Journal of Molecular Neuroscience最新文献

Lactate metabolism and its epigenetic modification, lactylation, are emerging regulators in neurological disorders, yet their roles in spinal cord injury (SCI) remain unclear. Here, we mined SCI transcriptomes from GEO and identified 13 differentially expressed lactylation-related genes (DE-LRGs), with lactate dehydrogenase A (LDHA) significantly upregulated. Immune-infiltration analysis linked LDHA to T cells gamma delta, and Mfuzz time-series clustering showed dynamic LDHA upregulation during acute SCI, which was validated in GSE45006. Random forest and ROC analyses supported the diagnostic value of LDHA. PPI and GeneMANIA networks positioned LDHA at the intersection of lactate metabolism and immune regulation. Drug prediction with Enrichr/DSigDB and docking highlighted folic acid and quercetin dihydrate as candidate compounds. GSVA/GSEA indicated LDHA enrichment in immune activation, metabolic regulation, and stress-response pathways. Immunofluorescence in a rat SCI model confirmed sustained LDHA elevation from 1 to 3 days around the lesion. Importantly, Western blot validation (3 days post-injury) demonstrated increased nuclear HIF-1α and p-STAT3^Y705 (total STAT3 unchanged) together with elevated CXCL1, IL-6, and CCL2 and the infiltration marker MPO/CD68; these changes were attenuated by LDHA inhibition (FX11) and partially rescued by exogenous lactate, supporting an LDHA → lactate → HIF-1α/STAT3 → chemokine/infiltration axis in acute SCI. Collectively, our data identify LDHA as a key lactylation-related regulator in SCI that contributes to pathogenesis via metabolic reprogramming and immune modulation, highlighting its promise as a diagnostic biomarker and therapeutic target. 

Brain tumors present a significant diagnostic and therapeutic challenge due to their heterogeneity and the limitations of conventional monitoring tools. Liquid biopsy, particularly the analysis of cell-free DNA (cfDNA) from biofluids, has emerged as a transformative, minimally invasive approach in neuro-oncology. By analyzing tumor-derived genetic and epigenetic alterations in cfDNA, this method offers a comprehensive molecular profile of a patient’s total tumor burden. Cerebrospinal fluid (CSF) has proven to be a superior source of tumor-derived cfDNA compared to plasma, overcoming the barrier posed by the blood-brain barrier. Clinically, cfDNA analysis enables non-invasive diagnosis, real-time monitoring of treatment response, early detection of acquired resistance, and sensitive surveillance for minimal residual disease. It has demonstrated utility across various histologies, including gliomas, medulloblastoma, brain metastases, and primary central nervous system lymphoma. However, the key limitations still include the low abundance of tumor-derived cfDNA in biofluids, particularly plasma, and the invasiveness of CSF collection, which restrict broader clinical application. This review adds value by integrating the WHO 2021 molecular framework for brain tumor classification, providing histology-specific insights into cfDNA applications. It emphasizes CSF as the superior analyte for cfDNA detection, discusses the emerging roles of minimal residual disease (MRD) monitoring and adaptive therapies, and highlights advances in multi-omics and AI-driven approaches. By explicitly focusing on these novel aspects, this study strengthens the clinical positioning of cfDNA liquid biopsy in neuro-oncology and its prospective role in precision medicine.

Graphical Abstract

Brain tumor management faces challenges from ambiguous imaging and the risks of invasive biopsy, such as sampling bias. cfDNA analysis, particularly from CSF, offers a transformative solution. This minimally invasive liquid biopsy approach overcomes these limitations by enabling real-time monitoring of treatment response, early detection of resistance, and a comprehensive molecular profile of the tumor, paving the way for personalized neuro-oncology. The figure has been created by created by BioRender (https://BioRender.com/r08v107).

Alzheimer’s disease (AD) is prevalent in more than 55 million worldwide, a figure estimated to almost triple by 2050, highlighting the need for highly effective treatments. However, despite the large expenditure of research over several decades, over 90% of clinical trials—countless amyloid-β–targeted drugs among them—have failed, stressing the shortcomings of reductionist, one-target approaches. More and more, AD is viewed as a complex systems disorder, resulting from interlinked disruptions in proteostasis, neuroinflammation, vascular integrity, synaptic plasticity, and metabolic regulation. Such an understanding has transformed the therapeutic paradigm toward precision, multimodal treatment, integrating disease-modifying agents with biomarker-based diagnosis and patient stratification. Improved blood- and imaging-based biomarkers, new molecular targets, and drug-delivery technologies offer the hope for earlier intervention and more personalized treatment. Looking to the future, the way forward will rely on the integration of systems biology, computational modeling, and translational neuroscience into adaptive trial design able to tackle the heterogeneity of the disease. These developments combined constitute the progressive shift away from “one-size-fits-all” treatments towards a future of personalized, mechanism-based therapies in Alzheimer’s disease.

Background

Migraine is a complex neurological disorder. While acupuncture is effective in alleviating migraines, its molecular mechanisms remain unclear. This study aims to explore these mechanisms.

Methods

We used bioinformatics to identify differentially expressed microRNAs (miRNAs) in migraine patients after acupuncture. Subsequently, luciferase reporter assays were utilized to verify the interaction between miRNAs and their regulated target gene mRNAs. RT-qPCR and Western blot analyzed key miRNAs’ regulatory effects on target genes. We also employed Transwell migration assays and a nitroglycerin (NTG)-induced migraine mouse model to systematically evaluate acupuncture’s efficacy and mechanism.

Results

Bioinformatics analysis revealed a significant upregulation of Hsa-miR-550a-3-5p in the peripheral blood of migraine patients after acupuncture treatment. Hsa-miR-550a-3-5p could directly inhibit the mRNA and protein expression of platelet and endothelial cell adhesion molecule 1 (PECAM1), reducing nitroglycerin-induced human brain microvascular endothelial cells (HBMECs). Following the downregulation of PECAM1 by hsa-miR-550a-3-5p, the transendothelial migration capacity of monocytes-macrophages was significantly reduced, and reducing the secretion of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. Furthermore, it alleviates inflammation by regulating M2 macrophage polarization. In NTG-induced mice, acupuncture relieved migraine-like behaviors, an effect abolished by a miR-550a-3-5p inhibitor.

Conclusion

This study is the first to reveal that after acupuncture treatment, hsa-miR-550a-3-5p can be upregulated to target and inhibit PECAM1, reducing the transendothelial migration of inflammatory cells and the release of inflammatory cytokines, thereby alleviating migraine symptoms. This discovery provides scientific evidence for the efficacy of acupuncture and offers a new target for developing miRNA-based precision treatment strategies.

Endoplasmic reticulum (ER) stress and activation of the three unfolded protein response pathways, in particular the protein kinase RNA-like ER kinase (PERK) pathway, contribute to the pathophysiology of various neurodegenerative conditions including type 2 diabetes mellitus (T2DM). T2DM is an increasingly prevalent metabolic disorder affecting millions. Even with strict glucose control, patients with T2DM frequently experience mild cognitive impairment and exhibit a significantly increased risk of developing dementia. We previously demonstrated that impaired cognitive flexibility is associated with shortening of axon initial segment (AIS) length in the prefrontal cortex in the T2DM model db/db mice. The AIS plays the crucial roles of regulation of action potential initiation and neuronal output. Even subtle shortening of AIS length can reduce excitability of neurons. In this study, we hypothesized that ER stress mediates AIS shortening in diabetic conditions. Utilizing primary mouse cortical cultures, we show that sodium 4-phenylbutyrate, a well-documented ER stress inhibitor, prevents AIS shortening and PERK activation induced by the T2DM factor methylglyoxal. Exposure of cortical cultures to an established ER stress inducer tunicamycin caused dose-dependent reduction of AIS length in the generalized population of the neurons without affecting neuronal viability. Co-exposure to a PERK-specific inhibitor GSK2606414 prevented AIS shortening induced by tunicamycin. These results demonstrate ER stress is sufficient and necessary for AIS shortening in vitro. Our findings identify ER stress and AIS shortening as potential therapeutic targets in T2DM-related cognitive impairment.

After a status epilepticus (SE) event, the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome is activated, accompanied by morphological alterations in microglia and astrocytes, which are key features of inflammation. Antioxidants have been shown to inhibit NLRP3 inflammasome activation and suppress glial cell morphological alterations. In this study, firstly we evaluated the antiseizure effect of the antioxidant edaravone (EDA) at different doses on the convulsive behavior and epileptiform activity induced by pilocarpine (Pilo) in order to determine the most appropriate dose for subsequent experiments. Later, for the main study, we investigated the temporal expression of NLRP3 inflammasome components and glial cell morphological characteristics following SE to assess the efficacy of the EDA, using a rat model of SE induced by Pilo and conducted a temporal analysis of the protein expression of NLRP3, IL-1β, caspase-1 p20 and IL-10 by nano dot blotting. Additionally, Sholl analysis was performed to evaluate glial cell morphology. Our findings revealed an increase in the expression of NLRP3 inflammasome components after SE, accompanied by glial cell morphological changes characteristic of a reactive state. Furthermore, EDA significantly reduced NLRP3 expression, decreased IL-10 levels and mitigated SE-induced morphological alterations in glial cells.

While Parkinson’s disease (PD) is predominantly sporadic, various mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been linked to the autosomal recessive form of PD. PINK1, a serine/threonine protein kinase, holds a pivotal role in mitophagy - a process that selectively eliminates damaged mitochondria, overseeing mitochondrial quality control and ultimately safeguarding against neuronal cell loss in PD. Understanding the regulation of PINK1 stability is essential in comprehending PD pathology, given its involvement in a pro-survival pathway. Although some components of the ubiquitin-proteasome system (UPS) are recognized for mediating the proteolysis of PINK1, the specific enzyme(s) responsible for positively influencing PINK1 stability have remained elusive. In this study, we demonstrated that ubiquitin-specific protease 20 (USP20) functions as a novel deubiquitinating enzyme targeting PINK1. We found that USP20 positively regulates PINK1 levels by hydrolyzing Lys 48-linked polyubiquitin chains, promoting mitophagy under the treatment of mitochondrial depolarizing agent carbonyl cyanide m-chlorophenyl hydrazine (CCCP). Furthermore, CCCP treatment accelerates the deubiquitinating activity of USP20, facilitating the degradation of impaired mitochondria and enhancing mitochondrial quality control via PINK1 accumulation. Taken together, these findings unveil a novel enzyme, USP20, positively impacting PINK1 level and promoting CCCP-induced mitophagy. In addition, this study establishes a comprehensive map depicting how PINK1 can be regulated both positively and negatively through the coordinated action of multiple members in the UPS.

To investigate the anti-glioblastoma potential of the natural isoflavone formononetin, focusing on its impact on cell survival, proliferation, migration, mediated through a potential mechanism involving oxidative stress modulation. T98G glioblastoma cells were treated with formononetin (IC₃₀ = 16.20 µM, IC₅₀ = 24.64 µM). Cytotoxicity (MTT), proliferation (trypan blue), migration (wound healing), clonogenicity (colony formation), and apoptosis (Hoechst staining) were assessed. Gene expression (qRT-PCR) of survivin, cyclin D1, Bad, MMP-9, SOD, CAT, and GPX was analyzed. Antioxidant enzyme activity and total antioxidant capacity (TAC) were measured. Formononetin dose-dependently reduced cell viability, proliferation, migration, and colony formation, while inducing apoptosis. It downregulated survivin, cyclin D1, MMP-9, and, unregulated Bad. Paradoxically, it significantly increased the activity of SOD, CAT, and GPX enzymes and enhanced TAC. Formononetin exerts potent anti-glioblastoma effects by inducing apoptosis and inhibiting key cancer hallmarks, mediated through a unique mechanism involving the paradoxical activation of the cellular antioxidant system, ultimately disrupting redox balance.

Activation of α-2 adrenergic receptors (AR) may exert a protective role against neuronal injury. Clinically, dexmedetomidine (DEX), a selective α-2 AR agonist, has been shown to reduce brain dysfunction. Therefore, the aim of this study was to investigate whether DEX could prevent cognitive deficits induced by sepsis. Wistar rats were randomly assigned to five groups: (1) Sham; (2) sepsis induced by cecal ligation and puncture (CLP); (3) CLP + DEX; (4) CLP + idazoxan (IDA, an α-2 AR antagonist); and (5) CLP + IDA + DEX. At different time points after CLP, the hippocampus, prefrontal cortex, and amygdala were isolated for quantification of cytokines, α-2A and α-2C AR expression, and glutamate content. At 10 and 30 days post-CLP, cognitive function was assessed using the open field habituation, inhibitory avoidance, and novel object recognition tasks. DEX treatment improved performance across all cognitive tasks, and this effect was antagonized by co-administration of IDA. DEX reduced proinflammatory cytokine levels (IL-6 and IL-1β) 24 h after sepsis, and this anti-inflammatory effect was sustained at later time points, particularly for IL-1β in the hippocampus. Additionally, DEX decreased glutamate levels in the pre-frontal cortex and amygdala late after sepsis induction. DEX also regulated the expression of α-2 AR subtypes in a time- and region-specific manner. In conclusion, the protective effect of DEX on cognitive function appears to be the mainly affected by the regulation of glutamate levels, whose effects were receptor-dependent, in contrast to the majority of cytokines. However, it should be noted that the primary neuroprotective effect is driven by the direct, receptor-dependent functional agonism of DEX administered acutely after sepsis induction, and this acute mechanism subsequently triggers secondary, long-term structural adaptations that ultimately influence cognitive function.

Imaging genetics is an approach that explores the underlying mechanisms of brain disorders such as Alzheimer’s disease (AD) by analyzing the correlation between neuroimaging and genetic data. Traditional non-negative matrix factorization (NMF) algorithms are based on linear assumptions, which limits the potential of nonlinear feature extraction among multi-omics data. This study proposes a novel joint-connectivity-based deep semi-supervised non-negative matrix factorization (JCB-DSNMF) model to overcome this limitation and incorporate prior knowledge from both within and between different modalities of data. The model effectively integrates physiological constraints such as connectivity to identify regions of interest (ROI), risk genes, and risk SNP loci associated with AD patients. JCB-DSNMF outperformed other NMF-based algorithms, such as JDSNMF and NMF, in identifying and predicting biologically relevant biomarkers closely related to AD from essential modules. The accuracy of the selected features was further validated by constructing a diagnostic model with high classification accuracy, achieving an AUC value of 0.8621 on the test set. In particular, the brain region Putamen_L and the gene RALGAPB achieved AUC values of 0.903 and 0.924, respectively, highlighting the importance of these features in early AD diagnosis.