医学最新文献

JOURNAL/nrgr/04.03/01300535-202605000-00035/figure1/v/2025-10-21T121913Z/r/image-tiff The remodeling of axonal connections following injury is an important feature driving functional recovery. The reticulospinal tract is an interesting descending motor tract that contains both excitatory and inhibitory fibers. While the reticulospinal tract has been shown to be particularly prone to axonal growth and plasticity following injuries of the spinal cord, the differential capacities of excitatory and inhibitory fibers for plasticity remain unclear. As adaptive axonal plasticity involves a sophisticated interplay between excitatory and inhibitory input, we investigated in this study the plastic potential of glutamatergic (vGlut2) and GABAergic (vGat) fibers originating from the gigantocellular nucleus and the lateral paragigantocellular nucleus, two nuclei important for locomotor function. Using a combination of viral tracing, chemogenetic silencing, and AI-based kinematic analysis, we investigated plasticity and its impact on functional recovery within the first 3 weeks following injury, a period prone to neuronal remodeling. We demonstrate that, in this time frame, while vGlut2-positive fibers within the gigantocellular and lateral paragigantocellular nuclei rewire significantly following cervical spinal cord injury, vGat-positive fibers are rather unresponsive to injury. We also show that the acute silencing of excitatory axonal fibers which rewire in response to lesions of the spinal cord triggers a worsening of the functional recovery. Using kinematic analysis, we also pinpoint the locomotion features associated with the gigantocellular nucleus or lateral paragigantocellular nucleus during functional recovery. Overall, our study increases the understanding of the role of the gigantocellular and lateral paragigantocellular nuclei during functional recovery following spinal cord injury.

Alzheimer's disease is the most common type of cognitive disorder, and there is an urgent need to develop more effective, targeted and safer therapies for patients with this condition. Deep brain stimulation is an invasive surgical treatment that modulates abnormal neural activity by implanting electrodes into specific brain areas followed by electrical stimulation. As an emerging therapeutic approach, deep brain stimulation shows significant promise as a potential new therapy for Alzheimer's disease. Here, we review the potential mechanisms and therapeutic effects of deep brain stimulation in the treatment of Alzheimer's disease based on existing clinical and basic research. In clinical studies, the most commonly targeted sites include the fornix, the nucleus basalis of Meynert, and the ventral capsule/ventral striatum. Basic research has found that the most frequently targeted areas include the fornix, nucleus basalis of Meynert, hippocampus, entorhinal cortex, and rostral intralaminar thalamic nucleus. All of these individual targets exhibit therapeutic potential for patients with Alzheimer's disease and associated mechanisms of action have been investigated. Deep brain stimulation may exert therapeutic effects on Alzheimer's disease through various mechanisms, including reducing the deposition of amyloid-β, activation of the cholinergic system, increasing the levels of neurotrophic factors, enhancing synaptic activity and plasticity, promoting neurogenesis, and improving glucose metabolism. Currently, clinical trials investigating deep brain stimulation for Alzheimer's disease remain insufficient. In the future, it is essential to focus on translating preclinical mechanisms into clinical trials. Furthermore, consecutive follow-up studies are needed to evaluate the long-term safety and efficacy of deep brain stimulation for Alzheimer's disease, including cognitive function, neuropsychiatric symptoms, quality of life and changes in Alzheimer's disease biomarkers. Researchers must also prioritize the initiation of multi-center clinical trials of deep brain stimulation with large sample sizes and target earlier therapeutic windows, such as the prodromal and even the preclinical stages of Alzheimer's disease. Adopting these approaches will permit the efficient exploration of more effective and safer deep brain stimulation therapies for patients with Alzheimer's disease.

Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system, leading to a decline in patients' cognitive, motor, and emotional abilities. Neuroinflammation plays a significant role in the progression of these diseases. However, there is limited research on therapeutic approaches to specifically target neuroinflammation. The role of T lymphocytes, which are crucial mediators of the adaptive immune response, in neurodegenerative diseases has been increasingly recognized. This review focuses on the involvement of T lymphocytes in the neuroinflammation associated with neurodegenerative diseases. The pathogenesis of neurodegenerative diseases is complex, involving multiple mechanisms and pathways that contribute to the gradual degeneration of neurons, and T cells are a key component of these processes. One of the primary factors driving neuroinflammation in neurodegenerative diseases is the infiltration of T cells and other neuroimmune cells, including microglia, astrocytes, B cells, and natural killer cells. Different subsets of CD4 + T cells, such as Th1, Th2, Th17, and regulatory T cells, can differentiate into various cell types and perform distinct roles within the neuroinflammatory environment of neurodegenerative diseases. Additionally, CD8 + T cells, which can directly regulate immune responses and kill target cells, also play several important roles in neurodegenerative diseases. Clinical trials investigating targeted T cell therapies for neurodegenerative diseases have shown that, while some patients respond positively, others may not respond as well and may even experience adverse effects. Targeting T cells precisely is challenging due to the complexity of immune responses in the central nervous system, which can lead to undesirable side effects. However, with new insights into the pathophysiology of neurodegenerative diseases, there is hope for the establishment of a solid theoretical foundation upon which innovative treatment strategies that target T cells can be developed in the future.

JOURNAL/nrgr/04.03/01300535-202605000-00039/figure1/v/2025-10-21T121913Z/r/image-tiff Previous research has demonstrated the feasibility of repairing nerve defects through acellular allogeneic nerve grafting with bone marrow mesenchymal stem cells. However, adult tissue-derived mesenchymal stem cells encounter various obstacles, including limited tissue sources, invasive acquisition methods, cellular heterogeneity, purification challenges, cellular senescence, and diminished pluripotency and proliferation over successive passages. In this study, we used induced pluripotent stem cell-derived mesenchymal stem cells, known for their self-renewal capacity, multilineage differentiation potential, and immunomodulatory characteristics. We used induced pluripotent stem cell-derived mesenchymal stem cells in conjunction with acellular nerve allografts to address a 10 mm-long defect in a rat model of sciatic nerve injury. Our findings reveal that induced pluripotent stem cell-derived mesenchymal stem cells exhibit survival for up to 17 days in a rat model of peripheral nerve injury with acellular nerve allograft transplantation. Furthermore, the combination of acellular nerve allograft and induced pluripotent stem cell-derived mesenchymal stem cells significantly accelerates the regeneration of injured axons and improves behavioral function recovery in rats. Additionally, our in vivo and in vitro experiments indicate that induced pluripotent stem cell-derived mesenchymal stem cells play a pivotal role in promoting neovascularization. Collectively, our results suggest the potential of acellular nerve allografts with induced pluripotent stem cell-derived mesenchymal stem cells to augment nerve regeneration in rats, offering promising therapeutic strategies for clinical translation.

Mitochondrial dysfunction and oxidative stress are widely regarded as primary drivers of aging and are associated with several neurodegenerative diseases. The degeneration of motor neurons during aging is a critical pathological factor contributing to the progression of sarcopenia. However, the morphological and functional changes in mitochondria and their interplay in the degeneration of the neuromuscular junction during aging remain poorly understood. A defined systematic search of the PubMed, Web of Science and Embase databases (last accessed on October 30, 2024) was conducted with search terms including 'mitochondria', 'aging' and 'NMJ'. Clinical and preclinical studies of mitochondrial dysfunction and neuromuscular junction degeneration during aging. Twenty-seven studies were included in this systematic review. This systematic review provides a summary of morphological, functional and biological changes in neuromuscular junction, mitochondrial morphology, biosynthesis, respiratory chain function, and mitophagy during aging. We focus on the interactions and mechanisms underlying the relationship between mitochondria and neuromuscular junctions during aging. Aging is characterized by significant reductions in mitochondrial fusion/fission cycles, biosynthesis, and mitochondrial quality control, which may lead to neuromuscular junction dysfunction, denervation and poor physical performance. Motor nerve terminals that exhibit redox sensitivity are among the first to exhibit abnormalities, ultimately leading to an early decline in muscle strength through impaired neuromuscular junction transmission function. Parg coactivator 1 alpha is a crucial molecule that regulates mitochondrial biogenesis and modulates various pathways, including the mitochondrial respiratory chain, energy deficiency, oxidative stress, and inflammation. Mitochondrial dysfunction is correlated with neuromuscular junction denervation and acetylcholine receptor fragmentation, resulting in muscle atrophy and a decrease in strength during aging. Physical therapy, pharmacotherapy, and gene therapy can alleviate the structural degeneration and functional deterioration of neuromuscular junction by restoring mitochondrial function. Therefore, mitochondria are considered potential targets for preserving neuromuscular junction morphology and function during aging to treat sarcopenia.

Neural injuries can cause considerable functional impairments, and both central and peripheral nervous systems have limited regenerative capacity. The existing conventional pharmacological treatments in clinical practice show poor targeting, rapid drug clearance from the circulatory system, and low therapeutic efficiency. Therefore, in this review, we have first described the mechanisms underlying nerve regeneration, characterized the biomaterials used for drug delivery to facilitate nerve regeneration, and highlighted the functionalization strategies used for such drug-delivery systems. These systems mainly use natural and synthetic polymers, inorganic materials, and hybrid systems with advanced drug-delivery abilities, including nanoparticles, hydrogels, and scaffold-based systems. Then, we focused on comparing the types of drug-delivery systems for neural regeneration as well as the mechanisms and challenges associated with targeted delivery of drugs to facilitate neural regeneration. Finally, we have summarized the clinical application research and limitations of targeted delivery of these drugs. These biomaterials and drug-delivery systems can provide mechanical support, sustained release of bioactive molecules, and enhanced intercellular contact, ultimately reducing cell apoptosis and enhancing functional recovery. Nevertheless, immune reactions, degradation regulation, and clinical translations remain major unresolved challenges. Future studies should focus on optimizing biomaterial properties, refining delivery precision, and overcoming translational barriers to advance these technologies toward clinical applications.