauma or disease when homeostasis is disrupted. Distinct "microglial signatures" have been recorded physiological states injuries, with discrete sometimes overlapping pro- anti-inflammatory functions. involved neurological repair processes, such as neurovascular unit restoration synaptic plasticity, manage extent damage due to phenotype switching. The versatility cellular phenotypes beyond classical M1/M2 classification, well double-edge actions microglia neurodegeneration, indicate need further exploration cell dynamics contribution neurodegenerative processes. This review discusses homeostatic different subsets focusing neuropathological conditions. Also, we address feasibility targeting a therapeutic strategy diseases.

Language: Английский

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The Translational Potential of Microglia and Monocyte-Derived Macrophages in Ischemic Stroke

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: June 20, 2022

The immune response to ischemic stroke is an area of study that at the forefront research and presents promising new avenues for treatment development. Upon cerebral vessel occlusion, innate system activated by danger-associated molecular signals from stressed dying neurons. Microglia, cell population within central nervous which phagocytose debris modulate via cytokine signaling, are first become activated. Soon after, monocytes arrive peripheral system, differentiate into macrophages, further aid in response. activation, both microglia monocyte-derived macrophages capable polarizing phenotypes can either promote or attenuate inflammatory Phenotypes hypothesized increase neuronal damage impair recovery function during later phases stroke. Therefore, modulating neuroimmune cells adopt anti-inflammatory post current interest potential In this review, we outline biology explain their roles acute, subacute, chronic stages stroke, highlight development efforts target these context

Language: Английский

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Microglial phagocytosis and regulatory mechanisms after stroke

Journal of Cerebral Blood Flow & Metabolism, Journal Year: 2022, Volume and Issue: 42(9), P. 1579 - 1596

Published: May 1, 2022

Stroke, including ischemic stroke and hemorrhagic can cause massive neuronal death disruption of brain structure, which is followed by secondary inflammatory injury initiated pro-inflammatory molecules cellular debris. Phagocytic clearance debris microglia, the brain’s scavenger cells, pivotal for neuroinflammation resolution neurorestoration. However, microglia also exacerbate loss phagocytosing stressed-but-viable neurons in penumbra, thereby expanding area hindering neurofunctional recovery. Microglia constantly patrol central nervous system using their processes to scour environment start or cease phagocytosis progress depending on “eat me” “don’t eat me’’ signals surface. An optimal immune response requires a delicate balance between different phenotypic states regulate neuro-inflammation facilitate reconstruction after stroke. Here, we examine literature discuss molecular mechanisms pathways regulating microglial phagocytosis, resulting effects neural regeneration, as well potential therapeutic targets that might modulate phagocytic activity improve neurological function

Language: Английский

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Smart Liposomal Nanocarrier Enhanced the Treatment of Ischemic Stroke through Neutrophil Extracellular Traps and Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase-Stimulator of Interferon Genes (cGAS-STING) Pathway Inhibition of Ischemic Penumbra

ACS Nano, Journal Year: 2023, Volume and Issue: 17(18), P. 17845 - 17857

Published: Sept. 15, 2023

Brain inflammation is regarded as one of the leading causes that aggravates secondary brain injury and hinders prognosis ischemic stroke. After stroke, high quantities peripheral neutrophils are recruited to lesions release neutrophil extracellular traps (NETs), aggravation blood-brain barrier (BBB) damage, activation microglia, ultimate neuronal death. Herein, a smart multifunctional delivery system has been developed regulate immune disorders in brain. Briefly, Cl-amidine, an inhibitor peptidylarginine deiminase 4 (PAD4), encapsulated into self-assembled liposomal nanocarriers (C-Lipo/CA) modified by reactive oxygen species (ROS)-responsive polymers fibrin-binding peptide achieve targeting stimuli-responsive drug. In mouse model cerebral artery occlusion/reperfusion (MCAO), C-Lipo/CA can suppress NETs process (NETosis) further inhibit cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator interferon genes (cGAS-STING) pathway addition, MCAO mice treated with significantly mitigated reperfusion injury, reduction area infarction 12.1%, compared saline group about 46.7%. These results demonstrated C-Lipo/CA, which integrated microglia regulation, BBB protection, neuron survival, exerts potential therapy strategy maximize ameliorating mortality

Language: Английский

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