Journal of Molecular Neuroscience最新文献

Epilepsy is a long-term neurological disorder that leads to disability with neuropsychiatric comorbidities. Studies have shown that neurochemical imbalances involved in the disease are linked to heightened oxidative and inflammatory pathways, which significantly affect the severity of the disease. As a result, substances that have antioxidant and anti-inflammatory effects might help in managing the condition. Hence, this study investigated the effects of sabinene, a natural monoterpene in essential oils, against pentylenetetrazol-induced seizure kindling and neuropsychiatric comorbidities in mice, revealing insights into the neurochemical, antioxidant, and anti-inflammatory biochemical mechanisms involved. Male Swiss mice in adulthood were pretreated with sabinene (5 and 10 mg/kg) or diazepam (3 mg/kg) 30 min prior to pentylenetetrazol-induced seizures, with injections administered every other day for 28 days. We conducted behavioral assessments using a Racine scale (0–6) and evaluated comorbidities such as cognitive impairments and depression. Neurochemical, antioxidant and anti-inflammatory biochemical mechanisms of the antiepileptic effect of sabinene against pentylenetetrazol-induced kindling were analyzed in the prefrontal cortex and hippocampus, two brain regions largely involved in the disease’s onset and development. Sabinene inhibits pentylenetetrazol-induced seizures evidenced by the reduced frequency and severity of seizure episodes. Sabinene decreases motor activity, reverses pentylenetetrazol-associated spatial/non-spatial memory deficits, increases sociability, and lowers the depressive symptoms. These behavioral changes reversed by sabinene were accompanied by reduced prefrontal-hippocampal glutamate release and increase GAD enzyme. Consistent with this, sabinene elevated IL-10 in both brain areas while also increasing the levels of prefrontal pro-inflammatory cytokines, such as TNF-α and IL-1β. However, sabinene reduced TNF-α and IL-1β in the hippocampus, as well as oxidant markers (malondialdehyde, nitrite), and increased antioxidant systems in both brain regions compared to the pentylenetetrazol cohorts. Overall, sabinene’s antiepileptic and neuroprotective effects include modulating neurotransmitter imbalances, inhibiting oxidative stress, and modulating cortical neuroimmune dysfunction.

Oligoclonal band (OCB) analysis in cerebrospinal fluid (CSF) remains a cornerstone for the early diagnosis of multiple sclerosis (MS), with recent criteria highlighting the κ-free light chain (κ-FLC) index as a sensitive marker of intrathecal immunoglobulin synthesis. However, both approaches rely on lumbar puncture. To address the need for less invasive tools, this study employed proton nuclear magnetic resonance (¹H-NMR)-based serum metabolomics to explore whether peripheral metabolic signatures can distinguish immunophenotypic subgroups, namely OCB Type 1 and Type 2, in patients with suspected early-stage MS. To investigate whether targeted proton nuclear magnetic resonance (¹H-NMR) serum metabolomics can differentiate between individuals with OCB Type 1 (no intrathecal synthesis) and OCB Type 2 (definite intrathecal synthesis), as a step toward non-invasive metabolic stratification in possible early-stage MS. Serum samples (n = 49) were classified by OCB profile and analysed using targeted ¹H-NMR spectroscopy. All spectra were acquired at 298 K on a Bruker Avance Neo 600 MHz spectrometer. Metabolites were identified using Bruker BioRefCode libraries, and absolute quantification was performed using the ERETIC (Electronic Reference To access In vivo Concentrations) signal. Statistical analysis included age-adjusted univariate tests (t-test or Wilcoxon rank-sum, depending on normality) with false discovery rate (FDR) correction, followed by multivariate analyses including principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), variable importance in projection (VIP) scores, and ROC-AUC permutations using the pROC package in R. Of the quantified metabolites, Leucine emerged as a robust differentiator, showing significant elevation in OCB Type 2 after both age adjustment and multiple testing correction (p = 0.025, FDR-adjusted; VIP = 2.38; AUC = 0.74), and correlating moderately with the IgG index (r = 0.32, p = 0.026). Histidine, Glycine, Sarcosine, and Succinic acid met VIP > 1.5 thresholds but did not survive FDR correction and are therefore reported as exploratory candidates. This pilot study identifies Leucine as a promising serum biomarker candidate for early intrathecal immune activity. Although additional metabolites showed potential, their findings remain exploratory due to statistical limitations. These results highlight the potential of targeted serum metabolomics as a non-invasive adjunct in early MS risk stratification and support further validation studies incorporating κ-FLC data and longitudinal follow-up.

Hydrocephalus is a condition defined by excessive cerebrospinal fluid (CSF) relative to the brain volume. Congenital and infantile forms of hydrocephalus are both genetically and physiologically heterogenous. Among the candidate genes implicated in hydrocephalus, many are associated with cilia, a subcellular structure involved in CSF circulation and neurodevelopment. First, we provide an overview of 129 genes associated with human hydrocephalus and currently reported in the literature, categorized according to their possible involvement in ciliary structure, ciliary function, or cilia-mediated processes/signalling pathways. Intriguingly, there are large differences in the prevalence and manifestations of cilia-related hydrocephalus in humans as compared to rodents. Second, we address these differences by revisiting human and animal studies to outline potential cilia-related mechanisms and molecular signalling pathways contributing to hydrocephalus. We propose that our rapidly expanding understanding of cilia’s role in CSF circulation and brain development will support a more precise characterization of hydrocephalus subtypes, ultimately guiding the development of more personalized treatment strategies.

The ketogenic diet (KD), a high-fat, low-carbohydrate regimen, has been shown to exert neuroprotective effects in various neurological models. This study explored how KD—alone or combined with antibiotic-induced gut microbiota depletion—affects cognition and neuroinflammation in aging. Thirty-two male rats (22 months old) were assigned to four groups (n = 8): control diet (CD), ketogenic diet (KD), antibiotics with control diet (AB), and antibiotics with KD (KDAB). Diets were maintained for 10 weeks; during the final week, AB and KDAB groups received a broad-spectrum antibiotic cocktail (ampicillin 1 g/L, vancomycin 0.5 g/L, neomycin 1 g/L, and metronidazole 1 g/L) in drinking water. Cognitive abilities were evaluated using the Morris Water Maze and Novel Object Recognition Test. BDNF and inflammatory cytokines (TNF-α, IL-1β, IL-10) were measured in the hippocampus and prefrontal cortex. KD and KDAB groups exhibited increased β-hydroxybutyrate and reduced glucose levels, enhanced cognitive performance, elevated BDNF and IL-10, and decreased TNF-α and IL-1β compared to non-KD groups. Although antibiotic treatment alone caused only a transient impairment in spatial memory and was associated with reduced TNF-α levels, the ketogenic diet—irrespective of microbiota status—consistently improved cognitive performance and elevated neuroprotective markers. These findings suggest that KD appears to promote brain resilience during aging, even in the presence of microbiota disruption.

Collagen type XX alpha 1 (COL20A1) was recently found to be highly concentrated in perisynaptic Schwann cells (PSCs), the synaptic glia of the neuromuscular junction (NMJ), suggesting that COL20A1 plays important roles in PSCs and at the NMJ. To investigate this possibility, we generated mice lacking Col20a1 only in Schwann cells (Col20a1-SCKO) and globally (Col20a1-gKO). PSCs and NMJs were morphologically unchanged in adult Col20a1-SCKO mice despite these conditional mice exhibiting gait abnormalities. Additional analysis revealed roles of COL20A1 at regenerating NMJs. We found that loss of COL20A1 altered the time course of migrating Schwann cells associated with NMJs. It also inhibited the remodeling of the post-synaptic region that naturally occurs following reinnervation. However, the timing of NMJ reinnervation was unchanged in Col20a1-SCKO compared to control mice. We next examined adult Col20a1-gKO mice. These mice did not exhibit overt morphological differences compared to control mice. Col20a1-gKO mice also did not exhibit NMJ alterations despite presenting with increased mass of the extensor digitorum longus and soleus muscles. Together, these data provide important leads about potential roles of COL20A1 in healthy and injured adult PSCs, NMJs, and muscles.

Glioblastoma (GBM) represents one of the most aggressive brain tumors with a poor prognosis despite decades of research. Epigenetic regulation has emerged as a promising strategy for managing aggressive cancers, such as GBM, by modulating pro-tumorigenic gene expression. The role of pro-tumorigenic genes, such as oligodendrocyte transcription factor 2 (OLIG2), has been heavily associated with cancer progression and treatment resistance and is a potential target for GBM. The objective of this study is to analyze the effectiveness of various epigenetic regulators, including histone modifiers, DNA methylases, chromatin remodelers, and miRNAs, on OLIG2 expression, including the effectiveness of individual epigenetic regulators and their combinations. The effects of epigenetic regulators in GBM that are found in the literature were reviewed for their survival and co-expression with OLIG2. We found that KDM6B, BRG1, DNMT1, and HDAC2 were associated with significant co-expression with OLIG2 and decreased survival in GBM patients, reinforcing their suitability as targets. Additionally, miR-17-3p miRNAs associated with silencing OLIG2 as gene expression was downregulated in GBM. Additionally, this paper highlights the potential of combination therapies targeting multiple epigenetic pathways simultaneously. A kinase inhibitor (alisertib), together with JQ1, reduced the tumor growth of GBM cells in vivo more than either treatment alone, making combination therapies a promising solution.

Premature ovarian failure (POF) accelerates ovarian aging, leading to menstrual irregularities, reduced fertility, and decreased estrogen levels. Current hormone replacement therapy (HRT) cannot reverse the aging effects, highlighting the need for more targeted treatments. Genome-wide association studies (GWAS) and protein quantitative trait loci (pQTL) analyses can identify genetic variants and protein level changes associated with POF. Mendelian randomization (MR) evaluates the causal relationships between genetic variants and POF. pQTL analysis was conducted using plasma proteomics data from 54,219 participants and baseline cohort data of 34,557 individuals of European ancestry from the UK Biobank. GWAS data comprising 542 POF cases and 218,970 controls were obtained from the FinnGen database. MR analysis utilized inverse variance weighted (IVW), MR Egger, weighted median, and weighted mode methods. Colocalization analysis was performed using the “coloc” R package, and pathway enrichment analysis was conducted using the “clusterProfiler” package. Additionally, reverse MR analysis, molecular docking predictions, and summary data-based Mendelian randomization (SMR) analysis were performed. Finally, based on the scRNA-seq data of POF, analyses such as cell type annotation, gene set scoring, and cell–cell communication were performed. MR analysis identified significant causal relationships between specific proteins (BSG, CCL23, CTSC, FAP, IGSF21, LCN15, LILRB2, MUC16, PTN, SPINK1, TNFRSF1B, TNFRSF8, TNXB, and YJU2) and POF. Colocalization analysis indicated that key proteins (BSG, CCL23, FAP, and TNXB) share causal variants with POF traits. SMR analysis confirmed TNXB as a risk factor for POF. Finally, using the scRNA-seq data of POF, the expression of key gene sets was used to evaluate the scoring of different cell populations. Cell–cell communication analysis identified multiple communication pathways between high-scoring cell populations and other cell groups. The expression trend of key proteins was further verified by western blot assay. These findings are preliminary and require significant validation before clinical application. Combining pQTL and GWAS data, MR and colocalization analyses identified key proteins and genetic variants associated with POF, providing deeper insights into POF mechanisms and potential therapeutic targets.

Low-grade gliomas (LGGs) represent a complex and aggressive category of brain tumors. Despite recent advancements in molecular subtyping and characterization, the necessity to identify additional molecular subtypes and biomarkers remains. To delineate survival subtypes in LGG, we propose a deep learning (DL)-based multi-omics SurvivalNet (MOST) model. By integrating histological RNA-seq, miRNA-seq, and DNA methylation data obtained from The Cancer Genome Atlas (TCGA), we applied the MOST model to analyze data from 497 LGG patients. We employed consensus clustering to reveal heterogeneous subtypes, validated our findings using an internal validation set through a supervised classification algorithm, and further evaluated the robustness of our model in an independent external cohort. The DL-based MOST model identified two optimal patient subtypes with significant differences in survival (P = 3.07E − 16) and demonstrated a robust model fit (C = 0.92 ± 0.02). This multi-omics model was validated using external Chinese Glioma Genome Atlas (CCGA) datasets, including RNA-Seq (N = 497, C = 0.85), miRNA array (N = 89, C = 0.80), and DNA methylation (N = 89, C = 0.61). High-risk subcategories exhibited increased expression of the homeobox (HOX) family genes, regulation of cholesterol homeostasis, glycolysis, epithelial-mesenchymal transition pathway enrichment, and a high density of M2 macrophages. Our study utilized deep learning to identify multi-omics features associated with differential survival outcomes in patients with LGG. This work is anticipated to significantly enhance prognosis prediction for LGG due to its robustness within the cohorts.

Background

Neuroinvasive pathogens are capable of breaching the blood–brain barrier (BBB), and causing central nervous system infections. Although the response of human brain microvascular endothelial cells (hBMECs), the forefront cells of BBB has been extensively studied, the roles of astrocytes and pericytes in modulating BBB integrity during infection remain less defined.

Aims

The study aims for a meta-analysis of RNA-seq data to compare the transcriptional response of hBMECs alone and in co-culture with astrocytes and pericytes (BBB-spheroids) following infection with Neisseria meningitidis and Borrelia bavariensis. Subsequently, identifying the pathogen-specific gene signatures that regulates the signalling pathways associated with infection and BBB disruption.

Methods

Unique and shared differentially expressed genes (DEGs) of hBMECs and BBB-spheroids were identified and analysed for functional enrichment using DAVID. Protein–protein interaction networks were constructed and analysed in Cytoscape using MCODE and cytoHubba to identify infection-related hub genes.

Results

A large proportion of DEGs were unique to each BBB model during infection, 49% in Neisseria and 66% in Borrelia infection, whereas only 4.9% were shared. hBMECs predominantly expressed defence-related genes, whereas BBB-spheroids expressed genes linked to barrier function. Notably, IFIH1, IFIT1, IFIT3, ISG15, MX1, OAS1, and RSAD2 were identified as regulators of the BBB’s transcriptomic response to infection.

Conclusions

The meta-analysis highlights distinct yet complementary roles of endothelial cells and the supporting pericytes and astrocytes in BBB regulation to bacterial invasion. The identified hub genes may serve as key regulators of infection-driven inflammation and form potential diagnostic or prognostic targets.

Graphical Abstract