Molecular Neurobiology最新文献

Accumulating evidence suggests that oxidative stress plays a crucial role in the pathogenesis of Parkinson's disease (PD). The aims of this study were to identify oxidative stress-related hub genes, validate them through the construction of a diagnostic model, explore their interactions with miRNAs and transcription factors (TFs) and predict potential drug targets. Differentially expressed genes (DEGs) in the substantia nigra of PD patients were identified by analyzing a combination of datasets selected from the GEO database, including GSE7621, GSE20141, GSE49036, and GSE20163. The candidate genes associated with oxidative stress were screened by determining the overlap among the DEGs, oxidative stress-related genes (OSGs) and genes in key modules with the highest cor values identified via weighted gene coexpression network analysis (WGCNA). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to perform functional enrichment analysis of these candidate genes. The hub genes were identified via protein-protein interaction (PPI) analysis, and receiver operating characteristic (ROC) curves were constructed to assess the diagnostic value of each hub gene. Then, a diagnostic model was constructed via least absolute shrinkage and selection operator (LASSO) regression with the hub genes identified above, and the model was further validated in external validation datasets (GSE20292 and GSE20164). Gene-miRNA and gene-TF regulatory networks were predicted via the miRNet database, whereas candidate drugs were predicted via the Drug-Gene Interaction database. After analysis of the intersection of the 7975 DEGs, 434 OSGs, and 3582 genes identified through WGCNA, 76 candidate genes were identified. A total of 9 hub genes (JUN, KEAP1, SRC, GPX5, MMP9, TXN, MAPK3, GPX2, and IL1A) were identified via PPI and ROC curve analyses. A diagnostic model with the ability to reliably predict PD on the basis of the identified hub genes (AUC = 0.925) was constructed. Further analysis of these 9 genes revealed 64 targeted miRNAs, 35 TFs in regulatory networks and 86 potential therapeutic agents. Nine hub genes related to oxidative stress in the pathogenesis of PD were identified. These genes show strong diagnostic performance and could serve as therapeutic targets. These findings might facilitate the development of promising candidate biomarkers and potential disease-modifying therapies for PD.

Antidepressants are known for their neurotrophic effects, particularly through the regulation of brain-derived neurotrophic factor (BDNF) expression. Mirtazapine, a tetracyclic noradrenergic and specific serotonergic antidepressant (NaSSA) has been observed to upregulate BDNF, though its underlying mechanism remains unclear. In this study, we used the human neuroblastoma SH-SY5Y cell line to investigate whether mirtazapine could enhance BDNF translation by modulating serotonin and/or norepinephrine and their receptors. A 1-h stimulation with 1 or 10 µM mirtazapine led to downregulation of serotonergic receptors 5HT1A, while increasing ADRA2A and ADRB2 receptors. Mirtazapine at 10 µM upregulated endogenous BDNF after 3h, but not 1h stimulation. To investigate the translation of major BDNF transcripts, we used chimeric BDNF-luciferase constructs with the untranslated 5'UTR exons I, IIc, IV, or VI, and the long version of the 3'UTR. Luciferase assays and Western blotting revealed that mirtazapine selectively enhanced exon-IIc-BDNF-long3'UTR-Luciferase translation. This increase was associated with norepinephrine release and was inhibited by blocking ADRA2A or ADRB2 adrenoceptors for the exon-IIc-BDNF-long3'UTR-Luciferase, and ADR2B for endogenous BDNF. These findings provide a new perspective on the critical role of the noradrenergic system in mediating mirtazapine's effects on BDNF translation. We propose a novel mechanism of action in which mirtazapine promotes norepinephrine release and noradrenergic responses by upregulating ADRA2A and ADRB2 while downregulating serotonergic receptors.

This study investigates the association between serum mature brain-derived neurotrophic factor (mBDNF), its precursor proBDNF, and neurocognitive function in ART-naïve adults with HIV in sub-Saharan Africa, exploring the distinct roles of these neurotrophic factors in cognitive health. This cross-sectional analysis utilized stored baseline serum samples and neuropsychological test data from participants in the AIDS Clinical Trials Group (ACTG) A5199 study in the Johannesburg and Harare sites. Serum concentrations of mBDNF and proBDNF were quantified using ELISA. Neurocognitive function was assessed via standardized tests, with results adjusted for site-specific demographics. Linear and quantile regression models examined the relationship of mBDNF and proBDNF with a composite cognitive score (NPZ-6), and structural equation modeling (SEM) explored their association with individual cognitive test outcomes. The analysis involved 157 ART-naïve adults with HIV. Increased serum mBDNF levels showed a significant positive association with cognitive performance (β = 1.30, p = 0.02), while elevated proBDNF levels were linked to poorer outcomes, particularly affecting fine motor skills and speed (β =  - 0.29 to - 0.38, p ≤ 0.01). Quantile regression analysis highlighted mBDNF's stronger positive impact at higher cognitive performance percentiles (β = 1.04 (0.01, 2.06) at the 75th percentile), while proBDNF showed significant negative association at the 75th percentile (β =  - 0.26 (- 0.47, - 0.06)). The study highlights the positive association of mature BDNF and the negative association of proBDNF with cognitive function in HIV. These findings emphasize the need for longitudinal research to understand the temporal dynamics of neurotrophic factors during ART initiation and their potential as targets for neurocognitive interventions in HIV.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the gradual loss of neurons and the accumulation of amyloid plaques and neurofibrillary tangles. Despite advancements in the understanding of AD's pathophysiology, the cellular organization and interactions in the prefrontal cortex (PFC) remain elusive. Eight single-cell RNA sequencing (scRNA-seq) datasets from both normal controls and individuals with AD were harmonized. Stringent preprocessing protocols were implemented to uphold dataset integrity. Unsupervised clustering and annotation revealed 22 distinct cell clusters corresponding to 19 unique cell types. The spatial architecture of the PFC region was constructed using the CARD tool. Further analyses encompassed trajectory examination of Oligodendrocyte subtypes, evaluation of regulon activity scores, and spot clustering within white matter regions (WM). Differential expression analysis and functional enrichment assays unveiled molecular signatures linked to AD progression and were validated using microarray data sourced from neurodegenerative disorder patients. Our investigation employs scRNA-seq and spatial transcriptomics to uncover the cellular atlas and spatial architecture of the human PFC in AD. Moreover, our results indicate that Oligodendrocytes are more prevalent in AD patients, showcasing diverse subtypes and spatial organization within WM regions. Each subtype appears to be associated with distinct biological processes and transcriptional regulators, shedding light on their involvement in AD pathology. Notably, the Oligodendrocyte_C6 subtype is linked to neurological damage in AD patients, characterized by heightened expression of genes involved in cell-cell connections, cell membrane stability, and myelination. Additionally, 12 target genes regulated by NFIA were identified, which are upregulated in AD patients and associated with disease progression. Elevated PLXDC2 expression in peripheral blood was also identified, suggesting its potential as a non-invasive biomarker for early AD detection. Our study provides novel insights into the role of Oligodendrocytes in AD and highlights the potential of PLXDC2 as a blood biomarker for non-invasive diagnosis and monitoring of AD patients.

Sleep is pivotal to memory consolidation, and sleep deprivation (SD) after learning can impede this process, leading to memory disorders. In the present study, we aimed to explore the effects of acute sleep deprivation (ASD) on memory disorders and the underlying mechanisms. ASD model was induced by subjecting the mice to 6 h of SD following fear conditioning training. Different cohorts were used for behavioral, biochemical, and electrophysiological tests. Here, we showed that memory precision decline was induced by ASD, concomitant with a notable elevation in oxidative stress within PV interneurons, loss of PV, and disturbed neuronal oscillation in the CA1 region. Notably, chemogenetic activation of PV interneurons effectively ameliorated abnormal gamma oscillation and memory precision decline observed in ASD mice. Meanwhile, chemogenetic inhibition of PV interneurons successfully mimicked the abnormal brain oscillations and memory precision decline observed in ASD mice. Additionally, prior administration of the antioxidant medication N-acetylcysteine effectively reversed memory precision decline and mitigated PV loss and abnormal oscillation triggered by ASD. Collectively, our findings indicated that ASD increased oxidative stress in PV interneurons, thereby disrupting neural oscillation in the CA1 and ultimately leading to memory precision decline.

Although several studies have identified a distinct gut microbiota in individuals with acute ischemic stroke (AIS), there is a limited amount of research that has simultaneously investigated alterations in the oral and intestinal microbiota in AIS patients and their correlation with clinical prognosis. This was a prospective and observational single-center cohort study in which we included 160 AIS patients who were admitted within 24 h after a stroke event. We collected oral and rectal swab samples for analysis using 16S rRNA high-throughput sequencing. Our study revealed that patients with unfavorable outcomes after AIS showed early disruptions in their oral and intestinal microbiota. Rectal swabs showed increased levels of facultatively anaerobic bacteria in patients with a poor prognosis, while the oral cavity exhibited higher levels of anaerobic and opportunistic pathogenic bacteria. By employing machine learning analysis, we found that the microbiota composition at both rectal and oral sites could predict early and long-term outcomes. Moreover, patients with a poor prognosis displayed increased oral bacterial colonization in the rectal microbiota and altered interactions between the oral and gut microbiota. This study reveals distinct rectal and oral bacteria that could predict unfavorable outcomes for AIS patients. Monitoring the microbiota of various body sites during the early stages after admission may hold prognostic value and inform personalized treatment strategies. The presence of oral bacteria colonizing the intestines during the acute phase of stroke could serve as an early indication of poor outcomes for AIS patients.

Macrophages are fundamental cellular components of atherosclerotic plaques, and inhibition of macrophage inflammation can delay the development of atherosclerotic plaques. Sodium danshensu (SDSS) can inhibit inflammatory responses and thus delay atherosclerosis, but the specific mechanism remains unclear. The effect of SDSS in inhibiting atherosclerosis was confirmed by observing and detecting atherosclerotic plaque area, morphology and lipid levels in the aorta. The mechanism by which SDSS attenuated atherosclerotic plaques was elucidated by in vivo and in vitro detection of inflammation-related mRNA and protein expression. In addition, bioinformatics analysis, RT-qPCR and dual-luciferase assays were used to predict and validate the potential miRNAs of SDSS to attenuate atherosclerosis. miR-200a-2p mimic and inhibitor were then compared for their effects on the efficacy of SDSS. SDSS inhibited atherosclerotic plaque formation and suppressed the expression of MEKK3, TNF-α, and IL-1β as well as nuclear factor-κB (NF-κB) phosphorylation and nuclear translocation to attenuate inflammatory responses. Bioinformatic predictions combined with RT-qPCR results and dual-luciferase assays indicated that miR-200a-3p negatively regulated MEKK3 expression by directly targeting the 3'UTR region of MEKK3, thereby blocking MEKK3. Further studies showed that miR-200a-3p inhibitor, but not miR-200a-3p mimic, reversed the beneficial effects of SDSS on inflammation. SDSS inhibited macrophage inflammation by modulating the miR-200a-3p/MEKK3/NF-κB signaling pathway.

Pharmacological inhibition of the transient receptor potential melastatin 2 (TRPM2), an oxidative stress-activated calcium channel, was previously reported to be protective in Parkinson's disease (PD). However, the inhibitors used were not TRPM2 specific, so the involvement of this channel in PD remains unclear. Here, for the first time, Trpm2 partial (+ / -) and complete (- / -) knockout mice underwent stereotaxic surgery for PD induction. Six-hydroxydopamine was injected in the right striatum. On days 3 and 6, motor behavior tests (cylinder, apomorphine, and pole test) were performed. On day 7, brains were collected for dopaminergic neuron immunostaining. Our results showed that Trpm2 + / - male and female mice had reduced motor impairment and dopaminergic neuron death after PD induction. In addition, Trpm2 - / - male and female mice showed absent or lesser motor deficit and the dopaminergic neuronal loss was no longer observed. These findings suggest that TRPM2 is involved in the PD-like pathology and that targeting TRPM2 may possibly represent a potential neuroprotective strategy for PD.

Ischemic stroke is caused by interrupted cerebral blood flow and is a leading cause of mortality and disability worldwide. Significant advancements have been achieved in comprehending the pathophysiology of stroke and the fundamental mechanisms responsible for ischemic damage. Lactylation, as a newly discovered post-translational modification, has been reported to participate in several physiological and pathological processes. However, research on lactylation and ischemic stroke is scarce. This review summarized the current function of protein lactylation in other diseases or normal physiological processes and explored their potential link with the pathophysiological process and the reparative mechanism of ischemic stroke. We proposed that neuroinflammation, regulation of metabolism, regulation of messenger RNA translation, angiogenesis, and neurogenesis might be the bridge linking lactylation and ischemic stroke. Our study provided a novel perspective for comprehending the role of protein lactylation in the pathophysiological processes underlying ischemic stroke. Lactylation might be a promising target in drug development of ischemic stroke.