Fisetin Promotes Functional Recovery after Spinal Cord Injury by Inhibiting Microglia/Macrophage M1 Polarization and JAK2/STAT3 Signaling Pathway

Journal of Agricultural and Food Chemistry, Journal Year: 2024, Volume and Issue: 72(32), P. 17964 - 17976

Published: Aug. 3, 2024

Spinal cord injury (SCI) is one of the most serious health problems, with no effective therapy. Recent studies indicate that Fisetin, a natural polyphenolic flavonoid, exhibits multiple functions, such as life-prolonging, antioxidant, antitumor, and neuroprotection. However, restorative effects Fisetin on SCI underlying mechanism are still unclear. In present study, we found reduced LPS-induced apoptosis oxidative damage in PC12 cells reversed M1 polarization BV2 cells. Additionally, safely effectively promoted motor function recovery mice by attenuating neurological promoting neurogenesis at lesion. Moreover, administration inhibited glial scar formation, modulated microglia/macrophage polarization, neuroinflammation. Network pharmacology, RNA-seq, molecular biology revealed activation JAK2/STAT3 signaling pathway. Notably, Colivelin TFA, an activator signaling, attenuated Fis-mediated neuroinflammation inhibition therapeutic mice. Collectively, promotes functional after inhibiting Thus, may be promising drug for treatment SCI.

Language: Английский

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Molecular Mechanisms and Clinical Application of Multipotent Stem Cells for Spinal Cord Injury

Cells, Journal Year: 2022, Volume and Issue: 12(1), P. 120 - 120

Published: Dec. 28, 2022

Spinal Cord Injury (SCI) is a common neurological disorder with devastating psychical and psychosocial sequelae. The majority of patients after SCI suffer from permanent disability caused by motor dysfunction, impaired sensation, neuropathic pain, spasticity as well urinary complications, small number experience complete recovery. Current standard treatment modalities the aim to prevent secondary injury provide limited recovery lost functions. Stem Cell Therapy (SCT) represents an emerging approach using differentiation, paracrine, self-renewal capabilities stem cells regenerate injured spinal cord. To date, multipotent including mesenchymal (MSCs), neural (NSCs), hematopoietic (HSCs) represent most investigated types for in preclinical clinical studies. microenvironment has significant impact on survival, proliferation, differentiation transplanted cells. Therefore, deep understanding pathophysiology molecular mechanisms through which act may help improve efficacy SCT find new therapeutic approaches such stem-cell-derived exosomes, gene-modified cells, scaffolds, nanomaterials. In this literature review, pathogenesis action MSCs, NSCs, HSCs are comprehensively described. Moreover, treatment, optimal protocol cell administration, recent based or combined also discussed.

Language: Английский

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The acute spinal cord injury microenvironment and its impact on the homing of mesenchymal stem cells

Experimental Neurology, Journal Year: 2024, Volume and Issue: 373, P. 114682 - 114682

Published: Jan. 9, 2024

Language: Английский

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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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Aucubin promoted neuron functional recovery by suppressing inflammation and neuronal apoptosis in a spinal cord injury model

International Immunopharmacology, Journal Year: 2022, Volume and Issue: 111, P. 109163 - 109163

Published: Aug. 19, 2022

Language: Английский

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The Inflammatory Response after Moderate Contusion Spinal Cord Injury: A Time Study

Biology, Journal Year: 2022, Volume and Issue: 11(6), P. 939 - 939

Published: June 20, 2022

Spinal cord injury (SCI) initiates detrimental cellular and molecular events that lead to acute delayed neuroinflammation. Understanding the role of inflammatory response in SCI requires insight into temporal synthesis mediators. We subjected C57BL/6J mice investigated reactions. examined activation, recruitment, polarization microglia infiltrating immune cells, focusing specifically on tumor necrosis factor (TNF) its receptors TNFR1 TNFR2. In phase, TNF expression increased glial cells neuron-like followed by cells. TNFR2 levels phase were found preferentially neurons respectively. The was dominated infiltration granulocytes macrophages. Microglial/macrophage Arg1 from 1-7 days after SCI, an increase Itgam, Cx3cr1, P2ry12, which remained elevated throughout study. By 21 28 lesion core populated galectin-3+, CD68+, CD11b+ microglia/macrophages, surrounded a scar consisting GFAP+ astrocytes. Findings verified postmortem tissue individuals with SCI. Our findings support consensus future neuroprotective immunotherapies should aim selectively neutralize signaling while sustaining pro-regenerative processes.

Language: Английский

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Small extracellular vesicles derived from four dimensional-culture of mesenchymal stem cells induce alternatively activated macrophages by upregulating IGFBP2/EGFR to attenuate inflammation in the spinal cord injury of rats

Frontiers in Bioengineering and Biotechnology, Journal Year: 2023, Volume and Issue: 11

Published: April 28, 2023

Effectively reducing the inflammatory response after spinal cord injury (SCI) is a challenging clinical problem and subject of active investigation. This study employed porous scaffold-based three dimensional long-term culture technique to obtain human umbilical mesenchymal stem cell (hUC-MSC)-derived Small Extracellular Vesicles (sEVs) (three over time, "4D-sEVs"). Moreover, vesicle size, number, inner protein concentrations MSC 4D-sEVs contained altered profiles compared with those derived from 2D conditions. A proteomics analysis suggested broad changes, especially significant upregulation Epidermal Growth Factors Receptor (EGFR) Insulin-like Factor Binding Protein 2 (IGFBP2) in 2D-sEVs. The endocytosis allowed for binding EGFR IGFBP2, leading downstream STAT3 phosphorylation IL-10 secretion effective induction macrophages/microglia polarization pro-inflammatory M1 anti-inflammatory M2 phenotype, both vitro injured areas rats compressive/contusive SCI. reduction neuroinflammation delivery site epicenter led neuroprotection, as evidenced by number surviving neurons. Therefore, applying this novel 4D culture-derived could effectively curb increase tissue repair

Language: Английский

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Neuroprotective effects of tetramethylpyrazine on spinal cord injury-Related neuroinflammation mediated by P2X7R/NLRP3 interaction

European Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 964, P. 176267 - 176267

Published: Dec. 9, 2023

Language: Английский

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Trehalose enhances macrophage autophagy to promote myelin debris clearance after spinal cord injury

Cell & Bioscience, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 29, 2025

Abstract Background Myelin-laden foamy macrophages accumulate extensively in the lesion epicenter, exhibiting characteristics of autophagolysosomal dysfunction, which leads to prolonged inflammatory responses after spinal cord injury (SCI). Trehalose, known for its neuroprotective properties as an autophagy inducer, has yet be fully explored potential mitigate macrophage formation and exert therapeutic effects context SCI. Results We observed that trehalose significantly enhances phagocytosis clearance myelin a dose-dependent manner vitro. In vivo, administration markedly reduced debris accumulation, inhibited formation, suppressed responses, decreased fibrotic scarring, promoted axonal growth motor function recovery These beneficial may related overexpression transcription factor EB (TFEB), key regulator autophagy-lysosomal system, can rescue autophagic dysfunction inhibit responses. Additionally, on were abolished by chloroquine, inhibitor, suggesting trehalose’s candidate enhancing post-SCI. Conclusions Our findings underscore pivotal role modulating within macrophages, providing new perspectives treatment injury. Graphical abstract

Language: Английский

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Advances and New Therapies in Traumatic Spinal Cord Injury

Journal of Clinical Medicine, Journal Year: 2025, Volume and Issue: 14(7), P. 2203 - 2203

Published: March 24, 2025

Recovery from traumatic spinal cord injury (tSCI) is challenging due to the limited regenerative capacity of central nervous system restore cells, myelin, and neural connections. At clinical level, fundamental pillars treatment are reduction in secondary damage (neuroprotection) rehabilitation; these tools we have mitigate disability caused by (SCI). To date, treatments on which neuroprotection has been based prevention acute respiratory failure avoid hypoxia, early hemodynamic control, neuroprotective drugs surgical management. Optimizing control ensure adequate perfusion may be key management SCI. While agents like methylprednisolone fallen into disuse, several promising therapies currently being tested trials. In terms treatment, although their impact neurological recovery remains debated, appropriate bone decompression followed duroplasty selected cases increasingly recommended. Advances cell hold significant potential for enhancing both functional outcomes SCI patients. Moreover, emerging neuromodulation techniques, such as transcutaneous epidural stimulation, along with innovations rehabilitation technologies-such robotic systems exoskeletons-are becoming indispensable improving locomotion overall mobility individuals This article provides an update advances against tSCI, cellular therapies, new therapies.

Language: Английский

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