Molecular Neurobiology最新文献

Atherosclerosis (AS) is a leading cause of cardiovascular disease and stroke. Although mitochondria's role in AS is recognized, effective molecular targets are lacking. This study investigated mitochondria-associated signature biomarkers in AS, providing insights for mechanistic research and targeted therapy. AS-related transcripts were retrieved from public databases. Bioinformatics analyses (differential expression, machine learning, and expression verification) were integrated to screen biomarkers, and a nomogram was constructed. The functions, immune features, and single-cell expression (cellular landscape) of the identified biomarkers were analyzed. The L-lactate dehydrogenase B and SLC25A4 genes emerged as mitochondrial signature biomarkers in both tissues and blood samples from patients with AS. The nomogram exhibited robust performance in predicting the prevalence of AS. Notably, these biomarkers were significantly involved in pathways associated with the pathogenesis of AS, such as the Toll-like receptor pathway. Compared with the findings in control samples, 27 types of immune cells exhibited increased infiltration in AS samples, and the biomarkers generally displayed a strong negative correlation with these infiltrating immune cells. Nine cell types were annotated at the single-cell level, among which vascular smooth muscle cells (VSMCs) represented the key cell population, being characterized by high pyruvate metabolism activity. Furthermore, VSMCs were primarily engaged in cell-cell communication with macrophages. Additionally, the expression profiles of the biomarkers exhibited an inverted U-shaped dynamic pattern corresponding to the expression changes in VSMCs. This study identified two mitochondrial signature biomarkers, preliminarily revealed their potential roles in AS, provided new insights for targeted therapy research, and laid a foundation for unraveling mitochondria-related pathological mechanisms in AS.

Cognitive impairment (CI), spanning mild memory issues to severe dementia, impacts over 55 million people worldwide and have a significant effect that strains health, economy, and caregiving. Surprisingly, it occurs at any age. The glial cell ecosystem, particularly astrocyte-microglia crosstalk, is pivotal for brain homeostasis and cognitive function across the lifespan. Intriguingly, in recent discoveries, dysregulation of ecosystem contributes to neurodevelopmental disorders (NDDs), adult cognitive decline, and neurodegenerative diseases like Alzheimer's disease (AD), and astrocyte-derived interleukin-3 (IL-3), acting via the IL-3/CD123-related signals, may act as a key regulatory mediator of microglial function. Over the past few decades, extensive researches have been devoted to investigating aging-related regulatory factors with the aim of deciphering the "code" underlying cognitive developmental abnormalities, premature cognitive decline, and neurodegeneration. Astrocyte-microglia crosstalk governs age-dependent glial turnover via senescence-sensitive IL-3. Under pathological conditions, perturbed turnover's association with age-stratified CI and its regulators is poorly understood. This review integrates current evidence on glial crosstalk, cellular senescence, and repopulation to elucidate age-specific CI driven by dysregulated glial turnover, while identifying key biomarkers that can predict aging processes. Looking ahead, therapeutic strategies targeting the IL-3/CD123-related signals regulating glial crosstalk hold promise for advancing interventions in immune-mediated CI across the lifespan.

Mitochondrial dysfunction, oxidative stress, and neuroinflammation play a critical role in the occurrence and progression of Alzheimer's disease (AD). MicroRNAs (miRNAs) have been studied recently as potential therapeutic approaches for AD. In this study, we examined the function and underlying mechanism of microRNA-25802 (miR-25802), a newly discovered miRNA in an AD model. In order to evaluate the levels of oxidative stress, mitochondrial damage and neuroinflammation in neuroblastoma cells, four experimental groups were created: control group (neuroblastoma cells, SH-SY5Y), amyloid beta (Aβ)-induced neuroblastoma cells (SY5Y-Aβ), small extracellular vesicles (sEVs)-only group and miR-25802-loaded small extracellular vesicles (sEV-miR25802) administered group. Neuroinflammation, oxidative stress, mitochondrial damage, tau hyperphosphorylation, and Aβ accumulation were evaluated in Aβ-induced neuroblastoma cells. Oxidative stress was analyzed by measuring reactive oxygen species (ROS), malondialdehyde (MDA), lactate dehydrogenase (LDH), superoxide dismutase (SOD), and glutathione peroxidase 1 (GPX1). Inflammatory markers such as tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule 1 (ICAM1), and brain-derived neurotrophic factor (BDNF) mRNA levels, a neurotrophic factor, were evaluated by RT-qPCR. Neurofilament light chain (NfL), vascular endothelial growth factor-A (VEGF-A), macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein-1 (MCP-1) and cytochrome c (Cyt-c), mitochondrial transcription factor A (TFAM), PTEN-induced kinase 1 (PINK1) and dynamin-1-like protein (DNM1L) protein levels were determined by ELISA. Mechanistically, sEV-miR25802 were shown to provide anti-inflammatory and neuroprotective effects by regulating neuroinflammation, mitochondrial dysfunction, and oxidative stress. These findings reveal the regulatory role of miR-25802 on neuroinflammation, mitochondrial damage, and oxidative stress and suggest that it may be a potential therapeutic target for AD.

Hypoxic preconditioning is commonly used to improve the therapeutic efficacy of neural stem cells (NSCs) transplantation; however, the mechanisms by which hypoxia regulates intercellular communication in NSCs remain incompletely understood. As connexin 43 (Cx43) is a key component of gap junctional intercellular communication (GJIC), we investigated whether hypoxic preconditioning modulates Cx43 expression and function in NSCs and whether this pathway contributes to NSCs-mediated angiogenesis in a rat model of cerebral palsy (CP). In vitro, NSCs exposed to 1% oxygen for different durations showed maximal upregulation of Cx43 mRNA and protein after six hours of hypoxic preconditioning without inducing cell necrosis. Functional analyses demonstrated that hypoxia significantly enhanced Cx43-mediated GJIC and hemichannel activity. Following transplantation, hypoxia-preconditioned NSCs increased Cx43 expression in the perilesional region of CP rats, with peak levels observed at 1 week post-transplantation and prominent localization at the graft-host interface. Importantly, transplantation of hypoxia-preconditioned NSCs increased perilesional vessel density and proliferating endothelial cells, whereas shRNA-mediated Cx43 knockdown abolished the effects. These findings demonstrate that hypoxic preconditioning enhances Cx43 expression and function in NSCs, thereby promoting intercellular communication and contributing to NSCs-induced angiogenesis in CP rats. Targeting Cx43 signaling may represent a promising strategy to improve the therapeutic efficacy of NSCs-based therapies.

Sepsis frequently leads to multi-organ injury, with the highly metabolically active nervous system being particularly vulnerable, and ferroptosis has been implicated in driving disease progression. Although Salvianolic acid B (SalB), the most abundant water-soluble active component of Salvia miltiorrhiza Bunge., has demonstrated antioxidant and anti-inflammatory properties, its specific mechanisms in sepsis-associated hippocampal injury remain unclear. To investigate SalB's therapeutic potential against sepsis and its role in mitigating neural damage via ACSL4-mediated ferroptosis, a murine sepsis model was established by cecal ligation and puncture (CLP). SalB's efficacy was evaluated using 7-day survival rates, multi-organ biochemical markers, and critical treatment windows. Inflammatory cytokines were measured by ELISA, and hippocampal morphology was examined histologically. Mechanistic studies included Fe²⁺ staining and lipid peroxidation assays, while protein arrays and Western blotting clarified SalB's interaction with ACSL4, confirming its anti-ferroptotic role. Our results show that SalB significantly improved survival in CLP-induced septic mice, reduced levels of inflammatory factors, alleviated hippocampal neuronal damage, and preserved blood-brain barrier integrity. Data from biochemical assays and Western blot analysis indicated that SalB suppresses ferroptosis by modulating the ACSL4/GPX4 pathway, supporting its therapeutic role in septic hippocampal injury. Additionally, protein array and molecular docking studies provided evidence that SalB likely exerts its pharmacological activity by competitively inhibiting the substrate CoA binding to ACSL4 at amino acid residues LYS-572, LEU-574, and SER-607. In conclusion, SalB protects against sepsis-induced hippocampal injury by targeting ACSL4-mediated ferroptosis, offering a novel herbal-based strategic direction for sepsis treatment.

Retinoic acid (RA), a biologically active metabolite of vitamin A, acts as a potent signaling molecule regulating cell proliferation, differentiation, and apoptosis through nuclear RA receptors. RA influences expression of multiple genes, which are essential for development, neuronal differentiation, and synaptic plasticity. Long noncoding RNAs (lncRNAs), a class of regulatory RNAs, influence gene expression through chromatin organization, RNA processing and stability, translation, miRNA dynamics, and can also encode micropeptides. This review emphasizes the RA-mediated modulation of lncRNA expression through transcriptional and post-transcriptional mechanisms that influence differentiation and cell fate. This intricate RA-lncRNA crosstalk shapes tissue development and underlies the molecular pathology of various diseases. Both RA-signaling and lncRNA networks are involved in aging and age-related diseases. Furthermore, emerging RNA-based therapeutics such as RNA aptamers, RNA interference, and CRISPR-guided RNAs highlight their promise for treating age-related diseases. Exploring the crosstalk between RA and lncRNAs may provide novel opportunities for RNA-based therapeutic interventions targeting various diseases.

Friedreich's Ataxia (FRDA) is an early onset hereditary disorder with a strong neurodegenerative component caused by repeat expansions on the gene encoding for frataxin (FXN) that result in FXN deficiency. This deficit has been linked to a cascade of biochemical alterations, including mitochondrial dysfunction, oxidative stress and neuronal apoptosis, that drives the neurodegenerative process. FRDA is a very incapacitating disease and patients rely on very limited therapeutic alternatives, such as the recently approved drug omaveloxolone, to treat the oxidative stress. Nevertheless, previous studies have suggested the activation of the brain-derived neurotrophic factor (BDNF) may be a promising treatment to regulate FRDA pathophysiology. Herein, we characterize the effects of FXN deficiency in an in vitro model of primary cerebellar granule neurons (CGNs) derived from the FRDA mouse model YG8-800, as well as the therapeutic potential of BDNF partial agonism by the small molecule 7,8-dihydroxyflavone (7,8-DHF). We found evidence of mitochondrial dysfunction concomitant with DNA damage and enhanced cell death due to FXN deficiency in cultured neurons. The treatment with 7,8-DHF was able to reduce the markers of genotoxicity and apoptosis, without restoring the impaired mitochondrial function nor the total cell death, possibly through ferroptosis, revealing a partial neuroprotective effect insufficient to halt the neurodegenerative process in this in vitro model of FRDA.

Increased silent information regulator protein 2 (SirT2) expression in the prefrontal cortex (PFC) has been reported to be associated with the development of depression; however, its functional contribution to depression-like behavior and memory impairment remains incompletely understood. In this study, we examined alterations in SirT2 expression in the PFC of olfactory bulbectomized (OBX) mice, a well-established model of depression, and evaluated the effects of AK-7, a selective SirT2 inhibitor, on OBX-induced depression-like behavior and memory impairment. On day 21 after surgery, OBX mice exhibited depression-like behaviors and memory impairment, as evidenced by prolonged immobility, reduced sucrose preference and spontaneous alternation, and shortened passive avoidance latency. Expression of SirT2 and pro-inflammatory microglial markers increased significantly, while those of Ac-FoxO1, PPARγ, arginase-1, MBP, MAG, CNPase, and Caspr were decreased, in the PFC of OBX mice. AK-7 administration attenuated these behavioral and molecular alterations. SirT2, Ac-FoxO1, and PPARγ showed spatial overlap with the microglial marker Iba1. AK-7 reduced microglial activation-associated morphological changes and attenuated OBX-induced disruption of node of Ranvier formation. These results suggest that AK-7 administration attenuates depression-like behavior and memory impairment, with concurrent improvements in node of Ranvier organization and modulation of microglial polarization in the PFC. Furthermore, our findings suggest that dysregulated SirT2 signaling may be involved, at least in part, in the development of depression-like behavior and comorbid memory impairment, and represents a potential avenue for further investigation.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuron loss in the substantia nigra pars compacta, accompanied by oxidative stress and neuroinflammation. Novel multitarget neuroprotective strategies are required to overcome the limitations of current symptomatic treatments. The neuroprotective effects of Antrodia cinnamomea (AC) and citrate-stabilized silver nanoparticles (AgNPs), alone and in combination, were evaluated using a 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y cell model and a unilateral 6-OHDA rat model. Sixty-three rats were divided into nine experimental groups. Cell viability, behavioral tests, LC-MS/MS analysis of dopamine and acetylcholine, oxidative stress and inflammatory biomarkers, histopathological assessment, immunohistochemistry, and Western blot analyses of TH, α-synuclein, PI3K, Bcl-2, Caspase-3, and agmatinase were performed. 6-OHDA significantly reduced cell viability, impaired motor performance, and induced dopaminergic neuronal degeneration. AC treatment, particularly in combination with AgNPs, markedly improved cell survival, ameliorated behavioral deficits, and preserved neuronal architecture. Combined treatment significantly decreased MDA, TNF-α, and IL-1β levels, while restoring GSH and SOD activities. LC-MS/MS analysis demonstrated partial recovery of dopamine and acetylcholine levels. Increased TH and PI3K expression, reduced α-synuclein and Caspase-3 levels, and normalization of Bcl-2 and agmatinase were observed following AC + AgNP treatment. AC conjugated with citrate-stabilized AgNPs exerts significant neuroprotective effects in experimental PD by concurrently modulating oxidative stress, neuroinflammation, and apoptotic pathways, highlighting its potential as a multitarget therapeutic strategy.

Due to the high incidence and the lack of effective therapeutic strategies, neuropathic pain (NP) seriously influences patients' lives and health, highlighting the significance of exploring promising therapeutic targets. This study evaluated the function and underlying mechanisms of miR-217-5p in NP through rat models and microglia cell models, aiming to provide a theoretical basis for the clinical management of NP. The expression and regulatory effect of miR-217-5p in CCI rats were evaluated based on mechanical pain and heat pain. The microglia cells were stimulated with LPS, and the regulation of their M1 polarization, viability, inflammation, and oxidative stress by miR-217-5p was assessed to reveal the regulation of microglia-related neuroinflammation. Significant downregulation of miR-217-5p was observed in CCI rats and LPS-induced microglia. Overexpressing miR-217-5p could significantly alleviate mechanical pain, heat pain, and inflammation in CCI rats. Additionally, miR-217-5p also significantly suppressed M1 polarization, recovered cell viability, inhibited inflammation, and oxidative stress in microglia. NF1 was identified as the direct target of miR-217-5p, which was negatively regulated by miR-217-5p. The overexpression of NF1 could reverse the protective effect of miR-217-5p on LPS-induced microglia, which was hypothesized as the regulatory mechanism. Overexpressing miR-217-5p could be considered a potential therapeutic strategy for NP, which regulates NP progression through microglia-related neuroinflammation by targeting NF1.