Neural Regeneration Research最新文献

The interaction between the gut microbiota and cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling pathway in the host's central nervous system plays a crucial role in neurological diseases and enhances communication along the gut-brain axis. The gut microbiota influences the cAMP-PKA signaling pathway through its metabolites, which activates the vagus nerve and modulates the immune and neuroendocrine systems. Conversely, alterations in the cAMP-PKA signaling pathway can affect the composition of the gut microbiota, creating a dynamic network of microbial-host interactions. This reciprocal regulation affects neurodevelopment, neurotransmitter control, and behavioral traits, thus playing a role in the modulation of neurological diseases. The coordinated activity of the gut microbiota and the cAMP-PKA signaling pathway regulates processes such as amyloid-β protein aggregation, mitochondrial dysfunction, abnormal energy metabolism, microglial activation, oxidative stress, and neurotransmitter release, which collectively influence the onset and progression of neurological diseases. This study explores the complex interplay between the gut microbiota and cAMP-PKA signaling pathway, along with its implications for potential therapeutic interventions in neurological diseases. Recent pharmacological research has shown that restoring the balance between gut flora and cAMP-PKA signaling pathway may improve outcomes in neurodegenerative diseases and emotional disorders. This can be achieved through various methods such as dietary modifications, probiotic supplements, Chinese herbal extracts, combinations of Chinese herbs, and innovative dosage forms. These findings suggest that regulating the gut microbiota and cAMP-PKA signaling pathway may provide valuable evidence for developing novel therapeutic approaches for neurodegenerative diseases.

JOURNAL/nrgr/04.03/01300535-202511000-00030/figure1/v/2024-12-20T164640Z/r/image-tiff We previously demonstrated that inhibiting neural stem cells necroptosis enhances functional recovery after spinal cord injury. While exosomes are recognized as playing a pivotal role in neural stem cells exocrine function, their precise function in spinal cord injury remains unclear. To investigate the role of exosomes generated following neural stem cells necroptosis after spinal cord injury, we conducted single-cell RNA sequencing and validated that neural stem cells originate from ependymal cells and undergo necroptosis in response to spinal cord injury. Subsequently, we established an in vitro necroptosis model using neural stem cells isolated from embryonic mice aged 16-17 days and extracted exosomes. The results showed that necroptosis did not significantly impact the fundamental characteristics or number of exosomes. Transcriptome sequencing of exosomes in necroptosis group identified 108 differentially expressed messenger RNAs, 104 long non-coding RNAs, 720 circular RNAs, and 14 microRNAs compared with the control group. Construction of a competing endogenous RNA network identified the following hub genes: tuberous sclerosis 2 ( Tsc2 ), solute carrier family 16 member 3 ( Slc16a3 ), and forkhead box protein P1 ( Foxp1 ). Notably, a significant elevation in TSC2 expression was observed in spinal cord tissues following spinal cord injury. TSC2-positive cells were localized around SRY-box transcription factor 2-positive cells within the injury zone. Furthermore, in vitro analysis revealed increased TSC2 expression in exosomal receptor cells compared with other cells. Further assessment of cellular communication following spinal cord injury showed that Tsc2 was involved in ependymal cellular communication at 1 and 3 days post-injury through the epidermal growth factor and midkine signaling pathways. In addition, Slc16a3 participated in cellular communication in ependymal cells at 7 days post-injury via the vascular endothelial growth factor and macrophage migration inhibitory factor signaling pathways. Collectively, these findings confirm that exosomes derived from neural stem cells undergoing necroptosis play an important role in cellular communication after spinal cord injury and induce TSC2 upregulation in recipient cells.

Stroke is classified as ischemic or hemorrhagic, and there are few effective treatments for either type. Immunologic mechanisms play a critical role in secondary brain injury following a stroke, which manifests as cytokine release, blood-brain barrier disruption, neuronal cell death, and ultimately behavioral impairment. Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models. However, in clinical trials of anti-inflammatory agents, long-term immunosuppression has not demonstrated significant clinical benefits for patients. This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair, as well as the complex pathophysiologic inflammatory processes in stroke. Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies. Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke. Furthermore, epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management. In this review, we summarize current findings on the epigenetic regulation of the inflammatory response in stroke, focusing on key signaling pathways including nuclear factor-kappa B, Janus kinase/signal transducer and activator of transcription, and mitogen-activated protein kinase as well as inflammasome activation. We also discuss promising molecular targets for stroke treatment. The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke, leading to improved post-stroke outcomes.

JOURNAL/nrgr/04.03/01300535-202511000-00029/figure1/v/2024-12-20T164640Z/r/image-tiff Neuronal activity, synaptic transmission, and molecular changes in the basolateral amygdala play critical roles in fear memory. Cylindromatosis (CYLD) is a deubiquitinase that negatively regulates the nuclear factor kappa-B pathway. CYLD is well studied in non-neuronal cells, yet under-investigated in the brain, where it is highly expressed. Emerging studies have shown involvement of CYLD in the remodeling of glutamatergic synapses, neuroinflammation, fear memory, and anxiety- and autism-like behaviors. However, the precise role of CYLD in glutamatergic neurons is largely unknown. Here, we first proposed involvement of CYLD in cued fear expression. We next constructed transgenic model mice with specific deletion of Cyld from glutamatergic neurons. Our results show that glutamatergic CYLD deficiency exaggerated the expression of cued fear in only male mice. Further, loss of CYLD in glutamatergic neurons resulted in enhanced neuronal activation, impaired excitatory synaptic transmission, and altered levels of glutamate receptors accompanied by over-activation of microglia in the basolateral amygdala of male mice. Altogether, our study suggests a critical role of glutamatergic CYLD in maintaining normal neuronal, synaptic, and microglial activation. This may contribute, at least in part, to cued fear expression.

The progressive loss of dopaminergic neurons in affected patient brains is one of the pathological features of Parkinson's disease, the second most common human neurodegenerative disease. Although the detailed pathogenesis accounting for dopaminergic neuron degeneration in Parkinson's disease is still unclear, the advancement of stem cell approaches has shown promise for Parkinson's disease research and therapy. The induced pluripotent stem cells have been commonly used to generate dopaminergic neurons, which has provided valuable insights to improve our understanding of Parkinson's disease pathogenesis and contributed to anti-Parkinson's disease therapies. The current review discusses the practical approaches and potential applications of induced pluripotent stem cell techniques for generating and differentiating dopaminergic neurons from induced pluripotent stem cells. The benefits of induced pluripotent stem cell-based research are highlighted. Various dopaminergic neuron differentiation protocols from induced pluripotent stem cells are compared. The emerging three-dimension-based brain organoid models compared with conventional two-dimensional cell culture are evaluated. Finally, limitations, challenges, and future directions of induced pluripotent stem cell-based approaches are analyzed and proposed, which will be significant to the future application of induced pluripotent stem cell-related techniques for Parkinson's disease.