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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Nuclear receptor coactivator 4-mediated ferritinophagy contributes to cerebral ischemia-induced ferroptosis in ischemic stroke

Pharmacological Research, Journal Year: 2021, Volume and Issue: 174, P. 105933 - 105933

Published: Oct. 9, 2021

Language: Английский

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Neuronal Death Mechanisms and Therapeutic Strategy in Ischemic Stroke

Neuroscience Bulletin, Journal Year: 2022, Volume and Issue: 38(10), P. 1229 - 1247

Published: May 5, 2022

Abstract Ischemic stroke caused by intracranial vascular occlusion has become increasingly prevalent with considerable mortality and disability, which gravely burdens the global economy. Current relatively effective clinical treatments are limited to intravenous alteplase thrombectomy. Even so, patients still benefit little due short therapeutic window risk of ischemia/reperfusion injury. It is therefore urgent figure out neuronal death mechanisms following ischemic in order develop new neuroprotective strategies. Regarding pathogenesis, multiple pathological events trigger activation cell pathways. Particular attention should be devoted excitotoxicity, oxidative stress, inflammatory responses. Thus, this article, we first review principal underlying mediated these significant events, such as intrinsic extrinsic apoptosis, ferroptosis, parthanatos, pyroptosis, necroptosis, autophagic death. Then, further discuss possibility interventions targeting summarize present pharmacological achievements.

Language: Английский

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The concept of intrinsic versus extrinsic apoptosis

Biochemical Journal, Journal Year: 2022, Volume and Issue: 479(3), P. 357 - 384

Published: Feb. 11, 2022

Regulated cell death is a vital and dynamic process in multicellular organisms that maintains tissue homeostasis eliminates potentially dangerous cells. Apoptosis, one of the better-known forms regulated death, activated when cell-surface receptors like Fas are engaged by their ligands (the extrinsic pathway) or BCL-2-family pro-apoptotic proteins cause permeabilization mitochondrial outer membrane intrinsic pathway). Both pathways apoptosis lead to activation family proteases, caspases, which responsible for final demise so-called execution phase apoptosis. In this review, I will first discuss most common types on morphological basis. then consider detail molecular apoptosis, discussing how they response specific stimuli sometimes overlapping. In-depth knowledge cellular mechanisms becoming more important not only field biology but also its translational potential several pathologies, including neurodegeneration cancer.

Language: Английский

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Targeting Ferroptosis: Pathological Mechanism and Treatment of Ischemia‐Reperfusion Injury

Oxidative Medicine and Cellular Longevity, Journal Year: 2021, Volume and Issue: 2021(1)

Published: Jan. 1, 2021

Ischemia‐reperfusion (I/R) is a pathological process that occurs in many organs and diseases. Reperfusion, recovery of blood flow, reoxygenation often lead to reperfusion injury. Drug therapy early can reduce tissue injury cell necrosis caused by ischemia, leading irreversible I/R Ferroptosis was clearly defined 2012 as newly discovered iron‐dependent, peroxide‐driven, nonapoptotic form regulated death. considered the cause This discovery provides new avenues for recognition treatment key factor leads organ failure. Given important role ferroptosis injury, there considerable interest potential targeted wide range injury‐related Recently, substantial progress has been made applying various The development regulators expected provide opportunities Herein, we analytically review mechanism related diseases from perspectives myocardial cerebral ischemic renal

Language: Английский

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Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis

Cellular and Molecular Immunology, Journal Year: 2022, Volume and Issue: 19(8), P. 913 - 924

Published: June 8, 2022

Language: Английский

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Iron, ferroptosis, and ischemic stroke

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 165(4), P. 487 - 520

Published: March 13, 2023

Abstract Over 30 million people suffer from the consequences of ischemic stroke. The precise molecular mechanism neuronal damage during stroke remains unclear; therefore, effective treatment post‐ischemic a critical challenge. Recently, iron has emerged as crucial factor in post‐reperfusion injuries, participating cell peroxidation, excitotoxicity, and distinctive death pathway, namely, ferroptosis. Since is tightly regulated brain important for functions, imbalance its metabolism, including overload deficiency, been shown to impact outcomes. This review summarizes current understanding pathological events associated with discusses relevant drug development. image

Language: Английский

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Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Dec. 10, 2023

Abstract Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other modes, plays pivotal role in regulating tumorigenesis offers new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications posttranslational (PTMs) promote resistance, cancer progression, metastasis. Accumulating studies indicate that can transcriptionally translationally determine vulnerability to ferroptosis functions as driver nervous system diseases (NSDs), cardiovascular (CVDs), liver diseases, lung kidney diseases. In this review, we first summarize the core molecular mechanisms ferroptosis. Then, roles processes, including histone PTMs, DNA methylation, noncoding RNA regulation such phosphorylation, ubiquitination, SUMOylation, acetylation, ADP-ribosylation, are concisely discussed. The PTMs genesis cancers, NSD, CVDs, well application PTM modulators therapy these then discussed detail. Elucidating mediated by will facilitate development promising combination therapeutic regimens containing or PTM-targeting agents inducers be used overcome chemotherapeutic resistance could prevent addition, highlight potential approaches chemoresistance halt

Language: Английский

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Regulated cell death pathways in cardiomyopathy

Acta Pharmacologica Sinica, Journal Year: 2023, Volume and Issue: 44(8), P. 1521 - 1535

Published: March 13, 2023

Language: Английский

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Targeting pyroptosis as a preventive and therapeutic approach for stroke

Cell Death Discovery, Journal Year: 2023, Volume and Issue: 9(1)

Published: May 10, 2023

Stroke has caused tremendous social stress worldwide, yet despite decades of research and development new stroke drugs, most have failed rt-PA (Recombinant tissue plasminogen activator) is still the accepted treatment for ischemic stroke. complexity mechanism led to unsatisfactory efficacy drugs in clinical trials, indicating that there are many gaps our understanding Pyroptosis a programmed cell death (PCD) with inflammatory properties thought be closely associated regulated by GSDMD gasdermin family, which when cleaved Caspase-1/Caspase-11 into N-GSDMD pore-forming activity can bind plasma membrane form small 10-20 nm pores, would allow release factors IL-18 IL-1β before rupture, greatly exacerbating response. The pyroptosis occurs mainly border zone cerebral infarction, glial cells, neuronal cells brain microvascular endothelial (BMECs) all undergo after stroke, largely exacerbates breakdown blood-brain barrier (BBB) thus aggravates injury. Therefore, may good direction In this review, we focus on latest mechanisms action process regulates development. We also suggest potential therapeutic target pathway, providing additional strategies management role After microglia first rush damaged area polarize M1 M2 types. Under influence various stimuli, pyroptosis, pro-inflammatory factors, converted type; astrocytes under stimulation leading astrocyte due increased osmotic pressure membrane, resulting water absorption swelling until rupture. BMECs, main structural component BBB, stimulated released from astrocytes, destruction integrity ultimately causing more severe damage. addition, neutrophils mediate NETs rather than IL-10=interleukin-10; TGF-β = transforming growth factor-β; IL-18=interleukin-18; interleukin-1β; TNF-α tumor necrosis factor-α; iNOS=induced nitrogen monoxide synthase; MMPs=Matrix metalloproteinases; D; BMECs=brain cells; BBB barrier.

Language: Английский

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