Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications

Medicinal Research Reviews, Journal Year: 2021, Volume and Issue: 42(1), P. 259 - 305

Published: May 6, 2021

Abstract Ischemic stroke caused by arterial occlusion is the most common type of stroke, which among frequent causes disability and death worldwide. Current treatment approaches involve achieving rapid reperfusion either pharmacologically or surgically, both are time‐sensitive; moreover, blood flow recanalization often ischemia/reperfusion injury. However, even though neuroprotective intervention urgently needed in event exact mechanisms neuronal during ischemic still unclear, consequently, capacity for drug development has remained limited. Multiple cell pathways implicated pathogenesis stroke. Here, we have reviewed these potential pathways, including intrinsic extrinsic apoptosis, necroptosis, autophagy, ferroptosis, parthanatos, phagoptosis, pyroptosis. We also latest results pharmacological studies on summarized emerging targets with a focus clinical trials. These observations may help to further understand pathological events bridge gap between basic translational research reveal novel interventions.

Language: Английский

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Ferroptosis in cancer and cancer immunotherapy

Cancer Communications, Journal Year: 2022, Volume and Issue: 42(2), P. 88 - 116

Published: Feb. 1, 2022

Abstract The hallmark of tumorigenesis is the successful circumvention cell death regulation for achieving unlimited replication and immortality. Ferroptosis a newly identified type dependent on lipid peroxidation which differs from classical programmed in terms morphology, physiology biochemistry. broad spectrum injury tumor tolerance are main reasons radiotherapy chemotherapy failure. effective rate immunotherapy as new treatment method less than 30%. can be seen radiotherapy, chemotherapy, immunotherapy; therefore, ferroptosis activation may potential strategy to overcome drug resistance mechanism traditional cancer treatments. In this review, characteristics causes by briefly described. addition, three metabolic regulations its crosstalk with signaling pathways summarized. Collectively, these findings suggest vital role based interaction immunotherapy, thus, indicating remarkable treatment.

Language: Английский

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Clockophagy is a novel selective autophagy process favoring ferroptosis

Science Advances, Journal Year: 2019, Volume and Issue: 5(7)

Published: July 5, 2019

Autophagy-dependent cell death may hold the key to understanding molecular basis of ferroptosis.

Language: Английский

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Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 24(1), P. 449 - 449

Published: Dec. 27, 2022

Regulated cell death (RCD) has a significant impact on development, tissue homeostasis, and the occurrence of various diseases. Among different forms RCD, ferroptosis is considered as type reactive oxygen species (ROS)-dependent regulated necrosis. ROS can react with polyunsaturated fatty acids (PUFAs) lipid (L) membrane via formation radical L• induce peroxidation to form L-ROS. Ferroptosis triggered by an imbalance between hydroperoxide (LOOH) detoxification iron-dependent L-ROS accumulation. Intracellular iron accumulation are two central biochemical events leading ferroptosis. Organelles, including mitochondria lysosomes involved in regulation metabolism redox In this review, we will provide overview peroxidation, well key components ferroptotic cascade. The main mechanism that reduces ability glutathione (GSH). GSH, tripeptide includes glutamic acid, cysteine, glycine, acts antioxidant substrate peroxidase 4 (GPX4), which then converted into oxidized (GSSG). Increasing expression GSH inhibit We highlight role xc- GSH-GPX4 pathway regulate system xc-, composed subunit solute carrier family members (SLC7A11 SLC3A2), mediates exchange cystine glutamate across plasma synthesize GSH. Accumulating evidence indicates requires autophagy machinery for its execution. Ferritinophagy used describe removal major storage protein ferritin machinery. Nuclear receptor coactivator (NCOA4) cytosolic bind subsequent degradation ferritinophagy. During ferritinophagy, stored released becomes available biosynthetic pathways. dysfunctional response implicated variety pathological conditions. inducers or inhibitors targeting redox- metabolism-related proteins signal transduction have been developed. simultaneous detection intracellular extracellular markers may help diagnose treat diseases related damage.

Language: Английский

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RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells

Autophagy, Journal Year: 2019, Volume and Issue: 16(8), P. 1482 - 1505

Published: Nov. 4, 2019

Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms remain poorly understood. Here, we show that the RNA-binding protein ZFP36/TTP (ZFP36 ring finger protein) plays crucial role in regulating ferroptosis hepatic stellate cells (HSCs). Upon exposure to ferroptosis-inducing compounds, ubiquitin ligase FBXW7/CDC4 (F-box and WD repeat domain containing 7) decreased ZFP36 expression by recognizing SFSGLPS motif. FBXW7 plasmid contributed classical ferroptotic events, whereas impaired plasmid-induced HSC ferroptosis. Interestingly, inhibited macroautophagy/autophagy activation destabilizing ATG16L1 (autophagy related 16 like 1) mRNA. eliminated inhibitory action on ferroptosis, enhanced effect autophagy. Importantly, promoted mRNA decay via binding AU-rich elements (AREs) within 3ʹ-untranslated region. The internal mutation ARE region abrogated ZFP36-mediated instability, prevented plasmid-mediated resistance. In mice, treatment with erastin sorafenib alleviated murine liver fibrosis inducing HSC-specific overexpression Zfp36 erastin- or sorafenib-induced Noteworthy, analyzed fibrotic patients hepatocellular carcinoma receiving monotherapy. Attractively, monotherapy led downregulation, ferritinophagy activation, induction human HSCs. Overall, these results revealed novel molecular signaling pathways also identified ZFP36-autophagy-dependent as potential target for fibrosis.Abbreviations ARE: elements; ATG: autophagy related; BECN1: beclin 1; CHX: cycloheximide; COL1A1: collagen type I alpha 1 chain; ELAVL1/HuR: ELAV RNA FBXW7/CDC4: F-box 7; FN1: fibronectin FTH1: ferritin heavy chain GPX4/PHGPx: glutathione peroxidase 4; GSH: glutathione; HCC: carcinoma; HSC: cell; LSEC: sinusoidal endothelial MAP1LC3A: microtubule associated light 3 alpha; MDA: malondialdehyde; NCOA4: nuclear receptor coactivator PTGS2/COX2: prostaglandin-endoperoxide synthase 2; RBP: protein; ROS: reactive oxygen species; SLC7A11/xCT: solute carrier family 7 member 11; SQSTM1/p62: sequestosome TNF: tumor necrosis factor; TP53/p53: p53; UTR: untranslated region; ZFP36/TTP:

Language: Английский

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Characteristics and Biomarkers of Ferroptosis

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: Jan. 21, 2021

The induction and consequences of regulated cell death (RCD) are accompanied by changes in gene protein expression, biochemical pathways, as well morphology size. Such RCDs have a significant impact on development, tissue homeostasis, the occurrence progression disease. Among different forms RCD, ferroptosis appears to be main cause damage driven iron overload lipid peroxidation. In fact, dysfunctional ferroptotic response is implicated variety pathological conditions diseases, such neurodegenerative ischemia-reperfusion injury, tumorigenesis, infections, immune diseases. Ferroptotic can fine-tuned through various oxidative stress antioxidant defense coupling with metabolism, transcription, degradation machinery. Accordingly, series inducers or inhibitors targeting redox- metabolism-related proteins signal transduction been developed. Although this kind RCD has recently attracted great interest basic clinical research, detecting monitoring still faces challenges. mini-review, we not only summarize latest knowledge about characteristics vitro vivo , but also discuss specificity limitations current biomarkers ferroptosis.

Language: Английский

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Mitochondrial DNA stress triggers autophagy-dependent ferroptotic death

Autophagy, Journal Year: 2020, Volume and Issue: 17(4), P. 948 - 960

Published: March 18, 2020

Pancreatic cancer tends to be highly resistant current therapy and remains one of the great challenges in biomedicine with very low 5-year survival rates. Here, we report that zalcitabine, an antiviral drug for human immunodeficiency virus infection, can suppress growth primary immortalized pancreatic cells through induction ferroptosis, iron-dependent form regulated cell death. Mechanically, this effect relies on zalcitabine-induced mitochondrial DNA stress, which activates STING1/TMEM173-mediated sensing pathway, leading macroautophagy/autophagy-dependent ferroptotic death via lipid peroxidation, but not a type I interferon response. Consequently, genetic pharmacological inactivation autophagy-dependent ferroptosis pathway diminishes anticancer effects zalcitabine culture animal models. Together, these findings only provide new approach also increase our understanding interplay between autophagy damage response shaping death.Abbreviations: ALOX: arachidonate lipoxygenase; ARNTL/BMAL1: aryl hydrocarbon receptor nuclear translocator-like; ATM: ATM serine/threonine kinase; ATG: autophagy-related; cGAMP: cyclic GMP-AMP; CGAS: GMP-AMP synthase; ER: endoplasmic reticulum; FANCD2: FA complementation group D2; GPX4: glutathione peroxidase 4; IFNA1/IFNα: alpha 1; IFNB1/IFNβ: beta MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; MDA: malondialdehyde; mtDNA: DNA; NCOA4: coactivator PDAC: ductal adenocarcinoma; POLG: polymerase gamma, catalytic subunit; qRT-PCR: quantitative reaction; RCD: death; ROS: reactive oxygen species; SLC7A11: solute carrier family 7 member 11; STING1/TMEM173: stimulator cGAMP interactor TFAM: transcription factor A,

Language: Английский

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Recent Advances in Nanomaterial‐Based Nanoplatforms for Chemodynamic Cancer Therapy

Advanced Functional Materials, Journal Year: 2021, Volume and Issue: 31(22)

Published: March 8, 2021

Abstract Triggered by the endogenous chemical energy in tumor microenvironment (TME), chemodynamic therapy (CDT) as an emerging non‐exogenous stimulant therapeutic modality has received increasing attention recent years. The agents can convert internal hydrogen peroxide (H 2 O ) into lethal reactive oxygen species (ROS) hydroxyl radicals ( • OH) for oncotherapy. Compared with other modalities, CDT possesses many notable advantages, such tumor‐specific, highly selective, fewer systemic side effects, and no need external stimulation. Nevertheless, mild acid pH, low H content, overexpressed reducing substance TME severely suppressed efficiency. With rapid development of nanotechnology, some kinds nanomaterials have been utilized improved In particular, excellent photo‐, ultrasound‐, magnetic‐, stimuli‐response properties make it possible combination cancer shown superior anti‐cancer activity than monotherapies. Therefore, is necessary to summarize application nanomaterial‐based therapy. this review, various nanomaterials‐based nanoplatforms its combinational therapies are summarized discussed, aiming provide inspiration design better‐quality promote lay foundation future conversion clinical applications.

Language: Английский

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Inhibiting Ferroptosis through Disrupting the NCOA4–FTH1 Interaction: A New Mechanism of Action

ACS Central Science, Journal Year: 2021, Volume and Issue: 7(6), P. 980 - 989

Published: May 6, 2021

Ferroptosis is an iron-dependent form of oxidative cell death, and the inhibition ferroptosis a promising strategy with which to prevent treat neurological diseases. Herein we report new inhibitor 9a novel mechanism action. It demonstrated that nuclear receptor coactivator 4 (NCOA4), cargo for ferritinophagy, target 9a. Compound blocks by reducing amount bioavailable intracellular ferrous iron through disrupting NCOA4–FTH1 protein–protein interaction. Further studies indicate directly binds recombinant protein NCOA4383–522 effectively NCOA4383–522–FTH1 In rat model ischemic stroke, significantly ameliorates ischemic-refusion injury. With first ligand 9a, this work reveals NCOA4 drug target. Additionally, interaction inhibitor. This paves road development inhibitors against

Language: Английский

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Ferroptosis Mechanisms Involved in Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(22), P. 8765 - 8765

Published: Nov. 20, 2020

Ferroptosis is a type of cell death that was described less than decade ago. It caused by the excess free intracellular iron leads to lipid (hydro) peroxidation. Iron essential as redox metal in several physiological functions. The brain one organs known be affected homeostatic balance disruption. Since 1960s, increased concentration central nervous system has been associated with oxidative stress, oxidation proteins and lipids, death. Here, we review main mechanisms involved process ferroptosis such peroxidation, glutathione peroxidase 4 enzyme activity, metabolism. Moreover, association pathophysiology some neurodegenerative diseases, namely Alzheimer’s, Parkinson’s, Huntington’s also addressed.

Language: Английский

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