Cellular and Molecular Neurobiology最新文献

Mitochondrial dysfunction has been identified as a key factor in the pathophysiological changes associated with intracerebral hemorrhage (ICH). As the core of intracellular energy metabolism, mitochondrial homeostasis is highly dependent on the precise regulation of its mitochondrial quality control (MtQC) system. After ICH, dysfunctional mitochondria lead to impaired oxidative phosphorylation and cellular bioenergetic stress, inducing oxidative stress, inflammatory responses, and programmed cell death, further exacerbating cellular damage. To counteract this injury, cells activate a series of MtQC mechanisms for compensatory repair, including mitochondrial dynamics, mitochondrial biogenesis, mitophagy, and intercellular mitochondrial transfer. These stringent mechanisms help maintain the mitochondrial network, restore the integrity of mitochondrial structural and functional integrity, improve neural function, and mitigate brain injury. In this review, we discuss key evidence regarding the role of mitochondrial dysfunction in ICH, focusing on the MtQC mechanisms involved in ICH. We also summarize potential therapeutic strategies targeting MtQC to intervene in ICH, providing valuable insights for clinical applications.

Major depressive disorder (MDD) results from repeated and constant exposure to stress over prolonged periods. The highly variable response to stress and the low heritability suggests that MDD has a strong epigenetic basis. Studies show global dysregulation of histone modifications in both susceptible and resilient animals after chronic stress suggesting involvement of epigenetics in stress response in the brain. Given that the hippocampus and dentate gyrus (DG) show epigenetic changes in neurogenesis in Rodent models of stress that is known to be highly affected in MDD, we hypothesized that epigenetic changes might be involved in the advent of depressive phenotype during the progressive stress paradigm. To study the stress progression into the depression-like phenotype at the molecular level, we designed a novel progressive social defeat stress (PSDS) paradigm based on the popular chronic social defeat stress (CSDS) paradigm but involving only 5 days of defeat stress. Our molecular studies revealed consistent downregulation of H3K9me2 marks in the hippocampus and DG after the 4th day of stress while H3K27me2 showed an early upregulation in the hippocampus and a late downregulation after the 5th day of stress in the DG. In parallel, an early increase in phf8 and phf2 in hippocampus and DG, respectively, was observed. These findings of variable changes like repressive histone methylation marks and expression of corresponding demethylase genes after different durations of defeat stress, led to better understanding of the important role epigenetics play in stress progression into depression at molecular level in establishing resilient and susceptible phenotypes.

Alzheimer's disease (AD) is one of the most common causes of dementia in elderly populations. A multifactorial and complex etiology has hindered the establishment of successful disease-modifying and retarding treatments. An important molecular target that has a close link with the disease's pathophysiology is glycogen synthase kinase 3β (GSK-3β). GSK-3β is thought to be an important bridge between amyloid and tau pathologies, the two principle pathogenic hallmarks of the disease. In particular, its kinase activity is thought to be a contributing factor for initiating aberrant tau hyperphosphorylation toward neurodegenerative progression. To identify potential inhibitors for GSK-3β, a pharmacophore-based virtual screening was used on the VITAS-M Lab database, a large database of small molecules. A co-crystal ligand employed as the template allowed the screening of roughly 200,000 compounds. Compounds successfully screened were selected on the basis of the Phase screen score combining vector alignments, volume scores, and site matching parameters. Using a cutoff score of 1.7, 174 compounds were docked using the Glide tool for molecular docking to further identify potential high-affinity binding ligands. Finally, four chemicals with the best binding scores (cutoff Glide GScore values of - 8 kcal/mol) were identified. Among these, 3-(2-oxo-2H-chromen-3-yl)-N-(4-sulfamoylphenyl) benzamide (VL-1) and trimethylsilyl trifluoromethanesulfonate (VL-2) showed strong and stable binding interactions, as evidenced by molecular dynamics simulation (MDS). The results suggest that VL-1 and VL-2 may serve as promising lead compounds for GSK-3β-based anti-AD therapeutics. However, further in vivo mechanistic validation is warrantied to confirm their therapeutic applicability.

This study aimed to integrate genome-wide association studies (GWAS) with pharmacogenomics data to develop personalized pain and inflammatory therapeutics. Despite recent developments in the clinical utilities of pharmacogenomics, it needs more investigations for uncovering the complicated mechanisms of drugs from a genetic standpoint. The research addresses the increasing misuse of opioids during recovery, emphasizing personalized interventions for opioid use disorder (OUD). Key pain-related pathways were analyzed to uncover their interactions. Five GWAS traits, including pain, inflammatory biomarkers, immune system abnormalities, and opioid-related traits, were examined. Candidate genes extracted from GWAS datasets were refined through in silico analyses, including protein-protein interactions (PPIs), TF-miRNA coregulatory interactions, enrichment analysis (EA), and clustering enrichment analysis (CEA). A network of 50 highly connected genes was identified, with APOE emerging as a top candidate due to its role in cholesterol metabolism and opioid-induced lipid effects. Pharmacogenomics analysis highlighted significant gene annotations, including OPRM1, DRD2, APOE, GRIN2B, and GPR98, linking them to opioid dependence, neurological disorders, and lipid traits. Protein interaction analyses further validated these connections, with implications for epigenetic repair. Our findings reveal a strong association between APOE, opioid use, and Alzheimer's disease, suggesting potential for novel recovery strategies. Combining HDL-boosting drugs with pro-dopaminergic regulators like KB220 may help prevent relapse. This study underscores the importance of integrating genetic and pharmacogenomic data to advance personalized therapies.

Recent developments in neural circuit mapping and neurotherapy are changing our understanding of the dynamic network structure of the brain and offering new treatment options. In many neurological and psychiatric diseases, targeted control of specific brain circuits has proven to be a successful strategy to reduce cognitive, behavioral, and motor abnormalities. Sophisticated retrograde tracing techniques, transcranial magnetic stimulation (TMS), chemogenetics, optogenetics, and other technologies have greatly improved our ability to outline, observe, and control neuronal circuits with remarkable accuracy. These sophisticated techniques have revealed crucial information on neuroplasticity, circuit remodeling following injury, and the therapeutic potential of neuromodulatory interventions. Disorders include depression, anxiety, stroke, and neurodegenerative diseases are treated using techniques such as optogenetic stimulation, chemogenetic activation, and non-invasive brain stimulation to restore circuit function. Emerging multifunctional probes like Tetracysteine Display of Optogenetic Elements (Tetro-DOpE) provide real-time monitoring and modification of neuronal populations, improving circuit-level interventions' precision. At the same time, especially following severe brain injury and neurodegeneration, stem cell treatments combined with neurogenesis-promoting strategies show great promise in increasing circuit repair and functional recovery. The development of drug delivery methods like tailored nanoparticle systems and multifunctional probes is helping to improve the accuracy and safety of treatments by reducing off-target effects. These developments taken together draw attention to a notable shift toward precision neuromedicine. These techniques are meant to offer more efficient, focused, and specialized treatments for various neurological and psychiatric diseases by combining sophisticated circuit mapping with tailored therapeutic interventions.

Multiple Sclerosis (MS) is a chronic, inflammatory, and neurodegenerative disease of the Central Nervous System (CNS) that is characterized by immune dysregulation and neuroinflammation. Owing to the generation of neuroactive metabolites, the kynurenine pathway (KP), one of the key pathways of tryptophan metabolism, influences the pathogenesis of MS by regulating immune responses and neuronal homeostasis. KP dysregulation results in the overproduction of neurotoxic metabolites such as quinolinic acid (QUIN), characterized by the loss of homeostasis between the neuroprotective (e.g., kynurenic acid, KYNA) and neurotoxic (e.g., QUIN) metabolites, contributing to neuroinflammation, excitotoxicity, and neurodegeneration. Recent evidence suggests that exercise may serve as a non-pharmacological intervention to modulate KP and limit MS progression. Both acute and chronic exercise, especially high-intensity interval training (HIIT), have been demonstrated to decrease the systemic levels of these neurotoxic KP metabolites and increase the neuroprotective KYNA production. Through the modulation of cytokine profiles toward an anti-inflammatory response and Aryl Hydrocarbon Receptor (AhR) activation that promotes immune tolerance, exercise is also an important regulator of the immune response. These findings imply that exercise normalizes KP homeostasis, decreases neuro-axonal damage and improves neuroprotection in MS, but the mechanisms of exercise-induced KP regulation as well as its long-term therapeutic role in MS treatment need further investigation. This review highlights the therapeutic potential of exercise as a complementary approach to existing drugs to ameliorate neuroinflammation and neurodegeneration in MS.

Ischemic stroke is a common cerebrovascular disease accompanied by a large number of neuronal death and severe functional impairment. In recent years, the role of ferroptosis and ferritinophagy in neuronal death after cerebral infarction has attracted great interest in the field of ischemic stroke. Ferroptosis is a newly discovered programmed cell death pattern characterized by iron overload, dysregulation of the xCT/GSH/GPX4 system, and lipid peroxidation system, which is closely associated with neurological damage after ischemic stroke. Ferritinophagy is a selective autophagy mediated by NCOA4 that regulates intracellular iron metabolism, and can be regulated by factors such as intracellular iron content and HERC2-FBXL5-IPR2 axis. Under normal physiological conditions, ferritinophagy maintains the balance of intracellular iron elements, and excessive activation can cause ferroptosis. Here, we mainly review the general mechanisms of ferroptosis and ferritinophagy, and focus on the relationship between ischemic stroke and ferroptosis/ferritinophagy. Specifically, we explored the crosstalk of ferroptosis and ferritinophagy in ischemic stroke and outlined current treatment strategies and key challenges. These observations may help to further understand the pathological events of ischemic stroke and bridge the gap between basic and translational research to provide novel insights for its treatment.

Depression during pregnancy is often overlooked and undertreated. Ketamine has been shown to exert prompt and sustained antidepressant effects in patients with depression, although concerns of potential neurotoxicity prohibit its use in pregnant women. Here, we aim to investigate the neurobehavioral effects of subanesthetic ketamine on pregnant mice and their offspring. We found that pregnant C57BL/6 mice receiving ketamine (10 mg/kg/day intraperitoneal) from gestation day 15 to 17 exhibited less depression-like behaviors. Prenatal ketamine treatment induced male-specific reduction in depression- and anxiety-like behaviors in adult offspring, without alterations in social and memory performance. These behavioral outcomes were associated with a male-specific increase in dendritic spine density of dentate gyrus granule cells, while neither dendritic architecture nor hippocampal neurogenesis was affected. N-methyl-D-aspartate receptor subunits GluN2A and GluN3A were expressed at significantly higher levels in the hippocampus of male as compared to female mouse embryos, suggesting sex-dependent actions of ketamine on developing brain. Overall, our study showed that prenatal exposure to subanesthetic ketamine could exert long-lasting neurobehavioral effects in a sex-dependent manner, with male offspring being more resilient to stress. These findings may have implications concerning ketamine use during pregnancy, and also provide clues about the developmental origins of emotional problems.

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by fluctuating muscle weakness. MicroRNAs (miRNAs) have emerged as potential biomarkers for MG diagnosis, offering noninvasive and reliable detection. This systematic review and meta-analysis evaluated the diagnostic accuracy of miRNAs in MG. A comprehensive search of PubMed, Embase, and Google Scholar was conducted up to March 9, 2025. Eligible studies assessing miRNAs as MG biomarkers were selected on the basis of predefined criteria. Pooled sensitivity, specificity, and diagnostic odds ratios (DORs) were calculated via random effects model. Heterogeneity was assessed via I², and publication bias was evaluated via Deeks' funnel plot. Nine studies including 1,797 participants were analysed. The pooled sensitivity and specificity were 0.80 (95% CI: 0.75-0.84) and 0.71 (95% CI: 0.65-0.77), respectively, with an area under the curve (AUC) of 0.83. Bivariate heterogeneity analysis indicated moderate variability, the cause of which were identified using subgroup analysis with region, clinical subtypes and seropositivity as subgroups. miRNAs demonstrate strong diagnostic potential for MG, with good sensitivity and specificity. However, standardized methodologies and further validation in large, multicentre studies is warranted.

The multifunctional roles of alpha7 nicotinic acetylcholine receptors (α7nAChRs), ranging from cognitive enhancement, neuroprotection, and anti-inflammatory action, credit tagging this receptor as "unique" among the cholinergic receptor family. The uniqueness of α7nAChRs in neuronal function and communication lies in their high calcium permeability among the cholinergic receptor family. The ionotropic function of α7nAChRs is governed by protein kinases' post-translational modification (PTMs), which alter their expression and function, affecting neuronal communication. A decrease in the ionotropic function of α7nAChRs and its downstream signaling pathways is observed across many neurologic disorders. The loss of α7nAChRs, decreased cholinergic function, and increased acetylcholinesterase levels are commonly associated with neuronal degeneration, cognitive impairment, and decreased memory function. An extensive body of evidence suggests the cognitive benefits of simple nutraceutical supplementation, Vitamin D3 (VD), in many neurologic disorders (Skv et al. in Mol Neurobiol 61:7211-7238, 2024). The present review will, however, focus on recent and past evidence deciphering the unique properties of α7nAChRs crucial for brain function. We have also emphasized on the therapeutic benefits of VD supplementation in restoring cholinergic neurotransmission and α7nAChRs expression in various neuropsychiatric and neurologic disorders.