Neural Regeneration Research最新文献

JOURNAL/nrgr/04.03/01300535-202606000-00064/figure1/v/2026-02-11T151048Z/r/image-tiff Ferroptosis, a type of cell death that mainly involves iron metabolism imbalance and lipid peroxidation, is strongly correlated with the phagocytic response caused by bleeding after spinal cord injury. Thus, in this study, bulk RNA sequencing data (GSE47681 and GSE5296) and single-cell RNA sequencing data (GSE162610) were acquired from gene expression databases. We then conducted differential analysis and immune infiltration analysis. Atf3 and Piezo1 were identified as key ferroptosis genes through random forest and least absolute shrinkage and selection operator algorithms. Further analysis of single-cell RNA sequencing data revealed a close relationship between ferroptosis and cell types such as macrophages/microglia and their intrinsic state transition processes. Differences in transcription factor regulation and intercellular communication networks were found in ferroptosis-related cells, confirming the high expression of Atf3 and Piezo1 in these cells. Molecular docking analysis confirmed that the proteins encoded by these genes can bind cycloheximide. In a mouse model of T8 spinal cord injury, low-dose cycloheximide treatment was found to improve neurological function, decrease levels of the pro-inflammatory cytokine inducible nitric oxide synthase, and increase levels of the anti-inflammatory cytokine arginase 1. Correspondingly, the expression of the ferroptosis-related gene Gpx4 increased in macrophages/microglia, while the expression of Acsl4 decreased. Our findings reveal the important role of ferroptosis in the treatment of spinal cord injury, identify the key cell types and genes involved in ferroptosis after spinal cord injury, and validate the efficacy of potential drug therapies, pointing to new directions in the treatment of spinal cord injury.

JOURNAL/nrgr/04.03/01300535-202606000-00060/figure1/v/2026-02-11T151048Z/r/image-tiff Delayed neurocognitive recovery following anesthesia and surgery is a common complication in older adult patients. Synapses are fundamental to cognitive function. The activity of synapses heavily depends on the energy supplied by synaptic mitochondria, which are significantly influenced by oxidative stress. Sirtuin 3 is a histone deacetylase located in the mitochondrial matrix that plays a pivotal role in regulating mitochondrial function. However, it remains unclear whether and how sirtuin 3 is involved in the development of delayed cognitive recovery. Therefore, in this study, we investigated the potential role of sirtuin 3 in synapses during delayed neurocognitive recovery. Our results showed that anesthesia and surgery induced cognitive impairment in mice and reduced sirtuin 3 protein expression. Overexpression of sirtuin 3 inhibited opening of the mitochondrial permeability transition pore by reducing acetylation of K166 on cyclophilin D and also rescued cognitive impairment. Aged mice carrying the cyclophilin D-K166R mutation exhibited significantly reduced cognitive impairment. Similarly, administering the mitochondrial permeability transition pore blocker, cyclosporine A, effectively alleviated the decline in synaptic mitochondrial function and cognitive impairment caused by anesthesia and surgery in aged mice. These results indicate that the sirtuin 3/cyclophilin D-K166/mPTP signaling pathway in hippocampal synaptic mitochondria is involved in delayed neurocognitive recovery of aged mice, suggesting this pathway could serve as a potential target for treatment.

JOURNAL/nrgr/04.03/01300535-202606000-00071/figure1/v/2026-02-11T151048Z/r/image-tiff Multiple sclerosis is a severe autoimmune disorder that is mainly mediated by pathogenic cluster of CD4 + T cell subsets. Despite advancements in the management of multiple sclerosis, there is a critical need for more effective and safer treatments. In the present study, we administered Lycium barbarum glycopeptide to a mouse model of experimental autoimmune encephalomyelitis-an animal model of multiple sclerosis-and evaluated its effects on pathogenic CD4 + T cell activation both in vivo and in vitro . Lycium barbarum glycopeptide significantly mitigated the clinical severity of experimental autoimmune encephalomyelitis, as demonstrated by reduced demyelination and neuroinflammation. Moreover, Lycium barbarum glycopeptide treatment decreased the infiltration of peripheral leukocytes into the central nervous system and suppressed pro-inflammatory cytokine expression. Lycium barbarum glycopeptide also modulated pathogenic CD4 + T cell activation by inhibiting T helper 1/T helper 17 cell differentiation while promoting regulatory T cell expansion. Notably, no side effects were observed, suggesting the long-term safety and tolerability of Lycium barbarum glycopeptide. Furthermore, RNA sequencing data indicated that Lycium barbarum glycopeptide inhibits activator protein-1, an essential regulator of T cell activation and differentiation. This finding was supported by the reversal of T helper/T helper 17 cell response suppression upon AP-1 blockade. Collectively, these results highlight the potential of Lycium barbarum glycopeptide as an innovative therapeutic agent for CD4 + T cell-associated autoimmune or inflammatory diseases, such as multiple sclerosis.

Phosphatidylethanolamine is a major phospholipid class abundant in the brain, particularly in the inner leaflet of the plasma and mitochondrial membranes. Although it is primarily synthesized from phosphatidylserine via decarboxylation in mitochondria or from ethanolamine via the cytidine diphosphate-ethanolamine pathway in the endoplasmic reticulum, phosphatidylethanolamine that resides in mitochondria is preferentially produced locally and is distinct and separate from the pool of phosphatidylethanolamine made in the endoplasmic reticulum. Mitochondria-derived phosphatidylethanolamine is not only essential for mitochondrial integrity but also is exported to other organelles to fulfill diverse cellular functions. Neurons are highly enriched with phosphatidylethanolamine, and the importance of phosphatidylethanolamine metabolism in neuronal health has recently been recognized following its reported links to Alzheimer's disease, Parkinson's disease, and hereditary spastic paraplegia, among other neurological disorders. Indeed, disturbances in mitochondrial function and phosphatidylethanolamine metabolism and the resulting neuronal dysfunction are the common features of individuals suffering from these diseases, highlighting the great importance of maintaining proper phosphatidylethanolamine homeostasis in neurons. In this review, we summarize the current knowledge of phosphatidylethanolamine metabolism and its role in neuronal function with a special emphasis on the phosphatidylethanolamine biosynthetic pathway in mitochondria. We then review findings on how phosphatidylethanolamine biosynthesis is affected in major neurodegenerative diseases. Finally, we highlight promising future research areas that will help advance the understanding of neuronal phosphatidylethanolamine mechanisms and identify phosphatidylethanolamine-targeted therapeutic strategies for combating such brain diseases.

JOURNAL/nrgr/04.03/01300535-202606000-00056/figure1/v/2026-02-11T151048Z/r/image-tiff Cerebral small vessel disease is a major vascular contributor to cognitive impairment and dementia. However, there remains a lack of effective preventative or therapeutic regimens for cerebral small vessel disease. In this study, we investigated the potential therapeutic effects of MCC950, a selective NOD-like receptor family pyrin domain-containing protein 3 inhibitor, on cerebral small vessel disease pathogenesis and cognitive decline in spontaneously hypertensive rats. Our results showed that chronic administration of MCC950 (10 mg/kg) to spontaneously hypertensive rats inhibited NOD-like receptor family pyrin domain-containing protein 3 inflammasome activation, thereby considerably suppressing the production of pyroptosis executive protein gasdermin D and pro-inflammatory factors, including interleukin-1β and -18. A decrease in astrocytic and microglial activation was also observed. We also found that MCC950 significantly inhibited autophagy. More importantly, behavioral assessment indicated that MCC950 administration ameliorated impaired neurocognitive function, which was associated with improvements in neuropathological hallmarks in the cerebral small vessel disease brain, such as blood‒brain barrier breakdown, white matter damage, and endothelial dysfunction. Thus, our findings revealed that the NOD-like receptor family pyrin domain-containing protein 3 inflammasome is a key contributor to the onset or progression of cerebral small vessel disease and suggested the potential of NOD-like receptor family pyrin domain-containing protein 3-based therapy as a potential novel strategy for treating cerebral small vessel disease.

JOURNAL/nrgr/04.03/01300535-202606000-00081/figure1/v/2026-02-11T151048Z/r/image-tiff To perform various functions in the body, skeletal muscle is controlled and coordinated as a whole by nerves. However, there has been little research into whether the nerve control characteristics of different muscles are different, and the importance of these potential differences. In the present study, we used a three-dimensional imaging of solvent-cleared organ-compatible multi-tracer technique to explore the spatial distribution patterns of sensory and sympathetic neurons that innervate limb muscles. We integrated transcriptome sequencing datasets from mouse limb muscles in public databases and performed correlation analysis with neuronal spatial distribution data to reveal the unique effects of different types of neurons on muscle functional pathways. In terms of spatial distribution patterns, sympathetic neurons exhibited a more concentrated distribution than sensory and motor neurons. In addition, the neuronal innervation of limb muscles exhibited four different characteristics: sympathetic neuron-rich muscle, sensory neuron-rich muscle, neuron-sparse muscle, and motor neuron-rich muscle. Sensory neuron density was mainly associated with muscle contractile structure and cell pH, whereas sympathetic neuron density was associated with protein kinase activity, muscle vasculature, muscle calcium-dependent protein kinase activity, lipid transport, and vesicle release. Motor neuron density was mainly associated with protein kinase activity, cell adhesion, oxidoreductase activity, and exocytosis. These findings may contribute to a deeper understanding of how nerves cooperate to endow muscles with diverse physiological functions, thereby providing new insights and experimental evidence for the treatment of various neuromuscular diseases.

Neurodegenerative diseases, which are characterized by progressive neuronal loss and the lack of disease-modifying therapies, are becoming a major global health challenge. The existing neuromodulation techniques, such as deep brain stimulation and transcranial magnetic stimulation, show limitations such as invasiveness, restricted cortical targeting, and irreversible tissue effects. In this context, low-intensity transcranial ultrasound has emerged as a promising noninvasive alternative that can penetrate deep into the brain and modulate neuroplasticity. This review comprehensively assesses the therapeutic mechanisms, efficacy, and translational potential of low-intensity transcranial ultrasound in treating neurodegenerative diseases, with emphasis on its role in promoting neuronal regeneration, modulating neuroinflammation, and enhancing functional recovery. We summarize the findings of previous studies and systematically illustrate the potential of low-intensity transcranial ultrasound in regulating cell death mechanisms, enhancing neural repair and regeneration, and alleviating symptoms associated with neurodegenerative diseases. Preclinical findings indicate that low-intensity transcranial ultrasound can enhance the release of neurotrophic factors (e.g., brain-derived neurotrophic factor), promote autophagy to clear protein aggregates, modulate microglial activation, and temporarily open the blood-brain barrier to facilitate targeted drug delivery. Existing clinical trial data show that low-intensity transcranial ultrasound can reduce amyloid-β plaques, improve motor and cognitive deficits, and promote remyelination in various disease models. Early clinical trials suggest that low-intensity transcranial ultrasound may enhance cognitive scores in Alzheimer's disease and alleviate motor symptoms in Parkinson's disease, all while demonstrating a favorable safety profile. Past studies support the notion that by integrating safety, precision, and reversibility, low-intensity transcranial ultrasound can transform the treatment landscape for neurodegenerative disease. However, more advancements are necessary for future clinical application of low-intensity transcranial ultrasound, including optimizing parameters such as frequency, intensity, and duty cycle; considering individual anatomical differences; and confirming long-term efficacy. We believe establishing standardized protocols, conducting larger trials, and investigating the underlying mechanisms to clarify dose-response relationships and refine personalized application strategies are essential in this regard. Future research should focus on translating preclinical findings into clinical practice, addressing technical challenges, and exploring combination therapies with pharmacological or gene interventions.