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01 January 2025, Volume 20 Issue on line Previous Issue    Next Issue

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Plasma circulating cell-free DNA integrity and relative telomere length as diagnostic biomarkers for Parkinson’s disease and multiple system atrophy: a cross-sectional study Chao Ying, Chao Han, Yuan Li, Mingkai Zhang, Shuying Xiao, Lifang Zhao, Hui Zhang, Qian Yu, Jing An, Wei Mao, Yanning Cai 2025, 20 (on line):  1-11.  Abstract ( 118 )   PDF (4095KB) ( 34 )   Save In clinical specialties focusing on neurological disorders, there is a need for comprehensive and integrated non-invasive, sensitive, and specific testing methods. Both Parkinson’s disease and multiple system atrophy are classified as α-synucleinopathies, characterized by abnormal accumulation of α-synuclein protein, which provides a shared pathological background for their comparative study. In addition, both Parkinson’s disease and multiple system atrophy involve neuronal death, a process that may release circulating cell-free DNA (cfDNA) into the bloodstream, leading to specific alterations. This premise formed the basis for investigating cell-free DNA as a potential biomarker.   Cell-free DNA has garnered attention for its potential pathological significance, yet its characteristics in the context of Parkinson’s disease and multiple system atrophy are not fully understood. This study investigated the total concentration, nonapoptotic level, integrity, and cell-free DNA relative telomere length of cell-free DNA in the peripheral blood of 171 participants, comprising 76 normal controls, 62 patients with Parkinson’s disease, and 33 patients with multiple system atrophy. In our cohort, 75.8% of patients with Parkinson’s disease (stage 1–2 of Hoehn & Yahr) and 60.6% of patients with multiple system atrophy (disease duration less than 3 years) were in the early stages. The diagnostic potential of the cell-free DNA parameters was evaluated using receiver operating characteristic (ROC) analysis, and their association with disease prevalence was examined through logistic regression models, adjusting for confounders such as age, sex, body mass index, and education level. The results showed that cell-free DNA integrity was significantly elevated in both Parkinson’s disease and multiple system atrophy patients compared with normal controls (P < 0.001 for both groups), whereas cell-free DNA relative telomere length was markedly shorter (P = 0.003 for Parkinson’s disease and P = 0.010 for multiple system atrophy). Receiver operating characteristic analysis indicated that both cell-free DNA integrity and cell-free DNA relative telomere length possessed good diagnostic accuracy for differentiating Parkinson’s disease and multiple system atrophy from normal controls. Specifically, higher cell-free DNA integrity was associated with increased risk of Parkinson’s disease (odds ratio [OR]: 5.72; 95% confidence interval [CI]: 1.54–24.19) and multiple system atrophy (OR: 10.10; 95% CI: 1.55–122.98). Conversely, longer cell-free DNA relative telomere length was linked to reduced risk of Parkinson’s disease (OR: 0.16; 95% CI: 0.04–0.54) and multiple system atrophy (OR: 0.10; 95% CI: 0.01–0.57). These findings suggest that cell-free DNA integrity and cell-free DNA relative telomere length may serve as promising biomarkers for the early diagnosis of Parkinson’s disease and multiple system atrophy, potentially reflecting specific underlying pathophysiological processes of these neurodegenerative disorders. Related Articles | Metrics

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Targeting the glymphatic system to promote α-synuclein clearance: a novel therapeutic strategy for Parkinson’s disease Xiaoyue Lian, Zhenghao Liu, Zuobin Gan, Qingshan Yan, Luyao Tong, Linan Qiu, Yuntao Liu, Jiang-fan Chen, Zhihui Li​ 2025, 20 (on line):  1-18.  Abstract ( 49 )   PDF (3188KB) ( 103 )   Save The excessive buildup of neurotoxic α-synuclein plays a pivotal role in the pathogenesis of Parkinson’s disease, highlighting the urgent need for innovative therapeutic strategies to promote α-synuclein clearance, particularly given the current lack of disease-modifying treatments. The glymphatic system, a recently identified perivascular fluid transport network, is crucial for clearing neurotoxic proteins. This review aims to synthesize current knowledge on the role of the glymphatic system in α-synuclein clearance and its implications for the pathology of Parkinson’s disease while emphasizing potential therapeutic strategies and areas for future research. The review begins with an overview of the glymphatic system and details its anatomical structure and physiological functions that facilitate cerebrospinal fluid circulation and waste clearance. It summarizes emerging evidence from neuroimaging and experimental studies that highlight the close correlation between the glymphatic system and clinical symptom severity in patients with Parkinson’s disease, as well as the effect of glymphatic dysfunction on α-synuclein accumulation in Parkinson’s disease models. Subsequently, the review summarizes the mechanisms of glymphatic system impairment in Parkinson’s disease, including sleep disturbances, aquaporin-4 impairment, and mitochondrial dysfunction, all of which diminish glymphatic system efficiency. This creates a vicious cycle that exacerbates α-synuclein accumulation and worsens Parkinson’s disease. The therapeutic perspectives section outlines strategies for enhancing glymphatic activity, such as improving sleep quality and pharmacologically targeting aquaporin-4 or its subcellular localization. Promising interventions include deep brain stimulation, melatonin supplementation, γ-aminobutyric acid modulation, and non-invasive methods (such as exercise and bright-light therapy), multisensory γ stimulation, and ultrasound therapy. Moreover, identifying neuroimaging biomarkers to assess glymphatic flow as an indicator of α-synuclein burden could refine Parkinson’s disease diagnosis and track disease progression. In conclusion, the review highlights the critical role of the glymphatic system in α-synuclein clearance and its potential as a therapeutic target in Parkinson’s disease. It advocates for further research to elucidate the specific mechanisms by which the glymphatic system clears misfolded α-synuclein and the development of imaging biomarkers to monitor glymphatic activity in patients with Parkinson’s disease. Findings from this review suggest that enhancing glymphatic clearance is a promising strategy for reducing α-synuclein deposits and mitigating the progression of Parkinson’s disease. Related Articles | Metrics

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Metabolic reprogramming of astrocytes: emerging roles of lactate Zeyu Liu, Yijian Guo, Ying Zhang, Yulei Gao, Bin Ning 2025, 20 (on line):  1-15.  Abstract ( 66 )   PDF (9727KB) ( 19 )   Save Lactate serves as a key energy metabolite in the central nervous system, facilitating essential brain functions, including energy supply, signaling, and epigenetic modulation. Moreover, it links epigenetic modifications with metabolic reprogramming. Nonetheless, the specific mechanisms and roles of this connection in astrocytes remain unclear. Therefore, this review aims to explore the role and specific mechanisms of lactate in the metabolic reprogramming of astrocytes in the central nervous system. The close relationship between epigenetic modifications and metabolic reprogramming was discussed. Therapeutic strategies for targeting metabolic reprogramming in astrocytes in the central nervous system were also outlined to guide future research in central nervous system diseases. In the nervous system, lactate plays an essential role. However, its mechanism of action as a bridge between metabolic reprogramming and epigenetic modifications in the nervous system requires future investigation. The involvement of lactate in epigenetic modifications is currently a hot research topic, especially in lactylation modification, a key determinant in this process. Lactate also indirectly regulates various epigenetic modifications, such as N6-methyladenosine, acetylation, ubiquitination, and phosphorylation modifications, which are closely linked to several neurological disorders. In addition, exploring the clinical applications and potential therapeutic strategies of lactic acid provides new insights for future neurological disease treatments. Related Articles | Metrics

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Effects of Lycium barbarum polysaccharide on the activation of pathogenic CD4+ T cells in a mouse model of multiple sclerosis Mengdi Guo, Guozhen Deng, Bin Huang, Zhiyong Lin, Xue Yang, Linglin Dong, Zilin Wang, Yi Guo, Ming Yi, Weiyan Wang, Mei-Ling Jiang, Cun-Jin Zhang 2025, 20 (on line):  1-11.  Abstract ( 47 )   PDF (10132KB) ( 11 )   Save 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 (AP-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. Related Articles | Metrics

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Photobiomodulation repairs the blood–spinal cord barrier in a mouse model of spinal cord injury Yangguang Ma, Yi Liu, Dongsheng Pan, Jiawei Zhang, Zhuowen Liang, Yi Wang, Xueyu Hu, Zhe Wang, Tan Ding 2025, 20 (on line):  1-12.  Abstract ( 32 )   PDF (5759KB) ( 48 )   Save The blood–spinal cord barrier is crucial for preserving homeostasis of the central nervous system. After spinal cord injury, autophagic flux within endothelial cells is disrupted, compromising the integrity of the blood–spinal cord barrier. This disruption facilitates extensive infiltration of inflammatory cells, resulting in exacerbated neuroinflammatory responses, neuronal death, and impaired neuronal regeneration. Previous research has demonstrated that photobiomodulation promotes the regeneration of damaged nerves following spinal cord injury by inhibiting the recruitment of inflammatory cells to the injured site and restoring neuronal mitochondrial function. However, the precise mechanisms by which photobiomodulation regulates neuroinflammation remain incompletely elucidated. In this study, we established a mouse model of spinal cord injury and assessed the effects of photobiomodulation treatment. Photobiomodulation effectively cleared damaged mitochondria from endothelial cells in mice, promoting recovery of hindlimb motor function. Using microvascular endothelial bEnd.3 cells subjected to oxygen–glucose deprivation, we found that the effects of photobiomodulation were mediated through activation of the PINK1/Parkin pathway. Additionally, photobiomodulation reduced mitochondrial oxidative stress levels and increased the expression of tight junction proteins within the blood–spinal cord barrier. Our findings suggest that photobiomodulation activates mitochondrial autophagy in endothelial cells through the PINK1/Parkin pathway, thereby promoting repair of the blood–spinal cord barrier following spinal cord injury Related Articles | Metrics

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Davunetide promotes structural and functional recovery of the injured spinal cord by promoting autophagy Yituo Chen, Rongjie Liu, Wanta Cai, Liting Jiang, Kongbin Chen, Jingwei Shi, Junsheng Lou, Letian Yu, Chenyu Wu, Liangliang Yang, Kailiang Zhou, Wenfei Ni 2025, 20 (on line):  1-11.  Abstract ( 32 )   PDF (34961KB) ( 9 )   Save After spinal cord injury, programmed cell death is common. In this context, autophagy plays a crucial role in clearing cellular debris, while necroptosis exacerbates neuroinflammation and further damages neural structures. The neuroprotective drug davunetide has shown substantial therapeutic effects on brain diseases, but its role in treating spinal cord injury remains unclear. Therefore, the aim of this study was to investigate the effects of davunetide on cell death after spinal cord injury. To do this, we established a mouse model of spinal cord contusion and administered davunetide intranasally daily at a dose of 0.5 µg/5 µL. Mouse locomotor function was assessed using footprint analysis and Basso Mouse Scale scoring, while the extent of spinal cord injury was evaluated using Masson’s trichrome staining. The expression levels of proteins related to locomotor function and spinal cord injury were analyzed by Western blotting and immunofluorescence staining, and protein–protein interactions were evaluated using immunoprecipitation techniques. Our results demonstrated that davunetide not only reduced the size of the injury area but also promoted the recovery of locomotor function after spinal cord injury. Specifically, davunetide exerted its effects by enhancing autophagy and inhibiting necroptosis. Inhibition of autophagy reversed the protective effects of davunetide on necroptosis. Further investigation revealed that davunetide acted through the SIRT1-FOXO1-TFEB signaling pathway, which is key to its therapeutic effects. These findings suggest the potential of davunetide in the treatment of spinal cord injury and provide valuable insights into the underlying mechanisms. This study offers strong scientific evidence to support the development of new therapeutic strategies for spinal cord injury. Related Articles | Metrics

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Elucidation of the mechanism by which manganese-ferric Prussian blue nanozymes alleviate ischemic stroke damage in a mouse model Xue Li, Chengyun Hu, Shanshan Luo, Yanhong Zhang, Bilu Li, Chao Wu, Zhengyan Wu, Jia Zhang, Chaoliang Tang 2025, 20 (on line):  1-12.  Abstract ( 35 )   PDF (8717KB) ( 29 )   Save Ischemic stroke represents a significant global health challenge, frequently associated with intricate pathophysiological alterations. During ischemic stroke, the generation of reactive oxygen species markedly increases, leading to direct neuronal damage as well as initiating a cascade of inflammatory responses. This oxidative stress can also disturb the equilibrium of the gut microbiota, resulting in dysbiosis. In turn, an imbalance in gut microbiota can further exacerbate the production of reactive oxygen species and contribute to a pro-inflammatory environment within the body. This creates a vicious cycle that not only promotes the progression of stroke but also leads to adverse functional outcomes. The neuroinflammation and intestinal microbiota dysbiosis that occur following ischemic stroke are critical contributors to stroke progression and adverse functional outcomes. We previously developed manganese-ferric Prussian blue nanozymes, characterized by a multi-enzyme structure and a porous design, that exhibit strong antioxidant properties. However, the therapeutic effects of manganese-ferric Prussian blue nanozymes on ischemic stroke and their mechanisms of action remain have not been fully elucidated. To investigate this, we constructed a mouse model of middle cerebral artery occlusion and administered manganese-ferric Prussian blue nanozymes via gastric gavage. Our results demonstrated that these nanozymes substantially reduced infarct volume, improved neurological function, restored gut microbiota balance, and increased levels of short-chain fatty acids in the mouse model. Treatment of lipopolysaccharide-treated BV-2 cells with short-chain fatty acids markedly decreased the expression levels of components of the Toll-like receptor 4/nuclear factor kappa B signaling pathway, including Toll-like receptor 4, inhibitor of nuclear factor kappa-B kinase subunit alpha, and pp65. These findings suggest that manganese-ferric Prussian blue nanozymes can correct gut microbiota dysbiosis and increase short-chain fatty acid production by modulating the Toll-like receptor 4/nuclear factor kappa B signaling pathway, thereby providing therapeutic benefits in the context of ischemic stroke. Related Articles | Metrics

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Complex bioactive nanofibrous dura mater promotes the repair of traumatic brain injury Siyu Chen, Xiaopei Zhang, Qingxia Guo, Yuying Yan, Manfei Fu, Yuanfei Wang, Tong Wu 2025, 20 (on line):  1-18.  doi: 10.4103/NRR.NRR-D-25-00621 Abstract ( 78 )   PDF (31711KB) ( 48 )   Save Dura closure following the surgery of traumatic brain injury is important to keep the structural integrity of brain and serve as the barrier to prevent infection and the leakage of cerebrospinal fluid. Though artificial dural maters can provide barrier capability, the performance for injured neural cells repairing and neuroprotection in the stage of secondary injury are unsatisfied. Herein, we designed and manufactured a multilayered nanofiber dural mater for the repair of traumatic brain injury. The results showed that the multilayered nanofiber dural mater was able to promote the survival and neurite extension of SH-SY5Y cells following the injuries of neurite transection, oxygen and glucose deprivation and oxidative stress, respectively. Minocycline hydrochloride and insulin growth factor-1 were separately incorporated into fibers to realize the differentially dual release for the purpose of immunomodulation at early stage and exert neuroprotection ability during the repair process. In addition, the multilayered nanofiber dural mater promoted the increase of M2 polarization for microglia cells and the secretion of anti-inflammatory cytokines, enhancing the survival of neural cells. The capabilities of the multilayered nanofiber dural mater for antibacterial properties, anti-adhesion, barrier performance, anti-leakage and biocompatibility have also been verified. Taken together, such multilayered nanofiber dural mater has shown promising potential to serve as the substitutes for dura and promotingneural recovery after traumatic brain injury. Related Articles | Metrics

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Sex-Dependent Mechanisms of Neuropathic Pain After Spinal Cord Injury Revealed by Integrated Transcriptomic and Metabolomic Profiling in Rats Li Cheng, Peihui Zhou, Yijia Wang, Xintong Zhu, Yang Yang, Bin Cai, Hong Zeng, Li Wang 2025, 20 (on line):  1-10.  Abstract ( 16 )   PDF (11536KB) ( 4 )   Save Neuropathic pain (NP) following spinal cord injury (SCI) is characterized by persistent spontaneous pain and evoked pain responses, such as mechanical allodynia and thermal hyperalgesia. Although inflammatory and metabolic reprogramming have been implicated in central sensitization, the sex-dependent molecular mechanisms underlying SCI-induced NP remain insufficiently understood. In this study, we established a T3 lateral hemisection SCI model in rats and assessed behavioral outcomes alongside integrated transcriptomic and metabolomic profiling. Both male and female rats developed significant mechanical and thermal hypersensitivity after SCI, confirming the induction of NP. However, unbiased multi-omics analyses revealed distinct sex-dependent molecular programs. Male rats exhibited alterations in calcium signaling, serine metabolism, and sphingolipid metabolic pathways, whereas female rats showed prominent changes in T cell receptor signaling and histidine metabolism. These findings suggest that immune-metabolic interactions diverge between sexes and may underlie the observed differences in NP chronification after SCI. Our study highlights the importance of sex-dependent mechanisms in shaping neuroimmune and metabolic responses following SCI and provides novel insights into the molecular basis of central sensitization in NP. Related Articles | Metrics