Noncanonical feedback loop between “RIP3–MLKL” and “4EBP1–eIF4E” promotes neuronal necroptosis

MedComm, Год журнала: 2025, Номер 6(3)

Опубликована: Фев. 18, 2025

Stroke is a leading risk factor for disability and death. Necroptosis involved in stroke pathogenesis. However, the molecular mechanisms underlying necroptosis remain unclear. The mammalian target of rapamycin complex 1 (mTORC1) modulates gut epithelium. Eukaryotic translation initiation 4E (eIF4E)-binding protein-1 (4EPB1) one main downstream molecules mTORC1. This study addresses role 4EBP1-eIF4E pathway necroptosis. was found to be activated both necroptotic HT-22 mouse middle cerebral artery occlusion (MCAO) models. Functionally, 4EBP1 overexpression, eIF4E knockdown, inhibition suppressed necroptosis, respectively. Furthermore, positive feedback circuit observed between receptor-interacting protein-3 (RIP3)-mixed lineage kinase domain-like protein (MLKL) pathways, which RIP3-MLKL activates by degrading activating eIF4E. turn enhanced activation. activation derived from this loop may stimulate cytokine production, key associated with Finally, using MCAO model, application eIF4E, RIP3, MLKL inhibitors have regulatory mechanism similar that vitro study, reducing infarct volume improving neurological function mice.

Язык: Английский

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FOXO3-induced microRNA-128-3p promotes the progression of spinal cord injury in mice via regulating NLRP3 inflammasome-mediated pyroptosis

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Фев. 21, 2025

Spinal cord injury (SCI) remains a severe condition with an extremely high disability rate and complex pathophysiologic mechanisms. Pyroptosis, inflammatory form of cell death triggered by certain inflammasomes, has key role in variety diseases, including SCI. However, it is unclear whether microRNAs (miRNAs), novel regulators the SCI, are involved SCI-induced pyroptosis. Two GEO miRNA expression profiles (GSE158195 GSE90452) were downloaded, differentially expressed miRNAs analyzed bioinformatics methods. An vivo animal model vitro cellular SCI constructed female C57BL/6 mice BV-2 cells for studying possible roles FOXO3, miR-128-3p NLRP3-mediated pyroptosis Markers ROS, inflammation measured RT-qPCR, Western blotting, immunofluorescence, flow cytometry, enzyme-linked immunosorbent assays. Histopathological changes spinal tissue detected using hematoxylin eosin immunohistochemical. The Basso-Beattie-Bresnahan (BBB) score was used to evaluate motor function each group. Bioinformatics analysis GSE158195 GSE90452 datasets revealed significant downregulation miR-128-3p, phenomenon that consistently observed model. Functionally, upregulation improved functional behavioral recovery, relieved pathological injury, repressed oxidative stress, alleviated mouse models. We also confirmed Thioredoxin-interacting protein (TXNIP) target gene overexpression TXNIP can effectively reverse improvement Moreover, we found transcription factor FOXO3 facilitated expression, its resulted similar effects To best our knowledge, this first report demonstrating secondary through modulation pathway. Our results suggest FOXO3/miR-128-3p/TXNIP/NLRP3-mediated axis may be potential therapeutic

Язык: Английский

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Gallic acid alleviates ferroptosis by negatively regulating APOC3 and improves nerve function deficit caused by traumatic brain injury

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Март 6, 2025

Traumatic brain injury (TBI) is more common than ever and becoming a global public health issue. A variety of secondary injuries occur after TBI, including ferroptosis characterized by iron-dependent lipid peroxidation. Gallic acid kind traditional Chinese medicine, which has many biological effects such as anti-inflammatory antioxidant. We further investigated whether can improve the neurological impairment caused TBI targeting APOC3. Weighted gene coexpression network analyses (WGCNA) 3 kinds machine-learning algorithms were used to find potential biomarkers. Then HERB database was select herb that acted on target Finally, we selected drug APOC3 verified Western blotting. The effect improvement function studied Nissl staining FJB staining. cognitive ability mice explored through behavioral experiments. inhibit expression level thus TBI. It also reduce degeneration nerve tissue inhibiting deficit. experiment proved alleviate APOC3, then

Язык: Английский

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Emerging importance of m6A modification in liver cancer and its potential therapeutic role

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2025, Номер unknown, С. 189299 - 189299

Опубликована: Март 1, 2025

Язык: Английский

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Intranasal delivery of engineered extracellular vesicles promotes neurofunctional recovery in traumatic brain injury

Journal of Nanobiotechnology, Год журнала: 2025, Номер 23(1)

Опубликована: Март 21, 2025

Traumatic brain injury (TBI) is a leading cause of disability in adults, significantly affecting patients' quality life. Extracellular vesicles (EVs) derived from human adipose-derived mesenchymal stem cells (hADSCs) have demonstrated therapeutic potential TBI treatment. However, their limited targeting ability, short half-life, and low bioavailability present significant challenges for clinical application. In this study, we engineered extracellular (EEVs) by transfecting hADSCs with lentivirus incorporating ultra-small paramagnetic nanoparticles (USPNs), resulting EVs enhanced miRNA expression targeted delivery capabilities. These EEVs were administered intranasally to specifically target sites, effectively modulating the NF-κB signaling pathway suppress neuroinflammation. both vitro vivo assessments, exhibited superior efficacy promoting neurofunctional recovery neurogenesis after compared unmodified EVs. Furthermore, validation using organoid models confirmed EEVs' remarkable ability neuroinflammation, offering promising strategy

Язык: Английский

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Novel Insights into Neuroinflammatory Mechanisms in Traumatic Brain Injury: Focus on Pattern Recognition Receptors as Therapeutic Targets

Cytokine & Growth Factor Reviews, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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Mesenchymal stem cell exosomes therapy for the treatment of traumatic brain injury: mechanism, progress, challenges and prospects

Journal of Translational Medicine, Год журнала: 2025, Номер 23(1)

Опубликована: Апрель 11, 2025

Язык: Английский

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The Role of Casr Inhibition-Mediated M2 Microglial Transformation in Ischemic Preconditioning Against Stroke

Current Medical Science, Год журнала: 2025, Номер unknown

Опубликована: Фев. 21, 2025

Язык: Английский

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TAK1 at the crossroads of multiple regulated cell death pathways: from molecular mechanisms to human diseases

FEBS Journal, Год журнала: 2025, Номер unknown

Опубликована: Март 6, 2025

Regulated cell death (RCD), the form of that can be genetically controlled by multiple signaling pathways, plays an important role in organogenesis, tissue remodeling, and maintenance organism homeostasis is closely associated with various human diseases. Transforming growth factor-beta-activated kinase 1 (TAK1) a member serine/threonine protein family, which respond to different internal external stimuli participate inflammatory immune responses. Emerging evidence suggests TAK1 regulator at crossroad RCD including apoptosis, necroptosis, pyroptosis, PANoptosis. The regulation affects disease progression through therapeutic strategies targeting have been proposed for diseases, central nervous system cancers. In this review, we provide overview downstream pathways regulated its binding proteins. Their critical regulatory roles forms are also summarized. addition, discuss potential treatment specific focus on neurological disorders cancer.

Язык: Английский

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Pterostilbene improves neurological dysfunction and neuroinflammation after ischaemic stroke via HDAC3/Nrf1-mediated microglial activation

Cellular & Molecular Biology Letters, Год журнала: 2024, Номер 29(1)

Опубликована: Авг. 28, 2024

Stroke is a type of acute brain damage that can lead to series serious public health challenges. Demonstrating the molecular mechanism stroke-related neural cell degeneration could help identify more efficient treatment for stroke patients. Further elucidation factors regulate microglia and nuclear factor (erythroid-derived 2)-like 1 (Nrf1) may promising strategy treating neuroinflammation after ischaemic stroke. In this study, we investigated possible role pterostilbene (PTS) in Nrf1 regulation animal models ischaemia

Язык: Английский

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