Neuroreport最新文献

Purpose: Intracranial aneurysms represent the primary source of subarachnoid hemorrhage, ranking as the third most common cerebrovascular disorder after cerebral thrombosis and hypertension-related brain hemorrhage. As a member of the GATA family transcription factors, the role of zinc finger GATA-like protein 1 (ZGLP1) was unclear in intracranial aneurysm. In the present research, the specific effects of ZGLP1 on the proliferation and phenotypic transformation of human aerobic smooth muscle cells (HASMCs) were investigated.

Methods: Cell counting kit 8 and colony formation assays were performed to detect the growth of HASMCs. Cell migration was confirmed using transwell and wound healing assays. The apoptosis was analyzed using flow cytometry.

Finding: ZGLP1 knockdown inhibited the viability and colony formation ability of HASMCs. Importantly, ZGLP1 knockdown effectively promoted the apoptosis of HASMCs. The migration of HASMCs was remarkably inhibited by ZGLP1-specific small interfering RNA. Mechanistically, ZGLP1 knockdown inhibits the phosphorylation of protein kinase B (AKT) and cyclin D1 expression. In addition, ZGLP1 knockdown inhibited the expression of SMA and SM22α, while promoting the expression of OPN and MMP-2 in HASMCs, suggesting that ZGLP1 knockdown initiated the transformation from contractile phenotype to synthetic phenotype of HASMCs.

Conclusion: ZGLP1 knockdown induces apoptosis through the AKT pathway, and also induces the phenotypic transformation of HASMCs. ZGLP1 is a potential therapeutic target for intracranial aneurysm and deserves further research.

Objective: In this study, we investigated the interactions between brain regions at different scales in patients with mild cognitive impairment (MCI) to classify patients with MCI who may develop Alzheimer's disease (MCI-Converter (MCI-c)) and those with stable cognitive states (MCI-Stable (MCI-s)) at multiple spatial scales.

Methods: We divided the brain into 210, 40, and 12 regions, respectively, based on anatomical a priori, and then extracted six morphological features. Based on this, an intralayer structural brain network was constructed to detect connections between brain regions at different levels, and an interlayer network was constructed to explore connections between different spatial scales. Then these two networks were merged into a whole-brain network and trained the classifier after feature selection.

Results: Our study successfully identified meaningful connectivity features for precise classification, achieving an accuracy of 92.41%. In addition, some frequently reported abnormal brain regions were localized to more precise regions.

Conclusion: The human brain is a complex system with multiple spatial and temporal scales and multiple levels, showing a large number of emergent phenomena. Understanding the hierarchical relationship between brain structure and function is crucial. The network we constructed is not only important for MCI classification, but also holds promise for investigating other neurological conditions and elucidating brain development processes. Limitations include that model training and evaluation used only the Alzheimer's Disease Neuroimaging Initiative cohort; independent cohort validation is required to confirm generalizability. Moreover, integration with other imaging modalities (e.g. functional MRI and PET) may further improve prediction and will be explored in future work.

Background: Intracerebral hemorrhage (ICH) induces secondary brain injury, driven in part by oxidative stress caused by hemin, a toxic hemoglobin breakdown product. Cortical astrocytes, critical for maintaining redox homeostasis, are vulnerable to hemin-induced oxidative damage, exacerbating neuronal injury. Induced pluripotent stem cell-derived neural progenitor cells (iPSC-NPCs) have shown therapeutic potential in brain injury models by promoting neural repair, but their ability to protect astrocytes against hemin toxicity remains unexplored. We hypothesized that iPSC-NPCs coculture mitigates hemin-induced oxidative stress in astrocytes by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway.

Materials and methods: Astrocytes were exposed to hemin with or without iPSC-NPC coculture. We assessed cell viability, reactive oxygen species (ROS) accumulation, apoptosis, and the role of the Nrf2/HO-1 pathway using small-interfering RNA.

Results: iPSC-NPC coculture significantly reduced hemin-induced oxidative damage by promoting Nrf2 nuclear translocation and upregulating HO-1, thereby decreasing ROS and apoptosis. Silencing Nrf2 abolished these protective effects.

Conclusion: Our findings demonstrate that iPSC-NPCs protect astrocytes from hemin toxicity via the Nrf2/HO-1 pathway, suggesting a novel therapeutic strategy for ICH-induced oxidative injury.

Objective: Sepsis-associated encephalopathy (SAE) is a common and serious neurological complication of sepsis. This study aimed to investigate the mechanism of methyltransferase-like 3 (METTL3) in SAE-induced microglial pyroptosis and to identify new therapeutic targets for SAE treatment.

Methods: A SAE cell model was established using lipopolysaccharide (LPS)-treated BV-2 cells. The expression of interleukin-1β, interleukin-18, cleaved caspase-1, gasdermin D (GSDMD)-N, NOD-like receptor protein 3 (NLRP3), transforming growth factor beta receptor 3 (TGFBR3), and METTL3 was detected by. METTL3 was silenced in LPS-treated BV-2 cells to validate the role of METTL3 in microglial pyroptosis. Total N6-methyladenosine (m6A) content was measured. The binding of primary miRNA (pri-miR)-101-3p to DGCR8 and the m6A level of pri-miR-101-3p were analyzed by methylated RNA immunoprecipitation-qPCR. The expression of pri-miR-101-3p and miR-101-3p was measured by reverse transcription quantitative PCR. The downstream targets of miR-101-3p were predicted by databases, and the binding relationship between miR-101-3p and TGFBR3 was verified. Rescue experiments were performed to verify the role of METTL3/miR-101-3p/TGFBR3 axis in microglial pyroptosis.

Results: LPS treatment decreased cell viability and promoted interleukin-1β, interleukin-18, METTL3, cleaved caspase-1, GSDMD-N, and NLRP3. Silencing METTL3 inhibited microglial pyroptosis. Mechanistically, METTL3 promoted the binding of pri-miR-101-3p to DGCR8 through m6A modification and increased mature miR-101-3p expression. miR-101-3p targeted TGFBR3 and inhibited TGFBR3 expression. miR-101-3p overexpression or TGFBR3 downregulation partially reversed the inhibitory effect of silencing METTL3 on LPS-induced microglial pyroptosis.

Conclusion: METTL3 is upregulated in SAE, enhances miR-101-3p expression through m6A modification, and inhibits TGFBR3 expression, finally leading to microglial pyroptosis in SAE.

Background: Mild cognitive impairment (MCI) represents a critical window for intervention before Alzheimer's disease progression. This study investigated whether high-definition transcranial direct current stimulation (HD-tDCS) targeting the left dorsolateral prefrontal cortex (L-DLPFC) could modulate white matter microstructure and thereby influence cognitive function.

Methods: Twenty-four patients with MCI received 10 sessions of active HD-tDCS over the L-DLPFC. White matter integrity was assessed using diffusion tensor imaging (DTI) to quantify fractional anisotropy in corticospinal tracts (CSTs) and anterior thalamic radiations (ATR). Cognitive function was evaluated with the trail making test B (TMT-B), mini-mental state examination (MMSE), and Montreal cognitive assessment (MoCA) at baseline and postintervention. Forty healthy controls provided baseline DTI data.

Results: At baseline, patients with MCI showed significantly reduced fractional anisotropy in the bilateral CST and ATR compared with healthy controls. Following HD-tDCS, increases in fractional anisotropy were observed in these tracts. While MMSE and MoCA scores showed no significant change, TMT-B performance appeared to improve. Notably, increased fractional anisotropy in the left ATR showed an association with improved TMT-B performance (r = 0.467, P < 0.05).

Conclusion: The findings suggest that HD-tDCS targeting the L-DLPFC may promote microstructural remodeling in white matter tracts, evidenced by elevated fractional anisotropy within the corticospinal and anterior thalamic pathways. While global cognitive measures remained stable, a trend toward improved executive function (TMT-B) was observed, potentially associated with left ATR fractional anisotropy enhancement. This positions HD-tDCS as a candidate neuromodulatory intervention for MCI, warranting further investigation to confirm functional outcomes.

Objective: Acute stress enhances the activity of magnocellular neurons (MNs) by inducing long-term changes in excitatory inputs. We aim to investigate the mechanism underlying long-term potentiation (LTP) of glutamatergic inputs to paraventricular nucleus (PVN) MNs in stressed rats.

Methods: Rats were subjected to multiple stressors and randomly assigned to control and stress groups. In some experiments, stressed rats received intracerebroventricular (i.c.v.) injections of the β-adrenergic receptor (AR) antagonist or the β1-AR antagonist. Excitatory postsynaptic currents evoked by electrical stimulation in hypothalamic slices were recorded from PVN MNs using an Axopatch 200B amplifier. LTP of glutamatergic inputs to MNs was induced by electrical stimulation trains (100 Hz, 100 pulses, three times). Biocytin staining and immunohistochemistry were used to characterize the morphology of recorded neurons and detect β1-AR expression.

Results: Blockade of gamma-aminobutyric acid receptor, tetanic stimulation-induced glutamatergic LTP in MNs of nonstressed rats, which was significantly augmented in stressed rats. Blocking N-methy-D-aspartate receptors abolished LTP in nonstressed rats but revealed a novel LTP in stressed rats. I.c.v. administration of propranolol, or CGP 20712, before the stress procedure abolished this novel LTP in stressed rats. In contrast, administration of norepinephrine or a selective β1-AR agonist, dobutamine triggered the novel LTP in nonstressed rats. The novel LTP in stressed rats was abolished by intracellular inhibition of protein kinase A (PKA). β1-AR immunoreactivity was detected in PVN MN areas.

Conclusion: Acute stress enhances the β1-AR/PKA signaling, leading to long-term modifications of glutamatergic inputs in the hypothalamic PVN MNs in rats in vivo.

Background: Recent evidence suggests that neuroinflammation and synaptic dysfunction play crucial roles in linking obesity to the development of depression. Long-term consumption of a high-fat (HF) diet not only leads to metabolic disruptions in the body but also disturbs brain homeostasis, particularly affecting the amygdala, a key region involved in regulating depression.

Methods: This study explored the therapeutic potential of geniposide, a bioactive iridoid glycoside known for its antiinflammatory properties, in mitigating HF diet-induced depressive behaviors and amygdala pathology.

Results: Geniposide supplementation significantly improved HF diet-induced depression, as assessed through various behavioral tests including the open field test, forced swimming test, elevated plus maze test, and tail suspension test. Geniposide demonstrated notable synaptic protective effects, evidenced by an increase in the length of the active zone and postsynaptic density thickness, as well as a decrease in the synaptic cleft in the amygdala of HF diet-fed mice. Additionally, geniposide suppressed microglial activation, downregulated the expression of pro-inflammatory cytokines [interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α), IL-6], and reduced C3/C1q expression. Furthermore, geniposide administration markedly decreased the colocalization of C1q, a microglia-derived complement component, with postsynaptic density protein 95-positive puncta in the amygdala.

Conclusion: In summary, this study demonstrates that geniposide alleviates HF diet-induced depressive behaviors, which is associated with improved synaptic health and reduced neuroinflammation in the amygdala. These findings provide a mechanistic basis for the potential repurposing of geniposide in the management of obesity-related affective disorders.

Objective: This study investigates the role of pleckstrin homology-like domain family A member 1 (PHLDA1) in traumatic brain injury (TBI) and examines how its knockdown may mitigate neurological impairments associated with TBI, focusing on mitochondrial dysfunction, neuro-inflammation, and oxidative stress.

Methods: TBI was induced in rats, and PHLDA1 expression was assessed through qPCR and Western blot. Neurological functions were evaluated via grip strength, balance beam, and rotarod tests. Brain tissue samples were analyzed for edema, apoptosis, and mitochondrial activity. Additionally, the effects of PHLDA1 knockdown on protein kinase B/nuclear factor erythroid 2-related factor 2/sirtuin 3 (AKT/Nrf2/Sirt3) signaling were examined in H 2 O 2 -treated PC12 cells, with the AKT inhibitor MK-2206 used to explore pathway interactions.

Results: PHLDA1 levels were elevated in TBI rats, correlating with impaired neurological function, brain edema, and increased cell apoptosis. PHLDA1 knockdown improved motor performance, reduced edema, decreased apoptotic cell counts, and alleviated inflammation. Furthermore, it restored mitochondrial membrane potential and increased ATP production. In cell models, PHLDA1 knockdown reduced oxidative stress and enhanced AKT/Nrf2/Sirt3 pathway activation, which MK-2206 partially reversed. Additional experiments indicated that EZH2 inhibited PHLDA1 transcription by binding to its promoter.

Conclusion: PHLDA1 knockdown mitigates TBI-induced neurodegeneration by reducing oxidative stress and enhancing mitochondrial function through the AKT/Nrf2/Sirt3 pathway. These findings suggest that targeting PHLDA1 may offer a novel therapeutic approach for TBI.

Background: Transient global cerebral ischemia induces selective neuronal death, with pyramidal neurons in the hippocampal CA1 region degenerating while CA3 neurons remain intact. Although dendritic and spine alterations in CA1 neurons postischemia have been extensively studied, the morphological changes in surviving CA3 neurons remain poorly understood.

Methods: Using Golgi staining and three-dimensional reconstruction in a rat four-vessel occlusion ischemia model, we examined dendritic and spine dynamics in CA3 neurons. In addition, P0 cultured hippocampal neurons transfected with green fluorescent protein (GFP) were exposed to oxygen-glucose deprivation (OGD) in vitro , and dendritic morphological changes were monitored longitudinally.

Results: Transient ischemia triggered apical dendritic retraction in CA3 neurons 48 h post-injury, while basal dendrites remained unaffected. Apical dendritic branching also decreased at this time point. Spine density transiently increased at 12 and 24 h before normalizing by 48 h, with no significant shift in spine type proportions. In-vitro, surviving primary hippocampal neurons showed delayed dendritic shortening post-OGD, whereas degenerating neurons exhibited early dendritic elongation.

Conclusion: Surviving CA3 pyramidal neurons exhibit greater adaptability to ischemic stress compared with vulnerable CA1 neurons, possibly explaining their differential survival. Pharmacological stabilization of neuronal morphology may offer a promising therapeutic strategy for ischemic stroke.

Background: The mechanism of electroacupuncture (EA) pretreatment for cerebral ischemia-reperfusion injury (CIRI) is unclear. This study aimed to investigate whether EA pretreatment attenuates CIRI through the miR-124/nuclear factor kappa B (NF-κB)/Fas signaling pathway.

Methods: Following 7 days of EA pretreatment at Baihui (GV20), Fengfu (GV16), and Dazhui (GV14), CIRI rats were established. Neuroprotection was assessed using modified neurological severity score (mNSS), 2,3,5-triphenyltetrazolium chloride staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Neuronal ultrastructure was examined by electron microscopy. Immunofluorescence staining revealed pNF-κB and Fas expression patterns. Western blotting and real-time quantitative PCR were employed to quantify miR-124, NF-κB repressing factor (NKRF), pNF-κB/NF-κB ratio, Fas, FasL, fas-associated protein with death domain (FADD), caspase-3, and caspase-8 in the cerebral cortex.

Results: EA pretreatment reduced cerebral infarction volume, alleviated mNSS and cortical neuronal apoptosis. Moreover, EA pretreatment downregulated miR-124, pNF-κB/NF-κB/Fas, FasL, FADD levels and increased NKRF expression. The effect of EA pretreatment was enhanced by miR-124 inhibitor.

Conclusion: These findings suggest that EA pretreatment attenuated neuronal apoptosis through suppression of the miR-124/NF-κB/Fas signaling pathway in CIRI.