Xinyuan Li

Hypoxic-ischemic encephalopathy (HIE) is a severe perinatal brain injury that often leads to neurological impairments in survivors. Currently, effective therapeutic strategies for HIE remain limited and require further exploration. Emerging evidence indicates that microglia-mediated neuroinflammation plays a pivotal role in the pathophysiology of HIE. Nevertheless, clinically effective anti-inflammatory agents specifically targeting HIE are still lacking. Glycerol-3-phosphate (G3P) is a biologically significant metabolite involved in various cellular metabolic pathways. In this study, we investigated the neuroprotective effects of G3P against hypoxic-ischemic (HI)-induced brain injury by modulating microglial activation. In LPS-treated microglia, G3P suppressed the release of pro-inflammatory cytokines IL-6, IL-1β, and TNF-α, reduced reactive oxygen species (ROS) levels, restored mitochondrial membrane potential (MMP), and promoted a shift toward an anti-inflammatory microglial phenotype. In addition, G3P treatment in zebrafish showed no toxicity and significantly mitigated HI-induced oxidative stress, while suppressing both the recruitment and pro-inflammatory activation of mpeg1⁺ macrophages and lyzc⁺ neutrophils. Moreover, administration of G3P dramatically reduced infarct volume and alleviated neuronal loss in rats with hypoxic-ischemic brain damage (HIBD). Y-maze and Morris water maze tests demonstrated that G3P treatment significantly enhanced spatial learning and memory in HIBD rats. Furthermore, G3P markedly reduced the hyperactivation of microglia and astrocytes in both cortical and hippocampal regions. Mechanistically, Immunofluorescence and Western blot analyses revealed that G3P exerted anti-inflammatory effects by inhibiting cyclic GMP-AMP synthase -stimulator of interferon genes (cGAS-STING) signalling pathway and its downstream TBK1/the nuclear factor kappa B (NF-κB) signaling pathway. These findings highlight G3P as a promising therapeutic candidate for HIE.

Multiple sclerosis (MS) is characterized by demyelination and neuroinflammation. In a cuprizone (CPZ)-induced demyelination mouse model, proteomic analysis revealed the significant downregulation of a myelin basic protein-derived peptide (sequence: DTGILDSIGRFFS), which we have designated as NSDP1 (nervous system-derived peptide 1). In vitro, NSDP1 suppressed LPS-induced microglial activation in BV2 cells, reducing reactive oxygen species (ROS) production, downregulating pro-inflammatory markers (iNOS, TNF-α, IL-1β), and upregulating the expression of anti-inflammatory marker Arg-1. In vivo, NSDP1 administration via intracerebroventricular injection significantly mitigated CPZ-induced weight loss and demyelination in the corpus callosum. NSDP1 attenuated CPZ-induced demyelination, restoring expression of myelin proteins (MAG, MOG), increasing oligodendrocyte precursor cell (OPC) density, improving myelin sheath ultrastructure, and enhancing axonal myelination efficiency. Furthermore, NSDP1 attenuated CPZ-induced reactive gliosis, reducing both microglial activation and astrocytic reactivity in the corpus callosum. RNA sequencing revealed that NSDP1 modulated myelination-related pathways and correlated with improved locomotor recovery. Mechanistically, NSDP1 exerted its anti-inflammatory effects by inhibiting the cGAS-STING signaling pathway, as shown by reduced cGAS and STING expression in LPS-stimulated BV2 cells. The effects of NSDP1 on ROS and pro-inflammatory cytokine release were reversed by the STING activator DMX and mimicked by the STING inhibitor SN-011. Collectively, these findings identify NSDP1 as a downregulated myelin-derived peptide with potent therapeutic potential, which attenuates demyelination and suppresses neuroinflammation in demyelinating diseases by inhibiting the cGAS-STING pathway.

Objective: T o compare postoperative remission rates among different trigeminal nerve branches after microvascular decompression (MVD). Methods: We retrospectively analyzed patients with trigeminal neuralgia (TN) who underwent MVD in our department from January 2016 to December 2023 to investigate postoperative prognosis and factors associated with prognosis. Results: 275 patients with TN, including 5 patients with V1 division, had a remission. rate of 100.0% at 1 month, 3 months,6 months, 1 year and 2 years after surgery; 97.6% , 97.6% , 93.0% , 90.2% and 71.8% of patients with V1-2 division; The patients with V1-3 division were 86.5% , 80.6% , 74.3% , 66.7% and 64.5%; V2 division were 92.3% , 89.2% , 83.1% , 78.5% , 68.3%; V2-3 division were 95.0% , 90.5% , 75.7% , 60.8% and 51.3% ; V3 division were 88.2% , 82.0% , 74.0% , 66.0% and 58.3% Conclusions: Postoperative remission rate of non-V3 related branches (V1, V2,V1-2) is higher than V3 related branches (V3, V1-3, V2-3)

Multiple sclerosis (MS) is a chronic inflammatory neurologic disease characterized by the demyelinating injury of the central nervous system (CNS). It was reported that the mutant peptide came from myelin proteolipid protein (PLP) and myelin basic protein (MBP) might play a critical role in immunotherapy function of MS. However, endogenous peptides in demyelinating brain tissue of MS and their role in the pathologic process of MS have not been revealed. Here, we performed peptidomic analysis of freshly isolated corpus callosum (CC) from the brains of CPZ-treated mice and normal diet controls of male C57BL/6 mice by LC-MS/MS. Identified a total of 217 peptides were expressed at different levels in MS mice model compared with controls. By performed GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis, we found that the precursor protein of these differently expressed peptides (DEPs) were associated with myelin sheath and oxidative phosphorylation. Our study is the first brain peptidomic of MS mice model, revealing the distinct features of DEPs in demyelination brain tissue. These DPEs may provide further insight into the pathogenesis and complexity of MS, which would facilitate the discovery of the potential novel and effective strategy for the treatment of MS.

Multiple sclerosis (MS) is an incurable and progressive neurodegenerative disease that affects more than 2.5 million people worldwide and brings tremendous economic pressures to society. However, the pathophysiology of MS is still not fully elucidated, and there is no effective treatment. Demyelination is thought to be the primary pathophysiological alteration in MS, and our previous study found abnormal lipid metabolism in the demyelinated corpus callosum. Growing evidence indicates that central nervous system (CNS) demyelinating diseases never result from one independent factor, and the simultaneous participation of abnormal lipid metabolism, oxidative stress, and neuroinflammation could potentiate each other in the pathogenesis of MS. Therefore, a single omics analysis cannot provide a full description of any neurodegenerative disease. It has been demonstrated that oxidative stress and neuroinflammation are two reciprocal causative reasons for the progression of MS disease. However, the potential crosstalk between oxidative stress and neuroinflammation remains elusive so far. With an integrated analysis of targeted lipidomics and transcriptomics, our research presents the potential interaction between abnormalities of lipid metabolism, mitochondrial dysfunction, oxidative stress, and neuroinflammation in CNS demyelinating diseases. The findings of this paper may be used to identify possible targets for the therapy of CNS demyelinating diseases.

Background: PYGL has been reported as a glycogen degradation-related gene, which is up-regulated in many tumors. This study was designed to investigate the predictive value of high PYGL expression in patients with gliomas through bioinformatics analysis of the gene transcriptome and the single-cell sequencing data.Methods: The gene transcriptome data of 595 glioma patients from the TCGA database and the single-cell RNA sequencing data of 7,930 GBM cells from the GEO database were included in the study. Differential analysis was used to find the distribution of expression of PYGL in different groups of glioma patients. OS analysis was used to assess the influence of the high expression of PYGL on the prognosis of patients. The reliability of its prediction was evaluated by the AUC of ROC and the C-index. The GSEA be used to reveal potential mechanisms. The single-cell analysis was used to observe the high expression of PYGL in different cell groups to further analyze the mechanism of its prediction.Results: Differential analysis identified the expression level of PYGL is positively associated with glioma malignancy. OS analysis and Cox regression analyses showed high expression of PYGL was an independent factor for poor prognosis of gliomas (p < 0.05). The AUC values were 0.838 (1-year ROC), 0.864 (3-year ROC) and 0.833 (5-year ROC). The C index was 0.81. The GSEA showed that gene sets related to MTORC1 signaling, glycolysis, hypoxia, PI3K/AKT/mTOR signaling, KRAS signaling up and angiogenesis were differentially enriched in the high PYGL expression phenotype. The single-cell sequencing data analysis showed TAMs and malignant cells in GBM tissues expressed a high level of PYGL.Conclusion: The high expression of PYGL is an independent predictor of poor prognosis in patients with glioma.

Multiple sclerosis (MS) is a neurodegenerative disorder characterized by periodic neuronal demyelination, which leads to a range of symptoms and eventually to disability. The goal of this research was to use UPLC‐Orbitrap/MS to identify validated biomarkers and explore the metabolic mechanisms of MS in mice. Thirty‐two C57BL/6 male mice were randomized into two groups that were fed either normal food or 0.2% CPZ for 11 weeks. The mouse demyelination model was assessed by LFB and the expression of MBP by immunofluorescence and immunohistochemistry. The metabolites of the corpus callosum were quantified using UPLC‐Orbitrap/MS. The mouse pole climbing experiment was used to assess coordination ability. Multivariate statistical analysis was adopted for screening differential metabolites, and the ingenuity pathway analysis (IPA) was used to reveal the metabolite interaction network. We successfully established the demyelination model. The CPZ group slowly lost weight and showed an increased pole climbing time during feeding compared to the CON group. A total of 81 metabolites (VIP > 1 and P < 0.05) were determined to be enriched in 24 metabolic pathways; 41 metabolites were markedly increased, while 40 metabolites were markedly decreased in the CPZ group. The IPA results revealed that these 81 biomarker metabolites were associated with neuregulin signaling, PI3K‐AKT signaling, mTOR signaling, and ERK/MAPK signaling. KEGG pathway analysis showed that two significantly different metabolic pathways were enriched, namely, the glycerophospholipid and sphingolipid metabolic pathways, comprising a total of nine biomarkers. Receiver operating characteristic analysis showed that the metabolites (e.g., PE (16 : 0/22 : 6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z)), PC (18 : 0/22 : 4(7Z, 10Z, 13Z, 16Z)), cytidine 5 ^′‐diphosphocholine, PS (18 : 0/22 : 6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z)), glycerol 3‐phosphate, SM (d18 : 0/16 : 1(9Z)), Cer (d18:1/18 : 0), galabiosylceramide (d18:1/18 : 0), and GlcCer (d18:1/18 : 0)) have good discrimination ability for the CPZ group. In conclusion, the differential metabolites have great potential to serve as biomarkers of demyelinating diseases. In addition, we identified metabolic pathways associated with CPZ‐induced demyelination pathogenesis, which provided a new perspective for understanding the relationship between metabolites and CNS demyelination pathogenesis.