NEMO‐Binding Domain/IKKγ Inhibitory Peptide Alleviates Neuronal Pyroptosis in Spinal Cord Injury by Inhibiting ASMase‐Induced Lysosome Membrane Permeabilization

Advanced Science, Journal Year: 2024, Volume and Issue: 11(40)

Published: Sept. 3, 2024

Abstract A short peptide termed NEMO‐binding domain (NBD) has an inhibitory effect on nuclear factor kappa‐B (NF‐κB). Despite its efficacy in inhibiting inflammatory responses, the precise neuroprotective mechanisms of NBD spinal cord injury (SCI) remain unclear. This study aims to determine whether pyroptosis‐related aspects involved effects post‐SCI.Using RNA sequencing, molecular SCI are explored. The evaluation functional recovery is performed using Basso mouse scale, Nissl staining, footprint analysis, Masson's trichrome and HE staining. Western blotting, enzyme‐linked immunosorbent assays, immunofluorescence assays used examine pyroptosis, autophagy, lysosomal membrane permeabilization (LMP), acid sphingomyelinase (ASMase), NF‐κB/p38‐MAPK related signaling pathway.NBD mitigated glial scar formation, reduced motor neuron death, enhanced mice. Additionally, inhibits ameliorate LMP‐induced autophagy flux disorder post‐SCI. Mechanistically, alleviates LMP subsequently enhances by ASMase through NF‐κB/p38‐MAPK/Elk‐1/Egr‐1 cascade, thereby mitigating neuronal death. contributes restoration suppressing ASMase‐mediated depression, pyroptosis following SCI, which may have potential clinical application value.

Language: Английский

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ESCRT III Regulates Lysosomal Perinuclear Clustering by Inhibiting Kinesin 1 Leading to Agnps Cytotoxicity in Human Cells

Advanced Materials Interfaces, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Abstract Silver nanoparticles (AgNPs) are recognized for their strong antibacterial properties, particularly in applications such as wound and burn treatment; however, the mechanisms of AgNP‐induced cytotoxicity remain inadequately defined. This study investigates role lysosomal dysfunction cytotoxicity, focusing on perinuclear clustering (LPC) its relationship with cellular apoptosis. Human fibroblast HS27 cells treated 24 µg mL −1 AgNPs over 48 h, dynamics, localization, apoptosis rates analyzed through confocal microscopy flow cytometry. Protein expression levels charged multivesicular body protein 4B(CHMP4B) Kinesin 1, which central to transport membrane repair, examined via western blotting. The findings reveal that AgNP exposure leads LPC an increase a time‐dependent manner, accompanied by reduced 1 expression. Further, inhibition CHMP4B significantly promoted apoptosis, while overexpression mitigated cytotoxic effects, underscoring essential roles integrity. provides new insights into pathways disruption, suggests potential molecular targets reduce adverse effects therapeutic applications. These results lay foundation optimizing efficacy improving safety profile clinical settings.

Language: Английский

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Emerging roles of the acid sphingomyelinase/ceramide pathway in metabolic and cardiovascular diseases: Mechanistic insights and therapeutic implications

World Journal of Cardiology, Journal Year: 2025, Volume and Issue: 17(2)

Published: Feb. 24, 2025

Metabolic diseases have emerged as a leading cause of mortality from non-communicable diseases, posing significant global public health challenge. Although the association between ceramides (Cers) and metabolic is well-established, role acid sphingomyelinase (ASMase)/Cer pathway in these remains underexplored. This review synthesizes recent research on biological functions, regulatory mechanisms, targeted therapies related to ASMase/Cer conditions, including obesity, diabetes, non-alcoholic fatty liver disease, cardiovascular disease. The effects disease-related indicators, such glycolipid metabolism, insulin resistance, inflammation, mitochondrial homeostasis are elucidated. Moreover, this article discusses therapeutic strategies using inhibitors for inverse prevention treatment light possible efficacy blockade arresting progression diseases. These insights offered herein should provide insight into contribution offer tools develop interventions pathologies their severe complications.

Language: Английский

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Activation of FANCC attenuates mitochondrial ROS-driven necroptosis by targeting TBK1-dependent mitophagy in astrocytes after spinal cord injury

Theranostics, Journal Year: 2025, Volume and Issue: 15(9), P. 4188 - 4211

Published: March 18, 2025

Rationale: Necroptosis in astrocytes induced by mitochondrial dysfunction following spinal cord injury (SCI) significantly contributes to neuronal functional deficits. Mitophagy plays a crucial role clearing damaged mitochondria and inhibiting necroptosis. Fanconi anemia complementation group C (FANCC), member of the gene family, exerts protective facilitating mitophagy immune processes. However, FANCC SCI-induced astrocytic necroptosis underlying mechanisms remain unexplored. Methods: Astrocyte-specific conditional knockout (Fanccfl/fl-GFAP-Cre) mice, obtained mating Fanccfl/fl mice with GFAP-Cre served as model moderate thoracic contusion injuries. Using bulk single-nucleus RNA sequencing, we investigated after SCI. We assessed through quantitative PCR, western blotting, flow cytometry, immunofluorescence, transmission electron microscopy. Molecular were explored via co-immunoprecipitation, proteomics, molecular docking, confocal imaging. Computer virtual screening identified poliumoside activator. Histopathological staining assessments (gait analysis, Basso Mouse Scale, hindlimb reflex score) conducted evaluate therapeutic effects on Results: Astrocytic deficiency exacerbated damage, leading severe neurological Conversely, overexpression increased PTEN-induced kinase 1-Parkin expression, thereby activating reducing Proteomics revealed FANCC's interaction specific peptide TANK-binding 1 (TBK1), which further promoted mitophagy. Treatment activator improved neural pathology motor function recovery SCI mice. Conclusion: The current study indicated that interacts TBK1 consequently mediates Parkin translocation, activates mitophagy, inhibits astrocyte Our findings demonstrate neuroprotective potential for amelioration.

Language: Английский

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TREM2 Impedes Recovery After Spinal Cord Injury by Regulating Microglial Lysosomal Membrane Permeabilization‐Mediated Autophagy

Cell Proliferation, Journal Year: 2025, Volume and Issue: unknown

Published: May 4, 2025

ABSTRACT Microglia, considered as the main immune responder, play an important role in regulating neuroinflammation central nervous system (CNS) disorders. Our previous work found that TREM2 is highly expressed microglia and related to their functional state. However, specific of spinal cord injury has not yet been explored. To further investigate potential mechanism TREM2, we performed single‐cell sequencing on wild‐type (Wt) Trem2 −/− mice before after injury. Compared Wt mice, lysosome, autophagy membrane‐related pathways are more strongly activated suggesting may exert its effects by influencing lysosomal membranes autophagy. Mechanistically, demonstrated knockout can reduce nuclear translocation TFEB decreasing phosphorylation Syk. Furthermore, validated vitro vivo silencing promote repairing membrane permeabilization. Through immunofluorescence, 3D gait analysis, motor evoked experiments, H&E staining Masson staining, increased level rescue both histological recovery Collectively, these results only suggest microglial regulated a TREM2‐dependent LMP manner, but also, importantly, they provide promising clinical translation strategy based gene therapy for lysosome‐related

Language: Английский

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Rutin Attenuates Distraction Spinal Cord Injury by Inhibiting Microglial Inflammation Through Downregulation of P38 MAPK/NF-κB/STAT3 Pathway

Molecular Neurobiology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 19, 2024

Language: Английский

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