Thrombin induces ACSL4-dependent ferroptosis during cerebral ischemia/reperfusion

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Feb. 23, 2022

Abstract Ischemic stroke represents a significant danger to human beings, especially the elderly. Interventions are only available remove clot, and mechanism of neuronal death during ischemic is still in debate. Ferroptosis increasingly appreciated as cell after ischemia various organs. Here we report that serine protease, thrombin, instigates ferroptotic signaling by promoting arachidonic acid mobilization subsequent esterification gene, acyl-CoA synthetase long-chain family member 4 (ACSL4). An unbiased multi-omics approach identified thrombin ACSL4 genes/proteins, their pro-ferroptotic phosphatidylethanolamine lipid products, prominently altered upon middle cerebral artery occlusion rodents. Genetically or pharmacologically inhibiting multiple points this pathway attenuated outcomes models vitro vivo. Therefore, thrombin-ACSL4 axis may be key therapeutic target ameliorate injury stroke.

Language: Английский

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Molecular mechanisms of ischemia and glutamate excitotoxicity

Life Sciences, Journal Year: 2023, Volume and Issue: 328, P. 121814 - 121814

Published: May 25, 2023

Excitotoxicity is classically defined as the neuronal damage caused by excessive release of glutamate, and subsequent activation excitatory plasma membrane receptors. In mammalian brain, this phenomenon mainly driven glutamate receptors (GRs). common to several chronic disorders Central Nervous System (CNS) considered primary mechanism loss function cell death in acute CNS diseases (e.g. ischemic stroke). Multiple mechanisms pathways lead excitotoxic including pro-death signaling cascade events downstream receptors, calcium (Ca2+) overload, oxidative stress, mitochondrial impairment, synaptic cleft well altered energy metabolism. Here, we review current knowledge on molecular that underlie excitotoxicity, emphasizing role Nicotinamide Adenine Dinucleotide (NAD) We also discuss novel promising therapeutic strategies treat highlighting recent clinical trials. Finally, will shed light ongoing search for stroke biomarkers, an exciting field research, which may improve diagnosis, prognosis allow better treatment options.

Language: Английский

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Cellular recovery after prolonged warm ischaemia of the whole body

Nature, Journal Year: 2022, Volume and Issue: 608(7922), P. 405 - 412

Published: Aug. 3, 2022

Language: Английский

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Mitochondrial-targeted and ROS-responsive nanocarrier via nose-to-brain pathway for ischemic stroke treatment

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 13(12), P. 5107 - 5120

Published: June 20, 2023

Oxidative stress injury and mitochondrial dysfunction are major obstacles to neurological functional recovery after ischemic stroke. The development of new approaches simultaneously diminish oxidative resist is urgently needed. Inspired by the overproduced reactive oxygen species (ROS) at neuron mitochondria, multifunctional nanoparticles with ROS-responsiveness mitochondrial-targeted (SPNPs) were engineered, achieving specific targeting delivery controllable drug release penumbra. Due nose-to-brain pathway, SPNPs which encapsulated in a thermo-sensitive gel intranasal administration directly delivered penumbra bypassing blood‒brain barrier (BBB) enhancing efficiency. potential for stroke treatment was systematically evaluated

Language: Английский

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Clinical targeting of the cerebral oxygen cascade to improve brain oxygenation in patients with hypoxic–ischaemic brain injury after cardiac arrest

Intensive Care Medicine, Journal Year: 2023, Volume and Issue: 49(9), P. 1062 - 1078

Published: July 28, 2023

The cerebral oxygen cascade includes three key stages: (a) convective delivery representing the bulk flow of to vascular bed; (b) diffusion from blood into brain tissue; and (c) cellular utilisation for aerobic metabolism. All stages may become dysfunctional after resuscitation cardiac arrest contribute hypoxic–ischaemic injury (HIBI). Improving by optimising has been widely investigated as a strategy mitigate HIBI. However, clinical trials aimed at have yielded neutral results. Advances in understanding HIBI pathophysiology suggest that impairments pertaining should also be considered identifying therapeutic strategies management patients. Culprit mechanisms these include widening barrier due peri-vascular oedema mitochondrial dysfunction. An integrated approach encompassing both intra-parenchymal non-invasive neuromonitoring techniques aid detecting pathophysiologic changes enable patient-specific reducing severity

Language: Английский

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Improving Outcomes After Post–Cardiac Arrest Brain Injury: A Scientific Statement From the International Liaison Committee on Resuscitation

Circulation, Journal Year: 2024, Volume and Issue: 150(7)

Published: June 27, 2024

This scientific statement presents a conceptual framework for the pathophysiology of post–cardiac arrest brain injury, explores reasons previous failure to translate preclinical data clinical practice, and outlines potential paths forward. Post–cardiac injury is characterized by 4 distinct but overlapping phases: ischemic depolarization, reperfusion repolarization, dysregulation, recovery repair. Previous research has been challenging because limitations laboratory models; heterogeneity in patient populations enrolled; overoptimistic estimation treatment effects leading suboptimal sample sizes; timing route intervention delivery; limited or absent evidence that engaged mechanistic target; postresuscitation care, prognostication, withdrawal life-sustaining treatments. Future trials must tailor their interventions subset patients most likely benefit deliver this at appropriate time, through route, dose. The complexity suggests monotherapies are unlikely be as successful multimodal neuroprotective therapies. Biomarkers should developed identify with targeted mechanism quantify its severity, measure response therapy. Studies need adequately powered detect effect sizes realistic meaningful patients, families, clinicians. Study designs optimized accelerate evaluation promising interventions. Multidisciplinary international collaboration will essential realize goal developing effective therapies injury.

Language: Английский

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Single-nucleus RNA sequencing reveals glial cell type-specific responses to ischemic stroke in male rodents

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 24, 2024

Neuroglia critically shape the brain´s response to ischemic stroke. However, their phenotypic heterogeneity impedes a holistic understanding of cellular composition early lesion. Here we present single cell resolution transcriptomics dataset acute infarction. Oligodendrocyte lineage cells and astrocytes range among most transcriptionally perturbed populations exhibit infarction- subtype-specific molecular signatures. Specifically, find infarction restricted proliferating oligodendrocyte precursor (OPCs), mature oligodendrocytes reactive astrocytes, exhibiting transcriptional commonalities in injury. OPCs are involved shared immuno-glial cross talk with stroke-specific myeloid cells. Within perilesional zone, osteopontin positive accumulate close proximity CD44

Language: Английский

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Polyphenylalanine-Baicalein Nanomicelles Reduce Nerve Cell Apoptosis and Inflammation to Enhance Neuroprotection and Poststroke Rehabilitation

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

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Questioning Glutamate Excitotoxicity in Acute Brain Damage: The Importance of Spreading Depolarization

Neurocritical Care, Journal Year: 2022, Volume and Issue: 37(S1), P. 11 - 30

Published: Feb. 22, 2022

Abstract Background Within 2 min of severe ischemia, spreading depolarization (SD) propagates like a wave through compromised gray matter the higher brain. More SDs arise over hours in adjacent tissue, expanding neuronal damage. This period represents therapeutic window to inhibit SD and so reduce impending tissue injury. Yet most neuroscientists assume that course early brain injury can be explained by glutamate excitotoxicity, concept immediate release promotes downstream There are many problems with being unseen culprit, practical has yielded zero therapeutics past 30 years. But basic science is also flawed, arising from dubious foundational observations beginning 1950s Methods Literature pertaining excitotoxicity 60 years critiqued. Results Excitotoxicity theory centers on excessive resulting hyperexcitation. instigates poststroke cascades subsequent secondary By contrast, argues although evokes some brief release, acute damage cascade neurons elicited metabolic stress SD, not release. The challenge we present here find new clinical targets based more informed science. motivated continuing failure industry develop drugs following ischemic stroke, traumatic injury, or sudden cardiac arrest. One important step recognize plays central role promoting We argue uncovering molecular biology initiation propagation essential because usually acutely injured unless them. how it shaped research then addressed, followed critique its fading relevance study Conclusions Spreading depolarizations better account for ischemia than does glutamate.

Language: Английский

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Expansion-enhanced super-resolution radial fluctuations enable nanoscale molecular profiling of pathology specimens

Nature Nanotechnology, Journal Year: 2023, Volume and Issue: 18(4), P. 336 - 342

Published: April 1, 2023

Expansion microscopy physically enlarges biological specimens to achieve nanoscale resolution using diffraction-limited systems1. However, optimal performance is usually reached laser-based systems (for example, confocal microscopy), restricting its broad applicability in clinical pathology, as most centres have access only light-emitting diode (LED)-based widefield systems. As a possible alternative, computational method for image enhancement, namely, super-resolution radial fluctuations (SRRF)2,3, has recently been developed. this not explored pathology date, because on own, it does sufficient routine use. Here, we report expansion-enhanced (ExSRRF), simple, robust, scalable and accessible workflow that provides of up 25 nm LED-based microscopy. ExSRRF enables molecular profiling subcellular structures from archival formalin-fixed paraffin-embedded tissues complex experimental specimens, including ischaemic, degenerative, neoplastic, genetic immune-mediated disorders. Furthermore, examples potential application show can be used identify quantify classical features endoplasmic reticulum stress the murine ischaemic kidney diagnostic ultrastructural human biopsies.

Language: Английский

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